Monosomy 7 and 7q- associated with myeloid malignancy

Blood Reviews (1997) 11,46-55 0 1997 Pearson Professional Ltd

State of the art

Monosomy 7 and 7q- associated with myeloid malignancy

E. Johnson, F. E. Cotter

An association between the complete or partial loss of chromosome 7 and preleukaemic myelodysplasia or acute myeloid leukaemia has been recognized from the early days of tumour cytogenetic analysis. Detection of such abnormalities usually heralds a poor prognosis. The loss of DNA on chromosome 7 has led to speculation that tumour-suppressor genes may play a significant role in this form of leukaemogenesis, although it may be part of a multistep process. A further association with leukaemia secondary to carcinogen exposure including previous chemotherapy or a number of congenital anaemias has increased the interest in discovering the gene or genes on chromosome 7. Banded chromosome analysis has suggested that there are two broad critical regions on the long arm of chromosome 7 at bands 7q22 and 7q34-q36 that may contain the relevant genes. Initial molecular analysis has confirmed these to regions to be of significance. The advent of fluorescence in-situ hybridization techniques has facilitated some definition of the 7q22 region, with identification of candidate genes for further functional analysis. It is becoming clear that there will be more than one gene on chromosome 7 involved in the leukaemic process and with the definition of these genes it may be possible to look for associations with different phenotypes and prognosis. As for the reason for chromosome 7 showing a particular predisposition to total or partial loss we may speculate that the DNA sequence and structure may confer a ‘fragility’ on the chromosome. A greater understanding of the DNA structure of the long arm may provide real insight into the mechanisms of leukaemia. We would like to speculate in the long term that this could lead to the ability to screen for leukaemia susceptibility and avoidance of ‘inducers’ in those at risk.

Monosomy 7 is one of the most frequent clonal chromosomal abnormalities associated with myelodysplasia (MDS) and the second most frequent numerical abnormality in acute myeloid leukaemia (AML).lm5 The first reports of monosomy 7 in association with myeloid disease date back to 1964 with Freireich’s report of three cases of

E. Johnson MRCP, F. E. Cotter PhD FRCP FRCPath, Molecular Haematology Unit, Institute of Child Health, London, UK.

Correspondence to: Dr Finbarr E. Cotter, Molecular Haematology Unit, Institute of Child Health, 30 Guilford Street, London WClN lEH, UK (Tel: +44(0)171 813 8191; Fax: (+44)(0)171 813 8100; E-mail: [email protected]).

refractory anaemia, granulocytic hyperplasia and a missing C group chromosome in marrow cells6 In this era (prior to chromosome banding), it is almost certain that these represented a chromosome 7 deletion. It is now established that there is a clear association between chromosome 7 alterations, MDS and AML in children and adults. The less well-established association with lymphoid malignancies is currently emerging. These changes may consist of long arm deletion (7q-) or total loss of the whole chromosome (monosomy 7) from bone marrow cells.1,4,7-25 The abnormalities occur in de novo MDUAML, in secondary cases following exposure to drugs, radiotherapy and toxins as well as

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Monosomy 7 and 7q- associated with MDS 47

constitutional disorders including Fanconi’s anaemia, congenital neutropenia and neurofibromatosis type 1. In all groups, the presence of chromosome 7 abnormalities defines a poor prognostic group. The majority of patients with MDS trans- form to a form of acute leukaemia resistant to therapy, including bone marrow transplantation (BMT). Fluorescence in situ hybridization (FISH) has accel- erated the study of these disorders at the cytogenetic and molecular levels.“,26s27 The loss of DNA associated with malignant progression suggests the presence of a tumour-suppressor gene (or genes) at these loci.28,29 No gene has been clearly implicated, although candidates have been suggested. The characterization of candidate genes is required to under- stand the mechanism of malignant transformation in these patients as it is not known, for example, whether both alleles of the putative suppressor gene need to be lost or whether loss of only one, i.e. gene dosage (haploinsufficiency), is more important. However, the loss of chromosome 7 material is almost certainly not the sole molecular abnormality. It is probable that this is not an initiating event, but occurs in cells already altered by a genetic event, per- mitting progression to clonal malignancy mediated by a gene on chromosome 7 as a secondary event.

CLASSIFICATION AND MANAGEMENT

A useful classification suggested originally for childhood monosomy by Luna-Fineman3’ although not entirely applicable to the adult disease, is an applicable classification for monosomy 7 and MDS in general. The division into three broad groups is suggested. These are:

De novo disorders: primary MDS, primary AML, infant monosomy 7 syndrome (IMo7) and juvenile chronic myeloid leukaemia (JCML). The latter is distinct in that, although a primary form of childhood myelodysplasia, it is rarely associated with monosomy 7. Secondary disorders following therapy for previous malignancy or exposure through occupation or otherwise to toxic substances. Aplastic anaemia is also included in this group. Constitutional disorders, including Fanconi’s anaemia, Kostmann’s syndrome (severe congenital neutropenia), Shwachman’s syndrome, neurofibromatosis type 1, familial monosomy 7 and, occasionally, Down’s syndrome.

The classification groups are discussed in more detail below.

De novo disorders

MDS arising spontaneously with no predisposing factors may be classified as primary or de novo disease. Clonal chromosome abnormalities occur in up to 79% of patients.23a3’ Trisomy 8, 5q-, monosomy 5, 7q-, monosomy 7 and 2Oq- are the predominant abnormalities. Chromosome 7 deletions occur at 7q22 and 7q32-36.5.20,23,‘2,33 Translocations involving chromosome 7 are unusual, although they have been reported in association with chromosome 1, resulting in trisomy for lq and monosomy for 7q.23.3M8 A recent study highlighted 7q32 deletions as associated with a particularly poor prognosis.39 Patients with monosomy 7/7q- will always do badly, no mat- ter which French-American-British (FAB) group is present.3i~4a~4i

Patients with monosomy 7 may present as classical MDS with abnormal erythroid, megakaryocyte and myeloid differentiation.8,4Z Monosomy 7 in lymphoid malignancy is unusuaP3 and lymphoblastoid cell lines from adults with 7q-/monosomy 7 retain heterozygosity for polymorphic markers on the long arm of chromosome 7.44 However, there are a few reports of monosomy 7 in lymphoid or biphenotypic leukaemias.24.45A’

Monosomy 7 in association with primary haematological malignancy occurs in 40% of MDS and 7% of AML in children, while in adults the prevalence is lower, occurring in 14% of adult MDS and 10% adult AML.10-‘2~30~48-j’ Monosomy 7 is usually a single-chromosome change in children but in adults is usually accompanied by other complex chromosomal rearrangements. With progression from MDS to AML, additional chromosomal abnormalities often occur. The age distribution is biphasic, with peak ages at 2-5 years and 60 years.3o No association with FAB groups32 occurs, although this classification is less applicable to children, in whom refractory anaemia with ring sideroblasts (RARS) is exceptionally rare, chronic myelomonocytic leukaemia (CMML) is more common, and two distinct groups, IMo7 and JCML, must be recognized. In childhood, unlike adulthood, there is a distinct male predominance (70-80%) of monosomy 7-associated MDS and AML.

Two conditions specific to young children deserve particular attention. JCML usually presents in boys aged 24 years, with characteristic facial and body rash, lymphadenopathy, hepatosplenomegaly, wasting and weight loss and typically with leucocytosis, thrombocytopenia, raised Hb F concentration (greater than 10%) and on bone-marrow morphology, features of CMML.‘3,54 Only 6% of JCMLs are reported to present with monosomy 7, although monosomy 7 may develop in association with

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progression to acute leukaemia. IMo7 typically presents at an even younger age range of 6 months-2 years. Pallor and bleeding due to anaemia and thrombocytopenia occur. Infections and leucocytosis are even more common than in JCML. Hepatos- plenomegaly occurs, but unlike in JCML, the rash is not seen and Hb F is not raised. All have monosomy 7 with refractory anaemia with excess of blasts (RAEB) or CMML morphology. A significant review of 68 cases of childhood MDS reported 19 with JCML (none with chromosome 7 abnormalities), 12 with IMo7 and 5 others with chromosome 7 affected (3 CMML, 2 RAEB).lS

Secondary monosomy 7

This group consists principally of adults. Occupational exposure to pesticides, organic solvents and petroleum derivatives are described in association with monosomy 7 in adults.20,55-57 However, no epi- demiological studies linking chromosome 7 abnormalities to such toxins in children have been reported. In childhood, secondary MDS is associated with cancer therapy.

At least 90% patients with therapy-induced MDS and AML (t-MDS and t-AML) have an abnormal karyotype and almost all of these have clonal aberrations affecting chromosomes 5 and 7 (-5, 5q-, -7, 7q-) .w* As with de novo disorders, trilineage dysplasia occurs with transformation to AML almost inevitably. The prognosis even with treatment is very poor. Monosomy 7 is particularly associated with use of alkylating agents and radiotherapy, with the risks increasing with age and the dose of drug. The risk peaks at 3-7 years after the treatment.1~22~59 As a greater proportion of patients survive a primary malignancy, an increase in the number of such t-MDS and t-AML cases is predicted. This is most relevant to patients in their teens and 20s who have survived childhood cancer. t-MDS and t-AML occur in l-2% of children treated for cancer”’ and chromosome 7 is involved in up to 60% of cases.61 Most of these patients were exposed to alkylating agents. Chromosome 5 abnormalities are observed in childhood cases but consider- ably fewer than in adult t-MDS and t-AML.

Aplastic anaemia has also been included in this secondary group. A follow-up of 38 patients with severe aplastic anaemia (SAA) showed that 5 developed MDS/AML, 3 with chromosome 7 abnormalities that were not detected at presentation.62 In addition, an association between SAA patients treated with granulocyte-colony stimulating factor (G-CSF) and the development of monosomy 7 MDS/AML has led to speculation that the cytokine may precipitate the latter.63,” However, prolonged survival brought about by

the cytokine may be unmasking a dysplasia as part of the course of the disease if the patient survives long enough.

Constitutional disorders

Congenital bone-marrow disorders predispose to leukaemia, usually via a myelodysplastic phase with a high incidence of clonal change involving chromosome 7. Monosomy 7 and 7q deletions in young children in association with congenital disorders, or as a familial condition, are particularly interesting in terms of the underlying molecular mechanisms. It is understandable that adults in their 5th-6th decades acquire genetic mutations in several critical genes and finally develop dysplasia with monosomy 7 at a relatively late age, as part of the ageing process. The occurrence in very young children is harder to explain in the light of the clear association of monosomy 7 in secondary MDWAML, suggesting that fetal toxin exposure may be important. The suspicion falls on inherited factors.65

Congenital neutropenia

The severe congenital neutropenias include congenital agranulocytosis or Kostmann’s syndrome, which presents in early infancy with extremely low granulocyte counts and infections.@ G-CSF is very effective, raising granulocyte counts and improving symp- toms.67s68 Mutations in the G-CSF receptor gene69 have been reported. However, there is an association between this therapy and the development of MDS or AML with monosomy 7, occurring with equal sex incidence.63~70~7’ A few cases of MDS and AML are reported in children who have not received growth factors,30,72 although chromosome 7 was not implicated in those. It is still not clear whether G-CSF really contributes to the development of MDS, AML and monosomy 7 or whether these developments are part of the natural history of the disease. It may be that G-CSF is enabling children to survive longer and experience the natural progression of this disorder to acute leukaemia, analogous to aplastic anaemia.

Shwachman’s syndrome

Shwachman’s syndrome is a rare autosomal recessive disorder of exocrine pancreatic dysfunction, skeletal abnormalities with short stature and haematological abnormalities, especially neutropenia or pancytope- nia.73 Progression to MDS and AML in association with monosomy 7 is widely recognized and occurs more commonly in boys.74

Monosomy 7 and lq- associated with MDS 49

NeuroJibromatosis type 1 JNFl)

Neurofibromatosis type 1 (NFI) is the commonest autosomal dominant genetic disease in humans. The gene, on chromosome 17, has been characterized and identified as a tumour suppressor whose loss of function appears to be associated with a variety of tumours of neural crest origin.75 The NFl gene also predisposes to the development of malignant myeloid disorders, which have a prevalence higher than expected in children with NF1.76,77 The risk of any malignant myeloid disorder, including JCML, in children with NFl is increased 200-500 fold.53,78 Children with NFl and MDS/AML may have loss of heterozygosity for an NFl allele, losing the normal allele and retaining the allele from the affected parent.79 Patients with NFl lack neurofibromin, the protein product of the NFl gene, which has sequence homology with GTPase-activating pro- teins (GAPS) which bind to and negatively regulate RAS, resulting in deregulated RAS activation. However, children with NFl and MDS/AML have a significantly increased incidence of monosomy 778 and those with NF-1 and JCML may acquire monosomy 7 during the course of their disease.*O The triad of NFl, monosomy 7 and MDS/AML tends to occur in boys and, although initial evidence suggested maternal inheritance of NF1,78 there is now evidence that NFl is not imprinted in haematopoietic cells.79 The association between NFl and leukaemia seems to occur only in young children and not in adults.8’ Activating RAS mutations occur in 30% of adult MDS and one study shows this to be specific to patients with monosomy 7.82 RAS mutations are also observed in childhood monosomy 7 cases.*3 The evidenceg4 supports the tumour-suppressor role for the NFl gene in haematopoietic cells, with neurofibromin being a regulator of RAS in early myelopoeisis.” The coexistence of RAS activation and monosomy 7 in MDS and the occurrence in boys with maternal inheritance of NFl, indicates that all these events may cooperate in the multistep process of leukaemogenesis.

Fanconi’s anaemia Fanconi’s anaemia (FA) is an autosomal recessive disorder characterized by pancytopnia, congenital anomalies, increased incidence of malignancy and spontaneous chromosome breakage.85 Leukaemia occurs in about 10% of FA patients and, of those with MDS or AML, 25% have chromosome 7 abnormalities.86-88 FA can be successfully treated by BMT, with 90% cured by allogeneic BMT but only if this occurs prior to the development of chromosome 7 abnormalities or leukaemic change.

Down’s syndrome

Down’s syndrome is associated with transient abnormal myelopoiesis (TAM), occurring in early infancy, and usually undergoes spontaneous remission. Some develop AML and the natural history of TAM is still unclear. The association with monosomy 7 is less widely recognized, with some studies confirming89-9’ and some excluding9’ its presence. However, one case of AML was shown, by FISH, to have the monosomy 7 clone affecting megakaryoblasts and not granulocytic cells9’ It is unlikely that the incidence of monosomy 7 in Down’s syndrome AML is higher than in the general population.

Familial monosomy 7 The familial occurrence of bone-marrow monosomy 7 has been reported,‘2.93-99 but only in one generation, with equal sex incidence, with a higher age at diagnosis compared to de novo cases and with no cases associated with consanguinity, so that the inheritance pattern is unclear. These patients have normal constitutional karyotypes with no abnormal chromosome breakage. Shannon proposed that a tumour-suppressor gene may be involved so that an inherited predisposition to cancer results from functional inactivation of one chromosome 7 allele, which is unmasked by loss of the normal chromosome 7 homologue. Familial cases would occur when siblings inherit the same abnormal allele (abnormality at the molecular level) on one chromosome 7 and then spontaneously lose the remaining protective homologous allele, in a haematopoietic progenitor cell developing 7q-lmono- somy 7 and hence deregulated growth and clonal expansion. In young children with non-familial monosomy 7, the first hit may occur in a parental gamete, during embryogenesis or even later after birth, again at the molecular level. A second hit then occurs spontaneously at a later stage resulting in loss of the 7q allele by deletion or monosomy. In cases of secondary MDS/AML, the first hit occurs following the toxic exposure and the second as above at a later stage. However, for this theory to be correct in familial cases, all siblings with monosomy 7 would have to share an abnormal allele on their remaining chromosome 7, inherited from the same parent (similar to familial retinoblastoma). With currently available probes, using restriction fragment length polymorphism (RFLP) analysis, this is not substantiated. Thus, the predisposing locus for familial monosomy 7 is not on the long arm of chromosome 7’oo,101 and must involve other genes not necessarily on chromosome 7. It is not altogether unexpected considering that, in contrast to the situation in retinoblastoma, where familial cases present earlier than non-familial cases,

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children with familial monosomy 7 tend to be older than those with de novo disease.

Genomic imprinting is a phenomenon whereby expression of a gene depends on the parental origin of the abnormal allele, which is inactive because it is imprinted. Several malignancies, e.g. Wilms’ tumour, have an inactivated copy of the tumour-suppressor gene through imprinting and thus preferential retention of alleles from the same parent. However, in unrelated and related patients, there is no consistent evidence to support genomic imprinting in monosomy 7.‘02,‘03

TREATMENT

In general, treatment for all patients with monosomy 7 or 7q- is inadequate. This cytogenetic abnormality identifies a group of MDS patients who always do badly, compared with 5q- and trisomy 8. Response to standard chemotherapy is poor, with a low remission rate. Allogeneic or unrelated donor BMT is usually the only chance of cure.‘7.40*54,1~1a7 Eighty per cent of children with monosomy 7 and MDS die within 5 years of diagnosis due to infection, transformation to resistant AML or myelofibrosis. Increase in the percentage monosomy 7 clone in the marrow, i.e. clonal evolution, is associated with disease progression in children and

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14

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RFLP Analysis Patients with Deletions

ELN

4 2 Patients COLl A2 DLX5+6 21 COLiA2

Breakpoints ASNS

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TACP 22.2 EPO 22.

E::

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ACHE ACHE PKANHl PLANHl CUTLl 3, CUTLl

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35

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4 2 Patients

Fig. A schematic representation of chromosome 7 showing the current knowledge of molecular karyotype by RELP and FISH analysis. Sites of breakage and associated genes are indicated.

adultsI In contrast, rare cases in which complete disappearance of the monosomy 7 clone has been documented, suggest that cure is possible if the chromosome 7-bearing clone is eradicated.16 This highlights the importance of accurately following the cytogenetic characteristics of all MDS patients by bone marrow examination. Transformation to AML with monosomy 7 is almost always fatal as is de novo AML with monosomy 7 at presentation.54 Some children and adults with apparent de novo AML have in fact experienced an undetected preleukaemic myelodysplastic phase with monosomy 7 developing during the progression to AML as retrospective studies have sometimes discov- ered.40 A prognostic scoring system for use in childhood MDS has been described. This is based on platelet count, HbF level and cytogenetic complexity (two or more clonal structural/numerical abnormalities), one point scored for each. A score of 0 gave 5-year survival of 61.6%, while a score of 2 or 3 resulted in 100% mortality by 5 years.”

MOLECULAR CYTOGENETICS OF CHROMOSOME 7 ALTERATIONS IN MDSlAML

Restriction fragment length polymorphism and karyotype analysis

Cytogenetic deletion mapping has shown that, in both AML and MDS, the chromosomes most commonly lost completely are 7 and Y, and that the region 7q22-36 is the extent of the deleted region in cases of partial loss on 7.5,20 7q22 and 7q32-34 represent the critical regions.4x22’44 Loss of heterozygosity (LOH) has been detected by RFLP analysis in 7 patients with 7q22 deletions (Fig.). The proximal breakpoints in these seven cases occurred between the genes for ery- thropoeitin (EPO), which was retained, and plasmino- gen activator inhibitor 1 (PLANHl), which was lost. More variability in the distal breakpoint at 7q34-35 is seen, which may or may not have involved the T-cell receptor beta (TCRB) gene. Another study using cosmid probes has demonstrated two critical regions, a 2-3 Mb-deleted region in proximal band 7q22 in 2 CML patients and a second 20 Mb region encompass- ing the terminal 7q22 band and the entire 7q31 band, in MDS/AML.lo8 Deletions are usually interstitial with variability in both breakpoints.32,‘09-“’ Studies of patients with primary and therapy-related MDS/AML has shownthat those without a visible chromosome 7 abnormality do not have molecular LOH by RFLP analysis.“~“’ The absence of LOH for 7q22 alleles in JCML with normal cytogenetic karyotypes is notable.l12 A high proportion of secondary

MDS/AML have losses in the same regions as primary disorders suggesting that, in both, the same gene(s) may be involved in deregulated myeloid growth in association with chromosome 7 abnormalities. Loss of at least one normal copy of one of these genes may be a critical step. When homozygosity, as well as hemizy- gosity, of a specific chromosomal region is found for a particular type of cancer, the existence of a tumour- suppressor gene is suggested. In monosomy 7, it is still unclear whether simply loss of one whole gene with the other remaining normal, haploinsufficiency, is enough to cause disease or whether there needs to be an additional mutation (or loss of function) on the remaining apparently healthy chromosome 7.

Fluorescence in situ hybidization

Most of the informative data are derived from adults. There are very few RFLP or FISH data from children because of the rarity of chromosome 7 deletions or other rearrangements as opposed to monosomy 7 in this group. However, it does support the involvement of the same critical regions as in adults. RFLP data and standard cytogenetic analysis generally agree in the detection of chromosome 7 abnormalities,“3 but these techniques have been boosted greatly by the introduction of FISH which, in patients with monosomy 7, allows disease progression and response to treatment to be followed by estimating the proportion of interphase cells with only one chromosome 7. Interphase FISH can determine the percentage monosomy 7 clone more accurately than metaphase analysis for several reasons. Far larger numbers of cells can be counted, many of which will be normal, but significant monosomy 7 clones can be identified although missed by metaphase FISH, in which divisions may be of normal cells.““L17 However, patients without monosomy 7 by standard or metaphase cytogenetics have not been shown to have a monosomy 7 clone by interphase FISH.“S Interphase FISH using chromosome 7- specific centromere probes would usually be performed in parallel with conventional cytogenetics, which is always the diagnostic gold standard. The retrospective study of fixed cell samples has shown the importance of karyotype evolution coincident with transformation to AML. FISH is useful to follow response to therapy, e.g. growth factors in MDS, and following BMT to detect relapse.

Newly available locus-specific cosmid and YAC probes have allowed more accurate definition of breakpoints in patients with MDS and chromosome 7 rearrangements.“’ A number of genes on chromosome 7q may be important (Fig.), e.g. acetylcholinesterase (ACHE),l19 erythropoietin (EPO),12’ asparagine synthetase (ASNS),‘@ and NEDD2, an


apoptosis regulatory gene mapped to 7q34.12’ Others need to be identified and, with ‘chromosome walking’ techniques using new YAC, PAC (Pl artificial chromosome; a vector containing approx 100-150 kb of DNA and relatively easy to manipulate) and cosmid probes from this region, this should be possible.

Interphase FISH can also be combined with immunophenotyping using lineage-specific antibodies. Hence, CD-34 positive cells can be identified and sig- nals compared with those from normal lymphocytes. These experiments support previous data suggesting that the chromosome aberrations in MDS are usually restricted to myeloid lineage.‘2’,‘23 Whole chromosome paints allow the identification of the chromosome origin of marker chromosomes, i.e. small fragments anonymous by standard cytogenetics. Not surpris- ingly, these are now widely reported in monosomy 7 patients.1’4s124 FISH will demonstrate the presence or absence of sequences incorporated within cosmid or YAC vectors and thus will help to define the minimum region of overlap in patients with deletions. Metaphase FISH is more accurate in this respect, although it is still difficult to obtain good-quality metaphase spreads from patient samples. Using whole chromosome paints, centromere probes and specific locus probes, translocations, inversions, ring chromosomes and deletions can be defined.27,‘25 The identification of probes that lie within a commonly deleted region on chromosome 7 will also allow the identification of putative tumour-suppressor genes.26

It is to be hoped that recent developments will allow even more accurate assessment of tumour samples. Multiplex FISH involves the hybridization of up to 27 different DNA probes simultaneously, using a pool of chromosome paints each labelled with a different fluorochrome. This colour karyotyping can be readily applied to monosomy 7 and 7q- and perhaps used as a screening test on any new MDS or AML patient. If abnormalities are found, then conventional cytogenet- its and FISH can be used to define these further.lZ6

CONCLUSION

Summary

The role of chromosome 7 in abnormal haematopoei- sis is still far from clear. There is still a relative scarcity of published data on childhood MDS with monosomy 7, making it difficult to compare with adult disease. However, it appears that the same regions on chromosome 7 are involved. Constitutional and other genetic factors play an essential role in children, whereas toxic exposure is of greater importance in adults. The male predominance in de novo MDS in children, in cases associated with NFl and in

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Shwachman’s syndrome but more equal sex incidence in Fanconi’s anaemia, Kostmann’s syndrome, familial monosomy 7 and in secondary cases suggest that the relationship with X-linked genes is complex.

Overall, submicroscopic loss of large segments of chromosome 7 DNA are uncommon in patients whose marrow does not show cytogenetically visible deletions. This still does not exclude small regions located between existing probes. All data suggest that chromosome 7 abnormalities are not the initiating event in MDS/AML. Additional genetic changes are certainly involved and ras-mediated signalling plays a significant role. It is likely that loss of function of a gene or genes on 7q contributes to leukaemic transformation Although there is no direct evidence, the haploinsufficiency theory is perhaps more attractive, with loss of one whole gene resulting in half the amount of a critical protein and this resulting in the abnormal phenotype.12’ Possibly, both gene dosage and tumour- suppressor mechanisms can lead to the development of MDS and its transformation to AML. A multistep process in monosomy 7-associated disorders is con- ceivable. Our current knowledge of the molecular pathogenesis of MDS is. currently sketchy, but with the recent identification of candidate genes in chromosome 7 bands q22 and q32-34 should lead to a greater understanding.

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Monosomy 7 and 7q- associated with myeloid malignancy