Atlas of Genetics and Cytogenetics in Oncology and Haematologyatlasgeneticsoncology.org/Journal/Arch2005Vol9Num1.pdf · 2008-12-10 · Atlas of Genetics and Cytogenetics in Oncology

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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TABLE OF CONTENTS Volume 9, Number 1, Jan-Mar 2005 Previous Issue / Next Issue

Genes CMKOR1 (2q37.3). Karin Broberg. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (1): 1-5. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/CMKOR1ID40108ch2q37.html

MAPRE1 (Microtubule-associated protein, RP/EB family, member 1) (20q11.1-11.23). Jennifer S Tirnauer. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (1): 6-14. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/MAPRE1ID455ch20q11.html

ERBB2 (erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian) ) (17q11.2-q12).

Patrizia Casalini, Marilena V Iorio. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (1): 15-35. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/ERBB2ID162ch17q11.html

TOP1 (topoisomerase (DNA) 1) (20q12-q13.1). Junko Horiguchi Yamada. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (1): 36-41. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/TOP1ID320ch20q11.html

WISP2 (Wnt-1-inducible signaling parthway protein-2) (20q12-13). Sushanta K. Banerjee, Snigdha Banerjee. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (1): 42-47. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/WISP2ID42814ch20q12.html

LHFP (lipoma HMGIC fusion partner) (13q12). Marleen Petit. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (1): 48-51. [Full Text] [PDF]

Atlas Genet Cytogenet Oncol Haematol 2005; 1 I

URL : http://AtlasGeneticsOncology.org/Genes/LHFPID248ch13q12.html

TFPT (TCF3/E2A fusion partner) (19q13.4). Enrica Privitera, Andrea Biondi. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (1): 52-55. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/TFPTID495ch19q13.html

VAV1 (vav 1 oncogene) (19p13.2). Shulamit Katzav. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (1): 56-62. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/VAV1ID195ch19p13.html

Leukaemias del(13q) in ALL. David Betts. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (1): 63-64. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/del13qALLID1188.html

t(14;21)(q11;q22). Jacques Boyer. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (1): 65-67. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t1421q11q22ID1180.html

t(1;14)(q21;q32) IRTA1/IGH. Mary Callanan, Dominique Leroux. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (1): 68-70. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t0114q21q32ID1375.html

t(1;6)(p35;p25). Jean loup Huret. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (1): 71-72. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t0106p35p25ID1378.html

t(1;14)(q21;q32) MUC1/IGH. Jacques Boyer. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (1): 73-75. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t0114q21q32MUC1ID1342.html

t(9;11)(q34;p15). Jean loup Huret. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (1): 76-77. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t0911q34p15ID1380.html

t(X;20)(q13;q13.3). Kavita S. Reddy, Kathy Richkind. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (1): 78-80. [Full Text] [PDF]

Atlas Genet Cytogenet Oncol Haematol 2005; 1 II

URL : http://AtlasGeneticsOncology.org/Anomalies/t0X20q13q13ID1381.html

t(16;21)(p11;q22) - updated. Jean Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (1): 81-86. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t1621.html

Solid Tumours Soft Tissue Tumors: Liposarcoma: Myxoid liposarcoma. Manuel Sánchez-Martín, Ines González-Herrero, Isidro Sánchez-Garcia. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (1): 87-95. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Tumors/MyxoidLipoSarcID5169.html

Uterus Tumours: an Overview. Roberta Vanni, Giuseppina Parodo. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (1): 96-108. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Tumors/UterusTumOverviewID5157.html

Soft Tissue Tumors: Low grade fibromyxoid sarcoma. Ioannis Panagopoulos, Fredrik Mertens, Nils Mandahl, Clelia Tiziana Storlazzi. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (1): 109-113. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Tumors/LowGradFibromyxSarcID5185.html

Soft Tissue Tumors: Soft Tissue Leiomyosarcoma. Jian-Hua Luo. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (1): 114-116. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Tumors/SoftTisLeiomyoSarcID5122.html

Soft tissue tumors: Lipoblastoma. Cristina Morerio, Claudio Panarello. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (1): 117-120. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Tumors/LipoblastomaID5155.html

t(16;21)(p11;q22) in Ewing tumours. Jean Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (1): 121-126. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Tumors/t1621p11q22EwingID5329.html

Cancer Prone Diseases LEOPARD syndrome. Maria Cristina Digilio. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (1): 127-132. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Kprones/LeopardID10084.html

Deep Insights

Atlas Genet Cytogenet Oncol Haematol 2005; 1 III

Some lessons from uniparental disomy (UDP) in the framework of comtemporary cytogenetics and molecular biology.

Eric Engel. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (1): 133-164. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Deep/UniparentDisomy2005ID20049.html

Case Reports A new case of t(1;11)(q21;q23) in a child with M1 ANLL.

Katell Le Du, Eric Jeandidier, Francine Garnache, Pierre Rohrlich, Jean-Luc Bresson, Marie-Agnès Collonge-Rame.

Atlas Genet Cytogenet Oncol Haematol 2005; 9 (1): 165-168. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/0111CollongeID100008.html

Translocation (X;20)(q13;q13.3): a nonrandom abnormality in four patients with myeloid disorders: case 1.

Kavita S. Reddy, Kathy Richkind. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (1): 169-171. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/0X20ReddyID100009.html

Translocation (X;20)(q13;q13.3): case 2. Kavita S. Reddy, Kathy Richkind. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (1): 172-174. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/0X20ReddyID100010.html



Educational Items Genetics and Public Health. Anne-Marie Laberge. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (1): 181-190. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Educ/GenetPublicHealthID30053ES.html

Glossary of Medical and Molecular Genetics. Louis Dallaire. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (1): 191-192. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Educ/GlossaryID30028ES.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2005; 1 IV

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Atlas Genet Cytogenet Oncol Haematol 2005; 1 V


CMKOR1

IdentityNote RDC1 was originally thought to be the receptor for VIP. Other names RDC1

GPRN159 G protein-coupled receptor chemokine orphan receptor 1 G protein-coupled receptor RDC1 homolog Hugo CMKOR1 Location 2q37.3

Telomeric to IQCA Centromeric to COPS8

DNA/RNADescription The genomic size has been estimated to approximately 12.5-13.5 kb.

RDC1 has previously been reported to contain only one exon of 1,09 kbp. However, the finding of a RDC1 transcript corresponding to four different regions with exon/intron boundaries in the BAC 514f21 suggests a more complex gene structure. The predicted amino acid sequence of exon 3 and 4 does not show any homology to the protein databases and, since they both contribute with stop codons, it could be questioned whether these sequences represent exons, or are part of an alternatively spliced 3' untranslated region of the gene.

Pseudogene None

Protein Description 362 amino acids; 41522 Da Expression RDC1 is expressed in embryological, juvenile as well as adult tissues.

Expression has been reported in e.g. bladder, spleen, heart, skeletal muscle, peripheral nervous system and placenta.

Localisation Integral membrane protein Function Orphan receptor, but its endogenous ligand has not yet been identified.

The protein is also a coreceptor for human immunodeficiency viruses (HIV). RDC1 belongs to a family of G-protein coupled receptors, which includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide (G) binding proteins.

Atlas Genet Cytogenet Oncol Haematol 2005; 1 -1-

Homology RDC1 displays homology to other members of the large family of G-protein coupled receptors.

MutationsGerminal Single nucleotide polymorphisms Somatic Translocations involving RDC1 and HMGA2 has been reported in three

lipomas (see below).

Implicated inEntity Lipoma, Disease Benign adipocyte tumor Prognosis Good Cytogenetics Translocations involving 2q35-37 and 12q13-15 have been reported

in six lipomas Hybrid/Mutated Gene

Fusion between RDC1 and HMGA2 has been reported in three lipomas with rearrangement involving 2q35-37 and 12q13-15. The breakpoint occurred after the third exon of HMGA2, the most common breakpoint of this gene, and in a previously unknown 3' part of the RDC1 gene. The RDC1 part of the fusion was over 300 bp.

Abnormal Protein

The functional impact of this fusion is most likely a truncation of HMGA2, since the RDC1 part contributes with a stop codon one amino acid downstream of the breakpoint.

Oncogenesis Not yet established Entity Tenosynovial giant cell tumours Disease Benign tumor of synovium and tendon sheath Prognosis Good Cytogenetics Translocations involving 1p11-13 and 2q35-37 have been reported in

eight cases of tenosynovial giant cell tumours. Hybrid/Mutated Gene

Four out of seven cases of tenosynovial giant cell tumours with aberrations of 2q35-37 had breakpoints in a BAC probe 260J21 (BACPAC, Oakland), which contains the RDC1 gene.

External links Nomenclature

Hugo CMKOR1 GDB CMKOR1 Entrez_Gene CMKOR1 57007 chemokine orphan receptor 1

Cards Atlas CMKOR1ID40108ch2q37 GeneCards CMKOR1 Ensembl CMKOR1


Genatlas CMKOR1 GeneLynx CMKOR1 eGenome CMKOR1 euGene 57007

Genomic and cartography

GoldenPath CMKOR1 - 2q37.3 chr2:237260443-237272991 + 2q37.3 (hg17-May_2004)

Ensembl CMKOR1 - 2q37.3 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] HomoloGene CMKOR1

Gene and transcription Genbank U73141 [ SRS ] U73141 [ ENTREZ ] Genbank AF030297 [ SRS ] AF030297 [ ENTREZ ] Genbank BC008459 [ SRS ] BC008459 [ ENTREZ ] Genbank BC036661 [ SRS ] BC036661 [ ENTREZ ] Genbank BM925428 [ SRS ] BM925428 [ ENTREZ ] RefSeq NM_020311 [ SRS ] NM_020311 [ ENTREZ ] RefSeq NT_086634 [ SRS ] NT_086634 [ ENTREZ ] AceView CMKOR1 AceView - NCBI TRASER CMKOR1 Traser - Stanford Unigene Hs.471751 [ SRS ] Hs.471751 [ NCBI ] HS471751 [ spliceNest ]

Protein : pattern, domain, 3D structure SwissProt P25106 [ SRS] P25106 [ EXPASY ] P25106 [ INTERPRO ]

Prosite PS00237 G_PROTEIN_RECEP_F1_1 [ SRS ] PS00237 G_PROTEIN_RECEP_F1_1 [ Expasy ]

Prosite PS50262 G_PROTEIN_RECEP_F1_2 [ SRS ] PS50262 G_PROTEIN_RECEP_F1_2 [ Expasy ]

Interpro IPR000276 GPCR_Rhodpsn [ SRS ] IPR000276 GPCR_Rhodpsn [ EBI ] CluSTr P25106 Pfam PF00001 7tm_1 [ SRS ] PF00001 7tm_1 [ Sanger ] pfam00001 [ NCBI-CDD ] Blocks P25106

Polymorphism : SNP, mutations, diseases SNP CMKOR1 [dbSNP-NCBI] SNP NM_020311 [SNP-NCI] SNP CMKOR1 [GeneSNPs - Utah] CMKOR1 [SNP - CSHL] CMKOR1] [HGBASE - SRS]

General knowledge Family Browser CMKOR1 [UCSC Family Browser]

SOURCE NM_020311


SMD Hs.471751 SAGE Hs.471751 Amigo function|G-protein coupled receptor activity, unknown ligand Amigo process|G-protein coupled receptor protein signaling pathway Amigo component|integral to membrane Amigo function|rhodopsin-like receptor activity PubGene CMKOR1

Other databases Probes

Probe CMKOR1 Related clones (RZPD - Berlin) PubMed

PubMed 6 Pubmed reference(s) in LocusLink

BibliographyCloning and expression of the human vasoactive intestinal peptide receptor.Sreedharan SP, Robichon A, Peterson KE, Goetzl EJ. Proc Natl Acad Sci U S A 1991; 88: 4986-4990. Medline 1675791 RDC1 may not be VIP receptor.Nagata S, Ishihara T, Robberecht P, Libert F, Parmentier M, Christophe J, Vassart G.Trends Pharmacol Sci 1992; 13: 102-103. Medline 1315461 A putative G protein-coupled receptor, RDC1, is a novel coreceptor for human and simian immunodeficiency viruses.Shimizu N, Soda Y, Kanbe K, Liu HY, Mukai R, Kitamura T, Hoshino H. J Virol 2000; 74: 619-626. Medline 10623723 Fusion of RDC1 with HMGA2 in lipomas as the result of chromosome aberrations involving 2q35-37 and 12q13-15.Broberg K, Zhang M, Strömbeck B, Isaksson M, Nilsson M, Mertens F, Mandahl N, Panagopoulos I. Int J Oncol 2002; 21: 321-326. Medline 12118328 Molecular cytogenetic mapping of recurrent chromosomal breakpoints in tenosynovial giant cell tumors.Nilsson M, Höglund M, Panagopoulos I, Sciot R, Dal Cin P, Debiec-Rychter M, Mertens F, Mandahl N. Virchows Arch 2002; 441: 475-480. Medline 12447678


Vascular gene expression in nonneoplastic and malignant brainMadden SL, Cook BP, Nacht M, Weber WD, Callahan MR, Jiang Y, Dufault MR, Zhang X, Zhang W, Walter-Yohrling J, Rouleau C, Akmaev VR, Wang CJ, Cao X, St Martin TB, Roberts BL, Teicher BA, Klinger KW, Stan RV, Lucey B, Carson-Walter EB, Laterra J, Walter KA. Am J Pathol 2004; 165: 601-608. Medline 15277233 REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed

BiblioGene - INIST Contributor(s)Written 11-

2004 Karin Broberg

CitationThis paper should be referenced as such : Broberg K . CMKOR1. Atlas Genet Cytogenet Oncol Haematol. November 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/CMKOR1ID40108ch2q37.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



MAPRE1 (Microtubule-associated protein, RP/EB family, member 1)

IdentityNote The original name EB1 came from a yeast two hybrid screen "End

Binding 1" is a nickname that was later applied when the protein was found to target to microtubule plus ends.

Other names EB1

Hugo MAPRE1 Location 20q11.1-11.23

EB1-GFP fluorescence on polymerizing microtubule plus ends in a living PtK1 cell.

DNA/RNADescription 22 Kb genomic locus, 5 introns Transcription 2540 bp open reading frame

Protein

Description 268 amino acids; 35 kDa; EB1 was cloned in yeast two-hybrid screen as

binding partner for the tumor suppressor APC (Adenomatous Polyposis Coli); EB1 is a microtubule plus end tracking protein (+tip). It contains a calponin homology domain and a leucine zipper

Expression EB1 is ubiquitously expressed. Protein levels remain similar throughout


the cell cycle. Localisation EB1 targets to the plus ends of microtubules when they are

polymerizing, producing a "comet tail" pattern. (Figure 1). The mechanism is treadmilling, in which new subunits are continually added at the tip. EB1 also shows additional weak binding to the microtubule lattice (along the length of the microtubule). EB1 targets to kinetochores moving anti-poleward. This is suspected to be due to binding to kinetochore microtubule plus ends rather than the kinetochore itself. Through its carboxyl terminus, EB1 localizes to centrosomes and spindle poles.

Function � The primary function identified to date is regulation of microtubule dynamic instability. Microtubules dynamically convert between growth (polymerization) and shrinkage (depolymerization). The transition from growth to shrinkage is called catastrophe, while the conversion from shrinkage to growth is called rescue. Microtubules also pause in their polymerization. EB1 reduces these pauses and reduces the frequency of catastrophes. EB1 increases the frequency of rescues. The net result is more stable, longer microtubules. This effect is predominantly seen during mitosis. � EB1 is important in maintaining the structure of the mitotic spindle. This is thought to be mediated by its effects on spindle microtubule dynamic instability. � EB1 is important in spindle positioning within the cell. This is thought to be due to its effects on astral microtubule dynamic instability. In budding yeast, EB1 also plays a role in positioning the mitotic spindle through the bud neck. In this case, it is through microtubule dynamics as well direct binding to a protein at the bud tip, creating a physical link between the microtubule end and the cell cortex. � EB1 plays a role in linking kinetochores to kinetochore microtubules, which is important for chromosome stability. It is not known whether it regulates kinetochore microtubule dynamics or end-on attachment. � EB1 also has an independent role in anchoring microtubule minus ends to centrosomes � Protein-protein interactions: Adenomatous Polyposis Coli (APC) tumor suppressor, polymerized tubulin (microtubules), p150glued/dynactin, CLIP-170, mDia, Pin2/TRF1, RhoGEF2 (drosophila), shortstop (drosophila)

Homology MAPRE2, MAPRE3

MutationsNote none known

Implicated inEntity Colon cancer Disease Truncation of the Adenomatous Polyposis Coli (APC) protein is seen in

Familial Adenomatous Polyposis (FAP) as well as most sporadic colon cancers. EB1 binds to the APC C-terminus, so its binding is lost in most truncations. Also lost are other APC binding partners including the transcription factor beta-catenin. The role of APC as a tumor suppressor


is thought to be through the beta-catenin pathway. Some evidence in the mouse suggests that this is true. However, there is increasing evidence that connections between APC and the cytoskeleton are important in cell migration, which could have an important role in colon cancer. One Italian FAP family has been reported in which APC is truncated distal to the beta-catenin binding site but including the EB1 binding site. There is no direct evidence of EB1 mutation in colon cancer, and a single report found no evidence of somatic mutations by reverse transcriptase single-strand conformational polymorphism (SSCP) analysis in 21 sporadic colorectal cancers and seven colorectal adenomas.

Entity Meduloblastoma Disease A single report showed that EB1 is transcriptionally elevated in pediatric

meduloblastoma. There is no direct evidence of EB1 mutation in meduloblastoma.

BreakpointsNote none known


Hugo MAPRE1 GDB MAPRE1

Entrez_Gene MAPRE1 22919 microtubule-associated protein, RP/EB family, member 1

Cards Atlas MAPRE1ID455ch20q11 GeneCards MAPRE1 Ensembl MAPRE1 Genatlas MAPRE1 GeneLynx MAPRE1 eGenome MAPRE1 euGene 22919


GoldenPath MAPRE1 - chr20:30871435-30901865 + 20q11.21 (hg17-May_2004)

Ensembl MAPRE1 - 20q11.21 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene MAPRE1

Gene and transcription


Genbank AL035071 [ SRS ] AL035071 [ ENTREZ ] Genbank U24166 [ SRS ] U24166 [ ENTREZ ] RefSeq NM_012325 [ SRS ] NM_012325 [ ENTREZ ] RefSeq NT_086910 [ SRS ] NT_086910 [ ENTREZ ] AceView MAPRE1 AceView - NCBI TRASER MAPRE1 Traser - Stanford Unigene Hs.472437 [ SRS ] Hs.472437 [ NCBI ] HS472437 [ spliceNest ]

Protein : pattern, domain, 3D structure SwissProt Q15691 [ SRS] Q15691 [ EXPASY ] Q15691 [ INTERPRO ] Prosite PS50021 CH [ SRS ] PS50021 CH [ Expasy ] Interpro IPR001715 Calponin-like [ SRS ] IPR001715 Calponin-like [ EBI ] Interpro IPR004953 EB1 [ SRS ] IPR004953 EB1 [ EBI ] CluSTr Q15691 Pfam PF00307 CH [ SRS ] PF00307 CH [ Sanger ] pfam00307 [ NCBI-CDD ] Pfam PF03271 EB1 [ SRS ] PF03271 EB1 [ Sanger ] pfam03271 [ NCBI-CDD ] Blocks Q15691 PDB 1PA7 [ SRS ] 1PA7 [ PdbSum ], 1PA7 [ IMB ] PDB 1UEG [ SRS ] 1UEG [ PdbSum ], 1UEG [ IMB ]

Polymorphism : SNP, mutations, diseases OMIM 603108 [ map ] GENECLINICS 603108 SNP MAPRE1 [dbSNP-NCBI] SNP NM_012325 [SNP-NCI] SNP MAPRE1 [GeneSNPs - Utah] MAPRE1 [SNP - CSHL] MAPRE1] [HGBASE - SRS]

General knowledge Family Browser MAPRE1 [UCSC Family Browser]

SOURCE NM_012325 SMD Hs.472437 SAGE Hs.472437 Amigo process|cell proliferation Amigo function|microtubule binding Amigo function|protein C-terminus binding Amigo process|regulation of cell cycle PubGene MAPRE1


Probe MAPRE1 Related clones (RZPD - Berlin)


PubMed PubMed 8 Pubmed reference(s) in LocusLink

BibliographyAPC Binds to the Novel Protein EB1.Su LK, Burrell M, Hill DE, Gyuris J, Brent R, Wiltshire R, Trent J, Vogelstein B, Kinzler KW. Cancer Res 1995; 55: 2972-2977. Medline 7606712 RP1, a new member of the adenomatous polyposis coli-binding EB1-like gene family, is differentially expressed in activated T cells.Renner C, Pfitzenmeier JP, Gerlach K, Held G, Ohnesorge S, Sahin U, Bauer S, Pfreundschuh M. J Immunol 1997; 159: 1276-1283. Medline 9233623 BIM1 encodes a microtubule-binding protein in yeast.Schwartz K, Richards K, Botstein D. Mol Biol Cell 1997; 8: 2677-2691. Medline 9398684 The adenomatous polyposis coli-binding protein EB1 is associated with cytoplasmic and spindle microtubules.Berrueta L, Kraeft SK, Tirnauer JS, Schuyler SC, Chen LB, Hill DE, Pellman D, Bierer BE. Proc Natl Acad Sci U S A 1998; 95: 10596-10601. Medline 9724749 Absence of somatic alterations of the EB1 gene adenomatous polyposis coli-associated protein in human sporadic colorectal cancers.Jais P, Sabourin JC, Bombled J, Rougier P, Lasser P, Duvillard P, Benard J, Bressac de Paillerets B. Br J Cancer 1998; 78: 1356-1360. Medline 9823979 EB1, a protein which interacts with the APC tumour suppressor, is associated with the microtubule cytoskeleton throughout the cell cycle.Morrison EE, Wardleworth BN, Askham JM, Markham AF, Meredith DM. Oncogene 1998; 17: 3471-3477. Medline 10030671 A cytokinesis checkpoint requiring the yeast homologue of an APC-binding protein.Muhua L, Adames NR, Murphy MD, Shields CR, Cooper JA. Nature 1998; 393: 487-491.


Medline 9624007 The APC-associated protein EB1 associates with components of the dynactin complex and cytoplasmic dynein intermediate chain.Berrueta L, Tirnauer JS, Schuyler SC, Pellman D, Bierer BE. Curr Biol 1999; 9: 425-428. Medline 10226031 EB/RP gene family encodes tubulin binding proteins.Juwana JP, Henderikx P, Mischo A, Wadle A, Fadle N, Gerlach K, Arends JW, Hoogenboom H, Pfreundschuh M, Renner C. Int J Cancer 1999; 81: 275-284. Medline 10188731 Yeast Bim1p promotes the G1-specific dynamics of microtubules.Tirnauer JS, O'Toole E, Berrueta L, Bierer BE, Pellman D. J Cell Biol 1999; 145: 993-1007. Medline 10352017 Regulation and function of the interaction between the APC tumour suppressor protein and EB1.Askham JM, Moncur P, Markham AF, Morrison EE. Oncogene 2000; 19: 1950-1958. Medline 10773885 Molecular linkage underlying microtubule orientation toward cortical sites in yeast.Korinek WS, Copeland MJ, Chaudhuri A, Chant J. Science 2000; 287: 2257-2259. Medline 10731146 Positioning of the mitotic spindle by a cortical-microtubule capture mechanism.Lee L, Tirnauer JS, Li J, Schuyler SC, Liu JY, Pellman D. Science 2000; 287: 2260-2262. Medline 10731147 The dynamic behavior of the APC-binding protein EB1 on the distal ends of microtubules.Mimori Kiyosue Y, Shiina N, Tsukita S. Curr Biol 2000; 10: 865-868. Medline 10899006 EB1 proteins regulate microtubule dynamics, cell polarity, and chromosome stability.Tirnauer JS, Bierer BE.


J Cell Biol 2000; 149: 761-766. Medline 10811817 Critical role for the EB1 and APC interaction in the regulation of microtubule polymerization.Nakamura M, Zhou XZ, Lu KP. Curr Biol 2001; 11: 1062-1067. Medline 11470413 Characterization of human MAPRE genes and their proteins.Su LK, Qi Y. Genomics 2001; 71: 142-149. Medline 11161807 Evidence that an interaction between EB1 and p150(Glued) is required for the formation and maintenance of a radial microtubule array anchored at the centrosome.Askham JM, Vaughan KT, Goodson HV, Morrison EE. Mol Biol Cell 2002; 13: 3627-3645. Medline 12388762 Dissecting interactions between EB1, microtubules and APC in cortical clusters at the plasma membrane.Barth AI, Siemers KA, Nelson WJ. J Cell Sci 2002; 115: 1583-1590. Medline 11950877 Drosophila EB1 is important for proper assembly, dynamics, and positioning of the mitotic spindle.Rogers SL, Rogers GC, Sharp DJ, Vale RD. J Cell Biol 2002; 158: 873-884. Medline 12213835 EB1 targets to kinetochores with attached, polymerizing microtubules.Tirnauer JS, Canman JC, Salmon ED, Mitchison TJ. Mol Biol Cell 2002; 13: 4308-4316. Medline 12475954 EB1-microtubule interactions in Xenopus egg extracts: role of EB1 in microtubule stabilization and mechanisms of targeting to microtubules.Tirnauer JS, Grego S, Salmon ED, Mitchison TJ. Mol Biol Cell 2002;13: 3614-3626. Medline 12388761 Characterization of functional domains of human EB1 family proteins.Bu W, Su LK.


J Biol Chem 2003; 278: 49721-49731. Medline 14514668 CLIP-170 interacts with dynactin complex and the APC-binding protein EB1 by different mechanisms.Goodson HV, Skube SB, Stalder R, Valetti C, Kreis TE, Morrison EE, Schroer TA. Cell Motil Cytoskeleton 2003; 55: 156-173. Medline 12789661 Crystal structure of the amino-terminal microtubule-binding domain of end-binding protein 1 (EB1).Hayashi I, Ikura M. J Biol Chem 2003; 278: 36430-36444. Medline 12857735 The microtubule plus-end proteins EB1 and dynactin have differential effects on microtubule polymerization.Ligon LA, Shelly SS, Tokito M, Holzbaur EL. Mol Biol Cell 2003;14: 1405-1417. Medline 12686597 A novel localization pattern for an EB1-like protein links microtubule dynamics to endomembrane organization.Mathur J, Mathur N, Kernebeck B, Srinivas BP, Hulskamp M. Biol 2003; 13: 1991-1997. Medline 14614826 Shortstop recruits EB1/APC1 and promotes microtubule assembly at the muscle-tendon junction.Subramanian A, Prokop A, Yamamoto M, Sugimura K, Uemura T, Betschinger J, Knoblich JA, Volk T. Curr Biol 2003; 13: 1086-1095. Medline 12842007 Adenomatous polyposis coli and EB1 localize in close proximity of the mother centriole and EB1 is a functional component of centrosomes.Louie RK, Bahmanyar S, Siemers KA, Votin V, Chang P, Stearns T, Nelson WJ, Barth AI. J Cell Sci 2004; 117: 1117-1128. Medline 14970257 Drosophila RhoGEF2 Associates with Microtubule Plus Ends in an EB1-Dependent Manner.Rogers SL, Wiedemann U, Hacker U, Turck C, Vale RD. Curr Biol 2004; 14: 1827-1833. Medline 15498490


EB1 and APC bind to mDia to stabilize microtubules downstream of Rho and promote cell migration.Wen Y, Eng CH, Schmoranzer J, Cabrera-Poch N, Morris EJ, Chen M, Wallar BJ, Alberts AS, Gundersen GG. Nat Cell Biol 2004; 6: 820-830. Medline 15311282 REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed


2004 Jennifer S Tirnauer

CitationThis paper should be referenced as such : Tirnauer JS . MAPRE1 (Microtubule-associated protein, RP/EB family, member 1). Atlas Genet Cytogenet Oncol Haematol. November 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/MAPRE1ID455ch20q11.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



ERBB2 (erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian) )

IdentityNote tyrosine-kinase receptor (RTK). The HER family of RTKs consists of

four receptors: epidermal growth factor receptor ( EGFR, also called HER-1 or erbB-1), HER-2 (also called erbB-2 or Neu), HER-3 and HER-4 (also called erbB-3 and erbB-4, respectively).

Other names v-erb-b2

HER2 NEU TKR1 NGL Her-2/neu C-erbB-2 Hugo ERBB2 Location 17q11.2-q12

DNA/RNADescription Sequence length 30528; CDS 3768. 27 exons; total exon length 4477,

max. exon length 969, min exon length 48. Number of SNPs 11. Polymorphisms: allelic variations at amino acid positions 654 and 655 of isoform (a) (positions 624 and 625 of isoform (b)) have been reported, with the most common Allele B1 (Ile-654/Ile-655); allele B2 (Ile-654/Val-655); allele B3 (Val-654/Val-655). This nucleotide polymorphism could be associated with development of gastric carcinoma and with breast cancer risk, particularly among younger women.

Transcription Alternative splicing results in several additional transcript variants, some encoding different isoforms and others that have not been fully characterized. � mRNA Transcript Variant : This variant (1) represents the shorter transcript but encodes the longer isoform (a) (protein: erbB-2 isoform (a)). � mRNA Transcript Variant : This variant (2) (protein: erbB-2 isoform (b) contains additional exons at its 5' end and lacks an alternate 5' noncoding exon, compared to variant (1). These differences result in


translation initiation at an in-frame, downstream AUG and an isoform (b) with a shorter N-terminus compared to isoform (a). � mRNA Transcript Variant : herstatin HER2-ECD 1300 bp alternative erbB-2 transcript that retains intron 8. This alternative transcript specifies 340 residues identical to subdomains I and II from the extracellular domain of p185erbB-2 followed by a unique C-terminal sequence of 79 aa encoded by intron 8. The herstatin mRNA is expressed in normal human fetal kidney and liver, but is at reduced levels relative to p185erbB-2 mRNA in carcinoma cells that contain an amplified erbB-2 gene. � mRNA Transcript Variant : An alternative transcript form of the human homologous gene erbB-2, containing an in-frame deletion encompassing exon 19, has been detected in human breast carcinomas.

Protein

HER2 protein: schematic representation

Receptor tyrosin-kinases (RTKs) are cell surface allosteric enzymes consisting of: � an extracellular ligand-binding domain (blue) � a single transmembrane (TM) domain has an extensive homology to the epidermal grow factor receptor (brown) � a cytoplasmic domain with catalityc activity (green)

Description erbB2 encodes an 185-kDa, 1255 amino acids, orphan receptor tyrosine

kinase, it displays potent oncogenic activity when overexpressed. The protooncogene consists of three domains: a single transmembrane domain that separates an intracellular kinase domain from an extracellular ligand-binding domain.

Expression HER2 protein is expressed in several human organs and tissues: normal epithelium, endometrium and ovarian epithelium and at neuromuscular level; prostate, pancreas, lung, kidney, liver, heart,


hematopoietic cells. HER2 expression is low in mononuclear cells from bone marrow, peripheral blood (PB) and mobilized PB. The higher expression has been found in cord blood-derived cells. Quiescent CD34+ progenitor cells from all blood sources and resting lymphocytes are HER2 negative, but the expression of this receptor is up-regulated during cell-cycle recruitment of progenitor cells. Similarly, it increases in mature, hematopoietic proliferating cells, underlying the correlation between HER2 and the proliferating status of hematopoietic cells.

Localisation Plasma membrane Function ACTIVATION AND INTERACTIONS :

For the other member of the HER family, ligand binding induces receptor homo- or heterodimerization, which is essential for TKs activation and subsequent recruitment of target proteins, in turns initiating a complex signaling cascade that leads into distinct transcriptional programs. There are several HER-specific ligands. HER2, which apparently has no direct or specific ligand, plays a major coordinating role in the HER network because of its ability to enhance and stabilize the dimerization: each receptor with a specific ligand appears in fact to prefer HER-2 as its heterodimeric partner. HER-2-containing heterodimers are characterized by extremely high signaling potency because HER-2 dramatically reduces the rate of ligand dissociation, allowing strong and prolonged activation of downstream signaling pathways.

SIGNALING AND CELLULAR : The most important intracellular pathways activated by HER2 are those involving mitogen activated protein kinase and phosphatidylinositol-3 kinase. HER2 expression in cancer, besides its role in proliferation, enhances and prolongs those survivals signals, associating up-regulation of this receptor to the malignant phenotype. At the same time, and depending on cellular status, the role of this receptor in controlling cell fate can also lead to differentiation and apoptosis.

PHYSIOLOGICAL : Role in development and differentiation:

� HER2 has several non-oncogenic roles in regulating growth, differentiation, apoptosis and/or remodeling in normal mammary glands. Dominant-negative forms of HER2 have significant defects in mammary development and lactation. � HER2 has an important role in development and function of heart. Cre-Lox technology to mutate erbB-2 specifically in ventricular cardiomyocytes leads to a severe cardiomyopathy. This is inferred also by the adverse cardiac side effects observed in breast cancer patients treated with the monoclonal anti-HER2 Ab Trastuzumab. � HER2 has a role in control of Schwann cell myelination and it has been demonstrated that HER2 signaling is also critical for oligodendrocyte differentiation in vivo. � HER2 has a dual role in both muscle spindle maintenance and


survival of myoblasts. Muscle-specific HER2 KO results in fact in viable mice with a progressive defect in proprioception due to loss of muscles spindles.

Homology Homolog to Avian erythroblastic leukemia viral (v-erb-b) oncogen 2

MutationsSomatic The Cancer Genome Project and Collaborative Group sequenced the

erbB-2 gene from 120 primary lung tumors and identified 4% that had mutations within the kinase domain; in the adenocarcinoma subtype of lung cancer, 10% of cases had mutations. In non small cell lung cancer (adenocarcinoma) the following erbB-2 mutations were found: insertion/duplication of GCATACGTGATG at nucleotide 2322 of the erbB-2 gene, resulting in a 4-amino acid insertion (AYVM) at codon 774. insertion of CTGTGGGCT at nucleotide 2335 of the erbB-2 gene, resulting in a 3-amino acid insertion (VGS) starting at codon 779; a 2-bp substitution in the erbB-2 gene, TT-CC at nucleotides 2263 and 2264, resulting in a leu755-to-pro (L755P) substitution; In a glioblastoma a 2740G-A transition in the erbB-2 gene that caused a glu914-to-lys substitution (E914K). In a gastric tumor a 2326G-A transition in the erbB-2 gene that caused a gly776-to-ser (G776S) substitution. In an ovarian tumor, a 2570A-G transition in the erbB-2 gene that caused an asn857-to-ser (N857S) substitution.

Implicated inEntity Hematological malignancies Disease HER2 expression can be detected in blast cells from patients with

hematological malignancies including acute lymphoblastic leukemia (ALL). It could be used as a potential target for the application of HER2-directed treatment strategies in ALL including vaccination approaches.

Entity Bladder cancer Prognosis HER2 is overexpressed in 25% to 40% of several human tumors and

associated with the malignancy of the disease, high mitotic index and a shorter survival time for the patient. Overexpression of ErbB-2 is associated with transitional cell carcinoma of the bladder. HER2 overexpression occurs in muscle-invasive urothelial carcinomas of the bladder and is associated with worse survival; amplifications of erbB-2 gene are also frequently linked to alterations of the TOP2A gene in bladder cancer.

Entity Breast carcinoma Prognosis HER-2 overexpression, occurring in 25-30% of human breast cancers,

is associated to shorter time to relapse and lower overall survival. Overexpression of the erbB-2 gene, is associated with tumor aggressiveness, and with patient responsiveness to doxorubicin, cyclophosphamide, methotrexate, fluorouracil (CMF), and to paclitaxel,


whereas tamoxifen was found to be ineffective and even detrimental in patients with HER2-positive tumors. In Paget's disease of breast, HER2 protein overexpression is caused by amplification of the erbB-2 gene. HER2 has a role in this disease of the breast, where the epidermis of the nipple is infiltrated by large neoplastic cells of glandular origin. It seems that binding of heregulin-alfa to the receptor complex on Paget cells results in chemotaxis of these breast cancer cells.

Entity Cervical cancer Prognosis HER2 may be activated in the early stage of pathogenesis of cervical

carcinoma in geriatric patients and is frequently amplified in squamous cell carcinoma of the uterine cervix.

Entity Childhood Medulloblastoma Prognosis Overexpression of HER2 in medulloblastoma is associated with poor

prognosis and metastasis and HER2-HER4 receptor heterodimerization is of particular biological significance in this disease.

Entity Colorectal cancer Prognosis Overexpression of HER2 occurs in a significant number of colorectal

cancers. It was significantly associated with poor survival and related to tumor progression in colorectal cancer.

Entity Oral squamous cell carcinoma Prognosis E6/E7 proteins of HPV type 16 and HER2 cooperate to induce

neoplastic transformation of primary normal oral epithelial cells. Overexpression of HER2 receptor is a frequent event in oral squamous cell carcinoma and is correlated with poor survival.

Entity Gastric cancer Prognosis HER2 amplification/overexpression does not seem to play a role in the

molecular pathogenesis of most gastrinomas. However, mild gene amplification occurs in a subset of them, and overexpression of this receptor is associated with aggressiveness of the disease. HER2 is correlated with tumor histological differentiation and is associated with poor prognosis in well-differentiated gastric adenocarcinoma.

Entity Germ-cell testicular tumor Prognosis A significant correlation was observed between HER2 overexpression

and clinical outcome in germ-cell testicular tumors. Entity Cholangiocarcinoma Prognosis Increased HER2 expression contributes to the development of


cholangiocarcinogenesis into an advanced stage associated with tumor metastasis. In addition, overexpression of HER2 and COX-2 correlated directly with tumor differentiation.

Entity Lung cancer Prognosis HER2 is overexpressed in less than 20% of patients with non-small cell

lung cancer (NSCLC) and studies have shown that overexpression of this receptor is correlated with a poor prognosis in both resected and advanced NSCLC.

Entity Osteosarcoma Prognosis Higher frequency of HER2 expression has been observed in samples

from patients with metastatic disease at presentation and at the time of relapse, and it correlates with worse histologic response and decreased event-free survival.

Entity Ovarian cancer Prognosis Patients with HER2-overexpression have a significantly worse

prognosis compared to patients with HER2-negative tumors. Entity Pancreatic adenocarcinoma Prognosis Overexpression of HER-2 in pancreatic adenocarcinoma seems to be a

result of increased transcription rather than gene amplification. The coexpression of HER2 oncogene protein, epidermal growth factor receptor, and TGF-beta1 in pancreatic ductal adenocarcinoma is related to the histopathological grades and clinical stages of tumors.

Entity Primary Fallopian tube carcinoma Prognosis This disease is a rare form of female cancer where the HER2

overexpression plays a role in tumorigenesis. Entity Prostate cancer Prognosis The expression of ERBB2 in prostate cancer is relatively low, but is up-

modulated at onset of hormone resistance. Entity Salivary gland tumor Prognosis Several results demonstrated significant positive staining of HER2 in the

salivary tumorigenic tissue but not in the surrounding non-tumorigenic tissue, pointing to a biological role in the tumorigenic process.

Entity Synovial sarcoma Prognosis The presence of increased levels of HER2 in synovial sarcoma is


associated with a more favorable clinical course.

To be noted Possible therapeutic strategies: 1) growth inhibitory antibodies (like

Trastuzumab), used alone or in combination with standard chemotherapeutics; 2) tyrosin kinase inhibitors (TKI); 3)active immunotherapy, because the HER2 oncoprotein is immunogenic in some breast carcinoma patients.


Hugo ERBB2 GDB ERBB2

Entrez_Gene ERBB2 2064 v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian)

Cards Atlas ERBB2ID162ch17q11 GeneCards ERBB2 Ensembl ERBB2 CancerGene ERBB2 Genatlas ERBB2 GeneLynx ERBB2 eGenome ERBB2 euGene 2064


GoldenPath ERBB2 - chr17:35097919-35138441 + 17q12 (hg17-May_2004)

Ensembl ERBB2 - 17q12 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene ERBB2

Gene and transcription Genbank AB025285 [ SRS ] AB025285 [ ENTREZ ] Genbank AY208911 [ SRS ] AY208911 [ ENTREZ ] Genbank L29395 [ SRS ] L29395 [ ENTREZ ] Genbank M11767 [ SRS ] M11767 [ ENTREZ ] Genbank M12036 [ SRS ] M12036 [ ENTREZ ] RefSeq NM_001005862 [ SRS ] NM_001005862 [ ENTREZ ] RefSeq NM_004448 [ SRS ] NM_004448 [ ENTREZ ] RefSeq NT_086877 [ SRS ] NT_086877 [ ENTREZ ]


AceView ERBB2 AceView - NCBI TRASER ERBB2 Traser - Stanford Unigene Hs.446352 [ SRS ] Hs.446352 [ NCBI ] HS446352 [ spliceNest ]


Prosite PS00107 PROTEIN_KINASE_ATP [ SRS ] PS00107 PROTEIN_KINASE_ATP [ Expasy ]

Prosite PS50011 PROTEIN_KINASE_DOM [ SRS ] PS50011 PROTEIN_KINASE_DOM [ Expasy ]

Prosite PS00109 PROTEIN_KINASE_TYR [ SRS ] PS00109 PROTEIN_KINASE_TYR [ Expasy ]

Interpro IPR000494 EGFR_L [ SRS ] IPR000494 EGFR_L [ EBI ] Interpro IPR006211 Furin-like [ SRS ] IPR006211 Furin-like [ EBI ] Interpro IPR006212 Furin_repeat [ SRS ] IPR006212 Furin_repeat [ EBI ]

Interpro IPR009030 Grow_fac_recept [ SRS ] IPR009030 Grow_fac_recept [ EBI ]

Interpro IPR011009 Kinase_like [ SRS ] IPR011009 Kinase_like [ EBI ] Interpro IPR000719 Prot_kinase [ SRS ] IPR000719 Prot_kinase [ EBI ] Interpro IPR001245 Tyr_pkinase [ SRS ] IPR001245 Tyr_pkinase [ EBI ] Interpro IPR008266 Tyr_pkinase_AS [ SRS ] IPR008266 Tyr_pkinase_AS [ EBI ]

Interpro IPR004019 YLP_motif [ SRS ] IPR004019 YLP_motif [ EBI ] CluSTr P04626

Pfam PF00757 Furin-like [ SRS ] PF00757 Furin-like [ Sanger ] pfam00757 [ NCBI-CDD ]

Pfam PF00069 Pkinase [ SRS ] PF00069 Pkinase [ Sanger ] pfam00069 [ NCBI-CDD ]

Pfam PF01030 Recep_L_domain [ SRS ] PF01030 Recep_L_domain [ Sanger

] pfam01030 [ NCBI-CDD ] Pfam PF02757 YLP [ SRS ] PF02757 YLP [ Sanger ] pfam02757 [ NCBI-CDD ] Smart SM00261 FU [EMBL] Smart SM00219 TyrKc [EMBL] Prodom PD000001 Prot_kinase[INRA-Toulouse]

Prodom P04626 ERB2_HUMAN [ Domain structure ] P04626 ERB2_HUMAN [ sequences sharing at least 1 domain ]

Blocks P04626 PDB 1N8Z [ SRS ] 1N8Z [ PdbSum ], 1N8Z [ IMB ] PDB 1QR1 [ SRS ] 1QR1 [ PdbSum ], 1QR1 [ IMB ]

Polymorphism : SNP, mutations, diseases OMIM 164870 [ map ] GENECLINICS 164870 SNP ERBB2 [dbSNP-NCBI]


SNP NM_001005862 [SNP-NCI] SNP NM_004448 [SNP-NCI] SNP ERBB2 [GeneSNPs - Utah] ERBB2 [SNP - CSHL] ERBB2] [HGBASE - SRS]

General knowledge Family Browser ERBB2 [UCSC Family Browser]

SOURCE NM_001005862 SOURCE NM_004448 SMD Hs.446352 SAGE Hs.446352

Enzyme 2.7.1.112 [ Enzyme-SRS ] 2.7.1.112 [ Brenda-SRS ] 2.7.1.112 [ KEGG

] 2.7.1.112 [ WIT ] Amigo function|ATP binding Amigo function|ErbB-3 class receptor binding Amigo process|cell proliferation Amigo process|electron transport Amigo function|electron transporter activity Amigo function|epidermal growth factor receptor activity Amigo component|extracellular region Amigo component|integral to membrane Amigo function|iron ion binding Amigo component|membrane Amigo function|non-membrane spanning protein tyrosine kinase activity Amigo process|protein amino acid phosphorylation Amigo process|protein amino acid phosphorylation Amigo function|protein serine/threonine kinase activity Amigo function|protein-tyrosine kinase activity Amigo function|receptor activity Amigo function|receptor signaling protein tyrosine kinase activity Amigo function|transferase activity

Amigo process|transmembrane receptor protein tyrosine kinase signaling pathway

Amigo process|transmembrane receptor protein tyrosine kinase signaling pathway

BIOCARTA Role of ERBB2 in Signal Transduction and Oncology BIOCARTA Trefoil Factors Initiate Mucosal Healing PubGene ERBB2

Other databases Other Somatic mutation (COSMIC-CGP-Sanger)


database Probes

Probe ERBB2 Related clones (RZPD - Berlin) PubMed


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Medline 10550311 The HER-2/neu receptor tyrosine kinase gene encodes a secreted autoinhibitor.Doherty JK, Bond C, Jardim A, Adelman JP, Clinton GM. Proc Natl Acad Sci U S A 1999; 96: 10869-10874. Medline 10485918 Pathobiologic identification of two distinct breast carcinoma subsets with diverging clinical behaviors.Ménard S, Casalini P, Tomasic G, Pilotti S, Cascinelli N, Bufalino R, Perrone F, Longhi C, Rilke F, Colnaghi MI. Breast Cancer Res Treat 1999; 55: 169-177. Medline 10481944 Identification of a novel promoter and exons of the c-ERBB-2 gene.Nezu M, Sasaki H, Kuwahara Y, Ochiya T, Yamada Y, Sakamoto H, Tashiro H, Yamazaki M, Ikeuchi T, Saito Y, Terada M. Biochem Biophys Res Commun 1999; 258: 499-505. Medline 10329415 Primary cancer of the fallopian tube with transitional differentiation. Clinical and pathological assessment of 6 cases.Rabczynski JK.Kochman AT. Neoplasma 1999; 46: 128-131. Medline 10466438 Overexpression of p53 and HER-2/neu and c-myc in primary fallopian tube carcinoma.Chung TK, Cheung TH, To KF, Wong YF. Gynecol Obstet Invest 2000; 49: 47-51. Medline 10629373 A dual role of erbB2 in myelination and in expansion of the schwann cell precursor pool.Garratt AN, Voiculescu O, Topilko P, Charnay P, Birchmeier C. J Cell Biol 2000; 148: 1035-1046. Medline 10704452 The ErbB signaling network: receptor heterodimerization in development and cancer.Olayioye MA, Neve RM, Lane HA, Hynes NE. EMBO J 2000; 19: 3159-3167. (REVIEW) Medline 10880430 Pathogenesis of Paget's disease: epidermal heregulin-alpha, motility factor, and the HER receptor family.


Schelfhout VR, Coene ED, Delaey B, Thys S, Page DL, De Potter CR. J Natl Cancer Inst 2000; 92: 622-628. Medline 10772679 Population-based, case-control study of HER2 genetic polymorphism and breast cancer risk.Xie D, Shu XO, Deng Z, Wen WQ, Creek KE, Dai Q, Gao YT, Jin F, Zheng W. J Natl Cancer Inst 2000; 92: 412-417. Medline 10699071 Role of p53 in HER2-induced proliferation or apoptosis.Casalini P, Botta L, Ménard S. J Biol Chem 2001; 276: 12449-12453. Medline 11278558 HER-2/neu overexpression as a poor prognostic factor for patients with metastatic breast cancer undergoing high-dose chemotherapy with autologous stem cell transplantation.Kim YS, Konoplev SN, Montemurro F, Hoy E, Smith TL, Rondon G, Champlin RE, Sahin AA, Ueno NT. Clin Cancer Res 2001; 7: 4008-4012. (REVIEW) Medline 11751494 Response to Cyclophosphamide, Methotrexate, and Fluorouracil in lymph node-positive breast cancer according to HER2 overexpression and other tumor biologic variables.Ménard S, Valagussa P, Pilotti S, Gianni L, Biganzoli E, Boracchi P, Tomasic G, Casalini P, Marubini E, Colnaghi MI, Cascinelli N, Bonadonna G. J Clin Oncol 2001; 19: 329-335. Medline 11208823 Untangling the ErbB signalling network.Yarden Y.Sliwkowski MX. Nat Rev Mol Cell Biol 2001; 2: 127-137.(REVIEW) Medline 11252954 c-erbB-2 and c-Met expression relates to cholangiocarcinogenesis and progression of intrahepatic cholangiocarcinoma.Aishima SI, Taguchi KI, Sugimachi K, Shimada M, Sugimachi K, Tsuneyoshi M. Histopathology 2002; 40: 269-278. Medline 11895493 ErbB2 is required for muscle spindle and myoblast cell survival.Andrechek ER, Hardy WR, Girgis-Gabardo AA, Perry RL, Butler R, Graham FL, Kahn RC, Rudnicki MA, Muller WJ. Mol Cell Biol 2002; 22: 4714-4722.


Medline 12052879 ERBB-2 overexpression and cyclooxygenase-2 up-regulation in human cholangiocarcinoma and risk conditions.Endo K, Yoon BI, Pairojkul C, Demetris AJ, Sirica AE. Hepatology 2002; 36: 439-450. Medline 12143054 Does HER2/neu expression provide prognostic information in patients with advanced urothelial carcinoma?Gandour-Edwards R, Lara PN, Jr., Folkins AK, LaSalle JM, Beckett L, Li Y, Meyers FJ, DeVere-White R. Cancer 2002; 95: 1009-1015. Medline 12209684 Her-2/neu expression and gene amplification in gastrinomas: correlations with tumor biology, growth, and aggressiveness.Goebel SU, Iwamoto M, Raffeld M, Gibril F, Hou W, Serrano J, Jensen RT. Cancer Res 2002; 62: 3702-3710. Medline 12097278 Evaluation of HER-2/neu gene amplification and protein expression in non-small cell lung carcinomas.Hirsch FR, Varella-Garcia M, Franklin WA, Veve R, Chen L, Helfrich B, Zeng C, Baron A, Bunn PA, Jr. Br J Cancer 2002; 86: 1449-1456. Medline 11986780 [Expression and clinical significance of p53 and c-erbB2 in geriatric women with cervical carcinoma].Huang YW, Li MD, Wu QL, Liu FY. Ai Zheng 2002; 21: 297-300. Medline 12451999 Characterization of the HER-2/neu oncogene by immunohistochemical and fluorescence in situ hybridization analysis in oral and oropharyngeal squamous cell carcinoma.Khan AJ, King BL, Smith BD, Smith GL, DiGiovanna MP, Carter D, Haffty BG. Clin Cancer Res 2002; 8: 540-548. Medline 11839675 Overexpression of c-erbB-2 protein correlates with chromosomal gain at the c-erbB-2 locus and patient survival in advanced colorectal carcinomas.Knosel T, Yu Y, Stein U, Schwabe H, Schluns K, Schlag PM, Dietel M, Petersen I. Clin Exp Met 2002; 19: 401-407. Medline 12198768


HER2-positive breast carcinomas as a particular subset with peculiar clinical behaviors.Ménard S, Balsari A, Casalini P, Tagliabue E, Campiglio M, Bufalino R, Cascinelli N. Clin Cancer Res 2002; 8: 520-525. Medline 11839672 Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy.Ozcelik C, Erdmann B, Pilz B, Wettschureck N, Britsch S, Hubner N, Chien KR, Birchmeier C, Garratt AN. Proc Natl Acad Sci USA 2002; 99: 8880-8885. Medline 12072561 Expression and gene copy number analysis of ERBB2 oncogene in prostate cancer.Savinainen KJ, Saramaki OR, Linja MJ, Bratt O, Tammela TL, Isola JJ, Visakorpi T. Am J Pathol 2002; 160: 339-345. Medline 11786427 Expression of c-erbB-2 oncogene protein, epidermal growth factor receptor, and TGF-beta1 in human pancreatic ductal adenocarcinoma.Zhang L.Yuan SZ. Hepatobiliary Pancreat Dis Int 2002; 1: 620-623. Medline 14607699 Immunohistological study of NM 23 and C-erbB-2 expression in primary tumor and metastases of colorectal adenocarcinoma.Delektorskaya VV, Perevoshchikov AG, Kushlinskii NE. Bull Exp Biol Med 2003; 135: 489-494. Medline 12910292 Identification of patients with transitional cell carcinoma of the bladder overexpressing ErbB2, ErbB3, or specific ErbB4 isoforms: real-time reverse transcription-PCR analysis in estimation of ErbB receptor status from cancer patients.Junttila TT, Laato M, Vahlberg T, Soderstrom KO, Visakorpi T, Isola J, Elenius K. Clin Cancer Res 2003; 9: 5346-5357. Medline 14614020 The role of ErbB2 signaling in the onset of terminal differentiation of oligodendrocytes in vivo.Kim JY, Sun Q, Oglesbee M, Yoon SO. J Neurosci 2003; 23: 5561-5571. Medline 12843257


A single nucleotide polymorphism in the transmembrane domain coding region of HER-2 is associated with development and malignant phenotype of gastric cancer.Kuraoka K, Matsumura S, Hamai Y, Nakachi K, Imai K, Matsusaki K, Oue N, Ito R, Nakayama H, Yasui W. Int J Cancer 2003; 107: 593-596. Medline 14520697 HER2/neu overexpression in the development of muscle-invasive transitional cell carcinoma of the bladder.Latif Z, Watters AD, Dunn I, Grigor KM, Underwood MA, Bartlett JM. Br J Cancer 2003; 89: 1305-1309. Medline 14520464 HER2 overexpression and doxorubicin in the adjuvant chemotherapy of resectable breast cancer.Moliterni A, Ménard S, Valagussa P, Biganzoli E, Boracchi P, Balsari A, Casalini P, Tomasic G, Marubini E, Pilotti S, Bonadonna G. J Clin Oncol 2003; 21: 458-462. Medline 12560435 Expression of her-2/neu on acute lymphoblastic leukemias: implications for the development of immunotherapeutic approaches.Muller MR, Grunebach F, Kayser K, Vogel W, Nencioni A, Brugger W, Kanz L, Brossart P. Clin Cancer Res 2003; 9: 3448-3453. Medline 12960136 Prognostic role of apoptotic, Bcl-2, c-erbB-2 and p53 tumor markers in salivary gland malignancies.Nagler RM, Kerner H, Ben Eliezer S, Minkov I, Ben Itzhak O. Oncology 2003; 64: 389-398. Medline 12759537 Correlation between encoded protein overexpression and copy number of the HER2 gene with survival in non-small cell lung cancer.Nakamura H, Saji H, Ogata A, Hosaka M, Hagiwara M, Kawasaki N, Kato H. Int J Cancer 2003; 103: 61-66. Medline 12455054 Molecular and immunohistochemical analysis of HER2/neu oncogene in synovial sarcoma.Nuciforo PG, Pellegrini C, Fasani R, Maggioni M, Coggi G, Parafioriti A, Bosari S. Hum Pathol 2003; 34: 639-645. Medline 12874758


HER-2 and TOP2A coamplification in urinary bladder cancer.Simon R, Atefy R, Wagner U, Forster T, Fijan A, Bruderer J, Wilber K, Mihatsch MJ, Gasser T, Sauter G. Int J Cancer 2003; 107: 764-772. Medline 14566826 HER-2/neu protein expression and gene alteration in stage I-IIIA non-small-cell lung cancer: a study of 140 cases using a combination of high throughput tissue microarray, immunohistochemistry, and fluorescent in situ hybridization.Tan D, Deeb G, Wang J, Slocum HK, Winston J, Wiseman S, Beck A, Sait S, Anderson T, Nwogu C, Ramnath N, Loewen G. Diagn Mol Pathol 2003; 12: 201-211. Medline 14639106 Her-2/neu expression in osteosarcoma increases risk of lung metastasis and can be associated with gene amplification.Zhou H, Randall RL, Brothman AR, Maxwell T, Coffin CM, Goldsby RE. J Pediatr Hematol Oncol 2003; 25: 27-32. Medline 12544770 E6/E7 proteins of HPV type 16 and ErbB-2 cooperate to induce neoplastic transformation of primary normal oral epithelial cells.Al Moustafa AE, Foulkes WD, Benlimame N, Wong A, Yen L, Bergeron J, Batist G, Alpert L, Alaoui-Jamali MA. Oncogene 2004; 23: 350-358. Medline 14724563 Solution structure of ADO1, a toxin extracted from the saliva of the assassin bug, Agriosphodrus dohrni.Bernard C, Corzo G, Adachi-Akahane S, Foures G, Kanemaru K, Furukawa Y, Nakajima T, Darbon H. Proteins 2004; 54: 195-205. Medline 14696118 HER-2 overexpression is an independent marker of poor prognosis of advanced primary ovarian carcinoma: a multicenter study of the GINECO group.Camilleri-Broet S, Hardy-Bessard AC, Le Tourneau A, Paraiso D, Levrel O, Leduc B, Bain S, Orfeuvre H, Audouin J, Pujade-Lauraine E. Ann Oncol 2004; 15: 104-112. Medline 14679128 Role of HER receptors family in development and differentiation.Casalini P, Iorio MV, Galmozzi E, Ménard S. J Cell Physiol 2004; 200: 343-350. (REVIEW) Medline 15254961


beta-Catenin and p53 analyses of a breast carcinoma tissue microarray.Chung GG, Zerkowski MP, Ocal IT, Dolled-Filhart M, Kang JY, Psyrri A, Camp RL, Rimm DL. Cancer 2004; 100: 2084-2092. Medline 14689059 Genetic and pathologic significance of 1p, 17p, and 18q aneusomy and the ERBB2 gene in colorectal cancer and related normal colonic mucosa.Cianciulli A, Cosimelli M, Marzano R, Merola R, Piperno G, Sperduti I, de l, I, Leonardo G, Graziano F, Mancini R, Guadagni F. Cancer Genet Cytogenet 2004; 151: 52-59. Medline 15120910 The expression and prognostic significance of HER-2 in colorectal cancer and its relationship with clinicopathological parameters.Essapen S, Thomas H, Green M, de Vries C, Cook MG, Marks C, Topham C, Modjtahedi H. Int J Oncol 2004; 24: 241-248. Medline 14719098 Amplification and overexpression of HER-2/neu in invasive ductal carcinomas of the pancreas and pancreatic intraepithelial neoplasms and the relationship to the expression of p21(WAF1/CIP1).Hermanova M, Lukas Z, Nenutil R, Brazdil J, Kroupova I, Kren L, Pazourkova M, Ruzicka M, Dite P. Neoplasma 2004; 51: 77-83. Medline 15190415 The role of HER2/neu expression and trastuzumab in non-small cell lung cancer.Hirsch FR.Langer CJ. Semin Oncol 2004; 31: 75-82.(REVIEW) Medline 14981584 Cell surface expression of epidermal growth factor receptor and Her-2 with nuclear expression of Her-4 in primary osteosarcoma.Hughes DP, Thomas DG, Giordano TJ, Baker LH, McDonagh KT. Cancer Res 2004; 64: 2047-2053. Medline 15026342 Her-2/neu gene amplification and response to paclitaxel in patients with metastatic breast cancer.Konecny GE, Thomssen C, Luck HJ, Untch M, Wang HJ, Kuhn W, Eidtmann H, du BA, Olbricht S, Steinfeld D, Mobus V, Von Minckwitz G, Dandekar S, Ramos L, Pauletti G, Pegram MD, Janicke F, Slamon DJ. J Natl Cancer Inst 2004; 96: 1141-1151.


Medline 15292386 ERBB2 amplification is superior to protein expression status in predicting patient outcome in serous ovarian carcinoma.Lassus H, Leminen A, Vayrynen A, Cheng G, Gustafsson JA, Isola J, Butzow R. Gynecol Oncol 2004; 92: 31-39. Medline 14751135 Clinical relevance of HER-2/neu expression in germ-cell testicular tumors.Mandoky L, Geczi L, Bodrogi I, Toth J, Csuka O, Kasler M, Bak M. Anticancer Res 2004; 24: 2219-2224. Medline 15330164 Synchronous overexpression of epidermal growth factor receptor and HER2-neu protein is a predictor of poor outcome in patients with stage I non-small cell lung cancer.Onn A, Correa AM, Gilcrease M, Isobe T, Massarelli E, Bucana CD, O'Reilly MS, Hong WK, Fidler IJ, Putnam JB, Herbst RS. Clin Cancer Res 2004; 10: 136-143. Medline 14734462 The prognostic and predictive value of immunohistochemically detected HER-2/neu overexpression in 361 patients with ovarian cancer: a multicenter study.Riener EK, Arnold N, Kommoss F, Lauinger S, Pfisterer J. Gynecol Oncol 2004; 95: 89-94. Medline 15385115 Lung cancer: intragenic ERBB2 kinase mutations in tumours.Stephens P, Hunter C, Bignell G, Edkins S, Davies H, Teague J, Stevens C, O'Meara S, Smith R, Parker A, Barthorpe A, Blow M, Brackenbury L, Butler A, Clarke O, Cole J, Dicks E, Dike A, Drozd A, Edwards K, Forbes S, Foster R, Gray K, Greenman C, Halliday K, Hills K, Kosmidou V, Lugg R, Menzies A, Perry J, Petty R, Raine K, Ratford L, Shepherd R, Small A, Stephens Y, Tofts C, Varian J, West S, Widaa S, Yates A, Brasseur F, Cooper CS, Flanagan AM, Knowles M, Leung SY, Louis DN, Looijenga LH, Malkowicz B, Pierotti MA, Teh B, Chenevix-Trench G, Weber BL, Yuen ST, Harris G, Goldstraw P, Nicholson AG, Futreal PA, Wooster R, Stratton MR. Nature 2004; 431: 525-526. Medline 15457249 REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed


2004 Patrizia Casalini; Marilena V Iorio


CitationThis paper should be referenced as such : Casalini P; Iorio MV . ERBB2 (erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian) ). Atlas Genet Cytogenet Oncol Haematol. December 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/ERBB2ID162ch17q11.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



TOP1 (topoisomerase (DNA) 1)

IdentityHugo TOP1 Location 20q12-q13.1, centromer to telomer

DNA/RNANote The sequence is split into 21 exons over 85kbp. Introns are 0.2-30 kbp

in size.

The star denotes intron 7 where chromosome translocation occurs. Description 21 exons with 20 introns Transcription 3.8 kb (single band) Pseudogene 2 pseudogenes. TOP1P1 on chromosome 1q23-q24, and TOP1P2 on

chromosome 22q12-q13.1.

Protein

The arrow indicates the breaking point of translocation, and the star denotes the sites

of point mutation. Note type I DNA topoisomerase, EC (5.99.1.2) Description 765 amino acids, about 100kDa; contains NLS in the N-term, a core

domain which recognizes its binding sequences, a link domain which connects the core and catalytic domains, and the catalytic domain in the C-term.

Expression Ubiquitous. The expression level is up-regulated along with cell


proliferation signals. Localisation Nucleus Function TOP1 catalyzes the breaking and rejoining of single DNA strand. Homology The core and catalytic domains are conserved between the human and

S.cerevisiae enzyme.

MutationsSomatic Translocation of chromosome t(11;20)(p15;q12) has been reported in

hematological malignancies (see below). Point mutations with amino acid substitution in the catalytic domain have been implicated in irinotecan-resistance.

Implicated inEntity t(11;20)(p15;q12) Disease de novo acute myeloid leukemia, acute monocytic leukemia, therapy-

related myelodysplastic syndrome/leukemia(t-MDS/AML) Prognosis poor (?) Hybrid/Mutated Gene NUP98/TOP1

Oncogenesis NUP98-TOP1 fusion protein has been proved to have leukemogenic

activities independent of topoisomerase activity.

Breakpoints

The breakpoints locate in intron 7, causing the fusion protein to lack the N-terminal

169 amino acids.The breakpoints locate in the repetitive elements or close to them which exist in intron 7 of TOP1 gene.


To be noted Point mutations W736stop and G737S were detected in lung non-small

cell carcinoma. The significance of mutations in catalytic domain has been suspected to be relevant to susceptibility to irinotecan.


Hugo TOP1 GDB TOP1 Entrez_Gene TOP1 7150 topoisomerase (DNA) I

Cards GeneCards TOP1 Ensembl TOP1 CancerGene TOP1 Genatlas TOP1 GeneLynx TOP1 eGenome TOP1 euGene 7150

Genomic and cartography GoldenPath TOP1 - chr20:39090876-39186541 + 20q12 (hg17-May_2004) Ensembl TOP1 - 20q12 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene TOP1

Gene and transcription Genbank AL035652 [ SRS ] AL035652 [ ENTREZ ] Genbank M60688 [ SRS ] M60688 [ ENTREZ ] Genbank M60706 [ SRS ] M60706 [ ENTREZ ] Genbank BC000943 [ SRS ] BC000943 [ ENTREZ ] Genbank BC004475 [ SRS ] BC004475 [ ENTREZ ] RefSeq NM_003286 [ SRS ] NM_003286 [ ENTREZ ] RefSeq NT_086910 [ SRS ] NT_086910 [ ENTREZ ] AceView TOP1 AceView - NCBI TRASER TOP1 Traser - Stanford Unigene Hs.472737 [ SRS ] Hs.472737 [ NCBI ] HS472737 [ spliceNest ]


Prosite PS00176 TOPOISOMERASE_I_EUK [ SRS ] PS00176 TOPOISOMERASE_I_EUK [ Expasy ]


Interpro IPR011010 DNA_brk_join_enz [ SRS ] IPR011010 DNA_brk_join_enz[ EBI ]

Interpro IPR001631 Topismerse_I [ SRS ] IPR001631 Topismerse_I [ EBI ]

Interpro IPR009054 Topismrse_insert [ SRS ] IPR009054 Topismrse_insert [ EBI ]

Interpro IPR008336 Topoisomer_I_N [ SRS ] IPR008336 Topoisomer_I_N [ EBI ]

CluSTr P11387

Pfam PF01028 Topoisom_I [ SRS ] PF01028 Topoisom_I [ Sanger

] pfam01028 [ NCBI-CDD ]

Pfam PF02919 Topoisom_I_N [ SRS ] PF02919 Topoisom_I_N [ Sanger

] pfam02919 [ NCBI-CDD ] Smart SM00435 TOPEUc [EMBL] Blocks P11387 PDB 1A31 [ SRS ] 1A31 [ PdbSum ], 1A31 [ IMB ] PDB 1A35 [ SRS ] 1A35 [ PdbSum ], 1A35 [ IMB ] PDB 1A36 [ SRS ] 1A36 [ PdbSum ], 1A36 [ IMB ] PDB 1EJ9 [ SRS ] 1EJ9 [ PdbSum ], 1EJ9 [ IMB ] PDB 1K4S [ SRS ] 1K4S [ PdbSum ], 1K4S [ IMB ] PDB 1K4T [ SRS ] 1K4T [ PdbSum ], 1K4T [ IMB ] PDB 1LPQ [ SRS ] 1LPQ [ PdbSum ], 1LPQ [ IMB ] PDB 1NH3 [ SRS ] 1NH3 [ PdbSum ], 1NH3 [ IMB ] PDB 1R49 [ SRS ] 1R49 [ PdbSum ], 1R49 [ IMB ]

Polymorphism : SNP, mutations, diseases OMIM 126420 [ map ] GENECLINICS 126420 SNP TOP1 [dbSNP-NCBI] SNP NM_003286 [SNP-NCI] SNP TOP1 [GeneSNPs - Utah] TOP1 [SNP - CSHL] TOP1] [HGBASE - SRS]

General knowledge Family Browser TOP1 [UCSC Family Browser]

SOURCE NM_003286 SMD Hs.472737 SAGE Hs.472737

Enzyme 5.99.1.2 [ Enzyme-SRS ] 5.99.1.2 [ Brenda-SRS ] 5.99.1.2 [ KEGG ] 5.99.1.2 [ WIT ]

Amigo function|DNA topoisomerase type I activity Amigo process|DNA topological change Amigo process|DNA unwinding PubGene TOP1



Probe TOP1 Related clones (RZPD - Berlin) PubMed


BibliographyStructure of the Human Type I DNA Topoisomerase Gene.Kunze N, Yang G, Doelberg M, Sundarp R, Knippers R, Richter A. J Biol Chem. 1991; 266(15): 9610-9616. Medline 1851751 The t(11;20)(p15;q11) chromosomal translocation associated with therapy-related myelodysplastic syndrome results in an NUP98-TOP1 fusion.Ahuja HG, Felix CA, Aplan PD Blood 1999; 94: 3258-3261. Medline 10556215 Potential Role for DNA Topoisomerase II Poisons in the Generation of t(11;20)(p15;q11) translocations.Ahuja HG, Felix CA, Aplan PD Genes Chromosomes Cancer 2000; 29: 96-105. Medline 10959088 Expression of NUP98/TOP1, but not of TOP1/NUP98, in a treatment-related myelodysplastic syndrome with t(10;20;11)(q24;q11;p15).Panagopoulos I, Fioretos T, Isaksson M, Larsson G, Billstrom R, Mitelman F, Johansson B Genes Chromosomes Cancer 2002; 34: 249-254. Medline 11979559 Point mutations in the topoisomerase I gene in patients with non-small cell lung cancer treated with irinotecan.Tsurutani J, Nitta T, Hirashima T, Komiya T, Uejima H, Tada H, Syunichi N, Tohda A, Fukuoka M, Nakagawa K Lung Cancer 2002; 35: 299-304. Medline 11844605 Generation of the NUP98-TOP1 fusion transcript by the t(11;20) (p15;q11) in a case of acute monocytic leukemia.Chen S, Xue Y, Chen Z, Guo Y, Wu Y, Pan J Cancer Genet Cytogenet 2003; 140: 153-156. Medline 12645654 Both NUP98/TOP1 and TOP1/NUP98 transcripts are detected in a de novo AML with t(11;20)(p15;q11).


Iwase S, Akiyama N, Sekikawa T, Saito S, Arakawa Y, Horiguchi-Yamada J, Yamada H. Genes Chromosomes Cancer 2003; 38: 102-105. Medline 12874791 NUP98-topoisomerase I acute myeloid leukemia-associated fusion gene has potent leukemogenic activities independent of an engineered catalytic site mutation.Gurevich RM, Aplan PD, Humphries RK Blood 2004; 104: 1127-1136. Epub 2004. Medline 15100157 A t(11;20)(p15;q11) may identify a subset of nontherapy-related acute myelocytic leukemia.Potenza L, Sinigaglia B, Luppi M, Morselli M, Saviola A, Ferrari A, Riva G, Zucchini P, Giacobbi F, Emilia G, Temperani P, Torelli G Cancer Genet Cytogenet 2004; 149: 164-168. Medline 15036893 REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed


2004 Junko Horiguchi Yamada

CitationThis paper should be referenced as such : Yamada JH . TOP1 (topoisomerase (DNA) 1). Atlas Genet Cytogenet Oncol Haematol. December 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/TOP1ID320ch20q11.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



WISP2 (Wnt-1-inducible signaling parthway protein-2)

IdentityNote WISP-2 is a member of the connective tissue growth factor/cysteine-rich

61/nephroblastoma overexpressed (nov) (CCN) family and is upregulated in the mouse mammary epithelial cell line C57MG transformed by Wnt-1 and in several non-invasive human breast tumor cell lines. WISP-2 is a serum and PMA (phorbol 12-myristate 13-acetate)-induced early responsive gene. Blocking the expression of this gene by WISP-2 antisense oligos or siRNA drastically reduce serum or PMA-induced cell proliferation in MCF-7 cells. Therefore, these studies suggest that WISP-2 signaling may be essential for mitogen-induced breast tumor cell proliferation.

WISP-2 expression is enhanced by important modulators of human breast cancer cell proliferation such as estrogen, progesterone and epidermal growth factor ( EGF) in MCF-7 cells. These effects, inhibited by appropriate antagonists, indicate that steroids and growth factor-induced upregulation of WISP-2 may be mediated through receptors.

The expression profile of WISP-2 gene in breast tumor biopsy tissue specimens are similar with that of in vitro studies and suggest that WISP-2 mRNA and protein levels are significantly higher in tumor samples as compared to the normal breast samples, and this expression is significantly correlated with the expression of estrogen receptor protein. However, within the tumor specimens, expression was predominant in the non-invasive carcinoma lesions as well as benign hyperplastic areas adjacent to the invasive tumors. Together, these findings suggest that bi-phasic regulation of WISP-2 signaling may be critical for initial events of growth, survivability and invasion of breast tumor cells.

WISP-2 also acts as a negative regulator in some cells including vascular smooth muscle cells.

Other names CCN5

rCop-1 CT58 CTGF-L Hugo WISP2


Location 20q12-13

DNA/RNANote Until now, three genes have been identified and isolated as members of

WISP sub-family. WISP-1/CCN4, WISP-2/CCN5 and WISP-3/CCN6 genes were localized in human chromosomes 8q24.1-q24.3, 20q12-q13 and 6q22-23, respectively and exhibit tissue specific patterns of expression. Nucleotide and protein sequence alignment studies have demonstrated a 30-40% sequence homology within WISP genes and their modular architecture is similar except in their C-terminal domains, which is absent in the WISP-2 gene.

Modular structure of individual genes of WISP sub-family of CCN family. Module

shown with color boxes are the predicted primary translational.

Protein Description The translation products of most of the CCN family members are

secreted proteins of 35-40 kDa and have been shown to contain four distinct structural modules: 1) an IGF-binding protein type (IGFBP) domain, 2) a Von Willebrand type C (VWC) domain; 3) a Thrombospondin-1 (TSP-1) domain and 4) a C-terminal Cysteine-knot (CT) domain (10). Although the functional roles of these multiple modules are unclear, they raise interesting questions as to the contribution of each individual module to the biological properties of the full-length proteins.

Expression Epithelial cells and vascular smooth muscle cells Localisation Adrenal gland, breast, colon, pancreas, uterus and ovary. Function Positive regulator of epithelial cells and negative regulator of vascular

smooth muscle cells.

Mutations


Somatic Amplified in breast tumor cells.

Implicated inDisease Breast cancer Disease Colon cancer Disease Macronodular adrenal hyperplasia


Hugo WISP2 GDB WISP2 Entrez_Gene WISP2 8839 WNT1 inducible signaling pathway protein 2

Cards Atlas WISP2ID42814ch20q12 GeneCards WISP2 Ensembl WISP2 CancerGene WISP2 Genatlas WISP2 GeneLynx WISP2 eGenome WISP2 euGene 8839


GoldenPath WISP2 - chr20:42777299-42789865 + 20q13.12 (hg17-May_2004)

Ensembl WISP2 - 20q13.12 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene WISP2

Gene and transcription Genbank AL139352 [ SRS ] AL139352 [ ENTREZ ] Genbank AF074604 [ SRS ] AF074604 [ ENTREZ ] Genbank AF083500 [ SRS ] AF083500 [ ENTREZ ] Genbank AF100780 [ SRS ] AF100780 [ ENTREZ ] Genbank AK129660 [ SRS ] AK129660 [ ENTREZ ] RefSeq NM_003881 [ SRS ] NM_003881 [ ENTREZ ] RefSeq NT_086910 [ SRS ] NT_086910 [ ENTREZ ]


AceView WISP2 AceView - NCBI TRASER WISP2 Traser - Stanford Unigene Hs.194679 [ SRS ] Hs.194679 [ NCBI ] HS194679 [ spliceNest ]

Protein : pattern, domain, 3D structure SwissProt O76076 [ SRS] O76076 [ EXPASY ] O76076 [ INTERPRO ] Prosite PS00222 IGF_BINDING [ SRS ] PS00222 IGF_BINDING [ Expasy ] Prosite PS50092 TSP1 [ SRS ] PS50092 TSP1 [ Expasy ] Prosite PS01208 VWFC_1 [ SRS ] PS01208 VWFC_1 [ Expasy ] Prosite PS50184 VWFC_2 [ SRS ] PS50184 VWFC_2 [ Expasy ] Interpro IPR000867 Insl_gro_fac_pr [ SRS ] IPR000867 Insl_gro_fac_pr [ EBI ] Interpro IPR000884 TSP1 [ SRS ] IPR000884 TSP1 [ EBI ] Interpro IPR001007 VWF_C [ SRS ] IPR001007 VWF_C [ EBI ] CluSTr O76076

Pfam PF00219 IGFBP [ SRS ] PF00219 IGFBP [ Sanger ] pfam00219 [ NCBI-CDD ]

Pfam PF00090 TSP_1 [ SRS ] PF00090 TSP_1 [ Sanger ] pfam00090 [ NCBI-CDD ]

Pfam PF00093 VWC [ SRS ] PF00093 VWC [ Sanger ] pfam00093 [ NCBI-CDD ] Smart SM00121 IB [EMBL] Smart SM00209 TSP1 [EMBL] Smart SM00214 VWC [EMBL] Blocks O76076

Polymorphism : SNP, mutations, diseases OMIM 603399 [ map ] GENECLINICS 603399 SNP WISP2 [dbSNP-NCBI] SNP NM_003881 [SNP-NCI] SNP WISP2 [GeneSNPs - Utah] WISP2 [SNP - CSHL] WISP2] [HGBASE - SRS]

General knowledge Family Browser WISP2 [UCSC Family Browser]

SOURCE NM_003881 SMD Hs.194679 SAGE Hs.194679 Amigo process|cell adhesion Amigo process|cell-cell signaling Amigo component|extracellular region Amigo function|insulin-like growth factor binding Amigo function|protein binding


Amigo process|regulation of cell growth Amigo process|signal transduction Amigo component|soluble fraction PubGene WISP2


Probe WISP2 Related clones (RZPD - Berlin) PubMed


BibliographyWISP genes are members of the connective tissue growth factor family that are up-regulated in wnt-1-transformed cells and aberrantly expressed in human colon tumorsPennica D, Swanson TA, Welsh JW, Roy MA, Lawrence DA, Lee J, Brush J, Taneyhill LA, Deuel B, Lew M, Watanabe C, Cohen RL, Melhem MF, Finley GG, Quirke P, Goddard AD, Hillan KJ, Gurney AL, Botstein D and Levine AJ. Proc Natl Acad Sci USA 1998; 95: 14717-14722 Medline 9843955 Identification and cloning of a connective tissue growth factor-like cDNA from human osteoblasts encoding a novel regulator of osteoblast functionsKumar S, Hand AT, Connor JR, Dodds RA, Ryan PJ, Trill JJ, Fisher SM, Nuttall ME, Lipshutz DB, Zou C, Hwang SM, Votta BJ, James IE, Rieman DJ, Gowen M and Lee JC. J Biol Chem 1999. 274: 17123-17131 Medline 10358067 Differential expression of WISP-1 and WISP-2 genes in normal and transformed human breast cell linesSaxena N, Banerjee S, Sengupta K, Zoubine MN and Banerjee SK. Mol Cell Biochem 2001; 228: 99-104 Medline 11855747 WISP-2 gene in human breast cancer: estrogen and progesterone inducible expression and regulation of tumor cell proliferationBanerjee S, Saxena N, Sengupta K, Tawfik O, Mayo MS and Banerjee S.K. Neoplasia 2003; 5: 63-73 Medline 12659671 Estrogen-induced genes, WISP-2 and pS2, respond divergently to protein kinase pathway.Inadera H. Biochem Biophys Res Commun 2003;.309: 272-278 Medline 12951045


Gene array analysis of macronodular adrenal hyperplasia confirms clinical heterogeneity and identifies several candidate genes as molecular mediatorsBourdeau I, Antonini SR, Lacroix A, Kirschner LS, Matyakhina L, Lorang D, Libutti SK and Stratakis CA. Oncogene 2004; 23: 1575-1585 Medline 14767469 The growth arrest-specific gene CCN5 is deficient in human leiomyomas and inhibits the proliferation and motility of cultured human uterine smooth muscle cells.Mason HR, Lake AC, Wubben JE, Nowak RA, Castellot JJ Jr. Mol Hum Reprod 2004; 10: 181-187 Medline 14981145 REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed


2004 Sushanta K. Banerjee, Snigdha Banerjee

CitationThis paper should be referenced as such : Banerjee SK, Banerjee S . WISP2 (Wnt-1-inducible signaling parthway protein-2). Atlas Genet Cytogenet Oncol Haematol. December 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/WISP2ID42814ch20q12.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

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LHFP (lipoma HMGIC fusion partner)

IdentityHugo LHFP Location 13q12

DNA/RNADescription Exon-intron structure not described. Transcription mRNA: ubiquitously: 2.4 kb; The ATG start codon is immediately

preceded by an in-frame stop codon, and matches the most important positions of the Kozak consensus sequence; the 3'-UTR contains a CA-repeat.

Pseudogene No pseudogenes according to pseudogene.org.

Protein 200 amino acids. Description Database searches with the predicted LHFP amino acid sequences

revealed no significant similarity to any known gene or protein or any known protein motif.

Expression Not known. Localisation Not known. Function Not known. Homology LHFP is a member of a family of proteins, which contains 6 members:

LHFP, LHFPL1, LHFPL2, LHFPL3, LHFPL4, LHFPL5.

MutationsSomatic HMGA2/LHFP fusion gene encoding the three DNA-binding domains of

HMGA2 followed by 69 amino acids encoded by frame-shifted LHFP sequences.

Implicated inEntity Solitary lipomas. Disease Benign tumors of adipose tissue Prognosis Can be surgically removed with no recurrence in most cases. Cytogenetics More than 60% of solitary lipomas have an aberrant karyotype: 2/3 of

these carry 12q15 rearrangements, most often translocations, affecting the HMGA2 gene: � 1/4 of the latter have chromosomal region 3q27-q28 (containing LPP) as 12q15 translocation partner (creating a HMGA2/LPP fusion


gene). � In the 3/4 others, multiple chromosomes have been found as translocation partner of 12q15, one of these being chromosomal region 13q12 (containing, amongst others, the LHFP gene).

Hybrid/Mutated Gene

HMGA2/LHFP hybrid gene containing the first three exons of HMGA2, which are followed by exon(s) of LHFP; under the regulation of the HMGA2 promoter.

Abnormal Protein

No known LHFP fusion protein. (HMGA2/LHFP fusion transcripts encode the three DNA-binding domains of HMGA2 followed by 69 amino acids encoded by frame-shifted LHFP sequences).


Hugo LHFP GDB LHFP Entrez_Gene LHFP 10186 lipoma HMGIC fusion partner

Cards Atlas LHFPID248ch13q12 GeneCards LHFP Ensembl LHFP CancerGene LHFP Genatlas LHFP GeneLynx LHFP eGenome LHFP euGene 10186


GoldenPath LHFP - 13q12 chr13:38815030-39075201 - 13q13.3 (hg17-May_2004)

Ensembl LHFP - 13q13.3 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene LHFP

Gene and transcription Genbank AF098807 [ SRS ] AF098807 [ ENTREZ ] Genbank AK129819 [ SRS ] AK129819 [ ENTREZ ] Genbank BC017824 [ SRS ] BC017824 [ ENTREZ ] RefSeq NM_005780 [ SRS ] NM_005780 [ ENTREZ ] RefSeq NT_086801 [ SRS ] NT_086801 [ ENTREZ ] AceView LHFP AceView - NCBI


TRASER LHFP Traser - Stanford Unigene Hs.507798 [ SRS ] Hs.507798 [ NCBI ] HS507798 [ spliceNest ]

Protein : pattern, domain, 3D structure SwissProt Q9Y693 [ SRS] Q9Y693 [ EXPASY ] Q9Y693 [ INTERPRO ] CluSTr Q9Y693 Blocks Q9Y693

Polymorphism : SNP, mutations, diseases OMIM 606710 [ map ] GENECLINICS 606710 SNP LHFP [dbSNP-NCBI] SNP NM_005780 [SNP-NCI] SNP LHFP [GeneSNPs - Utah] LHFP [SNP - CSHL] LHFP] [HGBASE - SRS]

General knowledge Family Browser LHFP [UCSC Family Browser]

SOURCE NM_005780 SMD Hs.507798 SAGE Hs.507798 PubGene LHFP


Probe LHFP Related clones (RZPD - Berlin) PubMed


BibliographyLHFP, a novel translocation partner gene of HMGIC in a lipoma, is a member of a new family of LHFP-like genes.Petit MMR, Schoenmakers EFPM, Huysmans C, Geurts JM, Mandahl N, Van de Ven WJM. Genomics 1999; 57: 438-441. Medline 10329012 Absence of HMGIC-LHFP fusion in pulmonary chondroid hamartomas with aberrations involving chromosomal regions 12q13 through 15 and 13q12 through q14.Rogalla P, Lemke I, Bullerdiek J. Cancer Genet Cytogenet 2002; 133: 90-93. Medline 11890997 Clustering of deletions on chromosome 13 in benign and low-malignant lipomatous tumors.


Dahlen A, Debiec-Rychter M, Pedeutour F, Domanski HA, Hoglund M, Bauer HC, Rydholm A, Sciot R, Mandahl N, Mertens F. Int J Cancer 2003; 103: 616-623. Medline 12494468 REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed


2005 Marleen Petit

CitationThis paper should be referenced as such : Petit M . LHFP (lipoma HMGIC fusion partner). Atlas Genet Cytogenet Oncol Haematol. January 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/LHFPID248ch13q12.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



TFPT (TCF3/E2A fusion partner)

IdentityOther names FB1

Hugo TFPT Location 19q13.4

DNA/RNADescription Genomic structure of six exons and five introns spanning about 10kb Transcription Two transcripts of 1.1kb and 1.2kb, expressed mainly in brain and in

hemopoietic cell lines. The rat ortholog, Amida, was found highly expressed also in rat testis. TATA less promoter, that can be transactivated "in vitro" by PU.1 and Ikaros 2. Orientation, minus strand.

Protein Description Conserved protein of 253 amino acids (in man) with two nuclear

localization signals (NLS) (n.68-75 and n.190-194) and a DNA binding domain located between the two NLSs.

Expression constitutive Localisation nuclear Function Overexpression of TFPT/Amida in cultured cells induces arrest in G2-M

and apoptosis. Biochemical studies indicate that TFPT/Amida interacts with Cdc2/CDK1 in mitosis and its overexpression results in a decrease of Cdc2/CDK1 activity (5).It is also suggested that the TFPT/Amida DNA binding activity is necessary for cell cycle inhibition and that Amida phophorylation by Cdc2/CDK1, detected "in vitro", might decrease this DNA binding activity.

Homology Very high homology with mouse and rat orthologs.

MutationsSomatic Involved in chromosome rearrangement in leukaemia.

Implicated inEntity Childhood pre-B ALL Note We detected 8 cases out of 200 : incidence about 4% of childhood

pre-B ALL Cytogenetics Following the position of the two involved genes, E2A on 19p13 and


FB1 on 19q13 an inv(19)(p13q13) appears more likely but a translocation t(19;19)(p13;q13) cannot be yet ruled out. Still pending

Hybrid/Mutated Gene E2A-FB1

Abnormal Protein

Since the chimeric transcripts so far analyzed contain the FB1 sequence fused out of frame to E2A and no truncated E2A protein was detected by Western blot, we suggest that no fusion protein is produced.

BreakpointsNote We detected different joining points in the transcripts of the different

analyzed cases indicating different breakpoints in a genomic region spanning exons 15-17 on TCF3 and exons 5-6 on TFPT.


Hugo TFPT GDB TFPT Entrez_Gene TFPT 29844 TCF3 (E2A) fusion partner (in childhood Leukemia)

Cards Atlas TFPTID495ch19q13 GeneCards TFPT Ensembl TFPT Genatlas TFPT GeneLynx TFPT eGenome TFPT euGene 29844


GoldenPath TFPT - 19q13.4 chr19:59302142-59310848 - 19q13.42 (hg17-May_2004)

Ensembl TFPT - 19q13.42 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] HomoloGene TFPT

Gene and transcription Genbank AF052052 [ SRS ] AF052052 [ ENTREZ ] Genbank BC001728 [ SRS ] BC001728 [ ENTREZ ] Genbank BC004281 [ SRS ] BC004281 [ ENTREZ ] Genbank BC007776 [ SRS ] BC007776 [ ENTREZ ] RefSeq NM_013342 [ SRS ] NM_013342 [ ENTREZ ] RefSeq NT_086907 [ SRS ] NT_086907 [ ENTREZ ]


AceView TFPT AceView - NCBI TRASER TFPT Traser - Stanford Unigene Hs.549150 [ SRS ] Hs.549150 [ NCBI ] HS549150 [ spliceNest ]

Protein : pattern, domain, 3D structure Polymorphism : SNP, mutations, diseases

SNP TFPT [dbSNP-NCBI] SNP NM_013342 [SNP-NCI] SNP TFPT [GeneSNPs - Utah] TFPT [SNP - CSHL] TFPT] [HGBASE - SRS]

General knowledge Family Browser TFPT [UCSC Family Browser]

SOURCE NM_013342 SMD Hs.549150 SAGE Hs.549150 PubGene TFPT


Probe TFPT Related clones (RZPD - Berlin) PubMed


BibliographyIdentification of a novel molecular partner of the E2A gene in childhood leukemia.Brambillasca F, Mosna G, Colombo M, Rivolta A, Caslini C, Minuzzo M, Giudici G, Mizzi L, Biondi A, Privitera E. Leukemia 1999; 13: 369-375. Medline 10086727 Molecular cloning and characterization of Amida, a novel protein which interacts with a neuron specific immediate early gene product Arc, contains novel nuclear localization signals and causes cell death in cultured cells.Irie Y, Yamagata K, Gan Y, Miyamoto K, Do E, Kuo C-H, Taira E, Miki N. J Biol Chem 2000; 275: 2647-2653. Medline 10644725 Promoter analysis of TFPT(FB1), a molecular partner of TCF3 (E2A) in childhood acute lymphoblastic leukemia.Brambillasca F, Mosna G, Ballabio E, Biondi A, Boulukos KE, Privitera E. Biochemical Biophysical Research Communications 2001; 288: 1250-1257. Medline 11700047 Heterozygous targeted disruption of E2A gene by an Inv(19)(p13;q13).


Roettgers S, Brambillasca F, Giudici G, Harbott J, Privitera E, Biondi A. The American Society of Hematology 44th Annual Meeting, Philadelphia, 2002 Arrest of cell cycle by Amida which is phosphorilated by Cdc2 kinase.Gan Y, Taira E, Irie Y, Fujimoto T, Miki N. Molec Cell Biochem 2003; 246: 179-185. Medline 12841360 REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed


2005 Enrica Privitera, Andrea Biondi

CitationThis paper should be referenced as such : Privitera E, Biondi A . TFPT (TCF3/E2A fusion partner). Atlas Genet Cytogenet Oncol Haematol. January 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/TFPTID495ch19q13.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



VAV1 (vav 1 oncogene)

IdentityOther names VAV

Hugo VAV1 Location 19p13.2

DNA/RNATranscription 2535 mRNA complete codons

Protein

Note Vav1 was discovered when DNA from five esophageal carcinomas were

tested for their transforming activity. This newly identified gene represented the sixth oncogene detected in Dr. Barbacid's laboratory and it was thus designated Vav1, after the sixth letter of the Hebrew alphabet. Vav1 was activated as an oncogene in vitro by replacement of 67 amino-acid residues of its amino-terminus (CH region) with 19 amino-acids residues of pSV2neo sequences, co-transfected as a selectable marker. Wild-type Vav1 produces minimal transformation of NIH3T3 murine fibroblasts only when the protein is grossly over-expressed. Removal of its amino terminus sequences (65 residues), thus mimicking its original mode of activation, is sufficient to induce Vav1 transformation.

Description Vav1 encodes a highly unique protein that contains numerous modular motifs known to play a role in tyrosine-mediated signal transduction cascades, such as a dbl homology (DH) region, which exhibits a guanine nucleotide exchange factor (GEF) activity towards the Rho family GTPases; a pleckstrin homology (PH) domain which interacts with polyphosphoinositides; a Src Homology 2 (SH2) and two Src Homology 3 (SH3) domains that mediate protein-protein interactions; a proline- rich motif that enables binding to SH3 -containing proteins, an acidic-rich (Ac) region and a 'calponin-homology' (CH) region, which functions as an actin-binding domain in other proteins and two nuclear localization signals(NLS). In fact, Vav1 is the only known Rho GEF that


combines in the same protein the DH/PH motifs and the structural hallmark of signal transducer proteins, the SH2 and SH3 domains.

Expression Vav1 is specifically expressed in the hematopoietic system. Function The Vav1 protein (95 kDa) is rapidly tyrosine-phosphorylated following

stimulation of various receptors on hematopoietic cells (TCR, BCR, IgE, etc). Vav1 can then function in various signaling cascades. First, as a tyrosine-phosphorylated protein, Vav1 operates as a guanine nucleotide exchange factor (GEF) for Rac1, Rac2 and RhoG. It is the only known GEF protein whose activity is regulated by tyrosine phosphorylation. As a regulator of activation of the Rho/Rac GTPases, Vav1 participates in several processes that require cytoskeletal reorganization, such as the formation of the immunological synapse (IS), phagocytosis, platelet aggregation and spreading. Vav1 can also function in GEF-independent pathways through its association with other proteins such as ZAP-70, SLP-76, Ly-GDI (an inhibitor of Rho/RacGTPases), Grb2 and cytoseketal proteins such as Zyxin. Vav1 plays a critical role in stimulation of NFAT (Nuclear Factor of Activated T cells), culminating in the production of numerous vital cytokines. Vav1 also leads to the induction of an intracellular calcium flux by regulating the activation of phospholipase Cg1 (PLCg1) via phosphoinositide 3-kinase (PI3K) dependent and -independent pathways. The activity of Vav1 also leads to the activation of NF-kB and the extracellular signal regulated kinase (ERK) mitogen-activated protein kinase (MAPK) signaling cascade. There is compelling evidence from studies of gene-targeted mice to indicate that Vav1 participates in the development and function of many types of immune cell such as the positive- and negative-selection events that are imposed on double-positive thymocytes

Homology Vav1 is one of a larger family of proteins that include Vav2 and Vav3 which unlike Vav1 are also ubiquitously expressed and the Vav homologues in Drosophila Melanogaster and in the nematode, C. elegans. These proteins are similar in their structure to Vav1, thus also functioning as signal transducer proteins.

MutationsSomatic Although, no mutants of Vav1 have been reported thus far in "real"

human tumors, it was recently found that Vav1 is expressed in the majority of 42 specimens of human neuroblastoma, suggesting a possible involvement of this protein in the neoplastic process in a subset of neuroblastomas. Furthermore, it was recently found to be involved in a large number of Pancreatic tumors.

Implicated inDisease Neuroblastoma Disease Pancreatic tumors

External links


Nomenclature Hugo VAV1 GDB VAV1 Entrez_Gene VAV1 7409 vav 1 oncogene

Cards Atlas VAV1ID195ch19p13 GeneCards VAV1 Ensembl VAV1 CancerGene VAV1 Genatlas VAV1 GeneLynx VAV1 eGenome VAV1 euGene 7409


GoldenPath VAV1 - 19p13.2 chr19:6723722-6808371 + 19p13.3 (hg17-May_2004)

Ensembl VAV1 - 19p13.3 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene VAV1

Gene and transcription Genbank AF030201 [ SRS ] AF030201 [ ENTREZ ] Genbank AF030202 [ SRS ] AF030202 [ ENTREZ ] Genbank AF030203 [ SRS ] AF030203 [ ENTREZ ] Genbank AF030204 [ SRS ] AF030204 [ ENTREZ ] Genbank AF030205 [ SRS ] AF030205 [ ENTREZ ] RefSeq NM_005428 [ SRS ] NM_005428 [ ENTREZ ] RefSeq NT_086894 [ SRS ] NT_086894 [ ENTREZ ] AceView VAV1 AceView - NCBI TRASER VAV1 Traser - Stanford Unigene Hs.116237 [ SRS ] Hs.116237 [ NCBI ] HS116237 [ spliceNest ]

Protein : pattern, domain, 3D structure SwissProt P15498 [ SRS] P15498 [ EXPASY ] P15498 [ INTERPRO ] Prosite PS50021 CH [ SRS ] PS50021 CH [ Expasy ]

Prosite PS00479 DAG_PE_BIND_DOM_1 [ SRS ] PS00479 DAG_PE_BIND_DOM_1 [ Expasy ]

Prosite PS50081 DAG_PE_BIND_DOM_2 [ SRS ] PS50081 DAG_PE_BIND_DOM_2 [ Expasy ]


Prosite PS00741 DH_1 [ SRS ] PS00741 DH_1 [ Expasy ] Prosite PS50010 DH_2 [ SRS ] PS50010 DH_2 [ Expasy ] Prosite PS50003 PH_DOMAIN [ SRS ] PS50003 PH_DOMAIN [ Expasy ] Prosite PS50001 SH2 [ SRS ] PS50001 SH2 [ Expasy ] Prosite PS50002 SH3 [ SRS ] PS50002 SH3 [ Expasy ] Interpro IPR001715 Calponin-like [ SRS ] IPR001715 Calponin-like [ EBI ] Interpro IPR003247 CH_type [ SRS ] IPR003247 CH_type [ EBI ] Interpro IPR002219 DAG_PE-bind [ SRS ] IPR002219 DAG_PE-bind [ EBI ] Interpro IPR001331 GDS_CDC24 [ SRS ] IPR001331 GDS_CDC24 [ EBI ] Interpro IPR001849 PH [ SRS ] IPR001849 PH [ EBI ] Interpro IPR011036 PH_related [ SRS ] IPR011036 PH_related [ EBI ] Interpro IPR000219 RhoGEF [ SRS ] IPR000219 RhoGEF [ EBI ] Interpro IPR000980 SH2 [ SRS ] IPR000980 SH2 [ EBI ] Interpro IPR001452 SH3 [ SRS ] IPR001452 SH3 [ EBI ] Interpro IPR003096 SM22_calponin [ SRS ] IPR003096 SM22_calponin [ EBI ] CluSTr P15498 Pfam PF00307 CH [ SRS ] PF00307 CH [ Sanger ] pfam00307 [ NCBI-CDD ]

Pfam PF00130 DAG_PE-bind [ SRS ] PF00130 DAG_PE-bind [ Sanger

] pfam00130 [ NCBI-CDD ] Pfam PF00169 PH [ SRS ] PF00169 PH [ Sanger ] pfam00169 [ NCBI-CDD ]

Pfam PF00621 RhoGEF [ SRS ] PF00621 RhoGEF [ Sanger ] pfam00621 [ NCBI-CDD ]

Pfam PF00017 SH2 [ SRS ] PF00017 SH2 [ Sanger ] pfam00017 [ NCBI-CDD ] Pfam PF00018 SH3 [ SRS ] PF00018 SH3 [ Sanger ] pfam00018 [ NCBI-CDD ] Smart SM00109 C1 [EMBL] Smart SM00033 CH [EMBL] Smart SM00233 PH [EMBL] Smart SM00325 RhoGEF [EMBL] Smart SM00252 SH2 [EMBL] Smart SM00326 SH3 [EMBL] Prodom PD000093 SH2[INRA-Toulouse]

Prodom P15498 VAV_HUMAN [ Domain structure ] P15498 VAV_HUMAN [ sequences sharing at least 1 domain ]

Prodom PD000093[INRA-Toulouse]

Prodom P15498 VAV_HUMAN [ Domain structure ] P15498 VAV_HUMAN [ sequences sharing at least 1 domain ]

Blocks P15498 Polymorphism : SNP, mutations, diseases

OMIM 164875 [ map ] GENECLINICS 164875


SNP VAV1 [dbSNP-NCBI] SNP NM_005428 [SNP-NCI] SNP VAV1 [GeneSNPs - Utah] VAV1 [SNP - CSHL] VAV1] [HGBASE - SRS]

General knowledge Family Browser VAV1 [UCSC Family Browser]

SOURCE NM_005428 SMD Hs.116237 SAGE Hs.116237 Amigo function|diacylglycerol binding Amigo function|guanyl-nucleotide exchange factor activity Amigo process|intracellular signaling cascade Amigo component|nucleus Amigo function|transcription factor activity BIOCARTA BCR Signaling Pathway BIOCARTA Fc Epsilon Receptor I Signaling in Mast Cells BIOCARTA Ras-Independent pathway in NK cell-mediated cytotoxicity BIOCARTA Phospholipase C Signaling Pathway BIOCARTA Rac 1 cell motility signaling pathway BIOCARTA T Cell Receptor Signaling Pathway PubGene VAV1


Probe VAV1 Related clones (RZPD - Berlin) PubMed


BibliographyVav, a novel human oncogene derived from a locus ubiquitously expressed in hematopoietic cells.Katzav S, Martin-Zanca D, Barbacid M. Embo J 1989; 8: 2283-2290. Medline 2477241 The human VAV proto-oncogene maps to chromosome region 19p12-19p13.2.Martinerie C, Cannizzaro LA, Croce CM, Huebner K, Katzav S, Barbacid M. Hum Genet 1990; 86: 65-68. Medline 2253939 Product of vav proto-oncogene defines a new class of tyrosine protein kinase substrates.


Bustelo XR, Ledbetter JA, Barbacid M. Nature 1992; 356: 68-71. Medline 1311423 Tyrosine phosphorylation of vav proto-oncogene product containing SH2 domain and transcription factor motifs.Margolis B, Hu P, Katzav S, Li W, Oliver JM, Ullrich A, Weiss A, Schlessinger J. Nature 1992; 356: 71-74. Medline 1531699 A functional T-cell receptor signalling pathway is required for p95vav activity.Wu J, Katzav S, Weiss A. Mol Cell Biol 1995; 15: 4337-4346. Medline 7623828 Phosphotyrosine-dependent activation of Rac-1 GDP/GTP exchange by the vav proto-oncogene product.Crespo P, Schuebel KE, Ostrom AA, Gutkind JS, Bustelo XR. Nature 1997; 385: 169-172. Medline 8990121 Vav proteins, adaptors and cell signaling.Bustelo XR. Oncogene 2001; 20: 6372-6381. (REVIEW) Medline 11607839 Vav1 regulates phospholipase cgamma activation and calcium responses in mast cells.Manetz TS, Gonzalez-Espinosa C, Arudchandran R, Xirasagar S, Tybulewicz V, Rivera J. Mol Cell Biol 2001; 21: 3763-3774. Medline 11340169 Vav1 transduces T cell receptor signals to the activation of phospholipase C-gamma1 via phosphoinositide 3-kinase-dependent and -independent pathways.Reynolds LF, Smyth LA, Norton T, Freshney N, Downward J, Kioussis D, Tybulewicz VL. J Exp Med 2002; 195: 1103-1114. Medline 11994416 VAV proteins as signal integrators for multi-subunit immune-recognition receptors.Turner M, Billadeau DD. Nat Rev Immunol 2002; 2: 476-486. (REVIEW) Medline 12094222


Adaptors as central mediators of signal transduction in immune cells.Jordan MS, Singer AL, Koretzky GA. Nat Immunol 2003; 4: 110-116. (REVIEW) Medline 12555096 Vav masters of the world of cytoskeleton.Hornstein I, Alcover A, Katzav S. Cell Signalling 2004; 16: 1-11 . (REVIEW) Medline 14607270 Vav1: an oncogene that regulates specific transcriptional activation of T cells.Katzav S Blood 2004; 103: 2443-2451. (REVIEW) Medline 14592821 Ectopic expression of VAV1 reveals an unexpected role in pancreatic cancer tumorigenesis.Fernandez Zapico ME, Gonzalez Paz NC, Weiss E, Savoy DN, Molina JR, Fonseca R, Smyrk TC, Chari ST, Urrutia R, Billadeau DD. Cancer Cell. 2005 Jan;7(1):39-49. Medline 15652748 REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed


2005 Shulamit Katzav

CitationThis paper should be referenced as such : Katzav S . VAV1 (vav 1 oncogene). Atlas Genet Cytogenet Oncol Haematol. January 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/VAV1ID195ch19p13.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



del(13q) in ALL

IdentityNote Deletions of chromosome 13q are a non-random finding in a broad

spectrum of haematological neoplasms, including B-cell chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM) and (AML) IMAGE

Clinics and PathologyDisease Acute lymphoblastic leukaemia (ALL) Phenotype / cell stem origin

No specific immunophenotype observed

Epidemiology A del(13q) chromosome is found in approximately 2% of cases in both adult and childhood disease at presentation. Up to 4% of cases may have some loss of 13q material, either through full monosomy or unbalanced rearrangements. Incidence of chromosome 13 deletions is higher at relapse.

Prognosis May confer an increased risk of treatment failure but to date has not been shown to be an independent prognostic indicator.

CytogeneticsCytogenetics Morphological

Various breakpoints reported. The centromeric breakpoint is typically in the 13q12-14 region and telomeric between 13q21 and 13qter. Loss of all or part of 13q14 is common to almost all cases. Occurs as a sole event in approximately 10% of cases. There are also rare reports of translocations also leading to a partial 13q deletion. Monosomy 13 is also reported but occurs very rarely as a sole aberration. Under representation of chromosome 13 is often found in hypotriploid cases.

Additional anomalies

Most cases with del(13q) will have additional aberrations, but there is no consistent picture and the events can include the typical non-random events in ALL.

Genes involved and ProteinsNote Critical region in 13q14 appears to lie telomeric to RB1.

External linksOther database del(13q) in ALL Mitelman database (CGAP - NCBI)

Bibliography


Deletions in the 13q14 locus in adult lymphoblastic leukemia: Rate of incidence and relevance.Chung CY, Kantarjian H, Haidar M, Starostik P, Manshouri T, Gidel C, Freireich E, Keating M, Albitar M. Cancer 2000; 88: 1359-1364. Medline 10717617 Abnormalities of chromosome bands 13q12 to 13q14 in childhood acute lymphoblastic leukemia.Heerema NA, Sather HN, Sensel MG, Lee MK, Hutchinson RJ, Nachman JB, Reaman GH, Lange BJ, Steinherz PG, Bostrom BC, Gaynon PS, Uckun FM. J Clin Oncol 2000; 18: 3837-3844. Medline 11078497 New recurring cytogenetic abnormalities and association of blast cell karyotypes with prognosis in childhood T-cell acute lymphoblastic leukemia: a Pediatric Oncology Group report of 343 cases.Schneider NR, Carroll AJ, Shuster JJ, Pullen DJ, Link MP, Borowitz MJ, Camitta BM, Katz JA, Amylon MD. Blood 2000; 96: 2543-2549 Medline 11001909 Deletion of chromosomal region 13q14.3 in childhood acute lymphoblastic leukaemia.Cave H, Avet Loiseau H, Devaux I, Rondeau G, Boutard P, Lebrun E, Mechinaud F, Vilmer E, Grandchamp B. Leukemia 2001; 15: 371-376. Medline 11237059 Aberrations involving chromosome 13q12-14 are frequently secondary events in childhood acute lymphoblastic leukaemia.Kovacs BZ, Niggli FK, Betts DR. Cancer Genet Cytogenet 2004; 151: 157-161. Medline 15172754 Contributor(s)Written 11-

2004 David Betts

CitationThis paper should be referenced as such : Betts D . del(13q) in ALL. Atlas Genet Cytogenet Oncol Haematol. November 2004 .URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/del13qALLID1188.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



t(14 ;21)(q11;q22)

Clinics and PathologyDisease T-cell Acute lymphoblastic leukemia (T-ALL) Epidemiology Rare. Clinics One case reported: The patient was a 7-years-old female with high

white blood count with lymphoblasts positive for T-cell antigens; cerebrospinal fluid négative for malignant cells; superior mediastinal mass.

Prognosis The patient attained a complete remission with standard chemotherapy but relapsed and died after 4 months of therapy.


The t(14 ;21)(q11.2 ;q22)was accompanied with del(6)(q21). Cryptic t(14 ;21) translocation cases may exist.

Genes involved and ProteinsGene Name TCRA

Location 14q11.2 Protein T cell receptor Gene Name BHLHB1

Location 21q22 Note alias OLIG2 Dna / Rna This gene maps within a 9 to 12 Mb region of chromosome 21q22. Protein This gene was shown to possess a helix-loop-helix (bHLH) motif witch

inhibits the E2A function in transfection assays. E2A is required for normal T-cell differentiation.

Result of the chromosomal anomalyHybrid gene Note

Translocation of the BHLHB1 gene 130kb upstream of the TCRA enhancer. This translocation activates the BHLHB1 gene and produces high levels of BHLHB1 mRNA. Expression of HLHB1 inhibits E2A-mediated transcription activation in vitro.


Fusion Protein Note No fusion protein.

Oncogenesis Several helix-loop-helix (HLH) proteins are proposed to function as transcriptionnal regulatory factors based on their ability to bind in vitro the E-box motif of transcriptional enhancers. The observation that ectopic BHLHB1 expression can onhibit E2A activity suggests that BHLHB1 exerts its leukemogenic effects through a functional inhibition of E2A.

External linksOther database t(14 ;21)(q11;q22) Mitelman database (CGAP - NCBI)

Other database t(14 ;21)(q11;q22) CancerChromosomes (NCBI)

Bibliographyt(5;14)(q33-34;q11), a new recurring cytogenetic abnormality in childhood acute leukemia.Whitlock JA, Raimondi SC, Harbott J, Morris SW, McCurley TL, Hansen-Hagge TE, Ludwig WD, Weimann G, Bartram CR. Leukemia 1994; 8: 1539-1543. Medline 8090032 Cytogenetic abnormalities in adult acute lymphoblastic leukemia: correlations with hematologic findings outcome. A Collaborative Study of the Group Francais de Cytogenetique Hematologique.[No authors listed] Blood 1996; 87: 3135-3142. Erratum in: Blood 1996; 88: 2818. Medline 8605327 E2A deficiency leads to abnormalities in alphabeta T-cell development and to rapid development of T-cell lymphomas.Bain G, Engel I, Robanus Maandag EC, te Riele HP, Voland JR, Sharp LL, Chun J, Huey B, Pinkel D, Murre C. Mol Cell Biol 1997; 17: 4782-4791. Medline 9234734 The t(14;21)(q11.2;q22) chromosomal translocation associated with T-cell acute lymphoblastic leukemia activates the BHLHB1 gene.Wang J, Jani-Sait SN, Escalon EA, Carroll AJ, de Jong PJ, Kirsch IR, Aplan PD. Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3497-3502. Medline 10737801


Contributor(s)Written 11-

2004 Jacques Boyer

CitationThis paper should be referenced as such : Boyer J . t(14 ;21)(q11;q22). Atlas Genet Cytogenet Oncol Haematol. November 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t1421q11q22ID1180.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



t(1;14)(q21;q32) IRTA1/IGH

IdentityNote This translocation with IRTA1 involvement is different from

t(1;14)(q21;q32) with BCL9 involvement, from the t(1;14)(q21;q32) with FCGR2B involvement, and from the t(1;14)(q21;q32) with MUC1 involvement.

Clinics and PathologyDisease Multiple Myeloma and B-cell non-Hodgkins lymphoma Epidemiology Rare. 2 published cases : 1 in a multiple myeloma cell line. The

second in a case of gastric diffuse large B-cell lymphoma (DLBCL). Prognosis Unknown

Genetics The t(1;14) interrupts the IRTA gene locus (Immunoglobulin superfamily

Receptor Translocation Associated gene locus) which spans approximately 250kb, between the IRTA1 and IRTA2 genes.

Genes involved and ProteinsGene Name IRTA1

Location 1q21

Dna / Rna IRTA1 localises to the IRTA gene locus. Three IRTA1 transcripts of 2.5kb, 2.7kb and 3.5kb are possible due to alternate usage of 3 polyadenylation sites.

Protein The three alternate IRTA1 transcripts give rise to the same putative 515 amino acid protein. The protein shows a signal peptide, four extracellular Ig-type domains carrying three potential asparagaine (N)-linked glycosylation sites, a 16 amino acid transmmbrane and a 106 amino acid cytoplasmic domain with three putative consensus Src-homology 2 SH2 binding domains. These domains show similarity to both ITAM (Immunoreceptor Tyrosine-based Activation Motifs) and ITIM (Immunoreceptor Tyrosine-based Inhibition Motifs). The function of the protein is unknown. It is expressed in marginal zone B cells. In the extracellular domain IRTA1 protein shows homology to Ig superfamily receptors (47% identity and 51% similarity) and Fc receptor family (37% identity and 50% similarity). In the intracellular domain, IRTA1 shows striking homology to PECAM1 (31% identity and 45% homology).


Gene Name IGH

Location 14q32

Result of the chromosomal anomalyFusion Protein Description

Expression of IRTA1 fusion proteins. In the first case described the t(1;14) juxtaposes the IRTA1 gene to the C alpha constant gene in the same transcriptional orientation on the der(14) chromosome. An IRTA1/C alpha fusion protein results from this. The predicted fusion protein fuses the signal peptide and first two extracellular residues of IRTA1 to the C alpha encoded transmembrane and cytoplasmic domains. Overexpression of IRTA1 was not observed in other myeloma or lymphoma cell lines, regardless of the status of its chromosomal band 1q21. More recently long distance inverse PCR cloning identified a second case of IRTA1 translocation to IGH switch sequence (Switch gamma 3) in a case of gastric DLBCL. In contrast, IRTA2 gene (located telomeric of IRTA1 in the IRTA gene locus) shows frequent deregulation in Burkitt lymphoma and Multiple Myeloma cell lines with 1q21 abnormalities (mostly duplications or unbalanced translocations that lead to trisomy or tetrasomy 1q). IRTA1 is normally expressed in marginal zone B cells while IRTA2 is selectively expressed in centrocytes, marginal zone B cells and immunoblasts. IRTA1 and 2 have been independently cloned as FcRH4 and FcRH5 (Fc Receptor Homologues) from a human lymph node cDNA library.

External linksOther database t(1;14)(q21;q32) IRTA1/IGH Mitelman database (CGAP - NCBI)

Other database t(1;14)(q21;q32) IRTA1/IGH CancerChromosomes (NCBI)

BibliographyIRTA1 and IRTA2, novel immunoglobulin superfamily receptors expressed in B cells and involved in chromosome 1q21 abnormalities in B cell malignancy.Hatzivassiliou G, Miller I, Takizawa J, Palanisamy N, Rao PH, Iida S, Tagawa S, Taniwaki M, Russo J, Neri A, Cattoretti G, Clynes R, Mendelsohn C, Chaganti RS, Dalla-Favera R. Immunity. 2001; 14: 277- Medline 11290337 Rapid amplification of immunoglobulin heavy chain switch (IGHS) translocation breakpoints using long-distance inverse PCR.


Sonoki T, Willis TG, Oscier DG, Karran EL, Siebert R, Dyer MJ. Leukemia. 2004; 18: 2026-2031. Medline 15496980 Expression of the IRTA1 receptor identifies intraepithelial and subepithelial marginal zone B cells of the mucosa-associated lymphoid tissue (MALT).Falini B, Tiacci E, Pucciarini A, Bigerna B, Kurth J, Hatzivassiliou G, Droetto S, Galletti BV, Gambacorta M, Orazi A, Pasqualucci L, Miller I, Kuppers R, Dalla-Favera R, Cattoretti G. Blood. 2003; 102: 3684-3692. Medline 12881317 Identification of a family of Fc receptor homologs with preferential B cell expression.Davis RS, Wang YH, Kubagawa H, Cooper MD. Proc Natl Acad Sci U S A. 2001; 98: 9772-9777. Medline 11493702 Contributor(s)Written 12-

2004 Mary Callanan, Dominique Leroux

CitationThis paper should be referenced as such : Callanan M Leroux D . t(1;14)(q21;q32) IRTA1/IGH. Atlas Genet Cytogenet Oncol Haematol. December 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0114q21q32ID1375.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



t(1;6)(p35;p25)

Clinics and PathologyDisease Chronic lymphocytic leukemia (CLL) Phenotype / cell stem origin

unmutated status of IgVH (an unfavourable prognostic feature) was found in all cases.

Epidemiology 8 patients to date, representing 0.5% of CLL cases in a country based survey; sex ratio: 6 male/2 female patients, aged 33-81 yrs (med: 62.5 yrs).

Clinics Two cases in Binet stage A, 4 in stage B, 2 in stage C. Normal LDH values in 7 of 8.

Prognosis yet unknown (median follow up is only 28 mths), but 3 patients developed a diffuse large B-cell lymphoma (DLBCL), and 3 patients (2 of which with DLBCL) died at 29, 76, and 95 mths.

CytogeneticsAdditional anomalies

sole anomaly in three cases, with +12 in three cases, with 9q anomalies in three, del(11q) in two, 17p anomalies in two, 17q anomalies in two; del(11q), and 17p anomalies are poor prognostic factors in CLL.

Genes involved and ProteinsNote IRF4 (6p25.2) is possibly involved in the translocation. The gene in

1p35.3 is unknown.

External linksOther database t(1;6)(p35;p25) Mitelman database (CGAP - NCBI)

Other database t(1;6)(p35;p25) CancerChromosomes (NCBI)

To be noted Additional cases are needed to delineate the epidemiology of this rare

entity: you are welcome to submit a paper to our new Case Report section.


BibliographyTranslocation t(1;6)(p35.3;p25.2): a new recurrent aberration in "unmutated" B-CLL.Michaux L, Wlodarska I, Rack K, Stul M, Criel A, Maerevoet M, Marichal S, Demuynck H, Mineur P, Kargar Samani K, Van Hoof A, Ferrant A, Marynen P, Hagemeijer A. Leukemia 2005; 19: 77-82. Medline 15510210 Contributor(s)Written 01-

2005 Jean loup Huret

CitationThis paper should be referenced as such : Huret JL . t(1;6)(p35;p25). Atlas Genet Cytogenet Oncol Haematol. January 2005 . URL : http://AtlasGeneticsOncology.org/Anomalies/t0106p35p25ID1378.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



t(1;14)(q21;q32) MUC1/IGH

Clinics and PathologyNote The chromosomal band 1q21 is the third most frequent site of

rearrangement in non-Hodgkin's lymphoma after 14q32 and 18q21. Five genes mapped to this region (BCL9, MUC1, FCGR2B, MUM2, API2) some have been shown to be deregulated by juxtaposition with the IgH genes.

Disease B-cell non Hodgkin Lymphoma. (NHL) Epidemiology The MUC1 region is rearranged in 6% of tumors with 1q21 cytogenetic

aberration. Cytology No clear association with a particular NHL subtype has been reported. Prognosis Poor prognosis especially in diffuse large cell lymphoma.

May be associated with tumor progression.


A number of 1q21 abnormalities result in an unbalanced chromosome 1 translocation.

Additional anomalies

Caryotype often complex Usually detected with t(14;18)(q32;q21) and t(8;14)(q24;q32) as a secondary chromosomal abnormalitie.

Genes involved and ProteinsGene Name MUC1

Location 1q21 Note Located 8cM telomeric to BCL9; aliases of MUC1 are EMA and CD227 Dna / Rna 3.88 kb, 8 exons, 1721 bp, 2 transcripts Protein 122.1 kDa (1255 aa) Highly glycosylated protein.

The MUC1 protein can be expressed as a transmembrane or secreted protein. May be playing a role in adhesive functions and in cell-cell interactions, metastasis, signaling and is implicated in some adenocarcinomas. The EMA wich is equivalent to MUC1 occurs in lymphocyte-predominant Hodgkin's disease, plasmocytomas and T-cell lymphomas due to mechanisms other than 1q21 rearrangement.

Gene IgH


NameLocation 14q32

Result of the chromosomal anomalyHybrid gene Description

The translocation links sequences 2.4 kpb 3' of the MUC1 gene on chromosome 1 to the IGH4 switch region on chromosome 14. MUC1 gene is intact. The MUC1 gene is brought into proximity with the C gamma 4 and C alpha 2 loci. Dowstream of C alpha 2 is an enhancer element implicated in the activation of MUC1 expression.

Fusion Protein Description

No fusion protein

Oncogenesis Chromosomal translocation involving class switch recombination when DNA strand breaks are introduced into the switch regions of recombining CH genes. Activation of MUC1 translation and transcription. An important role for MUC1 in tumorigenesis has been demontrated in Muc-1 null mice. MUC1 is associated with delayed progression of the tumor. (selective advantage, inhibition of cell adhesion.) In addition to activation of MUC1, haploid loss of chromosome 1 long arm also contributes to oncogenesis in some tumors.

External linksOther database t(1;14)(q21;q32) MUC1/IGH Mitelman database (CGAP - NCBI)

Other database t(1;14)(q21;q32) MUC1/IGH CancerChromosomes (NCBI)

BibliographyMUC1 is activated in a B-cell lymphoma by the t(1;14)(q21;q32) translocation and is rearranged and amplified in B-cell lymphoma subsets.Dyomin VG, Palanisamy N, Lloyd KO, Dyomina K, Jhanwar SC, Houldsworth J, Chaganti RS. Blood, 2000; 95: 2666-2671 Medline 10753849 MUC1 dysregulation as the consequence of a t(1;14)(q21;q32) translocation in an extranodal lymphGilles F, Goy A, Remache Y, Shue P, Zelenetz AD. Blood 2000; 9: 2930-2936 Medline 10779441 Non-Hodgkin's Lymphoma: Molecular Features of B Cell Lymphoma.


Macintyre E, Willerford D, Morris SW. Hematology (Am Soc Hematol Educ Program) 2000; 180-204. Medline 11701542 Contributor(s)Written 01-

2005 Jacques Boyer

CitationThis paper should be referenced as such : Boyer J . t(1;14)(q21;q32) MUC1/IGH. Atlas Genet Cytogenet Oncol Haematol. January 2005 . URL : http://AtlasGeneticsOncology.org/Anomalies/t0114q21q32MUC1ID1342.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



t(9;11)(q34;p15)

Clinics and PathologyDisease Acute myelomonocytic leukemia (M4 ANLL) Etiology this leukemia case is likely to be treatment related (a lymphoma was

treated 4 yrs previously) Epidemiology only one case to date: a 65 yr old female patient Prognosis no data

Genes involved and ProteinsGene Name PRRX2

Location 9q34 Protein class II homeobox gene Gene Name NUP98

Location 11p15.4 Protein nucleoporin 98, a 98 kDa component of the nuclear pore complex

implicated in nucleo-cytoplasmic transport

Result of the chromosomal anomalyHybrid gene

Description 5'--> exon 11 of NUP98 is fused in frame with PRRX2 exon 2 to 3'

External linksOther t(9;11)(q34;p15) Mitelman database (CGAP - NCBI)


database Other database t(9;11)(q34;p15) CancerChromosomes (NCBI)



BibliographyA new translocation t(9;11)(q34;p15) fuses NUP98 to a novel homeobox partner gene, PRRX2, in a therapy-related acute myeloid leukemiaGervais C, Mauvieux L, Perrusson N, Helias C, Struski S, Leymarie V, Lioure B, Lessard M. Leukemia 2005; 19: 145-148. Medline 15496970 Contributor(s)Written 01-

2005 Jean loup Huret

CitationThis paper should be referenced as such : Huret JL . t(9;11)(q34;p15). Atlas Genet Cytogenet Oncol Haematol. January 2005 .URL : http://AtlasGeneticsOncology.org/Anomalies/t0911q34p15ID1380.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



t(X;20)(q13;q13.3)

Identity

Fig. 1. Partial karyotypes of the translocation t(X;20)(q13;q13.3) for cases 14 (top to

bottom; see case report section). Arrows indicate the derivatives 20 and X.

Clinics and PathologyDisease myelodysplastic syndromes (MDS): refractory anaemia with excess of

blasts (RAEB-RAEBt), refractory anaemia (RA), MDS sideroblastic anemia and MDS pancytopenia and thrombocytopenia most often (5 cases); polycytemia vera --> acute myeloid leukemia (AML)-M1; myelofibrosis -->acute leukemia

Epidemiology Only 7 cases to date and they are exclusively female: 0 Male/7 Female; found in older patients (Median age 61 years; range: 57-86)

Clinics Still poorly known



Sole abnormality in 5 MDS cases and accompanying changes +8, +9, del(13)(q21) and der(1;7)(q10;p10) in 2 cases that transformed to AML.

Cytogenetics Molecular

By FISH the cytogenetic breakpoint was proximal to AR gene and hence the breakpoint on X chromosome is t(X;20)(q11.2q12;q13.3)

Fig 2: X-centromere probe DXZ1 (green) hybridized to the normal X and the

derivative X (arrows). The androgen receptor (Xq12) AR (red) probe hybridized to derivative 20 and the normal X (arrows). The breakpoint on the X chromosome is proximal to AR. The karyotype is 46, X, t(X;20)(q13;q13.3).ish t(X;20)(q11.2q12;q13.3)(wcpX+,wcp20+,AR?;wcp20+, D20S180?,AR+,wcpX+). The revised breakpoints identified with FISH analysis are highlighted in bold.

External linksOther database t(X;20)(q13;q13.3) Mitelman database (CGAP - NCBI)

Other database t(X;20)(q13;q13.3) CancerChromosomes (NCBI)



Case Report

Translocation (X;20)(q13;q13.3): a nonrandom abnormality in four patients with myeloid disorders: case 1

Case Report


Case Translocation (X;20)(q13;q13.3): a nonrandom abnormality in four


Report patients with myeloid disorders: case 3 Case Report


BibliographyCharacterization by chromosome painting of balanced and unbalanced X chromosome translocations in myelodysplastic syndromesMichaux L, Wlodarska I, Mecucci C, Hernandez JM, Van Orshoven A, Michaux JL, Van den Berghe H Cancer Genet Cytogenet 1995; 82: 1722 Medline 7627929 Translocation (X;20)(q13.1;q13.3) as a primary chromosomal finding in two patients with myelocytic disorders.Gray BA, Cornfield D, Bent-Williams A and Zori RT. Cancer Genet Cytogenet 2003; 141: 169174. Medline 12606138 Translocation (X;20)(q13;q13.3): a nonrandom abnormality in four patients with myeloid disorders.Reddy KS, Richkind K, Ross M and Seirra R Cancer Genet Cytogenet 2005; 157: 70-73. Medline 15676151 Contributor(s)Written 01-

2005 Kavita S. Reddy, Kathy Richkind

CitationThis paper should be referenced as such : Reddy KS; Richkind K . t(X;20)(q13;q13.3). Atlas Genet Cytogenet Oncol Haematol. January 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0X20q13q13ID1381.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



t(16;21)(p11;q22)

Clinics and PathologyDisease de novo acute non lymphocytic leukemia (ANLL); to be noted is one

case of chronic myelogenous leukemia (CML) -blast crisis. Phenotype / cell stem origin

ANLL cases: mainly M1, M2, M4, M5a, M5b, or M7 ANLL; may be preceded by a myelodysplastic syndrome (MDS).

Epidemiology about 40 reported cases, mainly found in young adults; children cases are described; median age is about 30 yrs; balanced sex ratio

Clinics blood data: anemia, thrombocytopenia, mild hyperleucocytosis; with high monocytic cell count at times

Cytology myelocytic and monocytoid features are often present; eosinophils in the bone marrow are sometimes abnormal and/or elevated; erythrophagocytosis may be found

Prognosis seems poor: complete remission may not be achieved; there is high incidence of relapse within a year and a median of survival is about 22 months (cases herein reviewed)

Disease Ewing tumours Note t(16;21)(p11;q22) has been found in rare cases of Ewing tumours, a

paediatric neoplasm with small round-cells derived from neural crests cells usually associated with translocations involving EWSR1

Cytogenetics Ewing tumours are usually associated with a t(11;22)(q24;q12) with 5' EWSR1 - 3' FLI1 involvement, less often associated with t(21;22)(q22;q12) with 5' EWSR1 - 3' ERG involvement, rarely associated with t(2;22)(q36; q12) (5' EWSR1 - 3' FEV) or with t(17;22)(q21;q12) (5' EWSR1-3' ETV4)

Prognosis recent treatments have improved the prognosis of Ewing's tumours. The prognosis is mainly determined by the presence of metastases at the time of diagnosis

CytogeneticsAdditional anomalies

ANLL cases: found solely in about 60% of cases in at least a subclone; associated with +10, +8, or de(9q)/-9 in about 10% of cases each

Genes involved and Proteins


Gene Name FUS

Location 16p11 Protein RNA binding protein; member of the TET family, like EWSR1 Gene Name ERG

Location 21q22 Protein ETS transcription factor

Result of the chromosomal anomalyHybrid gene Description

5' FUS including exons 1 to 6, 7 or 8 - 3' ERG from exon 7, 8 or 9 to C-term.

Fusion Protein Description

N-term FUS transactivation domain fused to the C-term DNA binding ETS domain of ERG

Oncogenesis seems to act as a transcriptional activator

External linksOther database t(16;21)(p11;q22) Mitelman database (CGAP - NCBI)

Other database t(16;21)(p11;q22) CancerChromosomes (NCBI)

BibliographyAcute nonlymphoblastic leukemia with bone marrow eosinophilia and structural anomaly of chromosome 16.Mecucci C, Bosly A, Michaux JL, Broeckaert-Van Orshoven A, Van den Berghe H Cancer Genet Cytogenet. 1985; 17: 359-363. Medline 85254357 Translocation (8;21) and its variants in acute nonlymphocytic leukemia. The relative importance of chromosomes 8 and 21 to the genesis of the disease.Minamihisamatsu M, Ishihara T. Cancer Genet Cytogenet. 1988; 33: 161-173. Medline 3164243 Acute nonlymphocytic leukemia with t(16;21)Berkowicz M, Rosner E, Resnitzky P, Mamon Z, Ben-Bassat I, Ramot B Cancer Genet Cytogenet. 1990; 47: 139-140 Medline 2357684


16;21 translocation in acute nonlymphocytic leukemia with abnormal eosinophils: a unique subtype.Sadamori N, Yao E, Tagawa M, Nakamura H, Sasagawa I, Itoyama T, Tokunaga S, Ichimaru M, Nakamura I, Kamei T, et al. Acta Haematol. 1990; 84: 212-216. Medline 2125791 Translocation (16;21)(p11;q22) in acute monoblastic leukemia with erythrophagocytosis.Marosi C, Bettelheim P, Geissler K, Lechner K, Koller U, Haas OA, Chott A, Hagemeijer A. Cancer Genet Cytogenet. 1991; 54: 61-66. Medline 2065316 t(16;21)(p11.2;q22): a recurrent primary rearrangement in ANLL.Morgan R, Riske CB, Meloni A, Ries CA, Johnson CH, Lemons RS, Sandberg AA. Cancer Genet Cytogenet. 1991; 53: 83-90. Medline 2036642 t(16;21) in a Ph positive CML.Ferro MR, Cabello P, Garcia-Sagredo JM, Resino M, San Roman C, Larana JG. Cancer Genet Cytogenet. 1992; 60:210-211. No abstract available. Medline 1606569 The 8;21 chromosome translocation in acute myeloid leukemia is always detectable by molecular analysis using AML1.Maseki N, Miyoshi H, Shimizu K, Homma C, Ohki M, Sakurai M, Kaneko Y. Blood. 1993; 81: 1573-1579. Medline 8453103 Acute non-lymphocytic leukemia with t(16;21).Nobbs MC, Chan-Lam D, Howell RT, Kitchen C, Copplestone JA. Cancer Genet Cytogenet. 1993 ;70: 144-145. Review. Medline 8242597 Translocation (16;21)(p11;q22) in acute nonlymphocytic leukemia.Okada K, Takeichi M, Uchida H, Shirota T, Sakai N, Ito H. Cancer Genet Cytogenet. 1994; 75: 60-63. Medline 8039166 Fusion of the FUS gene with ERG in acute myeloid leukemia with t(16;21)(p11;q22).Panagopoulos I, Aman P, Fioretos T, Hoglund M, Johansson B, Mandahl N, Heim S, Behrendtz M, Mitelman F. Genes Chromosomes Cancer. 1994; 11: 256-262.


Medline 7533529 [Acute monoblastic leukemia (M5a) with dysmegakaryocytopoiesis associated with t(16;21) (p11;q22)]Satoh K, Miura I, Chubachi A, Ohtani H, Hirokawa M, Niitsu H, Miura AB. Rinsho Ketsueki. 1994; 35: 160-164. Review. Japanese. Medline 8139114 HLA-DR-, CD33+, CD56+, CD16- myeloid/natural killer cell acute leukemia: a previously unrecognized form of acute leukemia potentially misdiagnosed as French-American-British acute myeloid leukemia-M3Scott AA, Head DR, Kopecky KJ, Appelbaum FR, Theil KS, Grever MR, Chen IM, Whittaker MH, Griffith BB, Licht JD, et al.. Blood. 1994; 84: 244-255. Medline 7517211 Acute non-lymphoblastic leukaemia with t(16;21): case report with a review of the literature.Hiyoshi M, Koh KR, Yamane T, Tatsumi N Clin Lab Haematol 1995; 17: 243-246. Medline 96318536 Establishment and characterization of IRTA17 and IRTA21, two novel acute non-lymphocytic leukaemia cell lines with t(16;21) translocation.Hiyoshi M, Yamane T, Hirai M, Tagawa S, Hattori H, Nakao Y, Yasui Y, Koh KR, Hino M, Tatsumi N. Br J Haematol. 1995; 90: 417-424. Medline 7794765 Detection of minimal residual disease in cerebro-spinal fluid of a patient with acute myelogenous leukemia with t(16;21)(p11;q22) translocation by reverse transcriptase-polymerase chain reaction.Harigae H, Kobayashi M, Mihara A, Watanabe N. Tohoku J Exp Med. 1997; 183: 297-302. Medline 9549830 Consistent detection of TLS/FUS-ERG chimeric transcripts in acute myeloid leukemia with t(16;21)(p11;q22) and identification of a novel transcript.Kong XT, Ida K, Ichikawa H, Shimizu K, Ohki M, Maseki N, Kaneko Y, Sako M, Kobayashi Y, Tojou A, Miura I, Kakuda H, Funabiki T, Horibe K, Hamaguchi H, Akiyama Y, Bessho F, Yanagisawa M, Hayashi Y. Blood. 1997; 90: 1192-1199. Medline 9242552 Cytogenetic analysis of de novo acute myeloid leukemia with trilineage myelodysplasia in comparison with myelodysplastic syndrome evolving to acute myeloid leukemia.


Tamura S, Takemoto Y, Hashimoto-Tamaoki T, Mimura K, Sugahara Y, Senoh J, Furuyama JI, Kakishita E. Int J Oncol. 1998; 12: 1259-1262. Medline 9592183 Hemophagocytosis by leukemic blasts in a case of acute megakaryoblastic leukemia with t(16;21)(p11;q22).Imashuku S, Hibi S, Kuriyama K, Todo S. Int J Hematol. 1999; 70: 36-39. Medline 10446493 Chromosomal abnormalities in 478 children with acute myeloid leukemia: clinical characteristics and treatment outcome in a cooperative pediatric oncology group study-POG 8821.Raimondi SC, Chang MN, Ravindranath Y, Behm FG, Gresik MV, Steuber CP, Weinstein HJ, Carroll AJ. Blood. 1999; 94: 3707-3716. Medline 10572083 Myeloid differentiation antigen and cytokine receptor expression on acute myelocytic leukaemia cells with t(16;21)(p11;q22): frequent expression of CD56 and interleukin-2 receptor alpha chain.Shikami M, Miwa H, Nishii K, Takahashi T, Shiku H, Tsutani H, Oka K, Hamaguchi H, Kyo T, Tanaka K, Kamada N, Kita K. Br J Haematol. 1999; 105: 711-719. Medline 10354136 Acute myeloid leukemia possessing jumping translocation is related to highly elevated levels of EAT/mcl-1, a Bcl-2 related gene with anti-apoptotic functions.Okita H, Umezawa A, Fukuma M, Ando T, Urano F, Sano M, Nakata Y, Mori T, Hata J. Leuk Res. 2000; 24: 73-77. Medline 10634649 Cytogenetic profile of childhood and adult megakaryoblastic leukemia (M7): a study of the Groupe Francais de Cytogenetique Hematologique (GFCH).Dastugue N, Lafage-Pochitaloff M, Pages MP, Radford I, Bastard C, Talmant P, Mozziconacci MJ, Leonard C, Bilhou-Nabera C, Cabrol C, Capodano AM, Cornillet-Lefebvre P, Lessard M, Mugneret F, Perot C, Taviaux S, Fenneteaux O, Duchayne E, Berger R; Groupe Francais d'Hematologie Cellulaire. Blood. 2002; 100: 618-626. Medline 12091356 FUS/ERG gene fusions in Ewing's tumors.Shing DC, McMullan DJ, Roberts P, Smith K, Chin SF, Nicholson J, Tillman RM, Ramani P, Cullinane C, Coleman N. Cancer Res. 2003; 63: 4568-4576.


Medline 12907633 Breakpoint differentiation in chromosomal aberrations of hematological malignancies: Identification of 33 previously unrecorded breakpoints.Heller A, Loncarevic IF, Glaser M, Gebhart E, Trautmann U, Claussen U, Liehr T. Int J Oncol. 2004; 24: 127-136. Medline 14654949 Contributor(s)Written 02-

1998 Christine Pérot

Updated 01-2005 Jean Loup Huret

CitationThis paper should be referenced as such : Pérot C . t(16;21)(p11;q22). Atlas Genet Cytogenet Oncol Haematol. February 1998 .URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t1621.html Huret JL . t(16;21)(p11;q22). Atlas Genet Cytogenet Oncol Haematol. January 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t1621.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



Soft Tissue Tumors: Liposarcoma: Myxoid liposarcoma

IdentityNote Sarcomas are relatively rare malignant tumours and comprise less than

10% of all cancers. Classical classifications of sarcomas are based on the site of tumour (bone or soft tissue). Soft tissue sarcoma (STS) is the collective term used for malignancies arising in muscles, fat, vessels, the peripheral nervous system and fibrous tissue. Histopathologic examination of such tumours has revealed a large number of distinct entities, each displaying its own morphologic and clinical characteristics. Cytogenetic and molecular genetic analyses have shown that some of these STS are characterized by specific chromosomal translocations, whereas other STS show complex genetic aberrations. Liposarcoma is the most common soft tissue malignancy in adults accounting for at least 20% of all sarcomas in this age group. Myxoid-round cell liposarcoma is a subtype of liposarcoma characterized by the presence of the reciprocal chromosomal translocation t(12;16)(q13;p11). This translocation creates the FUS-DDIT3 chimeric gene.

Other names Myxoid-round cell liposarcoma

Classification Liposarcoma is a lipogenic tumour subclassified into four main histologic

groups, including well-differentiated liposarcoma (lipoma-like and sclerosing types), myxoid-round cell liposarcoma, pleomorphic liposarcoma, and dedifferentiated liposarcoma. The histologic group is predictive of both the clinical course of the disease and the ultimate prognosis.

Clinics and Pathology



Cytogenetics analyses have shown that several lipogenic tumours are characterized by specific chromosomal abnormalities, the best known was the reciprocal translocation t(12;16)(q13;p11) of myxoid-round cell liposarcoma, described about twenty years ago.This translocation results in a fusion gene consisting of the 5' part of the FUS (TLS) gene and the complete coding region of the CHOP gene (see fig.1).

Genes involved and ProteinsGene Name FUS (TLS)

Location 16p11 Dna / Rna The FUS gene consists of 15 exons located within 11 kb of genomic

DNA, and the exon 1 contains a 72-bp untranslated region and the translation initiation codon. The location of the FUS gene was identified as 16p11 by the site of the breakpoint in the translocation. The assignment was further narrowed to 16p11.2 by cytogenetic studies. FUS is rearranged in myxoid liposarcomas in the characteristic chromosomal translocation t(12;16)(q13;p11).

Protein The FUS protein, provisionally designated TLS (translocated in liposarcoma), and then called FUS, contains an RNA-recognition motif and is a component of nuclear riboprotein complexes. Lack of FUS in mice causes lethallity into neonatal period, it influences lymphocyte development in a non-cell-intrinsic manner, it has an intrinsic role in the proliferative responses of B cells to specific mitogenic stimuli, and it is


required for the maintenance of genomic stability. The involvement of a nuclear riboprotein in these processes in vivo indicates that FUS is important in genome maintenance.

Somatic mutation

Variants: FUS has been also shown a partner of gene fusions linked in other malignances: fused to ERG in acute myeloid leukaemia with t(16:21)(p11;q22), fused to CREB3L2 in low-grade fibromyxoid .sarcoma (LGFMS) by a translocation between chromosome bands 7q33-q34 (CREB3L2) and 16p11 (FUS) or fused to ATF1 in histiocytoma.

Gene Name DDIT3 (CHOP)

Location 12q13 Dna / Rna The DDIT3 gene was isolated from human cells and has a high level of

conservation with previously described hamster gene. Each is composed of 4 exons with intron/exon junctions maintained at identical positions. They showed 91% identity in amino acid sequence and 78% identity in nucleotide sequence. The gene is located on chromosome 12 (12q13.1-q13.2)

Protein CHOP (C/EBP-homologous protein) is a nuclear protein which was identified as a dominant-negative inhibitor of the transcription factors C/EBP and LAP. The protein also was called DDIT3 for DNA damage-inducible transcript 3' and GADD153 for 'growth arrest- and DNA damage-inducible gene. DDIT3 is consistently rearranged in myxoid liposarcomas in the characteristic chromosomal translocation t(12;16)(q13;p11). Its molecular characterization showed that the DDIT3 gene is fused with a gene on chromosome 16 named FUS.

Somatic mutation

Variants: An analysis of peripheral blood samples from 19 patients with myxoid liposarcoma linked to t(12;16) and from 1 patient with myxoid liposarcoma associated to t(12;22;20) chromosomal translocation, resulting in the fusion of the DDIT3 and EWS genes, found FUS-DDIT3 hybrid fragments in 3 patients with t(12;16) and the EWS-DDIT3 hybrid in the patient with the latter translocation.

Result of the chromosomal anomalyHybrid Gene


The FUS-CHOP fusion genes consist of the 5¼ promoter region and exons 1-5 or,

more rarely, 1-7 or 1-8 of FUS gene fused to the complete coding region, including exons 1-4 or 2-4, of CHOP (DDIT3) gene.

Fusion Protein

Description Myxoid liposarcoma tumor developed in a FUS-DDIT3 transgenic mice (40X objetive, H-E staining).

Oncogenesis Oncogenic properties Transcriptional control of the fusion gene is

dominated by the FUS housekeeping type of regulatory region, leading to stable expression of the fusion protein in tumor cells. The transforming properties of the FUS-DDIT3 fusion protein have been demonstrated in NIH 3T3 cells and fibroblasts. In the FUS-DDIT3 fusion, transcriptional activation is specifically conferred on the chimeric protein by the FUS segment after the translocation event. The portion of FUS that is present in the FUS-DDIT3 and FUS-ERG fusion proteins is similar and this part has been shown to be an autonomous transcriptional activation domain. The protein most likely functions as an abnormal transcription factor acting on a number of downstream target genes. Mouse models In vivo, mice expressing FUS-DDIT3 develop liposarcomas. Overexpression of FUS-DDIT3 transgene driven by the elongation factor 1alpha (EF1alpha) promoter to all tissues, results in most of the symptoms of human liposarcomas, including the presence of lipoblasts with round nuclei, accumulation of intracellular lipid, induction of adipocyte-specific genes and a concordant block in the differentiation program (see figure 2). No tumours of other tissues were found in these transgenic mice despite widespread activity of the EF1alpha promoter. This establishes FUS-DDIT3 overexpression as a key determinant of human liposarcomas and provided the first in vivo evidence for a link between a fusion gene created by a chromosomal


translocation and a solid tumour. In contrast, transgenic mice expressing high levels of DDIT3, which lacks the FUS domain, do not develop any tumour but consistently show the accumulation of a glycoprotein material within the terminally differentiated adipocytes, a characteristic figure of liposarcomas associated with FUS-DDIT3. However, transgenic mice expressing the altered form of DDIT3-FUS (created by the in frame fusion of the FUS domain to the carboxy end of DDIT3) developed liposarcomas. The characteristics of the liposarcomas arising in the DDIT3-FUS mice were very similar to those previously observed in the FUS-DDIT3 transgenic mice indicating that the FUS domain is required not only for transformation but also influences the phenotype of the tumor cells. These results provide evidence that the FUS domain of FUS-DDIT3 plays a specific and critical role in the pathogenesis of liposarcoma. In this sense, when mice expressing the FUS domain are crossed with DDIT3-transgenic mice to generate the double-transgenic FUSxDDIT3, these animals develop liposarcoma. These results provide genetic evidence that FUS and DDIT3 domains function in trans for the mutual restoration of liposarcoma, and identify a new mechanism of tumour-associated fusion genes which might have impact beyond myxoid liposarcoma.

BibliographyCytogenetic studies of adipose tissue tumors. II. Recurrent reciprocal translocation t(12;16)(q13;p11) in myxoid liposarcomas.Turc-Carel C, Limon J, Dal Cin P, Rao U, Karakousis C, Sandberg AA Cancer Genet Cytogenet 1986; 23: 291-299. Medline 3779625 Localization of the chromosomal breakpoints of the t(12;16) in liposarcoma to subbands 12q13.3 and 16p11.2Eneroth M, Mandahl N, Heim S, Willen H, Rydholm A, Alberts KA, Mitelman F. Cancer Genet Cytogenet 1990; 48: 101-107 Medline 2372777 Rearrangement of the transcription factor gene CHOP in myxoid liposarcomas with t(12;16)(q13;p11).Aman P, Ron D, Mandahl N, Fioretos T, Heim S, Arheden K, Willen H, Rydholm A, Mitelman F. Genes Chromosomes Cancer. 1992; 5: 278-285. Medline 1283316 Isolation, characterization and chromosomal localization of the human GADD153 gene.Park JS, Luethy JD, Wang MG, Fargnoli J, Fornace AJ Jr, McBride OW, Holbrook NJ. Gene 1992; 116: 259-267 Medline 1339368


CHOP, a novel developmentally regulated nuclear protein that dimerizes with transcription factors C/EBP and LAP and functions as a dominant-negative inhibitor of gene transcription.Ron D, Habener JF Genes Dev 1992; 6: 439-453. Medline 1547942 Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma..Crozat A, Aman P, Mandahl N, Ron D Nature 1993; 363: 640-644 Medline 8510758 Fusion of the dominant negative transcription regulator CHOP with a novel gene FUS by translocation t(12;16) in malignant liposarcoma.Rabbitts TH, Forster A, Larson R, Nathan P Nat Genet 1993; 4: 175-180 Medline 7503811 An RNA-binding protein gene, TLS/FUS, is fused to ERG in human myeloid leukemia with t(16;21) chromosomal translocationIchikawa H, Shimizu K, Hayashi Y, Ohki M Cancer Res 1994; 54: 2865-2868 Medline 8187069 Fusion of the FUS gene with ERG in acute myeloid leukemia with t(16;21)(p11;q22).Panagopoulos I, Aman P, Fioretos T, Hoglund M, Johansson B, Mandahl N, Heim S, Behrendtz M, Mitelman F Genes Chromosomes Cancer 1994; 11: 256-262 Medline 7533529 Characterization of the CHOP breakpoints and fusion transcripts in myxoid liposarcomas with the 12;16 translocation.Panagopoulos I, Mandahl N, Ron D, Hoglund M, Nilbert M, Mertens F, Mitelman F, Aman P Cancer Res 1994; 54: 6500-6503. Medline 7987849 Transcriptional activation by TAL1 and FUS-CHOP proteins expressed in acute malignancies as a result of chromosomal abnormalities.Sánchez-Garcia I, Rabbitts TH. Proc Natl Acad Sci U S A 1994; 91: 7869-7873. Medline 8058726


A novel effector domain from the RNA-binding protein TLS or EWS is required for oncogenic transformation by CHOP.Zinszner H, Albalat R, Ron D Genes Dev. 1994; 8: 2513-2526. Medline 7958914 Chimeric TLS/FUS-CHOP gene expression and the heterogeneity of its junction in human myxoid and round cell liposarcoma.Kuroda M, Ishida T, Horiuchi H, Kida N, Uozaki H, Takeuchi H, Tsuji K, Imamura T, Mori S, Machinami R, Am J Pathol 1995; 147: 1221-1227 Medline 7485386 Two distinct FUS breakpoint clusters in myxoid liposarcoma and acute myeloid leukemia with the translocations t(12;16) and t(16;21).Panagopoulos I, Mandahl N, Mitelman F, Aman P Oncogene 1995; 11: 1133-1137. Medline 7566973 Expression patterns of the human sarcoma-associated genes FUS and EWS and the genomic structure of FUS.Aman P, Panagopoulos I, Lassen C, Fioretos T, Mencinger M, Toresson H, Hoglund M, Forster A, Rabbitts TH, Ron D, Mandahl N, Mitelman F Genomics 1996; 37: 1-8 Medline 8921363 Genomic PCR detects tumor cells in peripheral blood from patients with myxoid liposarcoma.Panagopoulos I, Aman P, Mertens F, Mandahl N, Rydholm A, Bauer HF, Mitelman FGenes Chromosomes Cancer 1996; 17: 102-107. Medline 8913727 Identification of genes differentially expressed in TLS-CHOP carrying myxoid liposarcomas.Thelin-Jarnum S, Lassen C, Panagopoulos I, Mandahl N, Aman P Int J Cancer 1999; 83: 30-33 Medline 10449603 Fus deficiency in mice results in defective B-lymphocyte development and activation, high levels of chromosomal instability and perinatal death.Hicks GG, Singh N, Nashabi A, Mai S, Bozek G, Klewes L, Arapovic D, White EK, Koury MJ, Oltz EM, Van Kaer L, Ruley HE Nat Genet. 2000; 24: 175-179.. Medline 10655065 The chimeric FUS/TLS-CHOP fusion protein specifically induces liposarcomas


in transgenic mice.Perez-Losada J, Pintado B, Gutierrez-Adan A, Flores T, Banares-Gonzalez B, del Campo JC, Martin-Martin JF, Battaner E, Sánchez-Garcia I Oncogene 2000; 19: 2413-2422 Medline 10828883 Liposarcoma initiated by FUS/TLS-CHOP: the FUS/TLS domain plays a critical role in the pathogenesis of liposarcoma.Perez-Losada J, Sánchez-Martin M, Rodriguez-Garcia MA, Perez-Mancera PA, Pintado B, Flores T, Battaner E, Sánchez-Garcia I Oncogene 2000; 19: 6015-6022 Medline 11146553 Genetic characterization of angiomatoid fibrous histiocytoma identifies fusion of the FUS and ATF-1 genes induced by a chromosomal translocation involving bands 12q13 and 16p11.Waters BL, Panagopoulos I, Allen EF Cancer Genet Cytogenet 2000; 121: 109-116. Medline 11063792 Expression of the FUS domain restores liposarcoma development in CHOP transgenic mice.Perez Mancera PA, Pere Losada J, Sanchez Martin M, Rodriguez Garcia MA, Flores T, Battaner E, Gutierrez Adan A, Pintado B, Sanchez Garcia I Oncogene 2002; 21: 1679-1684 Medline 11896599 Understanding mesenchymal cancer: the liposarcoma-associated t(12;16)(q13;p11) chromosomal translocation as a model.PÈrez-Mancera PA. Genomics 2002; Vol.3, No.4: 237-244. Fusion of the FUS and BBF2H7 genes in low grade fibromyxoid sarcoma.Storlazzi CT, Mertens F, Nascimento A, Isaksson M, Wejde J, Brosjo O, Mandahl N, Panagopoulos I Hum Mol Genet. 2003; 12: 2349-2358. Medline 12915480 Current soft-tissue sarcoma classificationsDaugaard S. Eur J Cancer 2004; 40: 543-548. Medline 14962721 REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed



2004 Manuel Sánchez-Martín, Ines González-Herrero, Isidro Sánchez-Garcia.

CitationThis paper should be referenced as such : Sánchez-Martín M, González-Herrero I, Sánchez-Garcia I . Soft Tissue Tumors: Liposarcoma: Myxoid liposarcoma. Atlas Genet Cytogenet Oncol Haematol. November 2004 . URL : http://AtlasGeneticsOncology.org/Tumors/MyxoidLipoSarcID5169.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



Uterus Tumours: an Overview

IdentityNote Anatomically, uterine neoplasms may be localized at the corpus,

isthmus (the transition between the endocervix and uterine corpus) and cervix. The fallopian tubes and uterine ligaments may also undergo tumour tranformation. This overview will focus on uterine cervix and corpus tumours, including benign, pre-malignant and malignant lesions. They may affect the endometrium, muscles or other supporting tissue. Uterine tumours may be histologically typed according to several classification systems. Those used most frequently are based on the WHO (World Health Organization) International Histological Classification of Tumours and on the ISGYP (International Society of Gynecological Pathologists). The most widely-accepted staging system is the FIGO (International Federation of Gynecology and Obstetrics) one.

Classification According to WHO recommendations, the main UTERINE CERVIX

categories are: � Epithelial tumours

� Mixed epithelial and mesenchymal tumours

� Mesemchymal tumours � Mixed epithelial and mesenchymal tumours � Secondary tumours The main UTERINE CORPUS categories, once again according to WHO recommendations, are: � Epithelial tumours � Mesemchymal tumours

� Trophoblastic tumours � Secondary tumours

Clinics and PathologyNote Female pelvic gynaecological malignancies account for almost 15% of

all cancers in women. Uterine cancer is the most common, specifically endometrial cancer of the uterine corpus.

Disease UTERINE CERVIX NEOPLASIA Note In countries that have well-developed screening programs using the

Papanicolaou smear test to detect premalignant lesions, the incidence of invasive cervical cancer continues to decline. Age-standardised incidence rates vary from about 10 per 100,000 in most developed


countries to more than 40 (up to 100) per 100,000 in many of the developing countries. Worldwide, invasive cervical cancer is the second most common female malignancy after breast cancer, with 500,000 new cases diagnosed each year. Among benign lesions, endocervical polyps are the most common, while among malignant lesions, account for approximately 90%, and adenocarcinomas for approximately 10% of cervical cancers. Due to considerable ongoing evolution in understanding the pathobiology of cervix precursor lesions, there is a lack of uniform clinical, cytological and histological terminology, the most widely accepted being the modifications incorporated into the Bethesda System of cytological diagnosis. Carcinomas of the uterine cervix are thought to arise from precursor lesions, and different subtypes of human papilloma virus (HPV) are major etiological factors in disease pathogenesis. Only certain types of HPV cause cervical cancer: HPV 16, 18, 33, 35, 45, 56, called "high-risk" types, are associated with high-grade Squamous Intraepithelial Lesions (SIL) and invasive carcinomas, whereas "low- risk" HPV 6, 11, 42, 44 are associated with genital condyloma and low-grade SIL. 5% of cervical cancers are HPV DNA-negative.

Epidemiology

Pathology

Etiology

Epidemiologic studies report that factors increasing the likelihood of exposure to HPV, such as young age at first intercourse, a large number of sexual partners, race, high parity and low socioeconomic status, favour cervical cancer development. Latin America, the Caribbean, southern Asia, southeast Asia, and sub-Saharan Africa are areas with the highest incidence.

Clinics Early cervical cancer is usually asymptomatic. Approximately 80-90% of patients with cervical cancer experience abnormal vaginal bleeding. HPV causes a large spectrum of lesions ranging from relatively benign condyloma acuminatum to invasive squamous cell carcinomas. Epithelial neoplasia Endocervical polyp is the most common benign lesion found in the uterine cervix. It appears as a focal hyperplastic protrusion of the endocervical folds, including the epithelium and the stroma. Microscopically, a variety of histologic patterns are observed, depending on the prevalence of the tissue type. In situ or invasive carcinomas do not usually arise from this lesion. Fibroepithelial polyp, or stromal polyp, is a benign exophytic proliferation of the cervical stroma. It is composed of stellate-shaped cells growing chaotically, covered by stratified squamous epithelium, and is often seen in pregnant women. Microglandular hyperplasia is a common cervical lesion associated with oral contraception or with pregnancy in young women. Squamous intraepithelial lesion (SIL) is a precursor of squamous cell carcinoma and usually remains inactive for more than 20 years before it becomes invasive. SIL usually affects the transformation zone near the endocervical epithelium.

Three different diagnostic systems are used: - CIN (Cervical


Intraepithelial Neoplasia, CIN I, CIN II, CIN III), - SIL (Low grade SIL -LSIL - High grade SIL - HSIL), - Mild, Moderate or Severe Dysplasia. These systems correspond to: CIN I / LSIL / Mild dysplasia CIN II / Moderate dysplasia CIN III / Severe dysplasia CIN II and CIN III / HSIL Adenocarcinoma In Situ (AIS) is a precursor of invasive cervical adenocarcinoma, showing endocervical glandular atypia. 30-60% of AIS are associated with SIL. 50-90% of cases are associated with HPV 16 or 18. Squamous cell carcinoma (SCC) accounts for 80-90% of all cervical malignancies and for 60-80 % of invasive carcinomas. There are two major forms: microinvasive and invasive SCC. Diagnosis of the former is based on the presence of microinvasion foci. The invasive form may show heterogeneity at the microscopic level, and in most cases, infiltrating nests and clusters are characterised by an irregular, ragged contour. Adenocarcinoma accounts for 5-20% of all cervical malignancies, and has increased during the past 20-30 years, particularly among women under 35. The tumour possibly originates from the pluripotential cells of the subcolumnar endocervical epithelium. It appears in a variety of histologic patterns, including mucinous, endometrioid, clear cell, well- differentiated villoglandular and serous adenocarcinoma. Mesenchymal neoplasia:

� Leiomyomas are rarer than those appearing in the uterine corpus and have a similar macroscopical and microscopical appearence. They account for approximately 8% of all uterine smooth muscle tumors. � Leiomyosarcoma is very rare. Mixed epithelial and mesenchymal neoplasia: � Adenomyoma and papillary adenofibromas are rare polyp-like lesions composed of an admixture of fibroconnective tissue, smooth muscle and glandular elements. Adenomyomas may recur but behave benignly. � Malignant Mullerian Mixed Tumour (MMMT) is rarely seen in the cervix, compared with its much more common uterine counterpart. This lesion occurs in postmenopausal women and typically forms polypoid or peduncolated masses. Its histologic appearence differs from that of its uterine counterpart.

Precancerous changes in the cervix may be treated with cryosurgery, cauterization or laser surgery. Cervical conization may eventually prove to be therapeutic in many patients. Depending on the stage of the disease, surgery (early invasive cancer), combined with radiation, thermothera

� Mullerian adenosarcoma is rare. It is microscopically characterized by papillae covered by typical endocervical epithelium and malignant mesenchymal elements. Secondary tumours are uterine cervix tumours originating outside the cervix.

Treatment

py or chemotherapy (more advanced cases), are


treatments of choice. Prognosis

Early-stage cervical cancer and precancerous cervical conditions are almost 100% curable. The five-year relative survival rate for earliest-stage cervical cancer is 91%. Although death rates fell by 74% between 1955 and 1992 and continue to drop by about 2% a year, invasive cervical cancer continues to register significant morbidity and is a major cause of cancer deaths in women worldwide. Very recently, a "predictive score" system that separates the thermoradiosensitive group from the thermoradioresistant group of advanced cervical cancer has been developed on the basis of the expression profiles of 35 genes, selected by cDNA microarray analysis.

Disease UTERINE CORPUS NEOPLASIA Note Uterine cancer is the fourth most common malignancy in women,

following breast cancer, lung and colorectal cancer. However, as it is usually detected in early stages, it is not a common cause of cancer deaths. The most common corpus malignancy is the endometrial carcinoma (approximately 95%.); sarcomas represent only 4% and heterologous tumors such as rhabdomyosarcomas, osteosarcomas and chondrosarcomas the remaining 1%. The most common corpus benign tumor is leiomyoma, a proliferation of mesenchymal origin, occurring in approximately 77% of women of reproductive age, according to a study on serial uterine sections.

Clinics

Etiology The main risk factors for uterine corpus malignancy are obesity, nulliparity, late menopause, diabetes, hypertension and radiation therapy. 10-25% of patients with mesenchymal malignancy report the administration of pelvic radiation 5 to 25 years earlier. Benign endometrial neoplasia, such as endometrial polyps, hyperplasia and adenocarcinoma, may be associated with tamoxifen therapy, possibly mediated through its agonistic estrogenic properties. As regards leiomyoma, evidence supports genetic susceptibility. Concerning gestational trophoblastic diseases, hydatiform moles arise from abnormal conceptions and most choriocarcinoma and placental site trophoblastic tumours develop following complete moles.

Epidemiology The incidence of uterine malignancy varies widely throughout the world, with lower rates occurring in developing countries and higher rates in industrialized ones. Benign neoplasia, specifically leiomyomas, most commonly occur in women aged 35-49 years, but can be seen at any time between menarche and menopause. They are more common in black than in white women (3-9:1). Onset is frequently accompanied by metrorrhagia, menometrorrhagia, spotting and irregular bleeding, for both benign and malignant lesions, including trophoblastic diseases. Early pathological proliferation may sometimes be asymptomatic. Pain and pelvic pressure are usually manifestations of advanced disease.

Pathology Epithelial neoplasia: � Endometrial polyps are present in 24% of the general female population, mainly in women over 40 years of age. They may show


morphologically diverse patterns, related to patient hormone status, and consist of hyperplastic, cystically dilated glands in a fibrous stroma with large, thick-walled blood vessels. Endometrial polyps originate from monoclonal proliferation of mesenchyme and are not precancerous lesions, but endometrial epithelial invasive cancer (EIC) may be found in benign endometrial polyps, and endometrial polypoid masses may be malignant (adenosarcoma, malignant Mullerian mixed - MMMT -, endometrial stromal tumor). They may be associated with long-term tamoxifen therapy. � Endometrial hyperplasia (EH) is defined as a proliferation of glands of irregular size and shape with an increased gland/stroma ratio compared with proliferative endometrium. Morphologic alterations range from benign changes to premalignant disease. EH develops as a result of unopposed extrogenic stimulation. Association with polycystic ovarian disease has been described, but this entity is still a subject of debate. The WHO classification (adopted in 1994 and currently in use) distinguishes: typical (simple and complex) and atypical (simple and complex) hyperplasias. The latter confers signifcantly higher risk of progression to carcinoma. � Intraepithelial Carcinoma (EIC) is characterized by markedly atypical nuclei, identical to those seen in invasive serous carcinoma � Endometrial carcinoma is defined as an epithelial tumor, usually with glandular differentiation, arising in the endometrium and which has the potential to invade the myometrium and spread to distant sites. Type-I (related to estrogen) and Type-II (unrelated to estrogen) lesions are distinguished with respect to their biology and clinical course. Endometrioid carcinoma and serous carcinoma are the respective prototypes of the two groups. Major genetic alterations (see genes) seem to distinguish the two types, and histological classification of endometrial carcinoma may currently benefit from molecular analysis.

Endometrioid carcinoma is the most common endometrial malignancy, accounting for more than 75% of all endometrial cancers, and is relatively rare in pre-menopausal women. The histologic pattern resembles proliferative-phase endometrium and has less than 10% of squamous, serous, mucinous or clear differentiation. Both architectural and nuclear appearence are unavoidable criteria for grading lesions Serous carcinoma is a highly aggressive carcinoma, usually post-menopausal, accounting for 10% of endometrial carcinomas. Geographical distribution is worldwide, although a lower incidence is reported in Norway and Australia. Papillary architecture with cells showing marked cytologic atypia is common. Clear cell carcinoma comprises 1.6% of all uterine carcinomas and may have different architectural patterns, such as solid, papillary tubular and cystic. Mucinous carcinoma is defined by the presence of more then 50% of cells containing periodic acid-Shiff positive, diastase-resistant intracytoplasmic mucin. It is rare, and usually has a glandular architectural pattern.


Squamous cell carcinoma is extremely rare and is microscopically similar to its cervix counterpart Mixed carcinoma is defined as an endometrial carcinoma showing at least one other component comprising at least 10% of the tumour.

Small cell carcinomaID: 5310> is very uncommon and resembles small cell carcinoma of the lung. PATHOLOGY

� Leiomyoma

Transitional cell carcinoma is very rare and is defined by the presence of more than 90% of cells resembling urothelial transitional cells.

includes approximately 1-2% of tumours lacking either glandular or squamous differentiation. Mesenchymal neoplasia: These tumours arise primarily from two distinct tissues: myometrial muscle (leiomyosarcoma) and endometrial stroma (mesodermal and stromal sarcomas).

is a very common uterine smooth muscle proliferation, usually detected in women over 30 years old. Its growth is hormone- dependent, and typical nodules are composed of whorled, anastomosing fascicles of smooth muscle cells. Less typical lesions are grouped into specific subtypes.

� Leiomyosarcoma accounts for 1.3% of all uterine malignancies. Most of them are intramural, and nuclear atypia, high mitotic index and cell necrosis are the main diagnostic criteria.

� Miscellaneous mesenchymal tumors show no predominant muscle smoot or stromal differentiation and comprise: endometrial stromal and smooth muscle tumour (composed of an admixture of endometrial stromal and smooth muscle cells), adenomatoid tumour (a benign lesion of the uterine serosa and myometrium originating from the mesothelium and forming gland-like structures), other rare mesenchymal tumours (benign and malignant, such as lipoma

� Endometrial stromal nodule is a rare lesion present in women aged 23-75 years. The lesion may protrude into the uterine cavity or grow within the myometrium. Microscopically, the cells resemble normal proliferative-phase endometrial stromal cells. The lesion is benign, but a hysterectomy may be necessary in order to evaluate the margin.

� Endometrial stromal sarcoma (ESS) is a rare tumor (0.2% of all uterine cancers) invading, by definition, the miometrium. It is typically subdivided into low-grade (fewer than 5-10 mitoses per 10 HPF and minimal cellular atypia) and high-grade stromal sarcoma, although this division has recently been questioned.

, haemangioma, limphangioma, rhabdomyoma, rhabdomyosarcoma, liposarcoma, osteosarcoma, alveolar soft part sarcoma, etc) histologically identical to their counterparts arising in the usual sites.

� Adenofibroma usually occurs in postmenopausal women and tends to recur. It presents an admixture of epithelial and mesenchymal cells.

Mixed epithelial and mesenchymal neoplasia:

� Carcinofibroma is a very rare lesion whose behaviour is not yet


clear. It is composed of an admixture of malignant epithelial and benign mesenchymal cells. � Adenosarcoma is a rare biphasic tumour which may occur at any age. It is a low-grade neoplasm, with a potential for recurrence and metastasis. It is charaterized by benign epithelial and saromatous mesenchymal components.

� Partial hydatiform mole is an abnormal placenta grossly characterised by an admixture of normal and hydropic chorionic villi.

� Invasive hydatiform mole, usually subsequent to a complete mole, is composed of hydatiform mole villi within the myometrium.

� Placental site tumour is a rare neoplasm deriving from intermediate trophoblast cells in the placenta.

The vast majority of uterine corpus malignant tumours are highly curable since they present early symptoms and may often be diagnosed precociously. Knowledge of the surgicopathologic, as well as clinical, staging is crucial in developing an appropriate management plan. Surgical therapy is usually necessary for the majority of endometrial malignancies. Other adjuvant/adjunctive therapies such as radiation therapy, chemotherapy and hormonal therapy may be considered. Treatment for benign uterine corpus lesions depends on the symptoms, tumor size and location and age of the patient

Prognosis

� Carcinosarcoma (malignant mixed mesodermal sarcoma - MMMT), is still a debated entity: formerly classified among sarcomas, nowadays it is considered a variant of carcinoma, on the basis of recent clinical, histopathological, cytogenetic and molecular evidence. It accounts for 5% of all uterine corpus malignancies and is found in postmenopausal women. Microscopically it shows an admixture of carcinomatous and sarcoma-like elements, resulting in a characteristic biphasic appearance. It appears as a large, soft, polypoid mass involving the endometrium and myometrium. The carcinomatous component may be composed of papillary serous, endometrioid or clear cells, the stromal component of round or spindle cells. Gestational trophoblastic tumors: Gestational trophoblastic tumors are neoplastic disorders arising from placental trophoblastic tissue after abnormal fertilization.

� Complete hydatiform mole, is an abnormal placenta characterised by abnormal throphoblastic proliferation involving most chorionic villi.

� Gestational choriocarcinoma is a highly malignant, often metastatizing neoplasm composed of a disordered array of syncytiotrophoblastic and cytotrophoblastic elements, without chorionic villi.

Secondary tumours are uterine corpus tumours originating outside the uterus.

Treatment

Prognostic significance of hormone receptors in endometrial cancer has been reported; moreover, immunohistochemistry for both estrogen and progesterone receptors has been shown to correlate with FIGO grade as well as survival. HER-2/neu overexpression has been reported to be associated with a poor prognosis. Endometrioid


adenocarcinoma and adenosquamous carcinoma have the highest overall 5-year survival rates. (respectively 76% and 68%), clear cell and papillary serous carcinomas the lowest (respectively 51% and 46%). The evolution of sarcoma depends primarily on the extent and stage of the disease at diagnosis. Recurrences are very frequent. The overall 5-year survival rate is 15-25%. Among benign neoplasias, endometrial polyps may undergo malignant tranformation, while leiomyomas usually do not.

CytogeneticsNote The vast majority of endometrial cancers are sporadic. However,

hereditary predisposition to develop uterine carcinoma is associated with hereditary non-polyposis colorectal carcinoma (HNPCC) and Cowden syndrome. Germline mutations of the FH (fumarate hydratase) have been found to be involved in syndromes associated with uterine leiomyomas. Evidence supports the existence of genetic factors predisposing to non-syndromic uterine leiomyoma, although susceptibility genes have not yet been identifed.

Cytogenetics Morphological

� Endometrial stromal tumours are cytogenetically heterogeneous. The most common karyotypic changes involve chromosomes 6, 7, and 17. A subgroup of stromal lesions, including low-grade endometrial stromal sarcomas (more rarely in high-grade ESS) and endometrial stromal nodules are characterized b

UTERINE CERVIX: Karyotypic analysis on uterine cervix lesions is limited. No specific chromosome changes have been reported, although most lesions show cytogenetic abnormalities, including polyploidy. Chromosomes 5 and 17 are those most frequently involved in changes in carcinomas. UTERINE CORPUS:


� Endometrial polyps may show abnormal karyotypes, usually with a single or few changes. Three main cytogenetically-abnormal subgroups have been observed: (a) rearrangements in the 6p21-p22 region; (b) rearrangements in the 12q13-15 region; (c) rearrangements in the 7q22 region. At least for the subgroup with 6p21 rearrangement, it has been demonstrated that karyotypically aberrant cells belong to the stromal component of endometrial polyps.� Endometrial carcinomas do not show specific chromosome changes. Most of them are characterized by a hyperdiploid modal chromosome number. The majority show numerical chromosome changes, but cases with both numerical and structural abnormalities have been observed in the context of complex karyotypes. Non-random gains of 1q and 8q are frequently found. Correlations between karyotypic aberration patterns and histological differentiation have recently been reported, with the identification of different copy number changes among the different grades of type I carcinomas, between serous papillary and clear-cell carcinomas of type II, as well as between homologous and heterologous carcinosarcomas.

y t(7;17)(p15;q21)


translocation, resulting in the fusion of JAZF1 and JJAZ1 genes. � In Endometrial Malignant Mullerian Mixed Tumours, chromosome 8 or 8q. gains have been suggested to characterize a distinct cytogenetic subgroup. � Benign smooth muscle tumors are associated with abnormal karyotypes in almost 40-60% of cases. Different cytogenetically-abnormal subgroups have been recognized. Chromosomal structural changes at the 6p21, 12q13-15; 7q22, and trisomy 12 define those most frequently found; chromosome regions 1q42-44, 3q, and 10q are non-randomly involved in changes in a minority of cases. � Uterine leiomyosarcomas have complex cytogenetic karyotypes with numerical and structural aberrations and cytogenetic intratumoral heterogeneity. � Hydatiform moles have peculiar karyotypes: complete moles usually have a 46,XX karyotype of paternal origin, arising from an anuclear oocyte fertilized by an haploid 23,X sperm which undergoes replication. More rarely a 46,XY karyotype is found, arising from the fertilizaion of an anuclear oocyte by two haploid sperm. Incomplete moles (more than 90%) have a triploid karyotype and the presence of both maternal and paternal chromosomal material, due to ferilization of an haploid oocyte by two haploid sperm.

UTERINE CERVIX. A pronounced chromosomal instability in advanced cervical carcinomas has been observed by comparative genomic hybridization (CGH.). CGH profiles show 2q33-q37 deletions and 3q gains as characteristic changes. FISH analysis on squamous cell carcinoma showed an increased DNA copy number in chromosomes 3 and X in the development and progression from HSIL to cervical carcinoma. UTERINE CORPUS. CGH data on endometrial cancer confirm G-banding results, pinpointing a central role of 8q gains in the pathogenesis of carcinosarcomas and endometrial adenocarcinomas. CGH observation shows that atypical endometrial hyperplasia shares genomic abnormalities with endometrioid carcinoma, whereas simple endometrial hyperplasia shows no genomic imbalances.

Genes involved and ProteinsNote Notch1 exerts specific protective effects against HPV-induced

transformation through suppression of E6/E7 expression. In high-grade HPV-positive cervical lesions , down-regulation of the cell signaling molecule Notch1 allows for increased expression of E6 and E7 oncogenes, which promote malignant cervical cell transformation. A putative progression model for sporadic endometrioid adenocarcinoma developing through atypical endometrial hyperplasia has recently been proposed. Tumour initiation and progression are characterized by the acquisition of various molecular alterations. In this model, the most frequent, earliest events are the mutation of PTEN and K-ras, possibly followed by inactivation of e-cadherin (playing a role in progression) and later by p53 mutations, overexpressin of her/neu and


inactivation of p16. An alternative pathway may lead directly to a high-grade tumour type by p53 mutation and her2/neu amplification, respectively. Mutations in the MSH2/MSH6 complex seem to play a central role in endometrial carcinoma associated with HNPCC . Fusion of the JAZF1 and JJAZ1 genes is found in endometrial stromal lesions, possibly restricted to the classic histologic subset. Intragenic PTEN mutations are involved in the genesis of uterine carcinosarcomas with endometrioid-type carcinoma components. Complete moles show overexpression of several growth factors, including c-myc, epidermal growth factor, and c-erbB2, as compared to a normal placenta. On rare occasions, complete moles may be familial, inherited as an autosomal trait: they are biparental in origin and result from misexpression of imprinted genes. A candidate region of chromosome arm 19q13.4 has been identified. Germline mutations of the fumarate hydratase (FH) gene, located at 1q42.1, are involved in syndromic uterine leiomyomas. Very recently, loss of the FH gene has been demonstrated in a subgroup of nonsyndromic uterine leiomyoma characteried by 1q rearrangements. Dysregulation of the HMGA2 (12q15) and HMGA1 (6p21.3) genes has been observed in uterine leiomyomas, as well as in endometrial polyps.

BibliographyEndometrial cancer: biochemical and clinical correlates.Gurpide E J Natl Cancer Inst 1991; 83: 405-416,(Review) Medline 1999848

Genes Chromosomes Cancer 1992; 5: 260-263.

Clonal 6p21 rearrangement is restricted to the mesenchymal component of an endometrial polyp.Fletcher JA, Pinkus JL, Lage JM, Morton CC, Pinkus GS.

Medline 1384681 Prognostic significance of hormone receptors in endometrial cancer.Creasman WT Cancer 1993; 71: 1467-1470. Medline 8431882 Significance of chromosome 5 and 17 changes in the development of carcinoma of the cervix uteri.Atkin NB Cytogenet Cell Genet 2000; 91: 44-46 Medline 11173828


Endometrial cancer: Prevention, detection, management, and follow upElit L Can Fam Physician 2000 ;46: 887-892. (Review). Medline 10790821 HMGI-C and HMGI(Y) immunoreactivity correlates with cytogenetic abnormalities in lipomas, pulmonary chondroid hamartomas, endometrial polyps, and uterine leiomyomas and is compatible with rearrangement of the HMGI-C and HMGI(Y) genes.Tallini G, Vanni R, Manfioletti G, Kazmierczak B, Faa G, Pauwels P, Bullerdiek J, Giancotti V, Van Den Berghe H, Dal Cin P. Lab Invest 2000; 80: 359-369. Medline 10744071 Lack of MSH2 andMSH6 characterizes endometrial but not colon carcinomas in hereditary nonpolyposis colorectal cancer.Schweizer P, Moisio AL, Kuismanen SA,Truninger K,Vierumaki R,Salovaara R,Arola J,Butzow R,Jiricny J,Peltomaki P,Nystrom-Lahti M Cancer Res 2001; 61: 2813 -2815 Medline 11306449 PTEN mutations in uterine sarcomasAmant F, de la Rey M, Dorfling CM, van der Walt L, Dreyer G, Dreyer L, Vergote I, Lindeque BG, Van Rensburg EJ. Gynecol Oncol 2002; 85: 165-169 Medline 11925138 Blaunstein's Pathology of the Female Genital Tract,Kurman RJ, editor. 5th ed New York: Springer 2002 Specific down-modulation of Notch1 signaling in cervical cancer cells is required for sustained HPV-E6/E7 expression and late steps of malignant transformation.Talora C, Sgroi DC, Crum CP, Dotto GP Genes Dev 2002; 16: 2252-2263 Medline 12208848

Gunawan B, Baumhoer D, Schulten HJ, Emons G, Fuzesi L.

WHO classification of tumours: 2002 editions.Pathology and Genetics of Tumours ofthe Breast and Female Genital OrgansF.A. Tavassoli and M.R. Stratton Editors Polysomy 8 in three cases of homologous malignant mixed MÃ_llerian tumors of the uterus.


Anticancer Res 2003; 23: 1379-1383. Medline 12820397 Involvement of fumarate hydratase in nonsyndromic uterine leiomyomas: genetic linkage analysis and FISH studies.Gross KL, Panhuysen CI, Kleinman MS, Goldhammer H, Jones ES, Nassery N, Stewart EA, Morton CC. Genes Chromosomes Cancer 2004; 41: 183-190. Medline 15334541 Prediction of outcome of advanced cervical cancer to thermoradiotherapy according to expression profiles of 35 genes selected by cDNA microarray analysis.Harima Y, Togashi A, Horikoshi K, Imamura M, Sougawa M, Sawada S, Tsunoda T, Nakamura Y, Katagiri T. Int J Radiat Oncol Biol Phys 2004; 60: 237-248, Medline 15337562 Molecular detection of JAZF1-JJAZ1 gene fusion in endometrial stromal neoplasms with classic and variant histology: evidence for genetic heterogeneity.Huang HY;Ladanyi M;Soslow RA Am J Surg Pathol 2004; 28: 224-232. Medline 15043312 Recurrent DNA copy number changes revealed by comparative genomic hybridization in primary Merkel cell carcinomas.Larramendy ML, Koljonen V, Bohling T, Tukiainen E, Knuutila S. Mod Pathol 2004; 17: 561-567. Medline 15001998 Molecular genetic pathways in various types of endometrial carcinoma: from a phenotypical to a molecular-based classification.Lax SF Virchows Arch 2004; 444: 213-223. Medline 14747944 Analysis of chromosomes 3, 7, X and the EGFR gene in uterine cervical cancer progression.Marzano R, Corrado G, Merola R, Sbiroli C, Guadagni F, Vizza E, Del Nonno F, Carosi M, Galati M M, Sperduti I, Cianciulli AM Eur J Cancer 2004; 40: 1624-1629 Medline 15196550 Genomic aberrations in carcinomas of the uterine corpus.Micci F, Teixeira MR, Haugom L, Kristensen G, Abeler VM, Heim S.


Genes Chromosomes Cancer 2004; 40: 229-246 Medline 15139002 Cytogenetic and molecular genetic analyses of endometrial stromal sarcoma: nonrandom involvement of chromosome arms 6p and 7p and confirmation of JAZF1/JJAZ1 gene fusion in t(7;17).Micci F, Walter CU, Teixeira MR, Panagopoulos I, Bjerkehagen B, Saeter G, Heim S.Cancer Genet Cytogenet 2003; 144: 119-124. Medline 12850374 Molecular pathogenesis of uterine smooth muscle tumors from transcriptional profiling.Quade BJ, Wang TY, Sornberger K, Dal Cin P, Mutter GL, Morton CC. Genes Chromosomes Cancer 2004; 40: 97-108. Medline 1384681 Chromosomal amplifications,3q gain and deletions of 2q33-q37 arethe frequent genetic changes in cervical carcinomaRao PH, Arias-Pulido H, Lu XY, Harris CP, Vargas H, Zhang FF, Narayan G, Schneider A, Terry MB, Murty VV BMC Cancer 2004; 4: 5 Medline 15018632 Overrepresentation of 8q in carcinosarcomas and endometrial adenocarcinomas.Schulten HJ, Gunawan B, Enders C, Donhuijsen K, Emons G, Fuzesi L Am J Clin Pathol 2004; 122: 546-551. Medline 15487452 REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed Contributor(s)

11-2004 Roberta Vanni, Giuseppina Parodo Written

CitationThis paper should be referenced as such : Vanni R, Parodo G . Uterus Tumours: an Overview. Atlas Genet Cytogenet Oncol Haematol. November 2004 . URL : http://AtlasGeneticsOncology.org/Tumors/UterusTumOverviewID5157.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



Soft Tissue Tumors: Low grade fibromyxoid sarcoma

IdentityLow grade fibromyxoid sarcoma is a rare, low-grade malignant soft tissue neoplasm with a potential for local recurrences as well as distant metastases.

Hyalinizing spindle cell tumor with giant rosettes

Note

Other names

ClassificationLow grade fibromyxoid sarcoma belongs to the group of fibroblastic/myofibroblastic soft tissue tumors. Two main subtypes have been recognized: classical low grade fibromyxoid sarcoma and low grade fibromyxoid sarcoma with giant collagen rosettes.

Note

Clinics and PathologyDisease Low grade fibromyxoid sarcoma (LGFMS) Embryonic origin

upposed to be rare, but as it is difficult to diagnose the true incidence is unknown. Patients of any age may be affected, and the male:female ratio is 1:1. Low grade fibromyxoid sarcoma usually presents as a painless mass, typically in the proximal extremities.

Cellular origin unknown, but presumably of mesodermal derivation. Tumor cells show fibroblastic differentiation.

Etiology Unknown. No known risk factors. Epidemiology Low grade fibromyxoid sarcoma is s

Clinics

Pathology Classical cases of LGFMS display a mixture of hypocellular, collagen-rich areas and more cellular, myxoid areas. A characteristic feature is the whorling growth pattern, often seen at the transition from hypocellular to more cellular, myxoid areas. Mitotic figures are rare. A subset of LGFMS shows focal collagen rosettes.

Treatment The only consensus treatment for low grade fibromyxoid sarcoma is surgical excision.

Prognosis When radically excised, the prognosis is usually good. However, local recurrences have been reported in approximately 10% of the cases, and distant spreading occurs in 5-10% of the cases.

CytogeneticsNote In the Mitelman Database of Chromosome Aberrations in Cancer


(2004), 16 cases with clonal aberrations are included. Cytogenetics Morphological

The chromosomal translocation t(7;16)(q33;p11) is a characteristic feature. A few cases contain a supernumerary ring as the sole chromosomal abnormality. Comparative genomic hybridization allowed to assess the chromosomal origin of a supernumerary ring chromosome in one case. The analysis revealed gain of material from 7p14-pter, 7q31-q33, and 16p. FISH experiments using contigs of BAC clones were performed in two cases of low grade fibromyxoid sarcoma carrying a t(7;16) abnormality. The analysis revealed that the breakpoints were located within BAC clones RP11-388M20 (AC009088) in band 16p11.2, and RP11- 29B3 (AC022173) and RP11-377B19 (AC009263) in band 7q33; all the examined clones gave split signals on the derivative chromosomes 7 and 16. The FISH results for chromosome 7 identified a breakpoint region containing a single gene (LOC155008), which is homologous to Drosophila Bbf-2, encodes a B-ZIP transcription factor and named BBF2H7 (BBF2 human homolog on chromosome 7). The data for chromosome 16 suggested FUS as the other candidate target gene

Probes BAC clones RP11-388M20 (AC009088) and CTD-2594M1 in band 16p11.2.BAC clones RP11- 29B3 (AC022173), RP11-377B19 (AC009263) and CTD-2375H21 in band 7q33.

Genes involved and ProteinsNote

Gene Name

The t(7;16)(q33;p11) in two cases of low grade fibromyxoid sarcoma fuses the FUS gene to CREB3L2 (also named BBF2H7), a previously uncharacterized gene that is homologous to the Drosophila Bbf-2 gene. A further study of 59 low grade soft tissue tumors provided results indicating that this fusion gene is specific for LGFMS; all 12 fusion-positive cases in that series fulfilled the morphologic criteria for LGFMS, suggesting that reverse transcriptase polymerase chain reaction (RT-PCR) analysis for the detection of a FUS/CREB3L2 chimeric transcript may be a valuable tool in the differential diagnosis.

CREB3L2

Location Note Dna / Rna

7q34 Alternate symbols: BBF2H7, DKFZp586F2423, DKFZp686O19165. The entire CREB3L2 gene spans more than 120 kb genomic DNA and is composed of 12 exons. Exon 1, containing the initiation codon ATG, is the largest (454 bp), and exon 7 the smallest (59 bp). Exon 12 includes the termination TAA codon. Introns 1 and 9 are the largest (73132 bp) and smallest (281 bp), respectively. Using in silico analysis and RT-PCR methodology analysis, a 2400 bp cDNA was compiled containing a 1560 bp open reading frame by Storlazzi et al. (2003). RT-PCR analysis on cDNAs from 24 human tissues showed that CREB3L2 is expressed in most of the examined tissues. The strongest expression was found in placenta, lung, spleen and intestine, and the weakest in heart, brain, skeletal muscle, thymus, colon and leukocytes. In fetal


tissues, the weakest expression was detected in brain and heart. A splice variant, lacking exon 2, was found in placenta, spleen and fetal liver. Since northern blot analysis was not performed, the possibility of additional splice variants and the actual size of the normal CREB3L2 transcript is not determined yet. The cDNA clones with accession numbers BX649143 and BX648300 (5381 bp) indicate that the CREB3L2 mRNA might be longer than 7 kbp.

Protein

The 1560 bp open reading frame is coding for a 519 amino acid protein with an estimated molecular weight of 57 kDa. The amino acid sequence spanning residues 291-356 of the predicted human CREB3L2 protein contains a consensus B-ZIP domain highly similar to that in the CREB3L1(OASIS), CREB3L3 (CREB-H), CREB3L4 (CREB4 or AIBZIP), CREB3 (LUMAN) and Drosophila Bbf-2 transcription factors with 80, 60, 9, 56 and 71% identity, respectively. It also contains the amino acid sequence RRKKKEY that is exactly conserved among CREB, CREM, ATF1, ATF6 and CREBL1. The leucine zipper motif of BBF2H7 is similar to that in CREB-H and CREB4 (pattern L-X6-C-X6-L-X6-L-X6-L-X6-L; Fig. 5). It contains six repeats and consists of five leucines and one cysteine at the second heptad position (amino acid 328) of the leucine zipper. Downstream of the B-ZIP domain, CREB3L2 also contains a hydrophobic region, which was predicted to be an a-helical transmembrane domain (position 376-397; GTCLMVVVLCFAVAFGSFFQGY). This structural feature is also seen in the other members of the family, i.e. OASIS, CREB-H, CREB3 and CREB4.

Gene Name FUS

Location 16p11 Note Alternate symbols are: TLS, FUS1. The FUS gene is also rearranged in

myxoid liposarcoma with t(12;16)(q13;p11), which leads to its fusion with DDIT3. In acute myeloid leukaemia with t(16;21)(p11;q22) and in Ewing sarcoma with t(16;21)(p11;q22) as well, FUS is fused to the ERG gene, and in angiomatoid fibrous histiocytoma FUS is fused to ATF1.

Result of the chromosomal anomalyHybrid GeneNote Up to now, FUS/CREB3L2 chimeric transcripts were identified in 14

cases. The fusion points varied within FUS, but clustered to exons 5, 6 and 7. Small intronic insertions were also seen at the junction. In CREB3L2, all the fusion points have been found within exon 5.

Detection A detailed description of the RT-PCR protocols for analysis of FUS/CREB3L2 transcripts has been reported.


Fusion ProteinNote

The function of the FUS/CREB3L2 chimera is unknown but it is reasonable to assume that it will have similar consequences as the other FUS chimeric proteins in the cell. Thus, the B-ZIP-encoding domain of CREB3L2 comes under the control of the FUS promoter, which, in turn, may cause deregulation of genes normally controlled by CREB3L2. In addition, by fusing the B-ZIP domain of CREB3L2 to the N terminal part of FUS, the ability to dimerize with other members of the OASIS family could be affected. The FUS/CREB3L2 chimera might retain the ability, as do FUS/DDIT3 and FUS/ERG, to bind to RNA polymerase II via the N-terminal part of FUS but would lack the ability to recruit the transcription and translation factor Y-box binding protein-1 (YB-1) because of the replacement of the central and C-terminal parts of FUS by CREB3L2. Consequently, RNA splicing mediated by YB-1 also would be expected to be inhibited.

BibliographyHyalinizing spindle cell tumor with giant rosettes-a soft tissue tumor with mesenchymal and neuroendocrine features. An immunohistochemical, ultrastructural, and cytogenetic analysis.Bejarano PA, Padhya TA, Smith R, Blough R, Devitt JJ, Gluckman JL. Arch Pathol Lab Med 2000;124:1179-1184 Medline 10923080

Low grade fibromyxoid sarcoma. a further low-grade soft tissue malignancy characterized by a ring chromosome..

Medline 11106828

Mezzelani A, Sozzi G, Nessling M, Riva C, Della Torre G, Testi MA, Azzarelli A, Pierotti MA, Lichter P, Pilotti S. Cancer Genet Cytogenet 2000; 122: 144-148.

Folpe A, van den Berg E, Molenaar WM.

Low-grade fibromyxoid sarcoma and hyalinizing spindle cell tumor with giant rosettes share a common t(7;16)(q34;p11) translocation.

Medline 12960807

Low grade fibromyxoid sarcoma

World Health Organization Classification of Tumours.Pathology and Genetics of Soft Tissue and Bone Tumours.Editors: CDM Fletcher, KK Unni, F Mertens.IARC Press, Lyon 2002; pp: 104-105

Reid R, de Silva MVC, Paterson L, Ryan E, Fisher C. Am J Surg Pathol 2003; 27: 1229-1236.

Storlazzi CT, Mertens F, Nascimento A, Isaksson M, We

Fusion of the FUS and BBF2H7 genes in low grade fibromyxoid sarcoma.

jde J, Brosjo¨ O, Mandahl N,


Panagopoulos I. Hum Mol Genet 2003; 12:2349-2358. Medline 12915480 REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed

Contributor(s)12-2004

Written Ioannis Panagopoulos, Fredrik Mertens, Nils Mandahl, Clelia Tiziana Storlazzi

CitationThis paper should be referenced as such : Panagopoulos I, Mertens F, Mandahl N, Storlazzi CT . Soft Tissue Tumors: Low grade fibromyxoid sarcoma. Atlas Genet Cytogenet Oncol Haematol. December 2004 . URL : http://AtlasGeneticsOncology.org/Tumors/LowGradFibromyxSarcID5185.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology



Soft Tissue Tumors: Soft Tissue Leiomyosarcoma

IdentityNote Soft Tissue Leiomyosarcoma is a relatively rare malignant tumor. It may

be difficult to be distinguished from gastrointestinal stromal tumors and Schwann cell neoplasms. To make a correct identification of soft tissue leiomyosarcoma, immunostaining with several smooth muscle differentiation markers (actin, calponin and desmin), and negative staining results with S100 (to rule out Schwann cell neoplasm), c-kit and CD34 (to rule out gastrointestinal stromal tumors) is needed.

Clinics and PathologyClinics The annual new cases in the U.S. are over 6,000. The five year survival

rate after diagnosis is about 50%.

Phylogenetic tree of leimyosarcomas and normal smooth muscle. Expression levels of

92 cDNA sequences from table III through V were analyzed for 11 leiomyosarcoma tissues. Experiment cluster analysis was performed using Michael Eisen's cluster tool and tree view. Data input and normalization of individual experiments were performed in GeneSpringTM 4.2 before imported into cluster tool. Red indicates high expression


level, while green for low, black for no expression. The cutoff expression level for non-expressor was set at 200 arbitary units. Pathological grade (G) for each tumor is indicated, so is metastasis (r) if it is present.

Genes Soft tissue leiomyosarcoma was classified based on salient gene

expression characteristics. Three types of leiomyosarcoma were proposed: 1) "Simplification" of gene expression in leiomyosarcoma, characterized by dramatic down regulation of large number of genes; 2) "Inflammation related" gene expression, characterized by the prominent presence of lymphocyte specific genes in the analysis; and 3) "neural" gene expression, characterized by neuronal gene expression. Among these subtypes, simplification gene expression is associated with the poorest prognosis, while inflammation related one the best.

Prognosis Local recurrent tumor, positive surgical margins, >50 years age, >20 mitoses per high power field are adversely associated with survival.

BibliographyHistopathological grading of soft tissue tumours: Prognostic significance in a prospective study of 278 consecutive cases

Medline 2002420

Jensen OM, Hogh J, Ostgaard SE, Nordentoft AM, Sneppen O J of Path. 1991; 163: 19-24.

Pisters PW, Leung DH, Woodruff J, Shi W, Brennan MF

Analysis of prognostic factors in 1,041 patients with localized soft tissue sarcomas of the extremities

J Clin Oncol. 1996; 14: 1679-1689. Medline 8622088

Human Path 2003; 34: 549-558.

Gene expression analysis of human soft tissue leiomyosarcomasRen B, Yu YP, Jing L, Liu L, Michalopoulos GK, Luo JH, Rao UN

Medline 12827608

REVIEW articles

automatic search in PubMed Last year publications

automatic search in PubMed

Contributor(s)Written

12-2004 Jian-Hua Luo


CitationThis paper should be referenced as such : Luo JH . Soft Tissue Tumors: Soft Tissue Leiomyosarcoma. Atlas Genet Cytogenet Oncol Haematol. December 2004 . URL : http://AtlasGeneticsOncology.org/Tumors/SoftTisLeiomyoSarcID5122.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



Soft tissue tumors: Lipoblastoma

Classification Two forms of the tumor lesion have been described: encapsulated

circumscribed type (lipoblastoma), and a noncapsulated diffuse infiltrative type (lipoblastomatosis).

Clinics and PathologyDisease Benign uncommon soft-tissue tumor of embryonal fat.

Develops from embryonic remnants of white fat tissue.

arily occurs in young children (<3 years) prevalently male. Presents in superficial tissues of arms and legs (deeper in lipoblastomatosis), though mediastinum, retroperitoneum, trunk, head and neck may be affected. Lobulated tissue composed of immature fat cells separated by fibro-vascular septa and areas with a myxoid matrix. The lobules contain lipoblasts in different stages of differentiation, ranging from primitive, spindle-shaped cells to lipoblasts simulating mature fat cells. Differential diagnosis, particularly in older children or in diffuse lipoblastoma, include myxoid liposarcoma

Embryonic origin Epidemiology PrimClinics

Pathology

and atypical lipoma and may be based on distinct cytogenetic abnormalities. Surgical excision. These tumors have an excellent prognosis but local recurrence is possible expecially in diffuse lesions.

Treatment Prognosis


Pseudodiploid karyotype with clonal chromosomal rearrangements involving the 8q11-13 region. Gain of chromosome 8 is reported.


Detectable by metaphase and/or interphase FISH using specific PLAG1 probes.


Dual-color FISH analysis in a case of lipoblastoma with complex structural rearrangement: RP11-140I16 (PLAG1) (red) was cohybrized with RP11-299N14 (HAS2) (green). Arrow indicates PLAG1-HAS2 fusion signal on the der(8), arrowhead indicates the normal chromosome 8. The BAC clones were provided by Prof. M.Rocchi.

Probes RP11-140I16, BAC227k20, YAC164H5, RP11-299N14, YAC947h7.

Genes involved and ProteinsGene Name PLAG1 Location 8q12.1 Dna / Rna 7313 bp mRNA Protein PLAG1, (together with PLAGL1 and PLAGL2), belongs to a subfamily of

C2H2 zinc finger transcription factors that activate transcription.

Gene Name HAS2 Location 8q24.12

Gene Name COL1A2 Location 7q22.1

Result of the chromosomal anomalyHybrid GeneNote HAS2-PLAG1, COL1A2-PLAG1 Chromosomal rearrangements in tumor

tissue determine PLAG1 transcriptional up-regulation. Description The 8q12 rearrangement results in a promoter-swapping event, whereby the

PLAG1 promoter element is replaced by promoting regions from other genes,


notably hyaluronic acid synthase 2 (HAS2) or collagen 1 a 2 (COL1A2). 5' HAS2 - 3' PLAG1 fused after an 8q intrachromosomal rearrangement that determined the juxtaposition of band 8q12.1 to 8q24.1. The breakpoint of HAS2 gene is in intron 1, whereas its coding sequence starts at the first codon of exon 2. 5' COL1A2 - 3' PLAG1 has been described in one case of t(7;8)(p22;q13)

Transcript Alternative splicing variants which included or lacked PLAG1 exon 2. Fusion Protein

Description HAS2-PLAG1 and COL1A2-PLAG1 both encode a full-lenght PLAG1 protein.

BibliographyBenign lipoblastomatosis: an analysis of 35 casesChung EB, Enzinger FM. Cancer 1973; 32: 482-492. Medline 4353020 Chromosome abnormalities in two benign adipose tumors.Sandberg AA, Gibas Z, Saren E, Li FP, Limon J, Tebbi CK. Cancer Genet Cytogenet 1986; 22: 55-61. Medline 3456828 Lipoblastoma: a case with t(7;8)(q31;q13)Panarello C, Rosanda C, Morerio C, Russo I, Dallorso S, Gambini C, Ricco AS, Storlazzi T, Archidiacono N, Rocchi M. Cancer Genet Cytogenet 1998; 102: 12-14. Medline 9530333 Evidence of involvement of the PLAG1 gene in lipoblastomas.Astrom AK, D'Amore ESG, Sainati L, Panarello C, Morerio C, Mark J, Stenman G. Int J Oncol 2000; 16: 1107-1110. Medline 10811981 Evidence by spectral karyotyping that 8q11.2 is nonrandomly involved in lipoblastoma.Chen Z, Coffin CM, Scott S, Meloni-Ehrig A, Shepard R, Issa B, Forsyth DR, Sandberg AA, Brothman AR, Lowichik A. J Mol Diagn 2000; 2: 73-77. Medline 11272891 PLAG1 Fusion oncogenes in lipoblastoma.Hibbard MK, Kozakewich HP, Dal Cin P, Sciot R, Tan X, Xiao S, Fletcher J. Cancer Res 2000; 60: 4869-4872. Medline 10987300


PLAG1 alterations in lipoblastGisselsson D, Hibbard MK, Dal Cin P, Sciot R, Hsi B-L, Kozakewich HP, Fletcher JA. Am J Pathol 2001; 159: 955-962. Medline 11549588 Lipoblastoma and lipoblastomatosis: a report of two cases and review of the literature.Harrer J, Hammon G, Wagner T, Bolkenius M. Eur J Pediatr Surg 2001; 11: 342-349. (REVIEW) Medline 11719876 Atypical lipomatous tumor in a 14-year-old patient: distinction from lipoblastoma using FISH analysis.Kuhnen C, Mentzel T, Fisseler-Eckhoff A, Debiec-Rychter M, Sciot R. Virchows Arch 2002; 441: 299-302 Medline 12242528 Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: lipoma.Sandberg AA. Cancer Genet Cytogenet 2004; 150: 93-115. (REVIEW) Medline 15066317 PLAG1-HAS2 fusion in lipoblastoma with masked 8q intrachromosomal rearrangementMorerio C, Rapella A, Rosanda C, Tassano E, Gambini C, Romagnoli G, Panarello C. Cancer Genet Cytogenet 2005; 156: 183-184. Medline 15642402 REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed

Contributor(s)Cristina Morerio, Claudio Panarello Written 01-2005

CitationThis paper should be referenced as such : Morerio C, Panarello C . Soft tissue tumors: Lipoblastoma. Atlas Genet Cytogenet Oncol Haematol. January 2005 . URL : http://AtlasGeneticsOncology.org/Tumors/LipoblastomaID5155.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology



t(16;21)(p11;q22) in Ewing tumours

Clinics and PathologyDisease Ewing tumours

Note t(16;21)(p11;q22) has been found in rare cases of Ewing tumours, a paediatric neoplasm with small round-cells derived from neural crests cells usually associated with translocations involving EWSR1

Cytogenetics Ewing tumours are usually associated with a t(11;22)(q24;q12) with 5' EWSR1 - 3' FLI1 involvement, less often associated with t(21;22)(q22;q12) with 5' EWSR1 - 3' ERG involvement, rarely associated with t(2;22)(q36; q12) (5' EWSR1 - 3' FEV) or with t(17;22)(q21;q12) (5' EWSR1-3' ETV4)

Prognosis recent treatments have improved the prognosis of Ewing's tumours. The prognosis is mainly determined by the presence of metastases at the time of diagnosis

Disease de novo acute non lymphocytic leukemia (ANLL); to be noted is one case of chronic myelogenous leukemia (CML) -blast crisis.

Phenotype / cell stem origin

ANLL cases: mainly M1, M2, M4, M5a, M5b, or M7 ANLL; may be preceded by a myelodysplastic syndrome (MDS).

ound in young adults; children cases are described; median age is about 30 yrs; balanced sex ratio

Clinics

Epidemiology about 40 reported cases, mainly f

blood data: anemia, thrombocytopenia, mild hyperleucocytosis; with high monocytic cell count at times

Cytology myelocytic and monocytoid features are often present; eosinophils in the bone marrow are sometimes abnormal and/or elevated; erythrophagocytosis may be found

Prognosis seems poor: complete remission may not be achieved; there is high incidence of relapse within a year and a median of survival is about 22 months (cases herein reviewed)

CytogeneticsCytogenetics Molecular

ANLL cases: found solely in about 60% of cases in at least a subclone; associated with +10, +8, or de(9q)/-9 in about 10% of cases each

Genes involved and Proteins


Gene Name FUS

Protein

Location 16p11 RNA binding protein; member of the TET family, like EWSR1

Gene Name ERG

21q22

Location Protein ETS transcription factor

Result of the chromosomal anomalyHybrid GeneDescription

5' FUS including exons 1 to 6, 7 or 8 - 3' ERG from exon 7, 8 or 9 to C-term.

Fusion ProteinDescription N-term FUS transactivation domain fused to the C-term DNA binding

ETS domain of ERG Oncogenesis seems to act as a transcriptional activator

BibliographyAcute nonlymphoblastic leukemia with bone marrow eosinophilia and structural anomaly of chromosome 16.Mecucci C, Bosly A, Michaux JL, Broeckaert-Van Orshoven A, Van den Berghe H Cancer Genet Cytogenet. 1985; 17: 359-363. Medline 85254357 Translocation (8;21) and its variants in acute nonlymphocytic leukemia. The relative importance of chromosomes 8 and 21 to the genesis of the disease.Minamihisamatsu M, Ishihara T. Cancer Genet Cytogenet. 1988; 33: 161-173. Medline 3164243 Acute nonlymphocytic leukemia with t(16;21)Berkowicz M, Rosner E, Resnitzky P, Mamon Z, Ben-Bassat I, Ramot B Cancer Genet Cytogenet. 1990; 47: 139-140 Medline 2357684 16;21 translocation in acute nonlymphocytic leukemia with abnormal eosinophils: a unique subtype.


Sadamori N, Yao E, Tagawa M, Nakamura H, Sasagawa I, Itoyama T, Tokunaga S, Ichimaru M, Nakamura I, Kamei T, et al. Acta Haematol. 1990; 84: 212-216. Medline 2125791 Translocation (16;21)(p11;q22) in acute monoblastic leukemia with erythrophagocytosis.Marosi C, Bettelheim P, Geissler K, Lechner K, Koller U, Haas OA, Chott A, Hagemeijer A. Cancer Genet Cytogenet. 1991; 54: 61-66. Medline 2065316 t(16;21)(p11.2;q22): a recurrent primary rearrangement in ANLL.Morgan R, Riske CB, Meloni A, Ries CA, Johnson CH, Lemons RS, Sandberg AA. Cancer Genet Cytogenet. 1991; 53: 83-90. Medline 2036642 t(16;21) in a Ph positive CML.Ferro MR, Cabello P, Garcia-Sagredo JM, Resino M, San Roman C, Larana JG. Cancer Genet Cytogenet. 1992; 60:210-211. No abstract available. Medline 1606569 The 8;21 chromosome translocation in acute myeloid leukemia is always detectable by molecular analysis using AML1.Maseki N, Miyoshi H, Shimizu K, Homma C, Ohki M, Sakurai M, Kaneko Y. Blood. 1993; 81: 1573-1579. Medline 8453103 Acute non-lymphocytic leukemia with t(16;21).Nobbs MC, Chan-Lam D, Howell RT, Kitchen C, Copplestone JA. Cancer Genet Cytogenet. 1993 ;70: 144-145. Review. Medline 8242597 Translocation (16;21)(p11;q22) in acute nonlymphocytic leukemia.Okada K, Takeichi M, Uchida H, Shirota T, Sakai N, Ito H. Cancer Genet Cytogenet. 1994; 75: 60-63. Medline 8039166 Fusion of the FUS gene with ERG in acute myeloid leukemia with t(16;21)(p11;q22).Panagopoulos I, Aman P, Fioretos T, Hoglund M, Johansson B, Mandahl N, Heim S, Behrendtz M, Mitelman F. Genes Chromosomes Cancer. 1994; 11: 256-262. Medline 7533529 [Acute monoblastic leukemia (M5a) with dysmegakaryocytopoiesis associated


with t(16;21) (p11;q22)]Satoh K, Miura I, Chubachi A, Ohtani H, Hirokawa M, Niitsu H, Miura AB. Rinsho Ketsueki. 1994; 35: 160-164. Review. Japanese. Medline 8139114 HLA-DR-, CD33+, CD56+, CD16- myeloid/natural killer cell acute leukemia: a previously unrecognized form of acute leukemia potentially misdiagnosed as French-American-British acute myeloid leukemia-M3Scott AA, Head DR, Kopecky KJ, Appelbaum FR, Theil KS, Grever MR, Chen IM, Whittaker MH, Griffith BB, Licht JD, et al.. Blood. 1994; 84: 244-255. Medline 7517211 Acute non-lymphoblastic leukaemia with t(16;21): case report with a review of the literature.Hiyoshi M, Koh KR, Yamane T, Tatsumi N Clin Lab Haematol 1995; 17: 243-246. Medline 96318536 Establishment and characterization of IRTA17 and IRTA21, two novel acute non-lymphocytic leukaemia cell lines with t(16;21) translocation.Hiyoshi M, Yamane T, Hirai M, Tagawa S, Hattori H, Nakao Y, Yasui Y, Koh KR, Hino M, Tatsumi N. Br J Haematol. 1995; 90: 417-424. Medline 7794765 Detection of minimal residual disease in cerebro-spinal fluid of a patient with acute myelogenous leukemia with t(16;21)(p11;q22) translocation by reverse transcriptase-polymerase chain reaction.Harigae H, Kobayashi M, Mihara A, Watanabe N. Tohoku J Exp Med. 1997; 183: 297-302. Medline 9549830 Consistent detection of TLS/FUS-ERG chimeric transcripts in acute myeloid leukemia with t(16;21)(p11;q22) and identification of a novel transcript.Kong XT, Ida K, Ichikawa H, Shimizu K, Ohki M, Maseki N, Kaneko Y, Sako M, Kobayashi Y, Tojou A, Miura I, Kakuda H, Funabiki T, Horibe K, Hamaguchi H, Akiyama Y, Bessho F, Yanagisawa M, Hayashi Y. Blood. 1997; 90: 1192-1199. Medline 9242552 Cytogenetic analysis of de novo acute myeloid leukemia with trilineage myelodysplasia in comparison with myelodysplastic syndrome evolving to acute myeloid leukemia.Tamura S, Takemoto Y, Hashimoto-Tamaoki T, Mimura K, Sugahara Y, Senoh J, Furuyama JI, Kakishita E. Int J Oncol. 1998; 12: 1259-1262.


Medline 9592183 Hemophagocytosis by leukemic blasts in a case of acute megakaryoblastic leukemia with t(16;21)(p11;q22).Imashuku S, Hibi S, Kuriyama K, Todo S. Int J Hematol. 1999; 70: 36-39. Medline 10446493 Chromosomal abnormalities in 478 children with acute myeloid leukemia: clinical characteristics and treatment outcome in a cooperative pediatric oncology group study-POG 8821.Raimondi SC, Chang MN, Ravindranath Y, Behm FG, Gresik MV, Steuber CP, Weinstein HJ, Carroll AJ. Blood. 1999; 94: 3707-3716. Medline 10572083 Myeloid differentiation antigen and cytokine receptor expression on acute myelocytic leukaemia cells with t(16;21)(p11;q22): frequent expression of CD56 and interleukin-2 receptor alpha chain.Shikami M, Miwa H, Nishii K, Takahashi T, Shiku H, Tsutani H, Oka K, Hamaguchi H, Kyo T, Tanaka K, Kamada N, Kita K. Br J Haematol. 1999; 105: 711-719. Medline 10354136 Acute myeloid leukemia possessing jumping translocation is related to highly elevated levels of EAT/mcl-1, a Bcl-2 related gene with anti-apoptotic functions.Okita H, Umezawa A, Fukuma M, Ando T, Urano F, Sano M, Nakata Y, Mori T, Hata J. Leuk Res. 2000; 24: 73-77. Medline 10634649 Cytogenetic profile of childhood and adult megakaryoblastic leukemia (M7): a study of the Groupe Francais de Cytogenetique Hematologique (GFCH).Dastugue N, Lafage-Pochitaloff M, Pages MP, Radford I, Bastard C, Talmant P, Mozziconacci MJ, Leonard C, Bilhou-Nabera C, Cabrol C, Capodano AM, Cornillet-Lefebvre P, Lessard M, Mugneret F, Perot C, Taviaux S, Fenneteaux O, Duchayne E, Berger R; Groupe Francais d'Hematologie Cellulaire. Blood. 2002; 100: 618-626. Medline 12091356 FUS/ERG gene fusions in Ewing's tumors.Shing DC, McMullan DJ, Roberts P, Smith K, Chin SF, Nicholson J, Tillman RM, Ramani P, Cullinane C, Coleman N. Cancer Res. 2003; 63: 4568-4576. Medline 12907633 Breakpoint differentiation in chromosomal aberrations of hematological


malignancies: Identification of 33 previously unrecorded breakpoints.Heller A, Loncarevic IF, Glaser M, Gebhart E, Trautmann U, Claussen U, Liehr T. Int J Oncol. 2004; 24: 127-136. Medline 14654949 REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed


1998 Christine Pérot

Updated 01-2005 Jean Loup Huret

CitationThis paper should be referenced as such : Pérot C . t(16;21)(p11;q22). Atlas Genet Cytogenet Oncol Haematol. February 1998 .URL : http://AtlasGeneticsOncology.org/Tumors/t1621p11q22EwingID5329.html Huret JL . t(16;21)(p11;q22). Atlas Genet Cytogenet Oncol Haematol. January 2005 . URL : http://AtlasGeneticsOncology.org/Tumors/t1621p11q22EwingID5329.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



LEOPARD syndrome

IdentityNote LEOPARD syndrome is characterized by multiple lentigines, cardiac

anomalies, facial dysmorphisms, abnormalities of the genitalia in males, retardation of growth, and deafness. LEOPARD syndrome shares many features with Noonan syndrome, in which lentigines and deafness usually are not present. Molecular studies have demonstrated that LEOPARD and Noonan syndromes are allelic conditions.

Multiple-lentigines syndrome

cardiocutaneous syndrome

LEOPARD syndrome is an autosomal dominant multiple congenital anomaly syndrome, with high penetrance and markedly variable expression.

Other names

generalized lentiginosis

progressive cardiomyopathic lentiginosis Inheritance

ClinicsPhenotype and clinics

� Deafness is generally sensorineural, may be unilateral, but can be profound. Most cases have deafness diagnosed in childhood, but some are reported to have developed it in adult life.

The main clinical features of LEOPARD syndrome are multiple lentigines, congenital heart defect or electrocardiographic abnormalities, deafness, facial anomalies, urogenital malformations, skeletal anomalies, retardation of growth, and learning difficulties. � Diffuse lentiginosis is a characteristic of LEOPARD syndrome. Lentigines are brown macules, usually 2 to 8 mm in diameter, generally most heavily concentrated on the upper part of the trunk and neck, although they can also be present on the face, limbs, palms, soles and genitalia. The mucosae are characteristically spared. Lentigines are rarely present at birth and, classically, develop during childhood, increasing in number until puberty and darkening with age. Cafe-au lait patches as well as axillary freckling have also been described. � Structural cardiac defects can be detected in 70% of the patients. Hypertrophic cardiomyopathy is the most common defect. It is progressive and commonly involves the intraventricular septum. Pulmonary valve stenosis with valve leaflet dysplasia, partial atrioventricular canal and mitral valve anomalies can also be present. Arrhythmias include heart block, bundle branch block, and hemiblock.

� Facial anomalies include hypertelorism, palpebral ptosis, and large low-set ears. They occur in 90% of the patients. � A high prevalence of genitourinary abnormalities has been reported


especially in male patients. These include cryptorchidism, hypospadias, as well as malformations of the kidneys and collecting systems.

� Growth retardation is frequent. The adult height is generally below the 25th centile.

� Pectus carinatum or excavatum are detectable. In old age, there is a tendency to develop thoracic kyphosis.

� Mild mental retardation and learning difficulties, so as language defects related to deafness, can occur in patients with LEOPARD syndrome.

Legend: Typical multiple lentigines in a patient with LEOPARD syndrome Neoplastic risk

A distinct class of somatic mutations of PTPN11, appearing to have high gain-of-function levels, contributes to leukemogenesis. The identification of these mutations at a germinal level explains the higher prevalence of myeloproliferative disorders and acute leukemia among children with Noonan or LEOPARD syndrome. The RAS/MAPK pathway is deregulated in juvenile myelomonocytic leukemia due to mutations in NRAS, KRAS2 or NF1. It has be hypothesized that germline or somatic mutations in PTPN11 could also interfere with RAS/MAPK pathway. Multiple granular cell myoblastomas, a tumor believed to arise from Schwann cells, have been reported in one patient. Central giant cell granulomas presenting as cyst-like lesions in the mandible have also been described in LEOPARD syndrome. Choristoma, a congenital corneal tumor containing cellular elements of ectodermal derivatives, may occasionally coexist with LEOPARD syndrome.

Treatment beta-blockade or calcium channel blockers are most frequently used in treatment of obstructive cardiomyopathy. If there is no response to drug therapy, surgery for left ventricular outflow obstruction or transplantation can be indicated.


The use of lasers has been shown to be effective in the treatment of lentigines. Noninvasive agents such as tretinoin cream and hydroquinone cream used in combination have been shown to lighten lentigines after several months of application.

Prognosis The prognosis is mainly determined by the nature and severity of cardiac lesions. In fact, the major concern is that of hypertrophic cardiomyopathy, because of its association with arrhythmia and sudden death.

CytogeneticsNote Chromosome analysis is normal in patients with LEOPARD syndrome.

Genes involved and Proteins Gene Name PTPN11

Location

Function

LEOPARD syndrome has proved to be allelic to Noonan syndrome, with two recurrent PTPN11 mutations in exons 7 (Tyr279Cys) and 12 (Thr468Met). Additional mutations in exons 7, 12, and 13, different from the two common mutation hot spots, have been reported as a rare occurrence in the syndrome. All the mutations occur in exons that code for the protein tyrosine phosphatase (PTP) domain. Molecular and biochemical studies have shown that the mutations destabilize the catalytically inactive conformation of the protein, resulting in a gain of function. PTPN11 mutations are detectable in about 90% of patients with LEOPARD syndrome.

12q24.1 DNA/RNADescription It contains two Srd homology 2 (SH2) domains and a protein tyrosine

phosphatase domain (PTP); 15 exons. ProteinDescription 593 amino acids, 68 kD Expression highly expressed in human tissues, particularly abundant in heart, brain,

and skeletal muscle The protein-tyrosine phosphatases are a highly polymorphic set of molecules having a role in regulating the responses of eukaryotic cells to extracellular signals. They achieve this by regulating the phosphotyrosine content of specific intracellular proteins. The pathogenetic mechanism that cause PTPN11 mutations to specifically exhibit a dermatological phenotype and preferentially cardiac expresssion in hypertrophic cardiomyopathy is at present unclear.

MutationsGerminal

Bibliography


Multiple lentigines syndrome.Gorlin RJ, Anderson RC, Blaw M. Am J Dis Child 1969; 117: 652-662. Lentiginosis profusa syndrome (multiple lentigines syndrome).Selmanowitz VJ, Orentreich N, Felsenstein JM. Arch Dermatol 1971; 104: 393-401. Medline 5000391 The heart in lentiginosis.Somerville J, Bonham-Carter RE. Br Heart J. 1972; 34: 58-66. Medline 4258224 Multiple lentigines syndrome: Case report and review of the literature.Voron DA, Hatfield H, Kalkhoff RK. Am J Med 1976; 60: 447-456. Medline 1258892 Multiple lentigines syndrome (LEOPARD syndrome or progressive cardiomyopathic lentiginosis).Coppin BD, Temple IK. J Med Genet 1997; 34: 582-586. Medline 9222968 Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene.Digilio MC, Conti E, Sarkozy A, Mingarelli R, Dottorini T, Marino B, Pizzuti A, Dallapiccola B. Am J Hum Genet 2002; 71: 389-394. Medline 12058348 PTPN11 mutations in LEOPARD syndrome.Legius E, Schrander-Stumpel C, Schollen E, Pulles-Heintzberger C, Gewillig M, Fryns J-P. J Med Genet 2002; 39: 571-574. Medline 12161596 LEOPARD syndrome with a new association of congenital corneal tumor, choristoma.Choi W-W, Yoo J-P, Park K-C, Kim K-H. Pediatr Dermatol 2003;20:158-160. Medline 12657016 Correlation between PTPN11 gene mutations and congenital heart defects in Noonan and LEOPARD syndromes.


Sarkozy A, Conti E, Seripa D, Digilio MC, Grifone N, Tandoi C, Fazio VM, Di Ciommo V, Marino B, Pizzuti A, Dallapiccola B. J Med Genet 2003; 40: 704-708. Medline 12960218 Somatic mutations in PTPTN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia.Tartaglia M, Niemeyer CM, Fragale A, Song X, Buechner J, Jung A, Hahlen K, Hasle H, Licht JD, Gelb BD. Nat Genet 2003; 34: 148-150. Medline 12717436 Familial aggregation of genetically heterogeneous hypertrophic cardiomyopathy: a boy with LEOPARD syndrome due to PTPN11 mutation and his nonsyndromic father lacking PTPN11 mutations.Digilio MC, Pacileo G, Sarkozy A, Limongelli G, Conti E, Cerrato F, Marino B, Pizzuti A, Calabrò R, Dallapiccola B. Bith Defects Res A Clin Mol Teratol 2004;70:95-98. Medline 14991917

J Med Genet 2004; 41: e117.

PTPN11 mutations in patients with LEOPARD syndrome: A French multicentric experience.Keren B, Hadchouel A, Saba S, Sznajer Y, Bonneau D, Leheup B, Boute O, Gaillard D, Lacombe D, Layet V, Marlin S, Martier G, Toutain A, Beylot C, Baumann C, Verloes A, Cavé H, for the French Collaborative Noonan Study Group.

Medline 15520399

Clinical and molecular analysis of 30 patients with multiple lentigines LEOPARD syndrome.

J Med Genet 2004; 41: e68. Medline 15121796

Sarkozy A, Conti E, Digilio MC, Marino B, Morini E, Pacileo G, Wilson M, Calabrò R, Pizzuti A, Dallapiccola B.

A novel PTPN11 gene mutation bridges Noonan syndrome, multiple lentigines / LEOPARD syndrome and Noonan-like/multiple giant cell lesion syndrome.

Eur J Hum Genet 2004; 12: 1069-1072. Medline 15470362

Sarkozy A, Obregon MG, Conti E, Esposito G, Mingarelli R, Pizzuti A, Dallapiccola B.

Blood 2004; 104: 307-313.

Genetic evidence for lineage-related and differentiation stage-related contribution to somatic PTPN11 mutations to leukemogenesis in childhood acute leukemia.Tartaglia M, Martinelli S, Cazzaniga G, Cordeddu V, Iavarone I, Spinelli M, Palmi C, Carta C, Pession A, Arico M, Masera G, Basso G, Sorcini M, Gelb BD, Biondi A.


Medline 14982869 REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed Contributor(s)Written Maria Cristina Digilio 12-

2004

CitationThis paper should be referenced as such : Digilio MC . LEOPARD syndrome. Atlas Genet Cytogenet Oncol Haematol. December 2004 . URL : http://AtlasGeneticsOncology.org/Kprones/LeopardID10084.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



Some lessons from uniparental disomy (UDP) in the framework of comtemporary cytogenetics and molecular biology.

This is an ambitious title to deal with. Of course, UPD refers to the accidental presence of a chromosome pair or a chomosome segment derived from only one parent in a diploid individual. In fact, the information on this subject has grown so large that Pub Med, the webb-site of the US National Library of Medecine, by now lists over 550 original titles not to mention the so-call related articles. In the bulk of this material. I particulary like to stress the elegant contributions from Prs Lidia Larizza, Orsette Zuffardi and their colleagues on the role of parental chromosome 15 inversions in subsequent segmental deletions of that chromosome and their study of UBE3A mutations in AS. I also want to mention the wealth of information and observations that we owe to Pr A Schinzel and his group and to Dr Dietrich Kotzot in this area. Lidia, Albert, I thank you whole-heartedly, as well as the Organizing Committee and Dr Konstantin Miller for inviting me to address the Audience of this select ECA Meeting in Bologna. Thank you, indeed for your hospitality.


Slide 1

I thus started in the field at this most exciting period wich I call the Golden Years. Within two of these years, 1959 and 1960, the three major autosomal trisomies, G, E, and D, namely 21, 18 and 13 turned up along with three of the four more common sex chromosome anomalies. XXY, XXX, XO (the XYY would appear later), plus the first example of human chromosome mosaicism.


We all known the prestigious names of the Scientists listed here, wich include two illustrious pionneers of this Country, Marco Fraccaro and Paul Polani. These achievements had been acquired at the cost of great efforts, particulary with respect to the cultures of the solid tissues or marrow samples, needed to offer the sight of our chromosomes. Slide 2

EASIER CELL CULTURE PREPARATIONS :

Moorehead PS, Nowell PC, Mellman WJ, Batipps DM and Hungerford :

Chromosome preparations of leukocytes cultured from human peripheral blood

Exp Cell Research 1960, 20, 613In this context, the opportunity of using a few drops of venous blood for short term culture and chromosome studies with Phytohemagglutinin for blast tranformation of monolymphocytes represented a boon to all interested personnel. 1960 is precisely the time when I joined the MGH in Boston and began setting up there a Cytogenetic laboratory. Slide 3

Other notable discoveries occurred in the sixties in our field, including the sighting of some tiny deletions, but, just as happened in the early years of photography, the chromosomes appeared uniformely dark over a clear white background. This is not to say that we could not see very interesting details such as they dislpayed here, with the Ph1 chromosome, a dicentric 17-18 E chromosome and a D/D translocation - the later congenital - in this example of the clonal pattern of a leukemic cell at the blast phase of CML.

Slide 4


SPECIFIC CHROMOSOME IDENTIFICATION

(ANALYTICAL BANDING)

Casperson T, Zech L, Johansson C, Modest EJ.

Identification of human chromosomes by DNA-binding fluorescent agents.

Chromosoma. 1970 30:215-27.

Couturier J, Dutrillaux B, Lejeune J.

Specific fluorescence of R and G bands in human chromosomes.

CR Acad Sci 1973 276:339-342

As I just said earlier, the specfic identification, as of 1969-1970 of individual chromosomes by fluorochromes pionnered thanks to Caperson, Zech et al. and also obtained by other banding procedures devised by Seabright, Dutrillaux and other major contributors changed the whole ball game. And, it is under the benefit of so much technical sophistication that I shall now quickly review the cytogenetic results gained from the systematic studies of the product of first trimester spontaneous abortions. They all pointed to the high rate of gamete aneuploidy, as a fact of observation which served as the basic of the UPD concept and suggested the fairly simple idea that, sometimes, somehow a diploid individual might be conceived or could develop, with one of the 23 chromosome pairs from one single parent. Slide 5

AVORTEMENTS ANEUPLOÏDES DU PREMIER TRIMESTRE °

50 % DU TOTAL : 1/2 TRISOMIE AUTOSOMALE

1/5 MONOSOMIE X

1/3 POLYPLOÏDIE

HASSOLD T.J. & AL ANN. HUM. GENET. (Lond.) 41, 443-454, 1978.


We had come to learn that one half or so of these aborted fetuses showed major chromosome anomalies, half of them as a trisomy, one fifth as an X-monosomy and one third as a polyploidy, mostly triploidies.

Slide 6

PRINCIPALES TRISOMIES DES AVORTEMENTS ANEUPLOÏDES DU PREMIER

TRIMESTRE °

47, +16 32 %47, +21 13 %47, +15 10 % 47, +22 13 %

° CREASY M.R. & AL. : HUM. GENET. 31. 177-196. 1976.

And, among the trisomies, four of them largely prevailed, namely trisomy 16 in one third of the cases, and trisomies 21, 22 and 15, each accounting for about 10 % of the lot, thus making up altogether some two thirds of the trisomies observed in these abortuses.

And since, as a rule, meiotic mis-segregation must result in as many nullisomie as disomic gametes, it did not seem to me too far-fetched an idea to statistically envisage the following possibility, namely that coincidental fertilization and complementation of a nullisomic gamete by one disomic for a same chromosome might indeed occur, thus occasionally causing a diploid conceptus to derive one pair from only one parent.

Slide 7


Thus, on the basis of the figures documented for the rate of aneuploidy limited to these four autosomes and the X and making some asumptions wich I shall not her develop, it looked as follows :

for a toll of 20 % abortions of all conceptuses, one half of which were aneuploid, complementation at fertilization for these 5 member chromosomes causing UPD for one of these pairs might occur with the incidences reported here.

In brief, on those premisses, one might envisage 2 or 3 cases of putative UPD for one or the other of these 5 members every 10,000 births and even more when considering an abortion frequency of 50 % !

Slide 8

PUTATIVE CONSEQUENCES OF UNIPARENTAL DISOMY (as considered in 1979)

The birth of Mendelian non traditional inheritance

1) Homozygous traits inheritable from one carrier parent only

2) Father to son exceptional transmission of an X-linked trait

3) Xg(a-) daughters born to Xg(a+) legitimate fathers

4) Affected daughters born to recessiv


X-linked carrier mothers

5) Duplication of chromosomal markers - morphological or molecular - present in only one parent

If that were to happen what might be the occasionnal consequences of deriving one chromosome from one parent only?

Slide 9

American Journal of Medical Genetics 6: 137-143 (1980)

A New Genetic Concept: Uniparental Disomy and Its Potential Effect, Isodisomy Eric Engel

Institute of Medical Genetics, Geneva University School of Medicine, Geneva, Switzerland

In recent years, cytogenetic studies of spontaneous abortion products have disclosed a relatively high frequency of aneuploid embryos. These karyotypic anomalies chiefly stem from meiotic errors affecting the distribution of the chromosomes in one of two gametes. This information not only implies the remarkable frequency of gonocyte aneuploidy but also reveals the pre


And thus, after many months of cogitation, I came to spend one night, from a saturday to a sunday, to put down a draft of this idea in writing.

Slide 10

Once in print and published, the idea slept in the medical literature for some years because, at the time of the publication,1980, the means to trace the parental origin of a chromosome were still limited, awaiting the analyses of DNA polymorphisms as schematically shown here.

Given the four constrated alleles of a particular locus in two parents, each one can be traced through appropriate enzyme restriction, gel electrophoresis and adequate marking.

Slide 11

In this diagram from our book, individual 3 has an allele from each parent, as normal and individuals 4 and 5 have only paternal alleles, two contrasted ones for individual 4i.e. heterodisomy and two identical ones for offspring No. 5, the so-called isodisomy. Also it is of note that if this duplicated allele was that of a recessive trait, the individual would be affected.


Am. J. hum. Genet. 42: 215-216, 1988

Editorial : Uniparental Disomy: A Rare Consequence of the High Rate of Aneuploidy in Human Gametes

Dorothy Warburton Department of Genetics and development of Pediatrics, Columbia University. New York

Am. J. hum. Genet. 42: 217-225, 1988

Uniparental Disomy as Mechanism for Human Genetic Disease

J. Edward Spence, Ronald G. Perciccante, Guillian M. Greig. Huntington F. Willard. David H. Ledbetter. J. Fielding Hejtmancik, Marilyn S. Pollack, William E. O'Brien and Arthur L. Baudet Howard Hughes Medical Institute, Institute of Molecular Genetics and Department of Microbiology and Immunology, Baylor College of Medicine, Houston: Mercy Hospital, Watertown, NY: and Department of Medical Genetics, University of Toronto, Toronto

And this is precisely the mechanism which helped these investigators to uncover the first thoroughly analyzed and described case of UPD. It was one involving maternal chromosome 7, responsible for cystic fibrosis in an unusually short girl who carried Gly542Ter mutation in her CFTR gene.

This article, of Beaudet¹s lab, with Ledbetter among the Authors and Spence as the Senior Author, was not only featuring the first case ever sighted of non-traditional recessive inheritance through reduction to homozygosity of the recessive mutant only carried by one of the two parents. It also offered a most comprehensive review of the possible mechanisms leading to the occurrence of UDP.

Interestingly enough the journal Science rejected this report, apparently for describing a situation too exceptional for a broad readership; and, while accepted for publication by the American Journal of Human Genetic, the accompanying editorial almost echoed the very reasons why the other major publications had turned down the article.


Slides 12

UNIPARENTAL ISODISOMY REDUCTION TO HOMOZYGOSITY LEADING TO RECESSIVE

DISORDERS (1)

Recessive Disorders UDP type References

Pycnodysostosis 1 pat Gelb et al. (1998) Junctional epidermolysis bullosa, Herlitz type 1 mat Pulkkinen et al. (1997)

Spinal muscular atrophy III (juvenil type) 5 pat Brzustowicz et al; (1994)

Complement deficiency of C4A+C4B 6 pat Welch et al. (1990) Methylmalonic acidemia 6 pat Abramowicz et al. (1994)

Cystic fibrosis 7 mat Spence et al. (1988), Voss et al. (1989)

Osteogenesis imperfecta (COL1A2 mutation) 7 mat Spotila et al. (1992)

Cystic fibrosis and Kartagener syndrome 7 pat Pan et al. (1998)

Congenital chloride diarrhea 7 pat Hôglund et al. (1994) Chylomicronemia, familial 8 pat Benlian et al. (1996) Cartilage / hair hypoplasia 9 mat Sulisalo et al. (1997) Beta-thalassemia major 11 pat Beldjord et al. (1992) Complete congenital achromatopsia (rod monochr.) 14 mat Pentao et al. (1992)

Bloom syndrome (with Prader-Willi syndrome) 15 mat Woodage et al. (1994)

Hydrops fetalis alpha-thalassemia 16 pat N'go et al. (1993) Duchenne muscular dystrophy X mat Quan et al. (1994) Hemophilia A XY Vidaud et al. (1989)

EE (2/10/1998)

UNIPARENTAL ISODISOMY REDUCTION TO HOMOZYGOSITY LEADING TO RECESSIVE

CONDITION (part 2) 1999-2003

CONDITION UDP type AUTHORSHIP

Chediak-Higashi Syndrome 1 mat Dufourcq-Lagelouse et al 1999 Mapple Syrup Disease Type II 1 mat Lebo et al 2000


Congenital insensivity to pain, anhydrosis (CIPA) 1 pat Miura et al 2000

Herlitz junctional epidermolysis bullosa 1 pat Takizawa et al 2000

Mosaicism Rh+/Rh- 1 pat Miyoshi et al 2001 CIPA+Pyruvate kinase receptor deficiency 1 pat Indo et al 2001

Leber congenital amaurosis 1 pat Thomson et al 2002 Retinis, Usher type II 1 pat Rivolta et al 2002 Lactic acidosis (trifunctionnal protein deficiency) 2 mat Spiekerkoetter et al 2002

Idem idem idem Pseudohermaphroditism (5-alpha reductase deficiency) 2 pat Chavez et al 2000

Retinis pigmentosa (MERKT) 2 pat Thompson et al 2002 A-betalipoproteinemia 4 mat Yang et al 1999 21-Hydroxylase deficiency 6 pat Lopez-Guttierez et al 1998 Cystic fibrosis 7 mat Hehr et al 2000 Leigh syndrome 9 mat Tiranti et al 1999

EE july 2003

It is precisely at this junction that I would like to review the list of some thirty or so different recessive conditions traced to this very mechanism over the last 14 years. Some of these have indeed been observed more than once.

Slide 13


In some studies, particularly the first ones listed here, one can get some idea of the condition of reduction to homozygosity to recessive traits as compared to that of classical biparental recessive inheritance which ranges from up to 2 to 4 % in the series with more than 50 cases tested.

And, it is as much as I shall now devote to this aspect of non-traditional inheritance in UPD.

Slide 14

Nature 1989. 342: 281-5

Genetic imprinting suggested by maternal heterodisomy in nondeletion Prader-Willi syndrome.

Nicholls RD, Knoll JH, Butler MG, Karam S, Lalande M.

Howard Hughes Medical Institute; Havard Madical School, Boston, Massachusetts.

I now turn to another major player in the field of UPD, brought into action by Rob Nicholls et al, the phenomenon of genomic imprinting.

Slide 15


But, to bring that up, let me first refer to the well know and significant observation of a tiny 15q11q13 deletion in the Prader-Willi syndrome, by David Ledbetter and colleagues in 1981.

It did take wonderful eyes to detect such a small, albeit most important cytogenetics detail!

Slide 16


It was Rob Nicholls and colleagues¹ merit to establish that in the rarer cases of PWS without the tiny deletion, a chromosome pair 15 looked pink, painted exclusively of maternally segregating alleles and markers (!!). Thus, in these instances, these rarer cases showed maternal UPD 15, along with the lack of a paternal chromosome 15.

The obvious lesson to it was that an intact second maternal 15 could not substitute successfully for the missing paternal one. Therefore, in this instance, although normal looking, the second maternal chromosome 15 was lacking the genetic expression of a proper paternal one. Why was it so ? Indeed this very observation was to serve at the introduction of a still poorly understood phenomenon, genomic imprinting.

Slide 17

Definition : Genomic Imprinting

the epigenetic modification of certain genes through


methylation as a function of their parental origin

>> an "imprinted" gene is often considered to be an inactived gene

>> the result is functional hemizygosity (maternal or paternal) for some allelic pairs

>> imprint "relaxation" normally occurs early in gametogenesis

We can see on it a fairly simple reminder of the definition of genomic imprinting.

Slide 18

With time and patience, it was recognized that the imprinting disruption caused by the possession of a UPD pair could intervene as a cause of some previously known syndrome as well as a help in delineating some new ones.

UPDs, maternal or paternal, for chromosomes 6, 7, 11 and 15 have occured in a variable proportion of the listed syndromes, while both maternal and paternal UPD 14 each delineated a new syndrome.


Three other pairs came under suspicion of exercising harmful effects through a similar mechanism, although such an interference appears less and less certain for maternal chromosome 2, still quite likely for maternal chromosome 16 and definite for chromosome 20, both paternal and maternal, a topic in full evolution.

Slide 19

CHROMOSOME 20 "MICRO - IMPRINTING"

GNAS1 (GUANINE NUCLEOTIDE BINDING PROTEIN) 1

MAPS AT 20q13.3 MATERNALLY EXPRESSED (PATERNALLY INACTIVE) ENCODES ALPHA-SUBUNIT OF STIMULATORY G PROTEIN (Gsb) NEEDED FOR RECEPTOR STIMULATED cAMP GENERATION LOSS CAUSES RESISTANCE TO PTH

NNA1 (NEURONATIN) 2 MAPS AT 20q11.2 PATERNALLY EXPRESSED (MATERNALLY INACTIVE) ENCODED DEDUCED PROTEIN IS A PROTEOLIPID IMPORTANT ROLE IN EMBRYO-FETAL NERVOUS SYSTEM DEVELOPEMENT

1) LIU et al 2000 2) EVANS HK et al 2001

Both paternal and maternal chromosome 20 show an imprinting mark, which, on the maternal side, allows sensitivity to parathormone and, on the paternal side, expresses a protein essential for embryofetal neurologic development.

Slide 20


This slide shows what proportion of some well defined syndromes might be caused by a given uniparental pair proven responsible for disrupting the normal imprinting process.

Slide 21

The figures on slide 21 lend support to some extrapolation to evaluate the baseline frequency of a few of the viable UPDs involved as a cause disease.

Thus, if the PWS phenotype is in general viable and knows a clinical frequency of 1 in 20,000 live births, and if maternal UPD 15 serves as an etiology for some 25 % of these cases, one may infer that maternal UPD 15 occurs around once every 80,000 live births. And so on for several other UPDs causing a proportion of syndromic conditions of reasonably well documented overall frequencies.


Slide 22

So far we have in this lecture followed two leads, one looking at the UPDs recognized as the cause of recessive traits, the other as a cause of malformations through the normal process of genomic imprinting.

At this junction, in guise of more systematic approach, we can review, as shown here, the 47 possibilities of UPD for wholesale chromosomes, namely 22 paternal and 22 maternal pairs for the autosomes as well as 3 more pairs for the sex chromosomes, one maternal XX and two paternal ones, namely XX or XY.

Slide 23


TYPES OF MATERNAL OR PATERNAL UPD's KNOWN OR

UNDECTECTED

A) 18 KNOWN MATERNAL TYPES

1 2 4 6 7 8 9 10 12 1314 15 16 17 2021 22 X

B) 14 KNOWN PATERNAL TYPES

1 2 5 6 7 8 11 13 14 1516 21 22 XY

C) 5 KNOWN MATERNAL TYPES

3 5 11 18 19 D) 10 UNKNOWN PATERNAL

TYPES

3 4 9 10 1217 18 19 20 X

On this next slide, we show somewhat arbitrarily the chromosome numbers, maternal or paternal, which have contributed a monoparental pair in the make up of one purely and uniformly diploid genome, assuming that the available information allowed an exclusion of the mosaic compounded by an aneuploid component.

This review is comprised of 18 maternal and 14 paternal numbers, for a total of 32. Thus some 15 numbers are still currently without inclusion in a uniparental pair, if we disregard paternal 20 and paternal X, so far only noted in an aneuploid mosaic context.

Slides 24

TIMING OF THE FIRST IDENTIFICATION OF EACH OF 32 TYPES OF UPD's

YEAR TYPE AUTHORSHIP


1987 21 mat Créau-Goldberg et al

1988 7 mat Spence et al, Voss et al

1989 15 mat Nicholis et al 1989 XY Vidaud et al 1990 6 pat Weich et al 1991 11 pat Grundy et al

1991 4 mat Lindenbaum et al

1991 14 mat Temple et al 1991 14 pat Wang et al 1991 15 pat Malcolm et al 1992 16 mat Benett et al 1993 21 pat Blouin et al 1993 16 pat N'Go et al 1994 22 mat Schinzel et al

1994 5 pat Brzustowicz et al

1994 7 pat Höglund et al 1995 2 mat Harrison et al 1995 10 mat Jones et al 1995 13 mat Stallard et al 1995 13 pat Slater et al 1995 22 pat Miny et al 1996 8 pat Benlian et al

1996 6 mat Van den Berg Loonen

1997 1 mat Pulkkinen et al

1997 8 mat Piantadina et al

1997 9 mat Sulisalo et al 1997 X mat Quan et al 1998 1 pat Gelb et al 1998 20 mat Chuboda et al 1999 17 mat Genuardi et al


2002 2 pat Thomson et al

2002 12 mat Von Eggling et al

EE july 2003

Both these slides show the pace at which these uniparental pairs were uncovered since the first ones were identified.

We only see a few in the first decade following publication of the concept. Many more are documented in the 5 years from 91 to 95 and still quite a few are observed in the last 7 years till now, to the best of my knowledge.

It will be interesting to see which others will be detected in the forthcoming years to finally assume that those never seen are, may-be, lethal.

Slide 25

I would like to devote the rest of my talk to some peculiar machanisms of UPD formation. I have selected these examples because, to me, they illustrate some incredible twists of Nature.

I first aim at showing the role of some so-called non homologous or homologous Robertsonian translocations or centric fusions of acrocentric chromosomes.

You see here, at first glance, a non-homologous balanced translocation which, through an adjacent meiotic separation, produces a disomic


gamete. This segregant, upon fertilization, generate a trisomic conceptus. If UPD must result, of two possible new hits, one will take off the singly inherited number, leaving behind a UPD pair made of one free and one attached acrocentric chromosome.

According to Lisa Shaffer and colleagues, this will happen in 0,6 % or so of prenatally diagnosed Robersonian translocations but the toll will rise to about 4 % when prospecting a cohort of phenotypically abnormal carriers. On the other hand, two thirds of the bearers of homologous centric fusions will display a uniparental pair for the involved number.

Slide 26

On ths slide, precisely, a pattern of homologous centric fusion for chromosome 22 is found in a woman who aborts ten times in a row before producing a normal female offspring who, in turn, in due time will abort seven times.

Slide 27


Dealing in more details into this siuation, we see that eggs with the segregation of this homologous centric fusion can, upon fertilization, only produce monosomic or trisomic 22 inviable abortion products ! The only healthy offspring must have resulted from gamete complementation or, more likely, from the very early embryonic loss of parental 22. Such a luck in this case will not occur at the next generation in spite of 7 trials ending in as many abortions.

Slide 28


In the next example, an homologous 13/13 centric fusion or an isochromosome 13q (or an isodicentric 13) is found in a balanced woman withot a maternal 13. She thus examplifies a case of paternal UPD 13.

She, in turn, produces a balanced male offspring born after 5 spontaneous abortions. This balanced offspring carries the same 13/13 fusion as his mother, thus harboring a maternal UPD 13 without a traceable paternal13.

Here, amazingly, UPD 13 has taken place over two generations, once of paternal and once maternal origin, while the other parental 13 has not made its way in the embryonic cells ! A true miracle !

Slide 29


On this slide, we see how a parental 13/14 evidently non homologous Robertsonian translocation in a father ends up into an isochromosome 14 in a son with the syndrome of maternal UPD 14! An adjacent segregation has resulted into a nullisomy 14 in a paternal gamete whose deletion has been apparently patched up by duplication of the maternal 14 into an isochromosome, after fertilization.

Slide 30

And, since isochromosomes for acrocentrics have now just been mentioned, let me show, again from literature, some examples of UPD resulting from the presence of two isochromosomes per balanced individual genomes, namely one for each arm of a biarmed


chromosome such a number 1, 2 (twice), 4, 7 or 9. Besides, in the case of Eggerding et al, the short arm isochromosome 7 was paternal ad the isochromosome for the long arm was maternal in origin. Most remarkable, is not it?

Slide 31

Sometime the UPD does not involve the whole of a chromosome and remains confined to a segment of a pair as it arises from a somatic crossing over between two homologous non-sister chromatids. When interstitial, the segmental UPD results from two symmetrical breaks, which are shown here as the result of an ³interchromatid kiss² ! Mitotic segregation of the duplicated chromosomes, thereafter leads to mosaicism with one native and one reshuffled balanced cell line.

Slide 32


In other instances the segmental UPD is terminal and results from a single symmetrical break in each of two homologous non-sister chromatids, as seen here. Mosaicism involving two somatic cell types also results from this.

Slide 33


On this slide are presented examples of both types of segmental UPD, terminal or interstitial, as found for various chromosomes, 4, 6, 7, 11, 14, 20.

Some were discovered because of reduction to homozygosity causing recesive traits, while others involved imprinted domains and disrupted them.

Slide 34

Here are briefly reviewed some modes of UPD formation for more commonly affected member chromosomes.

Slide 35


This summary slide attempts to compile the information developed in this presentation.

Slide 36


This slide shows a source to find more information from a book written witn my friend and Colleague Stylianos Emmanuel Antonarakis which was published in 2002 by Liss-Wiley in New York.

Slide 37


My last slide is a symbol of my indebtedness to the many Authors who gave so much life to so simple an idea.

In this composite picture the dwarf sitting on the shoulders of the giant is the personn who sees the farthest.

My thanks go to Mr. Jean-Claude Malgouyres for assistance in preparing the graphic material for this lecture.

Contributor(s)


12-2003 Eric Engel Written

Citation

This paper should be referenced as such : Engel E . Some lessons from uniparental disomy (UDP) in the framework of comtemporary cytogenetics and molecular biology.. Atlas Genet Cytogenet Oncol Haematol. December 2003 . URL : http://AtlasGeneticsOncology.org/Deep/UniparentDisomyID20046.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



CASE REPORTS in HAEMATOLOGY (Paper co-edited with the European LeukemiaNet) A new case of t(1;11)(q21;q23) in a child with M1 ANLL Katell Le Du, Eric Jeandidier, Francine Garnache, Pierre Rohrlich, Jean-Luc Bresson, Marie-Agnès Collonge-Rame Clinics Age and sex : 21 months old old male patient Previous history : no preleukemia; No previous solid tumors.; prematurity (borth at 33 weeks of gestation), acute leukemia in the maternal grand-father Organomegaly : no hepatomegaly; no splenomegaly; no enlarged lymph nodes; no central nervous system involvement Blood WBC : 10.6 x 109/l; Hb : 7.1 g/dl; platelets : 71 x 109/l; blasts : 8% Survival Date of diagnosis: 29.04.04 Treatment : -one intrathecal injection (including methotrexate, steroids, and cytosine-arabinoside). Complete remission : None Relapse : - Survival : 8 mths + Karyotype Sample : bone marrow; culture time : 24h and 72h; banding : G and R banding Results : 46,XY,t(1;11)(q21;q23)[6] Other molecular cytogenetics technics : Fluorescence in Situ Hybridization was performed using a MLL dual color, break apart rearrangement probe and a chromosome 1 specific labeled spectrum green painting probe (ABBOTT). Other molecular studies results : MLL multiplex PCR [t(4;11), t(6;11), t(9;11), t(10;11), t(11;19)]: negative. ETO/AML1 : negative. MYH11/CBFB : negative. FLT3 mutations research : negative.


Other findings results : Meningeal punction : no blastic cells infiltration

bone marrow (MGG staining)

partial karyotype showing the t(1;11)(q21;q23)(R bands)


FISH results Comments To our knowledge, 26 cases of translocation t(1;11)(q21;q23) (involved the genes AF1q (1q21) and MLL(11q23) have already been described in the literature. All cases were acute leukemia except for one secondary myelodysplastic syndrome. In 14 cases (57 %), the translocation was the sole abnormality. The other 12 cases showed additional chromosomal abnormalities. This rare translocation is preferentially associated with AML4, AML5, or biphenotypic leukemia of infants or children. Only one case of AML M1/M2 in a 3-year-old female was reported with t(1;11)(q21;q23) as the sole karyotypic change. We present here the second case of AML1 with t(1;11)(q21;q23). The chid is in complete remission at 6 months after diagnosis. Internal links Atlas Card t(1;11)(q21;q23) Bibliography t(1;11)(q21;q23) The Cancer Genome Anatomy Project Mitelman Cases Quick Searcher. Translocation t(1;11)(q21;q23), a new subgroup within M4 acute nonlymphocytic leukemia. Meloni-Balliet AM, Morgan R, Piatt J, Sandberg AA. Cancer Genet Cytogenet 1989; 37: 239-271. Medline 2702626

Blood 1995; 85: 650-656. Medline 7833468

A novel gene, AF1q, fused to MLL in t(1;11)(q21;q23), is specifically expressed in leukemic and immature hematopoïetic cells. Tse W, Zhu W, Chen HS, Cohen A.

Ten novel 11q23 chromosomal partner sites. Harrison CJ, Cuneo A, Clark R, Johansson B, Lafage-Pochitaloff M, Mugneret F, Moorman AV, Secker-Walker LM. Leukemia 1998; 12: 811-822.


Medline 9593286

Busson-Le Coniat M, Salomon-Nguyen F, Hillion J, Bernard OA, Berger R. MLL-AF1q fusion resulting from t(1,11) in acute leukemia.

Leukemia 1999; 13: 302-306. Medline 1002590 Contributor(s) Written 01-

2005 Katell Le Du, Eric Jeandidier, Francine Garnache, Pierre Rohrlich, Jean-Luc Bresson, Marie-Agnès Collonge-Rame

Citation This paper should be referenced as such : Le Du K, Jeandidier E, Garnache F, Rohrlich P, Bresson JL, Collonge-Rame MA . A new case of t(1;11)(q21;q23) in a child with M1 ANLL. Atlas Genet Cytogenet Oncol Haematol. January 2005 . URL : http://AtlasGeneticsOncology.org/Reports/0111CollongeID100008.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



CASE REPORTS in HAEMATOLOGY (Paper co-edited with the European LeukemiaNet)


Kavita S. Reddy, Kathy Richkind Clinics Age and sex : 66 yrs old female patient Previous history : no preleukemia; no clinical information; Organomegaly : no hepatomegaly; no splenomegaly; no enlarged lymph nodes; no central nervous system involvement Blood WBC : 4.16 x 109/l; Hb : 13.5 g/dl; platelets : 103 x 109/l; Survival Relapse : - Status : no clinical information Survival : 1mth+ Karyotype Sample : BM; culture time : 24/48 hours unstimulated cultures; banding : G-banding Results : 46,X,t(X;20)(q13;q13.3)[3].ish t(X;20)(q11.2-12;q13.3) (wcpX+, wcp20+, AR_; wcp20+, D20S108+, AR+, wcpX+)/46,XX[18] Other findings results : In case 4, the breakpoint on X-chromosome was found to be more proximal between Xq11.2q-12 by FISH using androgen receptor probe


Fig. 1. Partial karyotypes of the translocation t(X;20)(q13;q13.3) for cases 14 (top to bottom). Arrows indicate the derivatives 20 and X.

Fig 2: Case 4: X-centromere probe DXZ1 (green) hybridized to the normal X and the derivative X (arrows). The androgen receptor (Xq12) AR (red) probe hybridized to derivative 20 and the normal X (arrows). The breakpoint on the X chromosome is proximal to AR. The karyotype is 46,X,t(X;20)(q13;q13.3).ish t(X;20)(q11.2q12;q13.3)(wcpX+, wcp20+, AR_; wcp20+, D20S180_, AR+, wcpX+). The revised breakpoints identified with FISH analysis are highlighted in bold. Internal links Atlas Card t(X;20)(q13;q13)

Translocation Case (X;20)(q13;q13.3): a nonrandom abnormality in four


Report patients with myeloid disorders: case 1

Case Report


Translocation (X;20)(q13;q13.3): a nonrandom abnormality in four Case

Report patients with myeloid disorders: case 3 Bibliography Michaux, I. Wlodarska, C. Mecucci, J.M. Hernandez, A. Van Orshoven, J.L. Michaux and H. Van den Berghe Cancer Genet Cytogenet 1995; 82: 1722.

Cancer Genet Cytogenet 2003; 141: 169174.

Translocation (X;20)(q13.1;q13.3) as a primary chromosomal finding in two patients with myelocytic disorders B.A. Gray, D. Cornfield, A. Bent-Williams and R.T. Zori

Cancer Genet Cytogenet 2005; 151: 70-73. Contributor(s) Written 01-


Citation This paper should be referenced as such : Reddy KS, Richkind K . Translocation (X;20)(q13;q13.3): a nonrandom abnormality in four patients with myeloid disorders: case 4.. Atlas Genet Cytogenet Oncol Haematol. January 2005 . URL : http://AtlasGeneticsOncology.org/Reports/0X20ReddyID100012.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



CASE REPORTS in HAEMATOLOGY (Paper co-edited with the European LeukemiaNet)


Kavita S. Reddy, Kathy Richkind Clinics Age and sex : 61 yrs old female patient Previous history : no preleukemia; A low-grade lobular and ductal carcinoma with a small percentage of intraductal breast disease treated with tamoxifen; Organomegaly : no hepatomegaly; no splenomegaly; no enlarged lymph nodes; no central nervous system involvement Blood WBC : 3.05 x 109/l; Hb : 8.1 g/dl; platelets : 62 x 109/l; Survival Treatment : induction treatment: topotecan and cytarabine Relapse : - Status : A Survival : 55 months + Karyotype Sample : PB; culture time : 24/48 hours unstimulated cultures; banding : G-banding Results : 46,X,t(X;20)(q13;q13.3),der(1;7)(q10;p10)[20]/46,XX[1]


Fig. 1. Partial karyotypes of the translocation t(X;20)(q13;q13.3) for cases 14 (top to bottom). Arrows indicate the derivatives 20 and X. Internal links Atlas Card t(X;20)(q13;q13)

Case Report


Case Report


Case Report


Bibliography Michaux, I. Wlodarska, C. Mecucci, J.M. Hernandez, A. Van Orshoven, J.L. Michaux and H. Van den Berghe

B.A. Gray, D. Cornfield, A. Bent-Williams and R.T. Zori

Cancer Genet Cytogenet 1995; 82: 1722. Translocation (X;20)(q13.1;q13.3) as a primary chromosomal finding in two patients with myelocytic disorders

Cancer Genet Cytogenet 2003; 141: 169174. Cancer Genet Cytogenet 2005; 151: 70-73.

Contributor(s) Written

Kavita S. Reddy, Kathy Richkind 01-2005





CASE REPORTS in HAEMATOLOGY (Paper co-edited with the European LeukemiaNet) Translocation (X;20)(q13;q13.3): a nonrandom abnormality in four patients with myeloid disorders: case 3. Kavita S. Reddy, Kathy Richkind Clinics Age and sex : 77 yrs old female patient Previous history : no preleukemia; no clinical information; Organomegaly : no hepatomegaly; no splenomegaly; no enlarged lymph nodes; no central nervous system involvement Blood Survival Relapse : - Status : no clinical information Karyotype Sample : BM; culture time : 24/48 hours unstimulated cultures; banding : G-banding Results : 46,X,t(X;20)(q13;q13.3)[10]/46,XX[10]


Fig. 1. Partial karyotypes of the translocation t(X;20)(q13;q13.3) for cases 14 (top to bottom). Arrows indicate the derivatives 20 and X. Internal links Atlas Card t(X;20)(q13;q13)

Case Report


Case Report


Translocation (X;20)(q13;q13.3): a nonrandom abnormality in four Case

Report patients with myeloid disorders: case 4 Bibliography Michaux, I. Wlodarska, C. Mecucci, J.M. Hernandez, A. Van Orshoven, J.L. Michaux and H. Van den Berghe Cancer Genet Cytogenet 1995; 82: 1722. Translocation (X;20)(q13.1;q13.3) as a primary chromosomal finding in two patients with myelocytic disorders B.A. Gray, D. Cornfield, A. Bent-Williams and R.T. Zori Cancer Genet Cytogenet 2003; 141: 169174. Cancer Genet Cytogenet 2005; 151: 70-73. Contributor(s) Written 01-






CASE REPORTS in HAEMATOLOGY (Paper co-edited with the European LeukemiaNet) Translocation (X;20)(q13;q13.3): a nonrandom abnormality in four patients with myeloid disorders: case 4. Kavita S. Reddy, Kathy Richkind

Clinics Age and sex : 66 yrs old female patient Previous history : no preleukemia; no clinical information; Organomegaly : no hepatomegaly; no splenomegaly; no enlarged lymph nodes; no central nervous system involvement Blood WBC : 4.16 x 109/l; Hb : 13.5 g/dl; platelets : 103 x 109/l; Survival Relapse : - Status : no clinical information Survival : 1mth+ Karyotype Sample : BM; culture time : 24/48 hours unstimulated cultures; banding : G-banding Results : 46,X,t(X;20)(q13;q13.3)[3].ish t(X;20)(q11.2-12;q13.3) (wcpX+, wcp20+, AR_; wcp20+, D20S108+, AR+, wcpX+)/46,XX[18] Other findings results : In case 4, the breakpoint on X-chromosome was found to be more proximal between Xq11.2q-12 by FISH using androgen receptor probe


Fig. 1. Partial karyotypes of the translocation t(X;20)(q13;q13.3) for cases 14 (top to bottom). Arrows indicate the derivatives 20 and X.

Fig 2: Case 4: X-centromere probe DXZ1 (green) hybridized to the normal X and the derivative X (arrows). The androgen receptor (Xq12) AR (red) probe hybridized to derivative 20 and the normal X (arrows). The breakpoint on the X chromosome is proximal to AR. The karyotype is 46,X,t(X;20)(q13;q13.3).ish t(X;20)(q11.2q12;q13.3)(wcpX+, wcp20+, AR_; wcp20+, D20S180_, AR+, wcpX+). The revised breakpoints identified with FISH analysis are highlighted in bold. Internal links Atlas Card t(X;20)(q13;q13) Case Translocation (X;20)(q13;q13.3): a nonrandom abnormality in four


Report patients with myeloid disorders: case 1

Case Report


Case Report


Bibliography Michaux, I. Wlodarska, C. Mecucci, J.M. Hernandez, A. Van Orshoven, J.L. Michaux and H. Van den Berghe Cancer Genet Cytogenet 1995; 82: 1722. Translocation (X;20)(q13.1;q13.3) as a primary chromosomal finding in two patients with myelocytic disorders B.A. Gray, D. Cornfield, A. Bent-Williams and R.T. Zori Cancer Genet Cytogenet 2003; 141: 169174. Cancer Genet Cytogenet 2005; 151: 70-73. Contributor(s) Written 01-





Genetics and Public Health

I - Introduction

II - Populations targeted by public health genetics interventions

III - Ethical, legal, and social implications of public health genetic interventions

III - 1. Use of genetic information: confidentiality and discrimination III - 2. DNA banks III - 3. Prenatal diagnosis, assisted reproduction and embryo selection

IV - Examples of the role of public health in genetics

IV - 1. Folic acid and neural tube defects IV - 2. Newborn screening IV - 3. Carrier screening in the context of reproductive decisions IV - 4. Prenatal screening for aneuploidy and neural tube defects IV - 5. Screening for genetic susceptibilities in adults IV - 6. Pharmacogenetics and ecogenetics IV - 7. Personalized Health Care and Genetic Information

Conclusion

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I - Introduction

The role of public health is to ensure that the basic conditions required for people to be healthy are present. Until recently, public health focused mostly on environmental causes and risk factors for disease, such as infections, cigarette smoking, diet, etc. Since the sequencing of the human genome has been completed, high hopes rest on the potential to prevent the impact of genetic risk factors or susceptibilities to disease. Advances in genetic knowledge and technology could be used to try to prevent disease and improve population health.


The perceived role of genetics in public health is changing, as is the definition of what is a genetic disease. The role of genetics in public health is broadened if we consider all the diseases for which genetics might play a role, either by the presence of a genetic susceptibility for the development of this disease or for response to treatment, or by the presence of protective genetic factors, such as in resistance to infection. One day, it might be possible to determine for each individual which genetic susceptibilities and protective factors each individual possesses, and act accordingly to prevent the occurrence of disease. In the meantime, the role of genetics in public health is mostly limited to monogenic diseases.

II - Populations targeted by public health genetics interventions

Public health considers the overall health of the population as a group, and not the health of each individual. Since resources for public health interventions are limited, priorities need to be established to determine which interventions will be most beneficial to the population as a whole. These priorities will be based on the characteristics of the disease, such as its prevalence, its severity, and treatment availability, as well as the amount of resources needed for the intervention. Monogenic diseases are rare. Is it justifiable to implement population-based interventions to identify a few rare cases of a particular genetic disease? There is no single right answer to this question. It depends on the burden these rare cases represent for society, on our ability to act to attenuate this burden, and on the value we place on obtaining an early diagnosis, compared to the complexity of detecting these cases and the amount of resources needed to detect them. For example, newborn screening for phenylketonuria is considered beneficial because it makes it possible for the children identified through screening, who would otherwise have developed severe mental retardation, to develop normally by following a special diet. In the majority of developed countries, all newborns are screened for phenylketonuria to detect a handful of cases, because the impact of treatment on these children’s potential ability to contribute to society is so great. On the other hand, similar newborn screening for Huntington disease is not being considered, because it is a late-onset disease for which there is no treatment and no clear benefit to an early diagnosis. Screening would not change the impact of the disease on the affected individuals or its burden on society. To improve the yield of a screening program for a genetic disease, one option is to target a population at higher risk of disease, often the families of affected cases. This approach limits the amount of resources needed for screening and increases the yield of screening. It unfortunately is limited by the fact that many new cases of genetic disease occur in individuals with no family history who would not be identified by family-based screening. In some cases, ethnic groups can be the target population of screening programs, when prevalence of the disease in questions is particularly high in that ethnic group. For example, Ashkenaze Jewish populations are screened for Tay-Sachs disease. In programs targeted at specific communities, it is important to ensure that the community is in favor of screening and that it does not become a source of stigmatization for the community.


III - Ethical, legal, and social implications of public health genetic interventions

III - 1. Use of genetic information: confidentiality and discrimination

The issue of confidentiality of genetic information is frequently raised. Genetic information is different from other types of personal information found in a medical

chart. First, genetic information does not change over time: the presence of a mutation or a polymorphism in an individual is immutable. Second, genetic

information about one individual has implications not only for the individual in question, but also for his/her family members, since the genetic abnormalities are heritable in most cases. In some cases, genetic information is used to confirm a

clinical diagnosis, but it is increasingly used to confer a level of risk or susceptibility for the development a specific condition. In that context, it is not surprising that some are worried that information about a specific genetic susceptibility might be used by

insurers or employers as a source of discrimination.

III - 2. DNA banks

Genetic research often requires the collection of DNA samples. Many DNA banks were formed from DNA samples collected for specific research projects or from blood samples collected for newborn screening. Once they have served their intended use,

what should now be done with these samples? Who do they belong to? Can the researcher use them for other purposes without the consent of those who gave these

samples? Can he only do it if he anonymizes the samples first? Or does the researcher need to contact each individual to renew his/her consent? To respect the autonomy of individuals who participated in previous research projects, it would be

necessary to contact them again to obtain renewed consent before using their samples for other research projects. On the other hand, these samples are easily

accessible and could be used to further scientific knowledge for the benefit of society without major negative impact on the individual who provided the sample, especially

if the samples are anonymized. In some cases, the nature of the prospective research will also influence the decision to use or not use samples from a DNA bank. Researchers and ethicists all over the world are faced with these issues. Institutional

review boards are assessing each research project based on its specific context, because no consensus has been reached for now on procedures for the use of DNA

banks in research.

III - 3. Prenatal diagnosis, assisted reproduction and embryo selection

Assisted reproduction has made it necessary to redefine fundamental concepts, such as paternity and maternity. We now use the terms biological mother, gestational mother (or surrogate mother), and social mother. We also differentiate between


biological father and social father. Before DNA tests, paternity was always assumed, but it is now possible to determine with strong certainty whether an individual is or isn’t a given child’s biological father. In the past, maternity was simply attributed to

the woman who had given birth to the child. But these days, it is possible for a woman to have an embryo conceived with her own eggs carried to term by another

woman. The first woman is then the biological mother, and the second the gestational mother. The social mother will be the one acting as a parent to the child in question. Assisted reproduction is not reserved for infertile couples anymore, but is also used

by couple who want to ensure that their child will be born without a specific hereditary disease, or even to make sure that their child will be a matched donor for an older sibling in need of a bone marrow transplant. Genetic tests performed on embryos

make it possible to select only embryos that fit certain criteria. For now, this technology is mostly used to avoid the birth of children with severe hereditary

childhood diseases, but it is feared that it opens the door to embryo selection based on other criteria, such as physical appearance or intellectual ability.

When a pregnant woman is offered the possibility of undergoing prenatal diagnosis for genetic diseases through amniocentesis or chorionic villous sampling, it implies that selective abortion is an option they will consider if the fetus is indeed affected

with a genetic disease. For some, this option is unacceptable for ethical, moral, and/or religious reasons. It raises the question of the legal status of the embryo, the

definition of human life and of a human being.

IV - Examples of the role of public health in genetics

There are already many examples of the role of public health in genetics. Better known examples deal with reproductive technologies (prenatal screening, carrier

screening) and newborn screening. More recent examples in the adult setting concern genetic susceptibility screening and pharmacogenetics.

IV - 1. Folic acid and neural tube defects

Neural tube defects (NTD) account for an important part of birth defect-related infantile mortality and morbidity. Their incidence tends to be decreasing over time

(secular trend). During the 1980s, studies have shown a decrease in the recurrence of NTD in subsequent pregnancies with the use of folic acid for women having

already had a child with a NTD. Since then, studies done in women with no family history of NTD have also shown lower incidence rates of children born with NTD in

women who took folic acid supplements. Even though the way in which folic acid acts to prevent NTD has not been elucidated, these observed findings have led to the

hypothesis that folic acid supplementation would be beneficial to all women planning a pregnancy, to prevent the birth of a child with a NTD.

Because the neural tube closes during the fourth week of gestation, it is recommended to start folic acid supplementation before conception. The minimal

dose needed to obtain an effect has not been established, but the usually recommended daily dose is 400 micrograms in women with no specific risk factor,

and should be started at least 3 months before conception. However,


supplementation often does not occur, either because women are not aware of the benefits of folic acid supplementation or because pregnancy was not planned.

To address this problem, some countries have decided to add folic acid to the food supply, most often in flour. This type of public health intervention has occurred in the past to prevent other diseases: iodized salt to prevent goiter, and vitamin D in milk to

prevent rickets. Folic acid fortification of flour has not been done without controversy. Some fear that folic acid fortification will mask vitamin B12 deficiency and delay its diagnosis. Others

worry about long-term effects of a folic acid-fortified diet or about potential interactions between folic acid and prescribed drugs. No study has shown that this

fortification strategy would be sufficient to reduce the incidence of NTD in the population. In spite of all that, many professional organizations have declared

themselves in favor of fortification. Folic acid fortification has been established at the end of the 1990s in many developed countries, most often in flour. Studies done

since fortification seem to show a significant reduction in the incidence of NTD in the population, even when accounting for the secular trend.

IV - 2. Newborn screening

for phenylketonuria (PKU) is the first example of population-based genetic screening. It was put in place in the U.S.A. in the early 1960s, thanks to the development by Dr

Robert Guthrie of a technique allowing the measurement of blood phenylalanine levels using blood samples collected on filter paper. Samples collected in this way are easy to store and ship, and can be preserved for extended periods of time. The technique itself is cheap and easy to perform. These characteristics have made it

possible to develop large-scale screening programs. Newborn screening for PKU is now performed by the state in most developed countries.

In the wake of newborn screening tests, a screening “system” was developed. Today, a newborn screening system includes sample collection and shipment to screening facilities, performance of the screening test in the laboratory, diffusion of test results to parents and referring physicians, and, for newborns with abnormal results, rapid access to specialized evaluation and appropriate care. In parallel, severe quality

control criteria have been established and voluntary laboratory quality control programs are managed by government agencies, such as the Center for Disease

Control in the U.S.A. Since the 1960s, other diseases have been added to newborn screening panels. The

list varies by region, but it almost always includes congenital hypothyroidism, and often includes galactosemia, tyrosinemia, sickle cell anemia, and/or congenital

adrenal hyperplasia. For all these diseases, a dietary-based or drug-based treatment is available to prevent the effects of the disease or attempt to control their

progression, and it seems preferable to start these treatments as early as possible. In the last few years, a new technology, tandem mass spectrometry (MS/MS), makes it possible to detect over 30 metabolic diseases during the newborn period, such as aminoacidemias, organic acidurias, and urea cycle defects, to name a few. The use of this technology for newborn screening is controversial for several reasons. Among the diseases that can be detected with MS/MS, some have a poorly defined natural

history. In those cases, it is difficult to predict what will happen to the affected newborn and the impact that early diagnosis and treatment could have. It is not clear


whether dietary treatment will be as effective in all cases. However, newborn screening using MS/MS would make it possible to learn more about these diseases, which might otherwise go undetected (even if symptomatic). In the U.S.A., advocacy

groups formed by parents of children with diseases detectable with MS/MS are lobbying for the addition of this technology to state-run newborn screening programs.

Those opposed to using MS/MS for newborn screening argue that there is no evidence that early diagnosis and treatment of these diseases will improve their

natural course, which goes against the criteria largely used to decide whether or not to add new diseases to newborn screening programs. They stress that the availability

of the technology and its capacity to detect disease does not mean that the information it provides is valuable for newborns.

Newborn screening for cystic fibrosis is also currently debated. Newborn screening programs for cystic fibrosis already exist in many regions of the world: in Wisconsin and Colorado (USA), in Brittany (France), and some regions of the United Kingdom and Australia. Some studies have shown that children identified through newborn screening achieve better nutritional status and/or better respiratory function than those diagnosed through symptoms, but these differences are mild and tend to

disappear over time. The main newborn screening criteria, as defined by the World Health Organization, state that an effective treatment must be available and that the

early application of that treatment must improve the health outcome of the child. Even though long term impact of early diagnosis of cystic fibrosis on the evolution of

disease has not been irrevocably established, some argue that early diagnosis is of benefit to parents because it avoids unnecessary anxiety related to delayed

diagnosis in a symptomatic child, and enables them to make informed reproductive decisions for future pregnancies. The benefit is not for the child itself, but for parents,

and it is not related to the early onset of effective treatment. According to this argument, it would be justifiable to screen for genetic conditions with no known

effective treatment but whose early diagnosis would be of value to the parents. In the case of cystic fibrosis, early diagnosis can possibly be of value to the child, but this

would not be the case for other diseases for which newborn screening has been advocated, such as Duchenne muscular dystrophy and Fragile X syndrome.

IV - 3. Carrier screening in the context of reproductive decisions

The first carrier-screening program for recessive diseases was developed in the Ashkenazi Jewish communities in New York and Washington, D.C., in the U.S.A.

With the support of the community and religious officials, a carrier-screening program for Tay-Sachs disease was established in the early 1970s, shortly after the discovery of the enzyme whose deficiency is the cause of the disease. Tay-Sachs disease then

had a relatively high prevalence in the Ashkenazi Jewish community. This disease causes progressive neurodegeneration starting in the first year of life and inevitably

leading to the child’s death, usually by four years of age. Both the community members and the health professionals involved agreed that this disease is so severe

that it would be preferable to take measures to avoid the birth of affected children. The screening strategy has been adapted to the needs and realities of the different

communities: in orthodox communities where selective abortion was not acceptable, premarital screening is performed and results are taken into account in the rabbi’s


decision to bless the marriage or not, which has been deemed acceptable by the community. Carrier screening programs for Tay-Sachs disease now exist in

Ashkenazi Jewish communities around the world. Thanks to these programs, the incidence of the disease has decreased by over 90% in these communities. In the wake of this success, other diseases with relatively high prevalence in Ashkenazi

Jewish communities have been added to carrier screening panels, such as Canavan disease and Gaucher disease, to name a few.

In response to the success of Tay-Sachs carrier screening in Ashkenazi Jewish communities, similar programs have been developed in other communities where an

autosomal recessive disease was highly prevalent in children, such as carrier screening for beta-thalassemia in Cyprus and Sardinia. These programs have also

led to drastic reductions in disease prevalence in these communities. Carrier screening programs for sickle cell anemia in African Americans in the U.S.A. in the

1970s have not had the same success, partly because the distinction between being a healthy carrier and having the disease was not made clear. This had led to

discrimination against carriers. Recently, the American College of Obstetrics and Gynecology has recommended

that all pregnant women be offered carrier screening for cystic fibrosis. This recommendation has been questioned by some, because screening is routinely offered when pregnancy is already ongoing and because cystic fibrosis is not

considered as severe as Tay-Sachs disease.

IV - 4. Prenatal screening for aneuploidy and neural tube defects

For a detailed discussion of what is available in prenatal diagnosis, see “Prenatal Diagnosis” section.

In terms of population health, it is of note that prenatal screening for chromosomal abnormalities and neural tube defects is offered to pregnant women in many

countries. These screening programs may be targeted at women with specific risk factors (i.e. according to maternal age), or to all pregnant women. In most cases,

newborns with chromosomal abnormalities or neural tube defect are born of mothers with no specific risk factors. A screening test done during pregnancy can identify those women at higher risk of carrying a fetus with one of these conditions. This

blood test, which measures a combination of serum and/or ultrasound markers, is not a diagnostic test: like all screening tests, it tends to be highly sensitive, but not

necessarily very specific. The role of a screening test is to detect all cases of the targeted condition, at the expense of a certain amount of false positive results. For prenatal screening, the test result is usually given as the probability that the fetus is affected, and the result is considered “positive” when this probability is higher than a specific threshold, usually between 1/400 and 1/200. Since this threshold is relatively low, there is inevitably a high proportion of false positive results, i.e. pregnancies with

test results above the threshold and considered at high risk of having an affected fetus, but whose fetus is actually not affected. In a screening context, we tolerate a

certain amount of false positive results that will have to undergo definitive diagnostic testing through amniocentesis and incur the associated risk of miscarriage. It is the price to pay to reduce as much as possible the rate of false negative results, i.e. a

result placing the risk below the threshold when the fetus is actually affected. These


screening programs have been developed to give women the possibility of terminating the pregnancy if the fetus is found to be affected. In general, this option is considered acceptable because most people consider these conditions to be severe

enough and prevalent enough to justify a population-based screening program. Those who consider termination to be unacceptable can select out of the screening

process.

IV - 5. Screening for genetic susceptibilities in adults

Since the sequencing of the human genome, advances in genetic knowledge has led us to consider the potential use of genetic information to assess individual

susceptibilty to disease. Although this is not widely possible yet, there are some examples of the use of genetic tests for that purpose. These examples raise

questions about the real clinical utility of that type of information at the individual level.

Hereditary hemochromatosis is an autosomal recessive disease. Individuals who suffer from this disease can develop cirrhosis of the liver, diabetes, and

cardiomyopathy. Symptoms are caused by a defect in iron metabolism, which leads to iron deposition in tissues. Two main mutations in the hemochromatosis gene have

been identified, C282Y and H63D. Most cases are C282Y homozygotes. Regular phlebotomies reduce iron deposition and can help prevent or reduce symptoms. For

that reason, hemochromatosis is considered an ideal target for population-based screening. The use of a genetic test as a screening test for hereditary

hemochromatosis is justified if we assume that penetrance of the disease is high, i.e. that most C282Y homozygotes will develop symptoms of hemochromatosis in their lifetime if untreated, and that they would benefit from early diagnosis and preventive treatment. Unfortunately, penetrance seems lower than previously thought: it seems

that only a minority of C282Y homozygotes actually develop symptoms of hemochromatosis in their lifetime. The value of population-based genetic screening

for hemochromatosis is being questioned. It is currently recommended to use transferrin saturation level as a screening test for hemochromatosis. This is a

biochemical index of iron overload, and is closer to the phenotype of hemochromatosis than the genetic test.

Factor V Leiden (FVL) is a variant of factor V, a coagulation factor. This variant is associated with an increased risk of thrombosis. Even though the presence of FVL in

an individual with a history of thrombosis can help explain the cause of the thrombosis, it does not usually change immediate treatment or long-term

management of that individual, who will be treated as any other individual with a personal history of thrombosis. On the other hand, not all individuals who have FVL will develop thrombosis. It is difficult to justify population-based screening for FVL, and especially to submit them to long-term prophylactic anticoagulation treatment,

which is associated with significant risks of bleeding. Other factors also influence the risk of thrombosis in these individuals, such as smoking and hormonal therapy, and

make it difficult to predict risk of thrombosis on an individual basis. As our knowledge of gene-environment interactions increases, it might be possible to

improve our assessment of individual disease susceptibility by using predictive models based on combinations of genetic and environmental risk factors. For now,


the impact of genetic susceptibility is difficult to assess, especially on an individual basis.

IV - 6. Pharmacogenetics and ecogenetics

Pharmacogenetics is a field of genetics focusing on the role of genetics in individual variability of drug response and side effect occurrence. If we can predict the pharmacologic response of a given individual to a specific drug based on the

presence or absence of a given genetic polymorphism, we could adjust dosage accordingly. Most genetic polymorphism studied until now have been in genes

involved in the metabolism or elimination of drugs. It is thought that these polymorphisms might accelerate or slow drug metabolism or drug elimination.

Ecogenetics is similar to pharmacogenetics, but focuses on the role of genetics in explaining the individual variability of response to environmental factors (carcinogens,

pesticides, food products, industria pollutants, etc.), instead of response to drugs. This information could be used in the workplace to identify individual workers at risk

of developing complications related to occupational exposure to specifc agents. There is the danger that this might be used to discriminate against those with genetic

susceptibility to develop complications, who might be refused employment. On the other hand, workers at low-risk of complications might be exposed to higher levels of

the agent in question if it gives them a false sense of security and protective measures are lessened, which would paradoxically put them at higher risk of actually

developing complications.

IV - 7. Personalized Health Care and Genetic Information

Some hope that a better understanding of genetic variability will help adapt treatments on the basis of an individual’s genetic characteristics and the risks and

benefits of the many treatment options available for that individual. This will depend on how fast knowledge will grow in pharmacogenetics and ecogenetics. In some

cases, the treatment will be the same, but the dose, duration or timing of treatment will be different according to the individual’s genotype. In other cases, treatment itself will be tailored for specific individual genotypes, targeting specific genetic differences.

Over time, a better understanding of genetic susceptibilities might help target preventive measures to individuals who can potentially benefit from them the most.

But, in the context of increasing health care costs, the use of resources to personalize health care based on genetic characteristics will have to be balanced

against its benefits.

Conclusion


The impact of genetics in public health is still limited, but is expected to grow in the near future, as genetic knowledge rapidly increases. Current examples of the use of

genetics in public health can serve as lessons for the future.

Contributor(s) 11-2004

Written Anne-Marie Laberge

Citation

This paper should be referenced as such : Laberge AM . Genetics and Public Health. Atlas Genet Cytogenet Oncol Haematol. November 2004 . URL : http://AtlasGeneticsOncology.org/Educ/GenetPublicHealthID30053ES.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



Glossary of Medical and Molecular Genetics: see

A

http://AtlasGeneticsOncology.org/Educ/GlossaryID30028ES.html This French / English glossary of medical and molecular genetics is intended for students in human and biological sciences as well as medical and para-medical personnel. It is mainly a tool for teaching and research. This glossary contains terminology frequently used in clinics and the laboratory. Within all areas of genetics the utilisation of terms in the glossary may also evolve with time or develop specific conations in different areas of study. There is no direct correspondence between the French and English terms defined in these glossaries. Certain terms exist in only one of these languages. Also the utilisation of a given term may differ to some extent between French and English. The definitions of terms common to both glossaries are not necessarily literal translations of one another. Suggestions, corrections as well as the addition of new terms are welcomed. We are grateful to the authors of those references who have contributed to the preparation of this glossary.

B C D E F G H I J K L M N O P Q R S T U V W X Y Z

SELECTED REFERENCES : Le génie du génome. Glossaire http://www.nature.ca/genome/02/022_pqr_f.cfm

Conseil de recherches médicales du Canada. et al. Vocabulaire du génie génétique : anglais-français avec index des termes français. Bibl. sc./Réf. Sc. & génie et Bibl. sc./Réf. Sc. santé et Bibl. Sc. hum. & soc./Réf. P 305 C132 28Université Laval biochimie médical-biochimie ouvrage de références http://www.ulaval.ca/fmed/bcx/refsci.html Université Laval. Ressources en génétique. Dictionnaires, Encyclopédies, Glossaires & Lexiques. http://www.bibl.ulaval.ca/ress/genetiquedictionnaires.html Institut Pasteur Terminologie du génie génétique - Lexique anglais - français http://www.pasteur.fr/recherche/DicoAF.html Human genome project information, Genome glossary http://www.ornl.gov/TechResources/Human_Genome/publicat/primer/glossary.html Glossaries : Human Genetics/Genome Project http://www.kumc.edu/gec/glossary.html Terminologie du génie génétique http://www.ens-lyon.fr/RELIE/PCR/glossary/glossary.htm Terminologie Génétique - Glossaire http://www.globenet.org/myonet/GENETIQUE/glossaire.html


Le grand dictionnaire terminologique, Office Québécois de la langue française http://www.granddictionnaire.com/btml/fra/r_motclef/index800_1.asp Schlindwein's B. Hypermedia Glossary Of Genetic Terms http://hal.weihenstephan.de/genglos/asp/genreq.asp?list=1 GeneTests (National Institute of Health) http://www.genetests.org/servlet/access?qry=ALLTERMS&db=genestar&fcn=term>report2=true&id=8888891&key=xFQGcJD8Bd6xV

Contributor(s) Written 11-

2004 Louis Dallaire

Citation

This paper should be referenced as such : Dallaire L . Glossary of Medical and Molecular Genetics. Atlas Genet Cytogenet Oncol Haematol. November 2004 . URL : http://AtlasGeneticsOncology.org/Educ/GlossaryID30028ES.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology


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Atlas of Genetics and Cytogenetics in Oncology and Haematologyatlasgeneticsoncology.org/Journal/Arch2005Vol9Num1.pdf · 2008-12-10 · Atlas of Genetics and Cytogenetics in Oncology