High frequency of BTG1 deletions in acute lymphoblastic leukemia in children with down syndrome

GENES, CHROMOSOMES & CANCER 51:196–206 (2012)

High Frequency of BTG1 Deletions in AcuteLymphoblastic Leukemia in Children withDown Syndrome

Catarina Lundin,1* Lars Hjorth,2 Mikael Behrendtz,3 Ann Nordgren,4 Lars Palmqvist,5 Mette Klarskov Andersen,6

Andrea Biloglav,1 Erik Forestier,7 Kajsa Paulsson,1 and Bertil Johansson1

1Departmentof Clinical Genetics,University and Regional Laboratories,Sk�ne University Hospital,Lund University,Lund,Sweden2Departmentof Pediatrics, Sk�ne University Hospital,Lund,Sweden3Departmentof Pediatrics,Link ping University Hospital,Link ping,Sweden4Departmentof Molecular Medicine and Surgery,Karolinska Institute,Stockholm,Sweden5Departmentof Clinical Chemistry and Transfusion Medicine,Sahlgrenska University Hospital,G˛teborg,Sweden6Departmentof Clinical Genetics,Rigshospitalet,Copenhagen,Denmark7Departmentof Clinical Sciences,Pediatrics,Universityof Ume�,Ume�,Sweden

Previous cytogenetic studies of myeloid and acute lymphoblastic leukemias in children with Down syndrome (ML-DS and

DS-ALL) have revealed significant differences in abnormality patterns between such cases and acute leukemias in general.

Also, certain molecular genetic aberrations characterize DS-related leukemias, such as GATA1 mutations in ML-DS and

deregulation of the CRLF2 gene in DS-ALL. Whether microdeletions/microduplications also vary between DS and non-DS

cases is presently unclear. To address this issue, we performed single nucleotide polymorphism array analyses of eight pedi-

atric ML-DS and 17 B-cell precursor DS-ALL. In the ML-DS cases, a total of 29 imbalances (20 gains and nine losses) and

two partial uniparental isodisomies (pUPDs) were detected. None of the 11 small (defined as <10 Mb) imbalances were

recurrent, nor were the pUPDs, whereas of the 18 large aberrations, three were recurrent—dup(1q), þ8 and þ21. In

contrast, several frequent changes were identified in the DS-ALL cases, which harbored 82 imbalances (30 gains and 52

losses) and four pUPDs. Of the 40 large changes, 28 were gains and 12 losses, with þX, dup(Xq), dup(1q), del(7p),

dup(8q), del(9p), dup(9p), del(12p), dup(17q), and þ21 being recurrent. Of the 40 microdeletions identified, several tar-

geted specific genes, with the following being repeatedly deleted: BTG1 and CDKN2A/B (29% of cases), ETV6, IKZF1, PAX5

and SERP2 (18%), and BTLA, INPP4B, P2RY8, and RB1 (12%). Loss of the SERP2 and INPP4B genes, encoding the stress-asso-

ciated endoplasmic reticulum protein family member 2 and the inositol polyphosphate 4-phosphatase-II, respectively, has

previously never been implicated in leukemia. Although deletions of the other genes have been associated with ALL, the

high frequency of BTG1 loss is a novel finding. Such deletions may characterize a clinical subgroup of DS-ALL, comprising

mainly boys with a high median age. In conclusion, ML-DS and DS-ALL are genetically distinct, with mainly gains in ML-DS

and deletions in DS-ALL. Furthermore, DS-ALL is characterized by several recurrent gene deletions, with BTG1 loss being

particularly frequent. VVC 2011 Wiley Periodicals, Inc.

INTRODUCTION

For >50 years, it has been known that children

with Down syndrome (DS) have an increased risk

of developing acute leukemia (Krivit and Good,

1957), with a cumulative risk of 2.1% at the age

of 5 years; this corresponds to a relative risk of �20 for myeloid leukemia (ML) and acute lympho-

blastic leukemia (ALL) in individuals with DS

(Hasle et al., 2000). Although ML is clearly over-

represented in DS (Hitzler and Zipursky, 2005),

ALL is still the most prevalent form of leukemia,

as it is in children without DS, comprising 60%

of DS-related leukemias (Hasle et al., 2000).

There is ample evidence that ML-DS and DS-

ALL are genetically quite distinct from pediatric

acute leukemias in general. In a review of the

cytogenetic features of DS-associated acute leu-

kemias, it was shown that ML-DS rarely display

rearrangements otherwise frequent in acute mye-

loid leukemia (AML), such as t(8;21)(q22;q22),

Additional Supporting Information may be found in the onlineversion of the article.

Supported by: Swedish Childhood Cancer Foundation; SwedishCancer Society; Swedish Research Council.

*Correspondence to: Catarina Lundin, Department of ClinicalGenetics, University and Regional Laboratories, Skane UniversityHospital, Lund University, Lund SE-221 85, Sweden.E-mail: [email protected]

Received 7 July 2011; Accepted 28 September 2011

DOI 10.1002/gcc.20944

Published online 10 November 2011 inWiley Online Library (wileyonlinelibrary.com).

VVC 2011 Wiley Periodicals, Inc.

11q23/MLL translocations and inv(16)(p13q22),

but have a higher frequency of dup(1q), del(6q),

del(7p), dup(7q), þ8, þ11, del(16q), and acquired

þ21. As regards DS-ALL cases, they significantly

more often harbor þX, t(8;14)(q11;q32) and

del(9p) but less often t(9;22)(q34;q11) and 11q23/

MLL translocations compared with non-DS-ALL

(Forestier et al., 2008). These leukemias are also

known to carry characteristic molecular genetic

aberrations, such as a high prevalence of mutated

GATA1 (at Xp11.23) in ML-DS (Wechsler et al.,

2002) and frequent deregulation of the CRLF2gene (Xp22.33/Yp11.3) and specific mutations of

JAK2 (9p24.1) in DS-ALL (Bercovich et al.,

2008; Kearney et al., 2009; Mullighan et al.,

2009; Russel et al., 2009). Whether the patterns

of cryptic copy number alterations, such as micro-

deletions, also vary between DS and non-DS leu-

kemias is largely unknown. Although several

single nucleotide polymorphism (SNP) array

studies of acute leukemias in children have been

reported (Kuiper et al., 2007; Mullighan et al.,

2007; Kawamata et al., 2008; Radtke et al., 2009;

Paulsson et al., 2010), only a few have addressed

DS-ALL; none has focused on ML-DS (Kawa-

mata et al., 2008; Kearney et al., 2009; Hertzberg

et al., 2010; Loudin et al., 2011). For this reason,

we have performed SNP array analyses of ML-

DS and DS-ALL to identify abnormalities that

may be characteristic for such leukemias and that

may have clinical ramifications.

MATERIALS AND METHODS

Patients

Between 1990 and 2011, 87 AML and 268 B-

cell precursor ALL cases in children/adolescents

(<18 years) were cytogenetically analyzed at the

Department of Clinical Genetics, Lund Univer-

sity, Sweden. Of the AML cases, 12 (14%) were

ML-DS and of the ALL patients, 12 (4.5%) had

DS. DNA from the time of diagnosis was avail-

able from five and eight of these ML-DS and

DS-ALL cases, respectively. For the present

SNP array study, DNA was also available from

three ML-DS and nine DS-ALL from the

Departments of Molecular Medicine and Surgery,

Karolinska Institute (Stockholm), Clinical Chem-

istry and Transfusion Medicine, Sahlgrenska Uni-

versity Hospital (Goteborg) and Clinical Sciences,

Pediatrics, University of Umea (Umea) in Swe-

den and from the Department of Clinical Genet-

ics, Rigshospitalet (Copenhagen) in Denmark.

Thus, a total of eight ML-DS and 17 DS-ALL

could be analyzed. The basic clinical and genetic

features of these cases are given in Tables 1 and

2. All DS-ALL cases had been analyzed prospec-

tively, or in some instances retrospectively, for

the presence of t(12;21)(p13;q22)/ETV6-RUNX1with FISH and/or RT-PCR; two (12%) of them

were positive for this fusion (Table 2). Nine of

the 17 DS-ALL cases (ALL1, ALL2, ALL6,

ALL7, ALL8, ALL14, ALL15, ALL16, and

TABLE 1. Clinical and Genetic Features of the Eight ML-DS Cases

CaseNo.

Sex/Age

WBC(�109/l)

Survival(months) Morphology

Karyotypeimbalances/UPDs identified by SNP array analysis

ML1 F/1 7.3 222þ M2 47,XX,ins(16;13)(q13;q12q14),þ21c/48,idem,þ8del(13)(q14.2q14.3),del(16)(q21q21),del(16)(q23.1q23.2),del(16)(q23.3q24.1),þ21

ML2 F/1 21 1 (DI) AML NOS 48,XX,þ8,t(17;21)(q21;q22),þ21cþ8,dup(20)(q13.12q13.13),þ21

ML3 F/1 51 191þ M7 49,XX,þ21c,þ21,þ22þ21,þ21,þ22

ML4 M/1 6.0 68þ M6 47,XY,i(7)(q10),þ21c [small clone with i(7)(q10)]del(3)(p14.1p14.1),þ21

ML5 M/2 11 209þ M1/M2 47,XY,der(10)t(1;10)(q23;p15),þ21c,der(22)t(11;22)(q13;p13)dup(1)(q24.2qter),UPD(9)(p21.3pter),del(9)(p21.3p21.3),UPD(9)(p13.3p21.3),dup(9)(p13.1p13.3), dup(11)(q13.1qter),dup(20)(q11.21q13.13),þ21

ML6 M/2 35 221þ M7 47,XY,add(7)(p?),þ21cdel(7)(p21.2),dup(13)(q31.3qter),þ21

ML7 F/3 3.3 55þ M7 47,XX,der(15)t(1;15)(p35;p13),þ21cdup(1)(p31.3p35.1),dup(1)(q32.1qter),del(5)(p13.2p13.2),þ21

ML8 M/4 8.6 150þ M7 52-54,XY,þ8,þ10,þ13,þ14,þ19,þ20,þ21c,þ22del(5)(p15.31p15.33),dup(6)(p22.2pter),þ8,þ10,del(11)(p11.2pter),dup(11)(q25q25),þ13,þ14, dup(19)(pterq13.2),þ20,þ21,þ21

AML NOS, acute myeloid leukemia not otherwise specified; DI, dead during induction therapy; DS, Down syndrome; F, female; M, male; ML, mye-

loid leukemia; SNP, single nucleotide polymorphism; UPD, uniparental isodisomy; WBC, white blood cell count; þ, still in complete remission 1.

BTG1 DELETIONS IN DS-ALL 197

Genes, Chromosomes & Cancer DOI 10.1002/gcc

ALL17; Table 2), from which metaphases were

available, were also analyzed with FISH as

regards t(X;14)(p22;q32)/t(Y;14)(p11;q32)/IGH@-CRLF2, using probes for the IgH@ locus and, in

rearranged cases, the X and Y centromeres; two

(22%) of the analyzed cases had t(X;14) and

t(Y;14), respectively (Table 2).

As the patients were treated according to dif-

ferent protocols since the early 1990s, no detailed

survival analyses have been performed in the

present study.

SNP Array Analyses

DNA was extracted from frozen bone marrow

(n ¼ 18), peripheral blood (n ¼ 4) or bone mar-

row cells in fixative (n ¼ 3), obtained at the time

of diagnosis, using phenol-chloroform or the

DNeasy Blood and Tissue kit (Qiagen, Sollen-

tuna, Sweden) according to the manufacturer’s

instructions. In all 25 cases (eight ML-DS and 17

DS-ALL), SNP array analysis was performed

using the Illumina 1M-duo bead Infinium BD

BeadChip platform, containing 1.2 million

TABLE 2. Clinical and Genetic Features of the 17 DS-ALL Cases

CaseNo.

Sex/Age

WBC(�109/l) EML

Survival(months)

Karyotypeimbalances/UPDs identified by SNP array analysis

ALL1a F/2 15 No 187þ 48,XX,þ21c,þmar þX,del(X)(p22.33p22.33),þ21

ALL2 F/3 2.8 No 18þ 47,XX,þ21cþ21

ALL3 F/3 42 No 63þ 47,XX,þ21cdel(X)(p22.33p22.33),UPD(12)(q24.11q24.13),þ21

ALL4 M/5 71 No 99þ Karyotypic failuredel(1)(q42.2),del(12)(p12.3p13.2),del(12)(q21.33q21.33),dup(17)(q21.31qter),þ21

ALL5 M/5 123 No 108þ 47,XY,der(4)t(X;4)(?;p16),þ21cdup(X)(q24qter),del(9)(p21.3p21.3),del(18)(p11.32),þ21

ALL6 M/5 7.0 No 12 (DCR1) 48-49,XY,?þ8,þ20,þ21c,þ21þX,del(5)(p15.1p15.1),del(9)(p21.3p21.3)x1-2,þ21,þ21

ALL7 M/6 25 No 165þ 47,XY,del(12)(p13p13),t(12;21)(p13;q22),þ21cdel(3)(p21.31p21.31),del(9)(p13.2p13.3),del(12)(p12.3p13.33),del(12)(q21.33q21.33),þ21

ALL8a M/8 65 No 32 (relapse) 47,dup(X)(q21q28),t(Y;14)(p11;q32),del(9)(p11p21),t(9;22)(q34;q11),del(11)(q22q25),þ21cdup(X)(q21.33qter),del(1)(p21.1p21.1),del(5)(q33.3q33.3),del(9)(p13.1p21.3),del(10)(p15.3p15.3),del(11) (q22.3),del(12)(q13.11q13.11),del(15)(q21.3q21.3),þ21

ALL9 F/8 0.5 No 115þ 55-59,X?,þ21c,incþX,del(1)(p11),dup(1)(q12qter),þ4,þ5,þ6,dup(9)(p13.1p21.2),þ11,þ14,dup(17)(q21.2qter),þ21,þ21,þ21, þ21

ALL10 F/8 16 No 75þ Karyotypic failureþX,del(9)(p21.3p21.3),þ21

ALL11 F/11 10 CNS 10 (DCR1) 49,XX,þ3,-4,þ5,t(6;20)(q13;q13),-8,i(9)(q10),-18,der(19)t(1;19)(q21;p13),þ21c,incdup(1)(q21.1qter),þ3,del(3)(q26.32q26.33),del(4)(q31.21q31.21),dup(5)(pterq31.3),del(5)(q14.3q14.3), del(5)(q31.3q32),UPD(6)(p21.1pter),del(6)(q12q15),del(7)(p12.1p12.2),del(8)(q21.3q22.1),dup(8) (q22.1qter),del(9)(p13.1),dup(9)(p13.1qter),del(13)(q14.2q14.2),UPD(17)(q11.2qter),þ21

ALL12 M/12 16 No 64þ 47,XY,del(12)(p13p13),t(12;21)(p13;q22),del(19)(p13p13),þ21cdel(3)(q26.2),del(12)(p12.3),dup(18)(p11.22pter),dup(20)(p11.21pter),þ21

ALL13a M/13 27 No <1 (DI) 47,XY,idic(7)(p11),þ21cdel(X)(p11.4p11.4),del(6)(p22.2p22.2),del(6)(q23.3q23.3),del(7)(p11.2),dup(7)(p11.1qter),del(10) (q25.1q25.1),del(12)(q21.33q21.33)x2,þ21

ALL14 F/13 7.5 CNS 12þ 47,XX,þ21cdel(3)(q13.2q13.2),del(13)(q14.11q14.11),del(13)(q14.2q14.2)x2,þ21

ALL15 M/14 14 No 14þ 47,XYc,t(X;14)(p22;q32),dic(7;16)(p11;p13.2),þ21cþX,del(1)(q32.1q32.1),del(4)(q31.21q31.21),del(7)(p11.2),del(12)(q21.33q22),del(13)(q14.11q14.11), del(16)(p13.2),del(16)(p12.1p12.3),dup(16)(p12.1p12.1),þ21

ALL16 F/15 5.9 No 62þ 47,XX,þ21cdel(3)(q13.2q13.2)x2,del(12)(q21.33q21.33),del(13)(q14.11q14.11),þ21

ALL17a M/16 13 No 2 (DCR1) 47,XY,t(8;14)(q11;q32),inv(12)(q13q24),der(14)t(8;14),þ21cdup(8)(q11.21qter),UPD(14)(q12qter),þ21

ALL, acute lymphoblastic leukemia; CNS, central nervous system; DCR1, dead in complete remission 1; DI, dead during induction therapy; DS,

Down syndrome; EML, extra-medullary leukemia; F, female; M, male; SNP, single nucleotide polymorphism; UPD, uniparental isodisomy; WBC,

white blood cell count; þ, still in complete remission 1.aThe original karyotypes of these cases have previously been reported by Lundin et al. (2009).

198 LUNDIN ETAL.


markers with a median physical distance between

markers of 1.5 kb (Illumina, San Diego, CA).

The analyses were done according to the manu-

facturer’s instructions, and data analysis was per-

formed using the BeadStudio 3.1.3.0 software

with Illumina Genome Viewer 3.2.9, extracting

probe positions from the GRCh37 genome build.

Constitutional copy number polymorphisms were

excluded based on comparisons with the Data-

base of Genomic Variants (http://projects.tcag.ca/

variation/) (Iafrate et al., 2004). Deletions most

likely corresponding to somatic rearrangements of

the T-cell receptor and immunoglobulin loci

were also excluded.

RESULTS

ML-DS Patients

Clinical features

Of the eight patients, four were males and four

females (sex ratio 1.0), with a median age of 1.5

years (range: 1–4 years). The median WBC count

was 9.8 � 109/l (range: 3.3–51). The morphologic

diagnoses were quite heterogeneous, comprising

four cases with M7, two M1 and/or M2, one M6

and one unclassifiable AML (secondary to a mye-

lodysplastic syndrome). All patients except one

are alive in complete remission 1 (CR1); one

patient died during induction therapy (Table 1).

Large genomic imbalances identified by SNP

array analysis

A total of 18 large imbalances (defined as �10

Mb) were identified among the ML-DS cases

(median two large imbalances per case; range:

0–8); there were 17 gains and one loss (Table 1,

Supporting Information Table 1 and Fig. S1).

Recurrent imbalances, found in two cases each,

comprised: (1) gain of 1q, with duplication of

1q32.1-qter in common; (2) gain of chromosome

8; and (3) additional chromosome 21.

Small genomic imbalances and UPDs identified

by SNP array analysis

A total of 11 small imbalances, i.e., <10 Mb,

all of which non-recurrent, were identified among

the ML-DS cases (median one small imbalance

per case; range: 0–4); there were three gains and

eight losses. No whole-chromosome UPDs were

found, whereas partial UPDs were seen in one

case harboring two different, non-overlapping 9p

UPDs (Table 1, Supporting Information Table 1

and Fig. S1).

DS-ALL Patients

Clinical features

Among the 17 patients, nine were males and

eight females (sex ratio 1.1), with a median age

of 8 years (range: 2–16 years). The median white

blood cell (WBC) count was 15 � 109/l (range:

0.5–123). Two patients had extra-medullary leu-

kemia at presentation, in both instances involving

the central nervous system. Events occurred in

five patients—three died in CR1, one died during

induction therapy and one died because of

relapse (Table 2).

Large genomic imbalances identified by SNP

array analysis

A total of 40 large imbalances were identified

among the DS-ALL cases (median one imbalance

per case; range: 0–13); there were 28 gains and 12

losses (Table 2, Supporting Information Table 2

and Fig. S2). Recurrent imbalances comprised:

(1) gain of chromosome X (seven cases), of which

five had þX and two had dup(Xq) with a com-

mon duplication of Xq24-qter; (2) gain of 1q in

two cases, with duplication of 1q21.1-qter in both

cases; (3) loss of 7p (two cases), with deletion of

7p11.2-pter in common; (4) gain of 8q (two

cases), with duplication of 8q22.1-qter in both

cases; (5) partial gain of chromosome 9 (two

cases), with a common duplication of

9p13.1-p21.2; (6) loss of 9p (two cases), with

deletion of 9p13.1-p21.3 in common; (7) loss of

12p (two cases), with deletion of 12p12.3-p13.33

in common; (8) gain of 17q (two cases), with a

common duplication of 17q21.31-qter; and (9)

additional chromosome 21 (two cases).

Small genomic imbalances identified by SNP

array analysis

A total of 42 small imbalances were found in

the DS-ALL cases (median two imbalances per

case; range: 0–7); there were two gains (involving

different chromosomes) and 40 losses (Table 2,

Supporting Information Table 2 and Fig. S2).

The following sub-bands were recurrently

deleted: (1) 12q21.33 (five cases, one of which

with a larger deletion involving also 12q22); (2)

9p21.3 (three cases); (3) 13q14.11 (three cases);

(4) Xp22.33 (two cases); (5) 3q13.2 (two cases);



(6) 4q31.21 (two cases); and (7) 13q14.2 (two

cases).

Recurrent gene deletions identified by SNP array

analysis

The following genes were recurrently deleted

in the DS-ALL cases (Table 3): (1) BTG1; lost

through focal deletions (i.e., involving only the

BTG1 gene) in four cases and through a slightly

larger deletion, involving one more gene, in one

case (29%); one of the focal deletions was homozy-

gous; (2) CDKN2A/B; lost in five cases (29%)—

three small (<10 Mb) and two large (�10 Mb)

deletions; (3) ETV6; lost in three cases (18%)—

one small and two large deletions; (4) IKZF1; lostin three cases (18%)—one small and two large

deletions; (5) PAX5; lost in three cases (18%)—

one small and two large deletions; (6) SERP2; lostthrough focal deletions in three cases (18%) (Fig.

1); (7) BTLA; lost in two cases (12%), one of which

with a homozygous deletion; (8) INPP4B; lost in

two cases (12%) (Fig. 2); (9) P2RY8; lost in two

cases (12%); and (10) RB1; lost in two cases (12%),

one of which harbored a homozygous deletion.

Uniparental isodisomies (UPDs) identified by SNP

array analysis

No whole-chromosome UPDs were identified,

whereas a total of four partial UPDs were found in

three cases; none of these were recurrent (Table

2, Supporting Information Table 2 and Fig. S2).

Partial imbalances/gene targets in common between

the ML-DS and DS-ALL cases

When comparing the SNP array findings in the

ML-DS and DS-ALL cases (Tables 1–3), the fol-

lowing sub-bands/gene targets were found to be

involved in both disorders: (1) deletion of 9p21.3/

CDKN2A/B (six cases: ML5, ALL5, ALL6,

ALL8, ALL10 and ALL11); (2) duplication of

1q32.1-qter (four cases: ML5, ML7, ALL9 and

ALL11); (3) deletion of 7p21.2-pter (three cases:

ML6, ALL13 and ALL15); (4) duplication of

9p13.1-p13.3 (three cases: ML5, ALL9 and

ALL11); and (5) deletion of 13q14.2/RB1 (three

cases: ML1, ALL11 and ALL14).

DISCUSSION

Although the present study is based on rela-

tively few ML-DS and DS-ALL cases, the SNP

array findings nevertheless strongly indicate that

these two disorders are genetically distinct, with

only a few changes in common, and that the pat-

terns of imbalances are different, with mainly

gains in ML-DS and deletions in DS-ALL. Fur-

thermore, DS-ALL was characterized by several

recurrent gene deletions, whereas no such gene

targets were identified in ML-DS.

All ML-DS patients were four years old or

younger and all of them, except one, are in CR1

(Table 1). This agrees well with previous studies

showing that ML-DS almost always develops at

an early age and that it is associated with a favor-

able outcome; ML-DS in older children, on the

TABLE 3. Recurrent Gene Deletions and their Locations in the 17 DS-ALL Cases

CaseNo.

BTG112q21.33

BTLA3q13.2

CDKN2A/B9p21.3

ETV612p13.2

IKZF17p12.2

INPP4B4q31.21

PAX59p13.2

P2RY8Xp22.33

RB113q14.2

SERP213q14.11

ALL1 XALL2ALL3 XALL4 X XALL5 XALL6 XALL7 X X XALL8 X X Xa

ALL9ALL10 XALL11 X X X X XALL12 XALL13 X XALL14 X X XALL15 X X X Xa XALL16 X X XALL17

ALL, acute lymphoblastic leukemia; DS, Down syndrome.aALL8 and ALL15 harbored t(Y;14)(p11;q32) and t(X;14)(p22;q32), respectively.

200 LUNDIN ETAL.


Figure

1.

ThreeDS-ALLcasesharboredfocaldeletionsoftheSERP2

gene.ThepositionsofFA

S(firstabnorm

alSN

P),LAS(lastabnorm

alSN

P),andtheSERP2

geneareaccordingto

theGRCh37genomebuild.



Figure

2.

TwoDS-ALLcasesharboreddeletionsoftheINPP4Bgene.ThepositionsofFA

S(firstabnorm

alSN

P),LAS(lastabnorm

alSN

P),andtheINPP4Bgene

areaccordingto

theGRCh37genomebuild.

202 LUNDIN ETAL.


other hand, is biologically and clinically quite dif-

ferent (Ravindranath et al., 1992; Creutzig et al.,

1996; Lie et al., 1996; Lange et al., 1998; Athale

et al., 2001; Gamis et al., 2003; Hasle et al.,

2008). Thus, our cohort is representative of ‘‘typi-

cal’’ ML-DS. As in pediatric AML in general

(Radtke et al., 2009), relatively few submicro-

scopic imbalances were identified by SNP array

analysis. In fact, large imbalances, which in prin-

ciple are cytogenetically visible, were more fre-

quent than small ones, of which none was seen in

more than one case (Supporting Information Ta-

ble 1 and Fig. S1). Among the large imbalances,

the only recurrent changes were gains, namely

dup(1q), þ8, and þ21—all these have previously

been reported to be particularly prevalent in ML-

DS (Forestier et al., 2008). Thus, relatively little

new information on additional genetic changes in

ML-DS was gained through the present SNP

array analysis, despite the high resolution level of

the platform used.

Of the 17 DS-ALL cases, five (29%) have died

(Table 2). Although treated according to different

protocols for approximately 20 years, this would

nevertheless seem to indicate a worse outcome of

DS-ALL as compared with pediatric ALL in gen-

eral in the Nordic countries during this time pe-

riod (Zeller et al., 2005) and would also agree

with several studies showing a poor prognosis of

DS-ALL, something that is often ascribed to

chemotherapy-related toxicity (Robison et al.,

1984; Blatt et al., 1986; Levitt et al., 1990; Dor-

delmann et al., 1998; Whitlock et al., 2005; Zeller

et al., 2005). Several recurrent large imbalances

were identified—gain of chromosome X material,

dup(1q), del(7p), dup(8q), dup(9p), del(9p),

del(12p), dup(17q), and þ21; only þX was de-

tected in more than two cases. Gain of chromo-

some X material and del(9p) have previously

been reported to be significantly more common

in DS-ALL than in non-DS-ALL (Forestier

et al., 2008). The pathogenetic consequences of

the nine large changes listed above are, with the

possible exception of del(7p), del(9p), and

del(12p) (see below), unknown. However, the

minimally gained chromosome X segment (Xq24-

qter) includes the SPANXB gene at Xq27, whose

overexpression has been suggested to play a func-

tional role in t(12;21)(p13;q22)/ETV6-RUNX1-pos-itive ALL (Lilljebjorn et al., 2007). Furthermore,

dup(1q)—one of the most common structural

changes in B-lineage ALL (Mitelman et al.,

2011)—has been associated with overexpression

of the DAP3 and UCK2 genes (Davidsson et al.,

2007). Whether SPANXB, DAP3, and UCK2 have

a pathogenetic impact in DS-ALL remains, how-

ever, to be determined.

The SNP array analysis revealed several dele-

tions associated with loss of specific genes in DS-

ALL (Table 3). Most of the targets, i.e., BTLA at

3q13.2, CDKN2A/B at 9p21.3, ETV6 at 12p13.2,

IKZF1 at 7p12.2, PAX5 at 9p13.2 and RB1 at

13q14.2, have previously been identified and dis-

cussed in several studies of pediatric ALL, in

some instances including children with DS

(Kuiper et al., 2007; Mullighan et al., 2007; Kawa-

mata et al., 2008; Kearney et al., 2009; Hertzberg

et al., 2010; Lilljebjorn et al., 2010; Paulsson

et al., 2010; Loudin et al., 2011). For example,

deletions of IKZF1, encoding the lymphoid tran-

scription factor IKAROS, have been associated

with high risk ALL and poor outcome (Collins-

Underwood and Mullighan, 2010). It may hence

be noteworthy that two of the three DS-ALL

cases with IKZF1 deletions succumbed to the

disease (Tables 2 and 3). Two of the DS-ALL

cases (ALL1 and ALL3; Table 3) had microdele-

tions of Xp22.33, resulting in loss of P2RY8. Inaddition, two cases had IGH@ translocations

involving Xp/Yp. Such rearrangements were

recently reported to deregulate the expression of

the CRLF2 gene, located in the vicinity of

P2RY8, in a large proportion of DS-ALL and to

be associated with IKZF1 deletions and a poor

prognosis (Mullighan et al., 2009; Russel et al.,

2009; Cario et al., 2010; Harvey et al., 2010;

Hertzberg et al., 2010; Yoda et al., 2010). How-

ever, only one of our four cases had loss of

IKZF1 (ALL15) and all but one (ALL8) are alive

in CR1 (Tables 2 and 3).

Three more regions were recurrently lost

through small, often focal, deletions in the DS-

ALL cases, namely 4q31.21, 12q21.33, and

13q14.11 (Table 3). As regards 4q31 and 13q14,

deletions involving these bands have previously

been identified by SNP array analyses of child-

hood ALL, including DS-ALL (Mullighan et al.,

2007; Kawamata et al., 2008; Kearney et al.,

2009). However, no gene targets were identified

in these studies. Herein, we could show that the

deletions comprised two genes in 4q31.21

(INPP4B and USP38) (Fig. 2) and only one gene,

SERP2 (Fig. 1), in 13q14.11. To the best of our

knowledge, neither USP38 (ubiquitin specific

peptidase 38) nor SERP2 (stress-associated endo-

plasmic reticulum protein family member 2) has

been associated with neoplasia, whereas INPP4B,coding for inositol polyphosphate 4-phosphatase-



II that regulates the phosphoinositide 3-kinase

(PI3K) signaling pathway, has recently been

implicated as a tumor suppressor gene in breast,

ovarian and prostate cancer (Gewinner et al.,

2009; Fedele et al., 2010; Hodgson et al., 2011).

Next to nothing is known about the role, if any,

of INPP4B in leukemia, apart from a single study

reporting INPP4B to be overexpressed in BCR/ABL1-positive childhood ALL compared with

other genetic subgroups (Ross et al., 2003).

BTG1 (a.k.a. B-cell translocation gene 1) at

12q21.33 was initially identified as a translocation

partner to MYC in a case of chronic lymphocytic

leukemia with t(8;12)(q24;q22) (Rimokh et al.,

1991). Subsequent studies have shown that BTG1

is a versatile player that is highly expressed in, for

example, lymphoid tissues and endothelial cells

and that negatively regulates cell proliferation, is

pro-apoptotic, plays a role in angiogenesis, stimu-

lates myoblast differentiation and is associated

with glucocorticoid (GC) responsiveness (Rimokh

et al., 1991; Rouault et al., 1992; Yoshida et al.,

2002; Kolbus et al., 2003; Lee et al., 2003; Iwai

et al., 2004; Busson et al., 2005). Interestingly,

van Galen et al. (2010) recently showed that loss

of BTG1 expression results in GC resistance and

that this may be overcome by re-expression of the

gene. Thus, BTG1 deletions in ALL may have

clinical ramifications. We identified BTG1 loss in

five (29%) of the DS-ALL cases, four of which

with focal deletions, making it the most common

gene deletion, together with CDKN2A/B, in this

disorder (Table 3). It may be noteworthy that four

of the five patients were boys and that the median

age was 13 (Table 2), whereas the male/female ra-

tio and median age of the non-BTG1 deleted

cases were 0.7 and eight years, respectively. This

may indicate that cases with BTG1 deletions rep-

resent a specific clinical subgroup of DS-ALL.

Since previous genome-wide analyses of DS-ALL

have not identified BTG1 deletions, perhaps

because of lower resolution levels (Kearney et al.,

2009; Hertzberg et al., 2010; Loudin et al., 2011),

further studies are needed to clarify this issue and

also to investigate whether loss of BTG1 has prog-

nostic implications. Previous SNP array analyses

of pediatric B-cell precursor non-DS-ALL have

shown that the BTG1 gene is deleted in approxi-

mately 7% (Mullighan et al., 2007), with such

deletions being particularly common (10–25%) in

t(12;21)-positive ALL (Kuiper et al., 2007; Mul-

lighan et al., 2007, 2008; Tsuzuki et al., 2007; Lill-

jebjorn et al., 2010). In fact, one of the two

t(12;21)-positive ALLs in the present study har-

bored a BTG1 deletion (ALL7, Tables 2 and 3).

Why BTG1 seems to be especially often targeted

in DS-ALL and in ALL with t(12;21) is unknown

and somewhat intriguing since there are no

obvious clinical similarities between these two

subgroups, although it may be noteworthy that

gain of chromosome 21 is one of the most com-

mon secondary changes in t(12;21)-positive ALL

(Forestier et al., 2007; Lilljebjorn et al., 2010).

Perhaps BTG1 deletions are associated with tris-

omy 21 as such, both as a constitutional and as an

acquired abnormality? However, considering that

no BTG1 deletions were seen in a recent, large

SNP array study of high hyperdiploid ALL

(Paulsson et al., 2010), a subtype characterized by

multiple gains, including trisomies and tetraso-

mies of chromosome 21 (Paulsson and Johansson,

2009), the possible association between þ21

and BTG1 loss is apparently not a general

phenomenon.

ACKNOWLEDGMENT

The SNP array experiments were performed

by Sciblu Genomics at Lund University, Lund,

Sweden.

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High frequency of BTG1 deletions in acute lymphoblastic leukemia in children with down syndrome