Jumping Translocations Involving 11q in a Non-Hodgkin Lymphoma

Jumping Translocations Involving 11q in a Non-Hodgkin Lymphoma Iskra Petkovic´, Josip Konja, Mara Dominis, and Maja Kasˇtelan

ABSTRACT: This paper presents the results of a cytogenetic analysis in an 11-year-old boy with nonHodgkin lymphoma. The investigation was performed on slides obtained from short-term culture of lymph node cells. The analyses revealed an abnormal clone with loss of the Y, gain of an X chromosome, t(3;22), trisomy 11, and three cytogenetically-related subclones with jumping translocations involving 11q13 as the common breakpoint region. This region is an unusual site of chromosome breakage in jumping translocations, and has not been reported thus far. Contrary to most published reports, the jumping translocation in our patient is associated with long survival. © Elsevier Science Inc., 1999. All rights reserved.

INTRODUCTION The terms unstable or jumping translocations (JT) indicate rare types of unbalanced chromosome rearrangements involving a common breakpoint on a donor chromosome and translocations to various receptor sites. Jumping translocations have been described in SV40 transformed human fibroblasts [1], rarely in constitutional chromosome aberrations [2, 3] and malignant diseases [4–17]. To our knowledge, this rare and unusual phenomenon has been reported in some 21 cases of malignant diseases, including 14 patients with leukemia, 6 cases of malignant lymphoma, and 1 case of solid tumor. Jumping translocations have been associated with poor prognosis, and chromosome number 1 has been identified as the donor chromosome in most cases reported thus far. In this article, we report a case of non-Hodgkin lymphoma (NHL) with unusual jumping translocations involving 11q13 as the common breakpoint region associated with long survival. MATERIALS AND METHODS Case Report An 11-year-old boy was admitted to our hospital for evaluation and treatment of enlarged lymph nodes in his neck,

From the University Children’s Hospital Zagreb (I. P.), Zagreb, Croatia; the Department of Pediatrics, Faculty of Medicine, University of Zagreb (J. K.), Zagreb, Croatia; the Clinical Hospital “Merkur” (M. D.), Zagreb, Croatia; and the University Hospital “Sestre Milosrdnice” (M. K.), Zagreb, Croatia. Address reprint requests to: Iskra Petkovic´ , Ph.D., University Children’s Hospital Zagreb, Cytogenetic Laboratory, Klaic´ eva 16, 10 000 Zagreb, Croatia. Received July 31, 1998; accepted March 10, 1999. Cancer Genet Cytogenet 114:121–125 (1999)  Elsevier Science Inc., 1999. All rights reserved. 655 Avenue of the Americas, New York, NY 10010

left suprascapular and supraclavicular regions. Lymph nodes were hard and painless on palpation. On admission, the right tonsil was hypertrophic with evidence of necrotic changes. No enlarged lymph nodes were observed in the axillary, right scapular, and inguinal regions. Computed tomography (CT) did not reveal tumors in the brain or abdomen. A normal finding was obtained by cytologic examination of a bone marrow biopsy, while analysis of the right tonsil was unsuccessful. After surgical removal of the lymph node, the histopathological examination and immunophenotype analysis revealed B-cell non-Hodgkin lymphoma. The architecture of the lymph node was effaced; diffuse proliferation of medium-sized tumor cells and macrophages (starry sky) were seen. The tumor cells were CD20-positive, IgM-positive, C-MYC was not done, EBV-LMP-negative. Determination of T- or B-immunophenotype was also performed on cells in suspension obtained from the involved lymph node. Characterization was done using monoclonal antibodies CD1, CD5, CD7, CD10, CD19, CD20, and HLA-DR (OKT antibodies, Ortho Diagnostics, Raritan, NJ, USA), as well as antibodies to human immunoglobins G, M, and A (Institute of Immunology, Zagreb, Croatia). The majority of cells stained with Bcell-specific antibodies (CD19, CD20, HLA-DR, anti human IgG, IgM, IgA), and less than 10% with T-cell specific antibodies (CD1, CD5, CD7). The boy was treated with chemotherapy for B-cell NHL. He was given iphosphamid, methotrexate, cyclophosphamid, and doxorubicin. The child responded well to the treatment, and regression of lymph nodes occurred. After cytostatic therapy, the tonsil was removed, and histopathological analysis revealed T-cell non-Hodgkin lymphoma. The architecture of the right tonsil was completely obliterated with proliferation of small-to-medium-sized lymphocytes with irregular nuclei and an inconspicuous

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Table 1 Cytogenetic findings Karyotype

No. of cells (%)

47,X,2Y,1X,t(3;22)(q27;q11),111 46,X,2Y,1X,t(3;22)(q27;q11),der(8)t(8;11) (p23;q13) 46,X,2Y,1X,t(3;22)(q27;q11),der(7)t(7;11) (q22;q13) 46,X,2Y,1X,t(3;22)(q27;q11),der(15)t(11;15) (q13;p11) 4n Total

73 (60.8) 21 (17.5) 19 (15.8)

rum at 378C. The cell suspension was then treated with colchicine, hypotonic solution, and fixed in the mixture of methanol and acetic acid. After three changes of the fixative, the slides were prepared and stained by a conventional and trypsin G-banding method [18]. Chromosomal aberrations were described according to the International System for Human Cytogenetic Nomenclature [19].

5 (4.2) 2 (1.7) 120

amount of cytoplasm. In the left tonsil, remnants of B-zone (CD20-positive) were seen, as well as the tumor cells with the same morphology as in the right tonsil. The cells were CD2-positive, CD3-positive, and some were CD4-positive (about 20% of tumor cells). The child was administered cytostatic therapy for T-cell NHL. Treatment was initiated with vincristine, adriablastin, cytosine-arabinoside, and methotrexate. The boy responded well to the treatment and was discharged from the hospital in complete remission. Seven years after the diagnosis he is in good general health and there is no evidence of recurrence. Cytogenetic Analysis Cytogenetic analysis of bone marrow and lymph node cells was carried out at diagnosis and before initiating therapy. Cells were cultivated for 24 hours in minimal essential medium supplemented with 20% human AB se-

RESULTS Chromosome investigation of bone marrow cells revealed a normal male karyotype. Cytogenetic analysis of lymph node cells revealed structural and numerical chromosome aberrations (Table 1). Most of the cells were in the diploid range, while two (1.7%) were near-tetraploid. Seventy-three (60.8%) of 120 investigated metaphases presented 47 chromosomes with a loss of chromosome Y, gain of chromosomes X and 11, and reciprocal translocations between chromosomes 3 and 22 (Fig. 1). Breakage and union occurred at regions 3q27 and 22q11 (Fig. 2). Forty-five (37.5%) cells presented 46 chromosomes, loss of chromosome Y, gain of chromosome X, t(3;22), and translocations of chromosome 11 long arm with breakpoint at 11q13 to different recipient chromosomes. In 21 (17.5%) metaphases this chromosome segment was translocated to the very distal region of chromosome 8 short arm (Fig. 3A). In 19 (15.8%) cells the same chromosome segment was translocated to the distal end of the short arm chromosome 7 (Fig. 3B). Five (4.2%) cells presented a derived chromosome 15 as the result of the translocation of 11qter→q13 onto the terminal region of its short arm (Fig. 3C).

Figure 1 A representative G-banded karyotype with 47,X,2Y,1X,t(3;22)(q27;q11),111.

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Figure 2 (A) Idiogram and (B) partial karyotypes showing the t(3;22)(q27;q11).

DISCUSSION In this report, we present unusual cytogenetic findings in a boy with B-cell NHL. Chromosome analysis revealed abnormal clone characterized by t(3;22), loss of the Y, gain of an X chromosome, trisomy 11, and three cytogeneticallyrelated subclones with jumping translocations involving one of chromosomes 11. A single breakpoint on 11q13 and three different telomeric receptor sites (8p, 7p, and 15p), resulting in partial trisomy for the long arm of chromosome 11, were identified. Translocation (3;22) is a nonrandom chromosome rearrangement in human B-cell NHL and was observed in 5% of adult non-Hodgkin lymphomas with clonal chromosomal abnormalities [20]. The clinical course of reported patients has been variable. This translocation is, however, rare in children. Recently, Mikraki et al. [21] and Shikano et al. [22] performed cytogenetic analysis of a large series of childhood NHL. Translocation (3;22) was detected in 1 of 72 children. Gain of chromosome 11 is a relatively frequent numeric aberration in NHL [23]. Trisomy 11 in our case is an intermediate step in clonal karyotype evolution followed by a break at 11q13. The short arm and the centromere of chromosome 11 were lost, while the long arm

was translocated to a telomeric region of 3 recipient chromosomes. Chromosome region 11q13 is very unstable in the human genome, prone to breakage and rearrangement. It is the location of a folate-sensitive fragile site and the BCL-1/PRAD-1 oncogene, and is a neoplasm-associated chromosome breakpoint [23, 24]. The breakpoints on band 11q13 are frequent in B-cell NHL, and are identified in t(11;14), del(11), and dup(11) [21–23]. The aberrations of 11q13 are closely related to overexpression of BCL-1/ PRAD-1, suggesting an important role in the pathogenesis of B-cell NHL [25, 26]. In our patient, the translocations between 11q13 and the terminal regions of 8p, 7p, and 15p were identified. It is possible that deregulation of the BCL1/PRAD-1 oncogene at 11q13 contributes to a proliferative advantage of the cells carrying JT. Jumping translocations are rare chromosome findings and have been described in some 21 cases [4–17]. These aberrations have not been consistently associated with a specific age group, sex, or type of malignancy and have been described in leukemia, lymphomas, and solid tumors. As in other reported cases, JT in our patient appeared in the course of clonal karyotypic evolution as secondary chromosome changes, and are thus not related to tumorigenesis, but to tumor progression.

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Figure 3 Partial G-banded karyotypes showing chromosomes involved in jumping translocations (A) der(8), (B) der(7), and (C) der(15).

In our patient, the donor segment is on chromosome 11 with a breakpoint at q13, not yet observed in this type of rearrangement. The frequent feature of JT is preferential involvement of heterochromatic segments of the donor and telomeric regions of the recipient chromosomes. In the majority (17/21) of thus far reported cases, the donor is chromosome 1, with the breakpoint in the proximity of a constitutive heterochromatin (1q11 or 1q21) which resulted in partial trisomy for 1q [4–6, 8–14, 16]. Only four reported cases of jumping translocations involved other donor chromosomes such as chromosomes 3, 9, 14, and 7. In 1994, Wlodarska et al. described a case of NHL with a common breakpoint in the vicinity of the heterochromatic segment of chromosome 9 and partial trisomy of 9q13→qter [7]. In 1988, Aledo et al. presented a girl with xeroderma pigmentosum and squamous cell carcinoma [17]. The authors identified a translocation involving 14q11 to different recipient chromosomes in cultured tumor cells. Reis et al. [15] reported a patient with AML-M5a and JT with a breakpoint at 3q13.3, and Najfeld et al. [12] recently described an unbalanced jumping translocation of 7q in leukemia cells. Receptor sites in JT are usually terminal chromosome regions. The investigations revealed a random involvement of the recipient chromosomes, with overrepresentation of 2q, 11q, 16q, and 13q telomeres [11]. In our patient, the recipient sites are telomeres of the short arm of chromosomes 7, 8, and 15. These regions are, however, uncommon recipient sites in JT reported thus far. A second interesting feature of the case described in this report is the unusually long survival of our patient. In the majority of reported cases, jumping translocations

I. Petkovic´ et al. have been associated with a poor prognosis and short survival. Shikano et al. reviewed 13 cases and suggested that jumping translocations themselves, and not the chromosomes involved in the rearrangement, may confer a selective growth advantage and be an adverse prognostic factor [9]. Our observations, however, do not support this suggestion. The presence of JT and survival of 7 years in our patient may indicate that JT are not associated with aggressive evolution of the disease and resistance to therapy. Thus, the clinical significance of jumping translocations appears more complex, and may depend on the chromosome segment involved, associated primary chromosome aberrations, and type of malignancies. Some chromosome changes, such as multisomy of the long arm of chromosome 1, are considered adverse prognostic factors, contributing to aggressive cell proliferation and resistance to therapy [27]. Thus, a poor clinical outcome in patients with jumping translocations involving the long arm of chromosome 1 may be due to the trisomy for 1q. The jumping translocations involving 3q13 as a common breakpoint region were reported in a case of aggressive leukemia without 1q trisomy [15]. Rearrangements affecting 3q13 are, however, rare in hematological malignancies, and their clinical significance is unknown [15]. On the other hand, Wlodarska et al. reported a case of follicular NHL of lowgrade malignancy and JT involving chromosome 9 [7]. The authors suggested that additional rearrangements of chromosomes 13 and 12 may contribute to the proliferative advantage of the cells carrying JT, and not the 9q trisomy per se. Our knowledge on the specificity, the molecular events, and biologic significance of chromosome changes is still limited. Additional cytogenetic and molecular investigations of non-Hodgkin lymphomas are necessary to understand the nature and clinical significance of chromosome aberrations, including jumping translocations. REFERENCES 1. Hoffschir F, Ricoul M, Lemieux N, Estrade S, Cassingena R, Dutrillaux B (1992): Jumping translocations originate clonal rearrangements in SV40-transformed human fibroblasts. Int J Cancer 52:130–136. 2. Von Ballestrem CL, Boavida MG, Zuther C, Carreiro MH, David D, Gal A, Schwinger E (1996): Jumping translocation in a phenotypically normal female. Clin Genet 49:156–159. 3. Duval E, van den Enden A, Vanhaesebrouck P, Speleman F (1994): Jumping translocation in a newborn boy with dup(4q) and severe hydrops fetalis. Am J Med Genet 52:214–217. 4. Gray BA, Bent-Williams A, Wadsworth J, Maiese RL, Bhatia A, Zori RT (1997): Fluorescence in situ hybridization assessment of the telomeric regions of jumping translocations in a case of aggressive B-cell non-Hodgkin lymphoma. Cancer Genet Cytogenet 98:20–27. 5. Roland B, Pinto A, Bowen T (1992): Jumping translocation involving 1q in a small noncleaved cell lymphoma. Am J Hum Genet Suppl. 51:A69. 6. Sawyer RJ, Swanson CM, Koller AM, North PE, Ross SW (1995): Centromeric instability of chromosome 1 resulting in multibranched chromosomes, telomeric fusions, and “jumping” translocations of 1q in a human immunodeficiency virus-related non-Hodgkin’s lymphoma. Cancer 76:1238– 1244.

Jumping Translocation in NHL 7. Wlodarska I, Mecucci C, De Wolf-Peeters C, Verhoef G, Weier HU, Cassiman JJ, Van Den Berghe H (1994): “Jumping” translocation of 9q in a case of follicular lymphoma. Cancer Genet Cytogenet 76:140–144. 8. Whang-Peng J, Lee EC, Sieverts H, Magrath IT (1984): Burkitt’s lymphoma in AIDS: cytogenetic study. Blood 63:818– 822. 9. Shikano T, Arioka H, Kobayashi R, Naito H, Ishikawa Y (1993): Jumping translocations of 1q in Burkitt lymphoma and acute nonlymphocytic leukemia. Cancer Genet Cytogenet 71:22–26. 10. Fitzgerald PH, Morris CM (1984): Telomeric association of chromosomes in B-cell lymphoid leukemia. Hum Genet 67:385–390. 11. Shippey CA, Layton M, Secker-Walker LM (1990): Leukemia characterized by multiple sub-clones with unbalanced translocations involving different telomeric segments: case report and review of the literature. Genes Chromosom Cancer 2:14– 17. 12. Najfeld V, Hauschildt B, Scalise A, Gattani A, Patel R, Ambinder EP, Silverman LR (1995): Jumping translocations in leukemia. Leukemia 9:634–639. 13. Huret JL, Tanzer J, Guilhot F, Frocrain-Herchkovitch C, Savage RK (1988): Karyotype evolution in the bone marrow of a patient with Fanconi anemia: breakpoints in clonal anomalies of this disease. Cytogenet Cell Genet 48:224–227. 14. Raimondi SC, Ragsdale ST, Behm F, Rivera G, Williams DL (1987): Multiple telomeric associations of a trisomic whole q arm of chromosome 1 in a child with acute lymphoblastic leukemia. Cancer Genet Cytogenet 24:87–93. 15. Reis MD, Dube ID, Pinkerton PH, Chen-Lai J, Robinson JB, Klock RJ, Senn JS (1991): “Jumping” translocations involving band 3q13.3 in a case of acute monocytic leukemia. Cancer Genet Cytogenet 51:189–194. 16. Ben-Neriah S, Abramov A, Lerer I, Polliack A, Leizerowitz R, Rabinowitz R, Abeliovich D (1991): “Jumping translocation” in a 17-month-old child with mixed-lineage leukemia. Cancer Genet Cytogenet 56:223–229. 17. Aledo R, Aurias A, Chretien B, Dutrillaux B (1988): Jumping translocation of chromosome 14 in a skin squamous cell car-

125 cinoma from a xeroderma pigmentosum patient. Cancer Genet Cytogenet 33:29–33. 18. Seabright M (1977): The use of proteolytic enzymes for the mapping of structural rearrangements in the chromosomes of man. Chromosoma 36:204–210. 19. ISCN (1991): Guidelines for Cancer Cytogenetics, Supplement to An International System for Human Cytogenetic Nomenclature. F Mitelman, ed. S. Karger, Basel. 20. Offit K, Jhanwar S, Ebrahim SAD, Filippa D, Clarkson BD, Chaganti RSK (1989): t(3;22)(q27;q11): a novel translocation associated with diffuse non-Hodgkin’s lymphoma. Blood 74:1876–1879. 21. Mikraki V, Jhanwar SC, Filippa DA, Wollner N, Chaganti RSK (1992): Distinct patterns of chromosome abnormalities characterize childhood non-Hodgkin’s lymphoma. Br J Haematol 80:15–20. 22. Shikano T, Ishikawa Y, Naito H, Kobayashi R, Nakadate H, Hatae Y, Takeda T (1992): Cytogenetic characteristics of childhood non-Hodgkin’s lymphoma. Cancer 70:714–719. 23. Prasad RK, Filippa DA, Richardson ME, Jhanwar SC, Chaganti SR, Koziner B, Clarkson BD, Lieberman PH, Chaganti RSK (1987): Cytogenetic and histologic correlations in malignant lymphoma. Blood 69:97–102. 24. Hecht F, Sutherland GR (1984): Fragile sites and cancer breakpoints. Cancer Genet Cytogenet 12:179–181. 25. De Boer CJ, Loyson S, Kluin PM, Kluin-Nelemans HC, Schuuring E, Van Krieken JHJM (1993): Multiple breakpoints within the BCL-1 locus in B-cell lymphoma: rearrangements of the cyclin D1 gene. Cancer Res 53:4148–4152. 26. Rimokh R, Berger F, Delsol G, Charrin C, Bertheas MF, Ffrench M, Garoscio M, Felman P, Coiffier B, Bryon PA, Rochet M, Gentilhomme O, Germain D, Magaud JP (1993): Rearrangement and overexpression of the BLC-1/PRAD-1 gene in intermediate lymphocytic lymphoma and in t(11q13)bearing leukemias. Blood 81:3063–3067. 27. Mamaeva SE, Mamaev NN, Jartseva NM, Belyaeva LV, Scherbakova EG (1983): Complete or partial trisomy for the long arm of chromosome 1 in patients with various hematologic malignancies. Hum Genet 63:107–112.