Gain of 1q in pediatric myelodysplastic syndromes

Leukemia Research 30 (2006) 1437–1441

Brief communication

Gain of 1q in pediatric myelodysplastic syndromes Cristina Morerio, Annamaria Rapella, Elisa Tassano, Edoardo Lanino, Concetta Micalizzi, Cristina Rosanda, Claudio Panarello ∗ Dipartimento di Ematologia ed Oncologia Pediatrica, IRCCS Istituto Giannina Gaslini, Largo G. Gaslini 5, 16147 Genova, Italy Received 16 December 2005; received in revised form 16 December 2005; accepted 22 December 2005 Available online 10 February 2006

Abstract The presence of acquired clonal cytogenetic abnormalities in hematopoietic cells is one of the diagnostic hallmarks of myelodysplastic syndromes (MDS). Such anomalies may help in defining prognostic groups. We analyzed eight pediatric MDS, and herein describe three new cases, one de novo and two therapy-related, presenting an unbalanced rearrangement of 1q: one of them resulted in a derivative chromosome 6 apparently identical to a previously described one. We also review all the cases of gain of 1q reported in de novo and therapy-related childhood MDS. © 2006 Elsevier Ltd. All rights reserved. Keywords: Childhood myelodysplastic syndrome; Cytogenetic abnormalities; Gain of 1q; Prognostic groups

1. Introduction Myelodysplastic syndromes (MDS) are heterogeneous clonal disorders of hematopoietic stem cells characterized by refractory cytopenia and multilineage dysplasia: typical of adult age patients in whom an indolent clinical course usually manifests, they are uncommon in childhood, where conversion to acute myeloid leukemia is frequent. The WHO classification of MDS has recently been modified and adapted to the peculiar characteristics of pediatric cases: according to Hasle et al. [1] there are three major categories with distinct biological and clinical features: myeloproliferative/myelodysplastic disease, including juvenile myelomonocytic leukemia (JMML) as the most common disorder of this category; transient myeloproliferative disorder associated with Down syndrome; myelodysplastic syndromes such as refractory cytopenia (RC), refractory anemia with excess of blasts (RAEB), RAEB in transformation to acute myeloid leukemia (RAEBT). Myelodysplastic syndromes can occur either de novo or secondary to cytotoxic ∗

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chemotherapy and/or radiotherapy for a previous malignancy. Nonrandom chromosome abnormalities are detected in about 50% of de novo and almost all therapy-related MDS (tMDS) patients [2,3]; most of these are complete or partial loss of chromosome 7, trisomy 8 and, in adults only, deletion of the long arm of chromosome 5. Unbalanced rearrangements involving the long arm of the chromosome 1 and leading to its trisomy are found in a consistent proportion of de novo and tMDS, most often in adults, but only episodically in children [2,4–6]. The occurrence of trisomy 1q may be underestimated, since it is often reported as an unbalanced translocation t(1;7), a rather common feature in MDS. Here we analyzed the karyotypes of our MDS cases and compared them to those reported in the literature in order to draw attention to this feature and to lend further insight into its clinical correlation. 2. Patients and methods A total of eight pediatric MDS diagnosed at our Institution from 1998 to 2005 were successfully karyotyped. Patients with either JMML or myelodysplastic features associated with inherited predisposition (e.g., Fanconi’s anemia,

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C. Morerio et al. / Leukemia Research 30 (2006) 1437–1441

Table 1 Clinical and cytogenetic data of MDS patients Case no.

Sex/agea

Disease

Karyotype

1 2 3 4 5 6 7 8

F/6 M/11 M/13 F/15 F/18 M/8 M/5 F/22

De novo RAEB Secondary to MB Secondary to NB De novo RC De novo RC De novo RC De novo RC Secondary to NB

48,XX,qdp(1)(q21q42),dup(3)(q12q26),+8,+19 46,XY,der(6)t(1;6)(q21;p21∼22) 46,XY,der(7)t(1;7)(q22;q22)/49,idem,+8,+9,+14 46,XX 46,XX 46,XY 47,XY,+8 46,X,-X,t(3;3)(p36;q21),add(4)(p1?6),+mar

Latency periodb 9 7

9

Treatment of MDS/survivalc alloBMT/2 alloBMT/1.5 0.5+ alloBMT/1 4+ alloBMT/3+ alloBMT/7+ 1.5+

MB: medulloblastoma; NB: neuroblastoma; alloBMT: allogeneic bone marrow transplantation. a Age (years) at onset of MDS. b Years between stop therapy for primary tumor and MDS diagnosis. c Years of survival from MDS diagnosis.

Shwachman syndrome, Blackfan-Diamond syndrome, neurofibromatosis, etc.) were excluded [1]. Five were de novo and three secondary to therapy (Table 1). Three of them presented a cell clone with gain of 1q in bone marrow (BM). 2.1. Patient 1 A 6-year-old girl was diagnosed with myelodysplasia (RAEB) in Iraq. She was treated in her country with transfusional support for 2 years; after identification of an unrelated donor match she was referred to our institution to receive marrow transplantation (BMT). Pre-transplant BM aspirate was severely hypocellular, with 18% myeloblasts. The patient died shortly after BMT with veno-occlusive disease of the liver, disseminated aspergillosis and severe hemorrhagic syndrome secondary to platelet transfusion refractoriness.

del(1p) and MYC-N amplification. Chemotherapy according to AIEOP-NB97 protocol included Ifosfamide, Doxorubicin, Etoposide, Carboplatin and Cyclophosphamide. Partial remission was consolidated with two cycles of metabolic radiotherapy (I131-MIBG) and myeloablative chemotherapy (Busulphan, Thiotepa and Melphalan) followed by autologous peripheral blood stem cell rescue. Treatment ended in complete remission after 12 additional cycles of low

2.2. Patient 2 A 7-month-old boy was diagnosed with medulloblastoma and was treated according to UKCCSG SNC 9204 Protocol. After surgical resection chemo- and radiotherapy (7.2 Gy—60 Co, posterior fossa) were administered for 14 months (Carboplatin, Etoposide, Cyclophosphamide, Vincristin, Thiotepa, Methotrexate). At 11 years of age he came to our observation with a history of cold abscesses responsive only to steroids, and a diagnosis of “streaking leukocyte syndrome”, or PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum and acne), was hypothesized, with possible cyclic neutropenia. Marrow was hyperplastic with trilinear myelodysplastic features, numerous abnormal megakaryocytes, hyperplastic and vacuolated myeloid series with partial deficit of myeloperoxidase, slight dyserythropoiesis. MDS was rated as refractory cytopenia; diagnosis came 9 years after stopping chemotherapy. Allogeneic BMT from a partially matched unrelated donor failed, and the patient died with disseminated aspergillosis. 2.3. Patient 3 A 6-year-old boy was diagnosed with stage IV neuroblastoma. Karyotype of neuroblasts was hyperdiploid with

Fig. 1. (a) Partial Q-banded karyotype. (b) FISH analysis using ␣-satellite probes of chromosomes 1 (red) and 6 (green). (c) FISH analysis using BAC probes RP11-59N15 at 6p22.2 (red) and RP11-30I17 at 1q12.1 (green). Hybridization signals at 6p22.2 are present only on normal chromosome 6 (arrow) while derivative 6 (arrowhead) exhibit only 1q21.1 signals.

C. Morerio et al. / Leukemia Research 30 (2006) 1437–1441

dose IL-2, 14 months after initial diagnosis. At the age of 13 years, repeated bleeding episodes prompted a diagnosis of deficit of platelet function; subsequently, platelet counts decreased and the patient came back to our observation 8 years after initial diagnosis. Marrow aspirate was normocellular with slight signs of myelodysplasia and 2% blasts. BMT from his HLA-identical sister has been planned for the near future.

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chromosome 1 with 6 (patient 2) or 7 (patients 1 and 3) or 4 (patient 8) painting probes (wcp) (Appligene OncorQbiogene, Illkirch, France), and ␣-satellite probes for chromosomes 1 (Oncor) and 6 (pEDZ6) (patient 2). The BAC probes RP11-59N15 for the locus on 6p22.2 and RP11-30I17 for 1q21.1 were also used (patient 2). Multiple-color FISH (M-FISH) was run on BM metaphases of patient 2 according to the manufacturer’s protocol with the SpectraVysion Assay (Vysis, Downers Grove, IL, USA).

2.4. Cytogenetic and fluorescence in situ hybridization (FISH) analyses

3. Results and discussion

Chromosome analyses by quinacrine-banding technique were performed on BM cultures from all patients, and on fibroblast cultures from a skin biopsy of a cold abscess from patient 2. FISH was carried out on BM metaphases according to the manufacturer’s protocol, cohybridizing whole-

The karyotypes of BM cells of eight patients are shown in Table 1. Of these, two out of five de novo MDS were abnormal, as were all three tMDS. Patient 1 showed a quadruplication of 1q, as well as duplication of 3q, trisomy 8 and 19, while patient 3 presented a

Table 2 Pediatric MDS with trisomy 1q Case no.a

Sex/age (y)

MDS subtype

Status/primary disease

Karyotype

Outcome

Ref.

7 26 12 513 1 1

M/17 F/17 M/16 F/18 F/18 F/15

MDS RAEB MDS RAEBT MDS RAb

De novo De novo De novo De novo De novo De novo

46,XY,t(1;7),−7/47,XXY,t(1;7),−7 46,XX,+der(1)t(1;7)(p11.2;p11.2),−7 48,XY,+der(1)t(1;7)(p11;p11),−7,+8,+21 46,XX,+der(1)t(1;7)(p11;p11),−7 46,XX,der(17)t(1;17)(q21;p11) 46,XX,qdp(3)(q21q27),der(15)t(1;15)(q11;p11)

nk D D D 4 y+ D

[12] [13] [8] [14] [15] [16]

11

M/16 M/16

RA RA

De novo De novo

46,XY,+der(1)t(1;7)(p11;p11),−7/49,idem,+8,+14,+21 45,XY,−7/47,XY,+der(1)t(1;7)(p11;p11),−7,+8

D D

[17] [18]

1 21

M/7 M/3

RAEB RAEBT

De novo De novo

c

D

[19] [20]

42

F/14

MDS

De novo

46,XY,der(7)t(1;7)(q11;q11) der(Y)t(Y;?)(q12;?),+der(Y),der(5)t(5;?)(q35;?),−17,+ der(17)t(17;?)(q21;?),der(22)t(1;22;?)(q11q32;p11;?),+16 der(7)t(1;7)(p10;q10),+8

D

[20]

5

M/1 F/15 M/d

RA RA RA

De novo De novo De novo

1 3 9 12 10

F/6 M/6 M/15 M/19 M/11

RAEB RAEB RA RA RAEBT

183

M/18 F/12 d d

2 3

M/11 M/13

Short follow up 9 y+ nk

[21] [22] [23]

De novo Sec/ALL Sec/ALL Sec/HD Sec/ALL

47,XY,+11,+21/48,idem,dup(1)(q21q42) 46,XX,der(19)t(1;19)(q12;p13) 46,XY,+der(1)t(1;7)(p11;p11),−7 → 47,XY,+der(1)t(1;7)(p11;p11),−7,+8 48,XX,qdp(1)(q21q42),dup(3)(q12q26),+8,+19 der(16)t(1;16)(q31;q12)f 47,XY,+der(1)t(1;7)(p11;p11),−7,+8 49,XY,+der(1)t(1;7)(p11;p11),−7,+8,+15,+21/46,XY,+der(1),−18 46,XY,der(1)t(1;11)(q32;q23),add(11)(q23)/47,idem,+21

D D D D Short follow up

[24] [24] [24] [25]

MDS RC MDSg MDSg

Sec Sec/PNET Sec Sec

47,XY,der(11)t(1;11)(q21;q23),+mar/48,idem,+mar 46,XX,der(6)t(1;6)(p12;p22)dup(6)(p22p22) −7,der(1;7)(q10;p10) −7,der(1;7)(q10;p10)

D D nk nk

[26] [7] [27] [27]

RC RC

Sec/MD Sec/NB

46,XY,der(6)t(1;6)(q21;p21∼22) 46,XY,der(7)t(1;7)(q22;q22)/49,idem,+8,+9,+14

D 0.5+

e

e

e

y, years; nk, not known; D, dead; RA, refractory anemia; ALL, acute lymphoblastic leukemia; HD, Hodgkin’s disease; PNET, primitive neuroectodermal tumor; MD, medulloblastoma; NB, neuroblastoma; BMT, bone marrow transplantation. a The patient number of the original series is reported. b Refractory cytopenia (RC) has recently been suggested as a more appropriate term than refractory anemia (RA) in childhood, since anemia is not always present [1]. c Patient progressed to leukemia despite treatment. d Childhood series, the single case is not specified. e Present study. f Very complex karyotype not reported here. g In this series of tMDS, chronic myelomonocytic leukemias are included.

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1;7 unbalanced translocation confirmed by wcp FISH. Moreover, wcp FISH did not display chromosome 1 rearrangement in patient 8. In patient 2 the karyotype of fibroblast cells from a cold abscess resulted normal, while the 1;6 unbalanced translocation revealed in BM was confirmed by FISH with wcp, and the RP11-30I17 signal (1q21.1) was retained on der(6) chromosome. The ␣-satellite probes of chromosomes 1 and 6 showed a unique centromere for the der(6). The hybridization with the RP11-59N15 at 6p22.2 to detect the possible duplication of that locus revealed the lack of signal on der(6), thereby placing the breakpoint centromeric to the band 6p22.2. M-FISH experiment did not show other chromosome anomalies. Mathews et al. [7] described a similar case of a tMDS pediatric patient with karyotype 46,XX,der(6)t(1;6)(p12;p22.2)dup(6)(p22.2p22.2), with a dicentric chromosome dic(1;6), suggesting a new characteristic rearrangement. The Q-band karyotype of our case was seemingly identical to the one described (Fig. 1a), but FISH experiments excluded the presence of the dicentric derivative chromosome and of the duplication of 6p22 band (Fig. 1b and c). The occurrence of three cases with gain of 1q out of eight pediatric MDS patients karyotyped at our institute prompted us to perform a literature search. To the best of our knowledge 25 cases (including the three reported here) of pediatric MDS have been associated with gain 1q (Table 2), two with a duplication or quadruplication of 1q21∼q42 region and 23 derived from an unbalanced translocation. In 14 of them (60.9%) the partner was chromosome 7: one normal chromosome 7 was lost and replaced by a derivative one composed of the short arm of 7 and the long arm of 1, thereby resulting in monosomy 7q and trisomy 1q [8]. In such cases the incidence of trisomy 1q may be underestimated, due either to the high frequency of total or partial monosomy 7 in pediatric and adult MDS [2,9], or to the fact that only the loss of 7q and not the gain of 1q is noticed. A comprehensive European study on 142 children with de novo MDS and 166 children with JMML [10] showed no significant difference in survival between cytogenetic favorable (normal karyotype) and unfavorable (chromosome 7 abnormalities and complex aberrations (≥three anomalies)) prognostic groups as identified previously in adults [11]. In adults Fonatsch et al. [9] hypothesized that the trisomy 1q not resulting from the t(1;7) was specific for a subgroup of MDS characterized by young age of onset and non-aggressive clinical course. The nine childhood cases reported to date (Table 2) with this feature seem to share the same poor prognosis as the t(1;7) group.

Acknowledgments The authors thank Antonella Casalaro for technical assistance; Prof. M. Rocchi (University of Bari, Italy) for pEDZ6, RP11-59N15 and RP11-30I17 clones. This work was supported by the Fondazione Gerolamo Gaslini, the Fondazione Carige and the Compagnia di S. Paolo.

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