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Inverted duplication dup(1)(q32q21) as sole aberration in lymphoid and myeloid malignancies
Cancer Genetics and Cytogenetics 188 (2009) 108e111
Short communication
Inverted duplication dup(1)(q32q21) as sole aberration in lymphoid and myeloid malignancies Ulrike Bachera, Susanne Schnittgerb, Andreas Gru¨neisenc, Torsten Haferlachb, Wolfgang Kernb, Claudia Haferlachb,* a
Interdisciplinary Clinic for Stem Cell Transplantation, University Cancer Center Hamburg (UCCH), Germany b MLLeMunich Leukemia Laboratory, Max-Lebsche-Platz 31, 81377 Munich, Germany c Department of Hematology and Oncology, Neuko¨lln Hospital, Berlin, Germany Received 21 April 2008; received in revised form 15 August 2008; accepted 2 September 2008
Abstract
Partial gains of chromosome 1q as isolated aberrations are rare occurrences in hematologic malignancies. A recent report of a sole duplication dup(1)(q21q32) in myelodysplastic syndrome (MDS) suggested an inferior prognosis. To further describe structural anomalies involving the 1q21 and 1q32 breakpoints, we present four cases with an inverted dup(1)(q32q21): three in B-cell precursor acute lymphoblastic leukemia (ALL) and one in MDS of the subtype refractory cytopenia with multilineage dysplasia and ringed sideroblasts. In all four cases, the aberration presented as the sole anomaly at diagnosis. In one of the ALL cases, relapse during chemotherapy, 5 months from diagnosis, was accompanied by clonal evolution; in another ALL case, early relapse appeared 51 days after allogeneic stem cell transplantation. Structural gains of 1q involving 1q32 and 1q21 breakpoints can occur in different hematological malignancies. The isolated occurrence of the inverted dup(1)(q32q21) may be interpreted as a typical primary alteration in B-lineage ALL paving the way to acquisition of additional abnormalities. Identification of more cases could further clarify the role of 1q duplications with the q21 and q32 breakpoints in hematological malignancies and better define the prognosis associated with sole aberration in the single entities. Ó 2009 Elsevier Inc. All rights reserved.
1. Introduction Structural gains of 1q are found in diverse hematological malignancies of both myeloid and lymphoid origin: In myelodysplastic syndromes (MDS), gain of 1q was described in ~15% of all cases [1,2]; in most cases, this resulted from unbalanced translocationsdfor example, with 7q [3] or 5q as partner chromosomes [4]. Most MDS cases showing gains of 1q exhibit additional chromosomal abnormalities [5e7]. Furthermore, in AML gain of 1q is usually accompanied by complex aberrations, as defined by the simultaneous occurrence of >3 clonal chromosomal abnormalities. With respect to the lymphoid malignancies, partial gain of 1q was described as the most frequent structural abnormality in the hyperdiploid subgroup of B-lineage ALL [6,8,9]. In Bnon-Hodgkin lymphoma (B-NHL), structural rearrangements of 1q most often affect the region 1q21~q22, usually embedded in complex aberrations [10,11].
Gains of 1q seem to occur only exceptionally as isolated aberration in hematologic malignancies [11]. Recently, however, there was a report of two MDS cases with a sole duplication dup(1)(q21q32) in association with transformation to secondary AML [5]. It thus remains to be defined whether the duplication dup(1)(q21q32) as sole aberration represents a specific chromosomal change in association with distinct hematological disorders, and the prognostic impact still needs to be defined [5]. Here we present four new cases with an inverted dup(1)(q32q21) chromosomal aberration (Fig. 1), three in B-cell precursor ALL and one in MDS, to deepen insight into this rare but apparently recurrent abnormality. In contrast to previously reported cases with dup(1)(q21q32), in all four of the cases described here the duplication was inverted.
2. Patients, materials, and methods * Corresponding author. Tel.: þ49-89-990-17300; fax: þ49-89-99017309. E-mail address: [email protected] (C. Haferlach). 0165-4608/09/$ e see front matter Ó 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.cancergencyto.2008.09.004
The four cases were sent to the MLL Munich Leukemia Laboratory for diagnostic analysis between January 2006
U. Bacher et al. / Cancer Genetics and Cytogenetics 188 (2009) 108e111
109
and December 2007 (Table 1). Diagnoses of the hematologic disorders were performed according to the WHO classification [12]. Cytogenetic analyses were done with chromosome banding from bone marrow following standard methods (Fig. 2) [13]. For further clarification of the 1q abnormalities fluorescence in situ hybridization (FISH) was performed with probes for the MEGF6 (previously EGFL3) and TP73 genes on 1p36 and for the ANGPTL1 and ABL2 genes on 1q25 on interphase nuclei (Fig. 3) as well as on metaphase chromosomes.
sole aberration in 16 of 20 metaphases. Trisomy of 1q was confirmed by FISH in 5 of 5 metaphases. The patient achieved complete remission after induction therapy according to a standard protocol for B-cell precursor ALL. In September 2007, before the third course of consolidation therapy and 5 months after diagnosis, relapse of the ALL occurred, with an infiltration of 25% of blasts in the peripheral blood. At this time, cytogenetic analysis revealed clonal evolution since the first manifestation of the disease, with three additional rearrangements: an unbalanced translocation t(1;17) involving the long arm of the chromosome carrying the inverted duplication, an insertion of the short arm of chromosome 8 (8p) into 7p, and formation of an isochromosome Xq. The karyotype thus was 46,Y,i(X)(q10),der(1) dup(1)(q32q21)t(1;17)(q42;q23),ins(7;8)(p21;p21p23p23), der(17)t(1;17)(q42;q23)[6]/46,XY[17]. Interphase FISH performed on a bone marrow smear confirmed partial trisomy of 1q in 76 of 100 nuclei. BCRABL and MLL rearrangements were excluded by means of polymerase chain reaction.
2.1. Case 1
2.3. Case 3
The first case is that of a 75-year-old man who presented in October 2007 with peripheral leukocytosis due to blast infiltration (25.7 109/L) (hemoglobin 10.0 g/dL, thrombocytes 35 109/L) and generalized lymphadenopathy. Immunophenotyping indicated diagnosis of a B-cell precursor ALL. Chromosomal banding analyses of the bone marrow revealed the inverted duplication dup(1)(q32q21) as sole abnormality in 6 of 20 metaphases. Interphase FISH revealed three signals for 1q25 in 47 of 100 interphase nuclei. In addition, BCR-ABL and MLL rearrangements were excluded by means of additional interphase FISH analyses. Therapy was started according to a protocol for the treatment of ALL in elderly patients. At writing (6 months after diagnosis), the patient was in complete remission after the first two courses of induction therapy.
The third case is that of a 36-year-old woman who received allogeneic stem cell transplantation for common ALL in January 2006, and developed early relapse only 6 weeks after allogeneic stem cell transplantation in March 2006. Karyotype analyses at this time revealed duplication dup(1)(q32q21) as sole anomaly in 17 of 20 metaphases. Interphase FISH confirmed the trisomy 1q in 85 of 100 interphase nuclei. BCR-ABL and MLL rearrangements were excluded by means of interphase FISH. Further, interphase FISH revealed mixed chimerism, with 89 nuclei with XX, but 11 nuclei with an XY constellation after sex-mismatched allogeneic stem cell transplantation. No cytogenetic data were available from the primary diagnosis.
2.2. Case 2
The fourth case is that of a 59-year-old man for whom bone marrow analysis was performed in November 2007, because of persistent anemia. Cytomorphology and histopathology in combination with immunohistochemistry analyses indicated refractory cytopenia with multilineage
Fig. 1. Schematic diagram of the inverted duplication dup(1)(q32q21).
The second case is that of a 51-year-old man diagnosed with common ALL in April 2007. Cytogenetic analysis of bone marrow revealed the inverted duplication dup(1)(q32q21) as
2.4. Case 4
Table 1 Diagnoses and results of karyotyping and fluorescence in situ hybridization (FISH) in four patients with an inverted dup(1)(q32q21) Case
Date, status
Entity
Karyotype
1 2
Oct. 2007 diagnosis April 2007 diagnosis Sept. 2007 relapse
B-cell precursor ALL B-cell precursor ALL B-cell precursor ALL
3
May 2005 diagnosis March 2006 relapse after allo-SCT Nov. 2007 diagnosis
B-cell precursor ALL B-cell precursor ALL RCMD-RS
46,XY,dup(1)(q32q21) 46,XY,dup(1)(q32q21) 46,Y,i(X)(q10),der(1)dup(1)(q32q21)t(1;17)(q42;q23), ins(7;8)(p21;p21p23p23),der(17)t(1;17)(q42;q23) n.a. 46XX,dup(1)(q32q21) 46,XY,dup(1)(q32q21)
4
% of nuclei with 3 signals for 1q25 98 n.a. 76 n.a. 85 12
Abbreviations: ALL, acute lymphoblastic leukemia; allo-SCT, allogeneic stem cell transplantation; n.a., not available; RCMD-RS, refractory cytopenia with multilineage dysplasia and ringed sideroblasts.
110
U. Bacher et al. / Cancer Genetics and Cytogenetics 188 (2009) 108e111
Fig. 2. Partial karyograms, showing the normal chromosome 1 on the left side and the aberrant chromosome 1 with an inverted duplication on the right.
dysplasia and ringed sideroblasts (RCMD-RS) according to the WHO classification, dysplasia being present in both megakaryopoiesis and erythropoiesis. There was no myelofibrosis or increase of blasts O5%. Cytogenetic analysis revealed the inverted duplication dup(1)(q32q21) as sole anomaly in 4 of 20 metaphases. Trisomy of 1q was confirmed by means of interphase FISH in 12 of 100 nuclei. At writing, the patient had not yet received any specific therapy. 3. Discussion We have presented four novel cases with an inverted duplication dup(1)(q32q21) as sole anomaly: three cases of B-cell precursor ALL and one case of MDS-RCMD (Figs. 1e3). Three of the cases were analyzed at diagnosis and one at relapse after allogeneic stem cell transplantation. We know of few reports on isolated duplications of 1q involving the q21 and q32 breakpoints. In MDS, two cases with an isolated dup(1)(q21q32) were recently reported, both with the RCMD subtype [5]. In one case, the duplication was present at diagnosis; 5 years later, clonal evolution with an additional trisomy 8 was detected, leading to the decision for allogeneic stem cell transplantation. In the second case, the karyotype was normal initially, but 6 years later, at transformation to secondary AML, clonal evolution with the dup(1)(q21q32) was detected. That patient died soon afterwards [5]. In a series of 205 MDS patients with trisomy 1q, the dup(1)(q21q32) was described in two cases, but whether there was an association with any other chromosomal aberrations was not mentioned [18]. Thus, the present RCMDRS case (our case 4) further confirms that sole duplications of the q21q32 region of chromosome 1 are recurrent aberrations in MDS.
Based on our case 4 and on the two cases reported by Alfaro et al. [5], it has to be assumed that 1q duplications with the respective breakpoints can occur either as a primary change or later during the process of transformation to secondary AML. Alfaro et al. [5] suggested an association with the leukemic transformation of MDS. Duplications of 1q had also previously been described to accompany the progress of MDS to secondary AML [14]. In accordance with their own two cases and some rare previous reports [15,16], Alfaro et al. [5] assumed that gain of 1q is in general associated with poor prognosis in MDS. Poor outcome had also been reported in pediatric MDS patients with gain of 1q [3], and inferior survival had been documented in MDS and AML with gain of 1q due to unbalanced translocations [4]. The other three of the present cases with inverted duplications dup(1)(q32q21) were B-cell precursor ALL. A literature review identified two cases of follicular lymphoma with a dup(1)(q21q32), both within complex karyotypes [10], but we know of no such report for ALL. Nonetheless, according to this report [10], it seems that there might be a specific association of the inverted duplication dup(1) (q32q21) and B-cell precursor ALL. In two of our cases, the duplication was present as sole aberration at diagnosis; in one case it was followed by clonal evolution and early relapse of the disorder, after 5 months. In our third B-cell precursor ALL case, the karyotype at initial diagnosis was not available, but the dup(1)(q32q21) was the sole anomaly at relapse after stem cell transplantation. Thus, the dup(1)(q32q21) might represent a typical primary alteration in B-cell precursor ALL paving the way to the acquirement of additional abnormalities. Although the effect of the inverted dup(1)(q32q21) on prognosis in ALL cannot yet be defined, the early relapse in two of these casesdin one case while the patient was still receiving chemotherapy, in the other case 6 weeks after allogeneic stem cell transplantationdmight indicate dismal prognosis. In trying to define the specific mechanisms underlying the respective 1q duplication, it has to be mentioned that the long arm of chromosome 1 is associated with high chromosomal instability in hematological neoplasia, probably because of to specific chromatin properties of this gene-rich region [7,11]. Furthermore, gene dosage effects might play a role for the specific effects of gains of 1q [9]. Cells
Fig. 3. Fluorescence in situ hybridization with probes for 1p36 (red) and 1q25 (green).
U. Bacher et al. / Cancer Genetics and Cytogenetics 188 (2009) 108e111
containing an extra copy of 1q might have a proliferative advantage, thus promoting the process of clonal evolution [7,17]. In addition, the distribution of so-called paralogous identical genetic regions, probably as a result of evolutionary duplications, has been suggested to confer the high level of instability in the 1q12~q21 region [19]. Finally, this region is known to be involved in diverse congenital malformation syndromes [20]. Fluorescence in situ hybridization (FISH) studies in several cases of B-cell precursor ALL or Burkitt lymphoma with gain of 1q revealed a common duplicated region of 93 kb at band 1q21.2, where putative oncogenes or tumor suppressor genes are mapped (SF3B4, OTUD7B, and MTMR11) [8]. Another candidate gene in possible association with neoplasm development in this region is ARNT, in 1q21 [11,21]. It must be emphasized that all four cases of this report showed an inverted duplication dup(1)(q32q21), whereas all previously described cases had a duplication dup(1)(q21q32). Whether this is of relevance remains unclear. In conclusion, inverted duplication of the 1q21~q32 region represents a distinct recurrent aberration which occurs in both myeloid lymphoid malignancies. This duplication probably shows a specific association with B-cell precursor ALL and seems to promote clonal evolution during the progress of hematological disorders. In MDS, there might be an association with leukemic transformation. More cases need to be identified, to further clarify the role of 1q duplications with the q21 and q32 breakpoints in hematological malignancies and to define the prognostic impact in the single entities. References [1] Haase D, Fonatsch C, Freund M, Wormann B, Bodenstein H, Bartels H, Stollmann-Gibbels B, Lengfelder E. Cytogenetic findings in 179 patients with myelodysplastic syndromes. Ann Hematol 1995;70:171e87. [2] Lee DS, Kim SH, Seo EJ, Park CJ, Chi HS, Ko EK, Yoon BH, Kim WH, Cho HI. Predominance of trisomy 1q in myelodysplastic syndromes in Korea: is there an ethnic difference? A 3-year multicenter study. Cancer Genet Cytogenet 2002;132:97e101. [3] Morerio C, Rapella A, Tassano E, Lanino E, Micalizzi C, Rosanda C, Panarello C. Gain of 1q in pediatric myelodysplastic syndromes. Leuk Res 2006;30:1437e41. [4] Johansson B, Brøndum-Nielsen K, Billstro¨m R, Schiødt I, Mitelman F. Translocations between the long arms of chromosomes 1 and 5 in hematologic malignancies are strongly associated with neoplasms of the myeloid lineages. Cancer Genet Cytogenet 1997;99:97e101. [5] Alfaro R, Pe´rez-Granero A, Dura´n MA, Besalduch J, Rosell J, Bernue´s M. dup(1)(q21q32) as a sole cytogenetic event is associated to a leukemic transformation in myelodysplastic syndromes. Leuk Res 2008;32:159e61. [6] Mitelman F, Johansson B, Mertens F, editors. Mitelman database of chromosome aberrations in cancer [Internet]. Updated February 2008. Available at http://cgap.nci.nih.gov/Chromosomes/Mitelman. Accessed November 24, 2008.
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[7] Djordjevic V, Jankovic G, Suvajdzic N, Marisavljevic D, Pantic M, Bogdanovic A, Sefer D, Dencic M, Colovic M. A der(14) t(1;14)(q12;p11) in chronic myelomonocytic leukemia. Cancer Genet Cytogenet 2005;160:89e93. [8] La Starza R, Crescenzi B, Pierini V, Romoli S, Gorello P, Brandimarte L, Matteucci C, Kropp MG, Barba G, Martelli MF, Mecucci C. A common 93-kb duplicated DNA sequence at 1q21.2 in acute lymphoblastic leukemia and Burkitt lymphoma. Cancer Genet Cytogenet 2007;175:73e6. [9] Paulsson K, Heidenblad M, Morse H, Borg A, Fioretos T, Johansson B. Identification of cryptic aberrations and characterization of translocation breakpoints using array CGH in high hyperdiploid childhood acute lymphoblastic leukemia. Leukemia 2006;20: 2002e7. [10] Itoyama T, Nanjungud G, Chen W, Dyomin VG, Teruya-Feldstein J, Jhanwar SC, Zelenetz AD, Chaganti RS. Molecular cytogenetic analysis of genomic instability at the 1q12-22 chromosomal site in B-cell non-Hodgkin lymphoma. Genes Chromosomes Cancer 2002;35: 318e28. [11] Busson-Le Coniat M, Salomon-Nguyen F, Dastugue N, Maarek O, Lafage-Pochitaloff M, Mozziconacci MJ, Baranger L, Brizard F, Radford I, Jeanpierre M, Bernard OA, Berger R. Fluorescence in situ hybridization analysis of chromosome 1 abnormalities in hematopoietic disorders: rearrangements of DNA satellite II and new recurrent translocations. Leukemia 1999;13:1975e81. [12] Jaffe ES, Harris NL, Stein H, Vardiman JW, editors. Pathology and genetics of tumours of haematopoietic and lymphoid tissuesWorld Health Organization Classification of Tumours. Lyon: IARC Press, 2001. [13] Schoch C, Schnittger S, Bursch S, Gerstner D, Hochhaus A, Berger U, Hehlmann R, Hiddemann W, Haferlach T. Comparison of chromosome banding analysis, interphase- and hypermetaphaseFISH, qualitative and quantitative PCR for diagnosis and for follow-up in chronic myeloid leukemia: a study on 350 cases. Leukemia 2002;16:53e9. [14] de Souza Fernandez T, Ornellas MH, Otero de Carvalho L, Tabak D, Abdelhay E. Chromosomal alterations associated with evolution from myelodysplastic syndrome to acute myeloid leukemia. Leuk Res 2000;24:839e48. [15] Ohyashiki JH, Ohyashiki K, Fujimura T, Kawakubo K, Shimamoto T, Iwabuchi A, Toyama K. Telomere shortening associated with disease evolution patterns in myelodysplastic syndromes. Cancer Res 1994;54:3557e60. [16] Satake N, Sakashita A, Kobayashi H, Maseki N, Sakurai M, Kaneko Y. Minimal residual disease in acute monocytic leukemia patient with trisomy 11 and partial tandem duplication of MLL. Cancer Genet Cytogenet 1997;96:26e9. [17] Morris CM, Fitzgerald PH, Neville MA, Wyld PJ, Beard ME. Does multisomy of chromosome 1q confer a proliferative advantage in B-cell acute lymphoblastic leukemia? Cancer 1984;54:48e53. [18] Lee DS, Kim SH, Seo EJ, Park CJ, Chi HS, Ko EK, Yoon BH, Kim WH, Chou HI. Predominance of trisomy 1q in myelodysplastic syndromes in Korea: is there as ethnic difference? A 3-year multicenter study. Cancer Genet Cytogenet 2002;132:97e101. [19] Bailey JA, Yavor AM, Massa HF, Trask BJ, Eichler EE. Segmental duplications: organization and impact within the current human genome project assembly. Genome Res 2001;11:1005e17. [20] Mazzarella R, Schlessinger D. Pathological consequences of sequence duplications in the human genome. Genome Res 1998;8: 1007e21. [21] Scrideli CA, Baruffi MR, Squire JA, Ramos ES, Karaskova J, Heck B, Tone LG. Acute monocytic leukemia and multiple abnormalities in a child with duplication of 1q detected by GTG-banding and SKY. Leuk Res 2005;29:1465e7.
Short communication
Inverted duplication dup(1)(q32q21) as sole aberration in lymphoid and myeloid malignancies Ulrike Bachera, Susanne Schnittgerb, Andreas Gru¨neisenc, Torsten Haferlachb, Wolfgang Kernb, Claudia Haferlachb,* a
Interdisciplinary Clinic for Stem Cell Transplantation, University Cancer Center Hamburg (UCCH), Germany b MLLeMunich Leukemia Laboratory, Max-Lebsche-Platz 31, 81377 Munich, Germany c Department of Hematology and Oncology, Neuko¨lln Hospital, Berlin, Germany Received 21 April 2008; received in revised form 15 August 2008; accepted 2 September 2008
Abstract
Partial gains of chromosome 1q as isolated aberrations are rare occurrences in hematologic malignancies. A recent report of a sole duplication dup(1)(q21q32) in myelodysplastic syndrome (MDS) suggested an inferior prognosis. To further describe structural anomalies involving the 1q21 and 1q32 breakpoints, we present four cases with an inverted dup(1)(q32q21): three in B-cell precursor acute lymphoblastic leukemia (ALL) and one in MDS of the subtype refractory cytopenia with multilineage dysplasia and ringed sideroblasts. In all four cases, the aberration presented as the sole anomaly at diagnosis. In one of the ALL cases, relapse during chemotherapy, 5 months from diagnosis, was accompanied by clonal evolution; in another ALL case, early relapse appeared 51 days after allogeneic stem cell transplantation. Structural gains of 1q involving 1q32 and 1q21 breakpoints can occur in different hematological malignancies. The isolated occurrence of the inverted dup(1)(q32q21) may be interpreted as a typical primary alteration in B-lineage ALL paving the way to acquisition of additional abnormalities. Identification of more cases could further clarify the role of 1q duplications with the q21 and q32 breakpoints in hematological malignancies and better define the prognosis associated with sole aberration in the single entities. Ó 2009 Elsevier Inc. All rights reserved.
1. Introduction Structural gains of 1q are found in diverse hematological malignancies of both myeloid and lymphoid origin: In myelodysplastic syndromes (MDS), gain of 1q was described in ~15% of all cases [1,2]; in most cases, this resulted from unbalanced translocationsdfor example, with 7q [3] or 5q as partner chromosomes [4]. Most MDS cases showing gains of 1q exhibit additional chromosomal abnormalities [5e7]. Furthermore, in AML gain of 1q is usually accompanied by complex aberrations, as defined by the simultaneous occurrence of >3 clonal chromosomal abnormalities. With respect to the lymphoid malignancies, partial gain of 1q was described as the most frequent structural abnormality in the hyperdiploid subgroup of B-lineage ALL [6,8,9]. In Bnon-Hodgkin lymphoma (B-NHL), structural rearrangements of 1q most often affect the region 1q21~q22, usually embedded in complex aberrations [10,11].
Gains of 1q seem to occur only exceptionally as isolated aberration in hematologic malignancies [11]. Recently, however, there was a report of two MDS cases with a sole duplication dup(1)(q21q32) in association with transformation to secondary AML [5]. It thus remains to be defined whether the duplication dup(1)(q21q32) as sole aberration represents a specific chromosomal change in association with distinct hematological disorders, and the prognostic impact still needs to be defined [5]. Here we present four new cases with an inverted dup(1)(q32q21) chromosomal aberration (Fig. 1), three in B-cell precursor ALL and one in MDS, to deepen insight into this rare but apparently recurrent abnormality. In contrast to previously reported cases with dup(1)(q21q32), in all four of the cases described here the duplication was inverted.
2. Patients, materials, and methods * Corresponding author. Tel.: þ49-89-990-17300; fax: þ49-89-99017309. E-mail address: [email protected] (C. Haferlach). 0165-4608/09/$ e see front matter Ó 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.cancergencyto.2008.09.004
The four cases were sent to the MLL Munich Leukemia Laboratory for diagnostic analysis between January 2006
U. Bacher et al. / Cancer Genetics and Cytogenetics 188 (2009) 108e111
109
and December 2007 (Table 1). Diagnoses of the hematologic disorders were performed according to the WHO classification [12]. Cytogenetic analyses were done with chromosome banding from bone marrow following standard methods (Fig. 2) [13]. For further clarification of the 1q abnormalities fluorescence in situ hybridization (FISH) was performed with probes for the MEGF6 (previously EGFL3) and TP73 genes on 1p36 and for the ANGPTL1 and ABL2 genes on 1q25 on interphase nuclei (Fig. 3) as well as on metaphase chromosomes.
sole aberration in 16 of 20 metaphases. Trisomy of 1q was confirmed by FISH in 5 of 5 metaphases. The patient achieved complete remission after induction therapy according to a standard protocol for B-cell precursor ALL. In September 2007, before the third course of consolidation therapy and 5 months after diagnosis, relapse of the ALL occurred, with an infiltration of 25% of blasts in the peripheral blood. At this time, cytogenetic analysis revealed clonal evolution since the first manifestation of the disease, with three additional rearrangements: an unbalanced translocation t(1;17) involving the long arm of the chromosome carrying the inverted duplication, an insertion of the short arm of chromosome 8 (8p) into 7p, and formation of an isochromosome Xq. The karyotype thus was 46,Y,i(X)(q10),der(1) dup(1)(q32q21)t(1;17)(q42;q23),ins(7;8)(p21;p21p23p23), der(17)t(1;17)(q42;q23)[6]/46,XY[17]. Interphase FISH performed on a bone marrow smear confirmed partial trisomy of 1q in 76 of 100 nuclei. BCRABL and MLL rearrangements were excluded by means of polymerase chain reaction.
2.1. Case 1
2.3. Case 3
The first case is that of a 75-year-old man who presented in October 2007 with peripheral leukocytosis due to blast infiltration (25.7 109/L) (hemoglobin 10.0 g/dL, thrombocytes 35 109/L) and generalized lymphadenopathy. Immunophenotyping indicated diagnosis of a B-cell precursor ALL. Chromosomal banding analyses of the bone marrow revealed the inverted duplication dup(1)(q32q21) as sole abnormality in 6 of 20 metaphases. Interphase FISH revealed three signals for 1q25 in 47 of 100 interphase nuclei. In addition, BCR-ABL and MLL rearrangements were excluded by means of additional interphase FISH analyses. Therapy was started according to a protocol for the treatment of ALL in elderly patients. At writing (6 months after diagnosis), the patient was in complete remission after the first two courses of induction therapy.
The third case is that of a 36-year-old woman who received allogeneic stem cell transplantation for common ALL in January 2006, and developed early relapse only 6 weeks after allogeneic stem cell transplantation in March 2006. Karyotype analyses at this time revealed duplication dup(1)(q32q21) as sole anomaly in 17 of 20 metaphases. Interphase FISH confirmed the trisomy 1q in 85 of 100 interphase nuclei. BCR-ABL and MLL rearrangements were excluded by means of interphase FISH. Further, interphase FISH revealed mixed chimerism, with 89 nuclei with XX, but 11 nuclei with an XY constellation after sex-mismatched allogeneic stem cell transplantation. No cytogenetic data were available from the primary diagnosis.
2.2. Case 2
The fourth case is that of a 59-year-old man for whom bone marrow analysis was performed in November 2007, because of persistent anemia. Cytomorphology and histopathology in combination with immunohistochemistry analyses indicated refractory cytopenia with multilineage
Fig. 1. Schematic diagram of the inverted duplication dup(1)(q32q21).
The second case is that of a 51-year-old man diagnosed with common ALL in April 2007. Cytogenetic analysis of bone marrow revealed the inverted duplication dup(1)(q32q21) as
2.4. Case 4
Table 1 Diagnoses and results of karyotyping and fluorescence in situ hybridization (FISH) in four patients with an inverted dup(1)(q32q21) Case
Date, status
Entity
Karyotype
1 2
Oct. 2007 diagnosis April 2007 diagnosis Sept. 2007 relapse
B-cell precursor ALL B-cell precursor ALL B-cell precursor ALL
3
May 2005 diagnosis March 2006 relapse after allo-SCT Nov. 2007 diagnosis
B-cell precursor ALL B-cell precursor ALL RCMD-RS
46,XY,dup(1)(q32q21) 46,XY,dup(1)(q32q21) 46,Y,i(X)(q10),der(1)dup(1)(q32q21)t(1;17)(q42;q23), ins(7;8)(p21;p21p23p23),der(17)t(1;17)(q42;q23) n.a. 46XX,dup(1)(q32q21) 46,XY,dup(1)(q32q21)
4
% of nuclei with 3 signals for 1q25 98 n.a. 76 n.a. 85 12
Abbreviations: ALL, acute lymphoblastic leukemia; allo-SCT, allogeneic stem cell transplantation; n.a., not available; RCMD-RS, refractory cytopenia with multilineage dysplasia and ringed sideroblasts.
110
U. Bacher et al. / Cancer Genetics and Cytogenetics 188 (2009) 108e111
Fig. 2. Partial karyograms, showing the normal chromosome 1 on the left side and the aberrant chromosome 1 with an inverted duplication on the right.
dysplasia and ringed sideroblasts (RCMD-RS) according to the WHO classification, dysplasia being present in both megakaryopoiesis and erythropoiesis. There was no myelofibrosis or increase of blasts O5%. Cytogenetic analysis revealed the inverted duplication dup(1)(q32q21) as sole anomaly in 4 of 20 metaphases. Trisomy of 1q was confirmed by means of interphase FISH in 12 of 100 nuclei. At writing, the patient had not yet received any specific therapy. 3. Discussion We have presented four novel cases with an inverted duplication dup(1)(q32q21) as sole anomaly: three cases of B-cell precursor ALL and one case of MDS-RCMD (Figs. 1e3). Three of the cases were analyzed at diagnosis and one at relapse after allogeneic stem cell transplantation. We know of few reports on isolated duplications of 1q involving the q21 and q32 breakpoints. In MDS, two cases with an isolated dup(1)(q21q32) were recently reported, both with the RCMD subtype [5]. In one case, the duplication was present at diagnosis; 5 years later, clonal evolution with an additional trisomy 8 was detected, leading to the decision for allogeneic stem cell transplantation. In the second case, the karyotype was normal initially, but 6 years later, at transformation to secondary AML, clonal evolution with the dup(1)(q21q32) was detected. That patient died soon afterwards [5]. In a series of 205 MDS patients with trisomy 1q, the dup(1)(q21q32) was described in two cases, but whether there was an association with any other chromosomal aberrations was not mentioned [18]. Thus, the present RCMDRS case (our case 4) further confirms that sole duplications of the q21q32 region of chromosome 1 are recurrent aberrations in MDS.
Based on our case 4 and on the two cases reported by Alfaro et al. [5], it has to be assumed that 1q duplications with the respective breakpoints can occur either as a primary change or later during the process of transformation to secondary AML. Alfaro et al. [5] suggested an association with the leukemic transformation of MDS. Duplications of 1q had also previously been described to accompany the progress of MDS to secondary AML [14]. In accordance with their own two cases and some rare previous reports [15,16], Alfaro et al. [5] assumed that gain of 1q is in general associated with poor prognosis in MDS. Poor outcome had also been reported in pediatric MDS patients with gain of 1q [3], and inferior survival had been documented in MDS and AML with gain of 1q due to unbalanced translocations [4]. The other three of the present cases with inverted duplications dup(1)(q32q21) were B-cell precursor ALL. A literature review identified two cases of follicular lymphoma with a dup(1)(q21q32), both within complex karyotypes [10], but we know of no such report for ALL. Nonetheless, according to this report [10], it seems that there might be a specific association of the inverted duplication dup(1) (q32q21) and B-cell precursor ALL. In two of our cases, the duplication was present as sole aberration at diagnosis; in one case it was followed by clonal evolution and early relapse of the disorder, after 5 months. In our third B-cell precursor ALL case, the karyotype at initial diagnosis was not available, but the dup(1)(q32q21) was the sole anomaly at relapse after stem cell transplantation. Thus, the dup(1)(q32q21) might represent a typical primary alteration in B-cell precursor ALL paving the way to the acquirement of additional abnormalities. Although the effect of the inverted dup(1)(q32q21) on prognosis in ALL cannot yet be defined, the early relapse in two of these casesdin one case while the patient was still receiving chemotherapy, in the other case 6 weeks after allogeneic stem cell transplantationdmight indicate dismal prognosis. In trying to define the specific mechanisms underlying the respective 1q duplication, it has to be mentioned that the long arm of chromosome 1 is associated with high chromosomal instability in hematological neoplasia, probably because of to specific chromatin properties of this gene-rich region [7,11]. Furthermore, gene dosage effects might play a role for the specific effects of gains of 1q [9]. Cells
Fig. 3. Fluorescence in situ hybridization with probes for 1p36 (red) and 1q25 (green).
U. Bacher et al. / Cancer Genetics and Cytogenetics 188 (2009) 108e111
containing an extra copy of 1q might have a proliferative advantage, thus promoting the process of clonal evolution [7,17]. In addition, the distribution of so-called paralogous identical genetic regions, probably as a result of evolutionary duplications, has been suggested to confer the high level of instability in the 1q12~q21 region [19]. Finally, this region is known to be involved in diverse congenital malformation syndromes [20]. Fluorescence in situ hybridization (FISH) studies in several cases of B-cell precursor ALL or Burkitt lymphoma with gain of 1q revealed a common duplicated region of 93 kb at band 1q21.2, where putative oncogenes or tumor suppressor genes are mapped (SF3B4, OTUD7B, and MTMR11) [8]. Another candidate gene in possible association with neoplasm development in this region is ARNT, in 1q21 [11,21]. It must be emphasized that all four cases of this report showed an inverted duplication dup(1)(q32q21), whereas all previously described cases had a duplication dup(1)(q21q32). Whether this is of relevance remains unclear. In conclusion, inverted duplication of the 1q21~q32 region represents a distinct recurrent aberration which occurs in both myeloid lymphoid malignancies. This duplication probably shows a specific association with B-cell precursor ALL and seems to promote clonal evolution during the progress of hematological disorders. In MDS, there might be an association with leukemic transformation. More cases need to be identified, to further clarify the role of 1q duplications with the q21 and q32 breakpoints in hematological malignancies and to define the prognostic impact in the single entities. References [1] Haase D, Fonatsch C, Freund M, Wormann B, Bodenstein H, Bartels H, Stollmann-Gibbels B, Lengfelder E. Cytogenetic findings in 179 patients with myelodysplastic syndromes. Ann Hematol 1995;70:171e87. [2] Lee DS, Kim SH, Seo EJ, Park CJ, Chi HS, Ko EK, Yoon BH, Kim WH, Cho HI. Predominance of trisomy 1q in myelodysplastic syndromes in Korea: is there an ethnic difference? A 3-year multicenter study. Cancer Genet Cytogenet 2002;132:97e101. [3] Morerio C, Rapella A, Tassano E, Lanino E, Micalizzi C, Rosanda C, Panarello C. Gain of 1q in pediatric myelodysplastic syndromes. Leuk Res 2006;30:1437e41. [4] Johansson B, Brøndum-Nielsen K, Billstro¨m R, Schiødt I, Mitelman F. Translocations between the long arms of chromosomes 1 and 5 in hematologic malignancies are strongly associated with neoplasms of the myeloid lineages. Cancer Genet Cytogenet 1997;99:97e101. [5] Alfaro R, Pe´rez-Granero A, Dura´n MA, Besalduch J, Rosell J, Bernue´s M. dup(1)(q21q32) as a sole cytogenetic event is associated to a leukemic transformation in myelodysplastic syndromes. Leuk Res 2008;32:159e61. [6] Mitelman F, Johansson B, Mertens F, editors. Mitelman database of chromosome aberrations in cancer [Internet]. Updated February 2008. Available at http://cgap.nci.nih.gov/Chromosomes/Mitelman. Accessed November 24, 2008.
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