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From www.bloodjournal.org by guest on June 14, 2017. For personal use only. RAPID COMMUNICATION LA23 Rearrangements in Non-Hodgkin's Lymphoma: Correlation With Histology, Immunophenotype, Karyotype, and Clinical Outcome in 217 Patients By Christian Bastard, Clotilde Deweindt, Jean Pierre Kerckaert, Bernard Lenormand, Annick Rossi, Francesco Pezzella, Christophe Fruchart, Christian Duval, Mathieu Monconduit, and Herve Tilly We have recently shown that an evolutionary conserved gene LAZ3, encoding a zinc finger protein, is disrupted and overexpressed in some B-cell lymphomas (mainly with a large cell component) that show chromosomal rearrangements involving 3q27. Because the breakpoints involved in these rearrangements are focused in a narrow major translocation cluster (MTC) on chromosome 3, we used genomic probes from thisregion t o study themolecular rearrangements of LAZ3 in a large series of patients (217) with non-Hodgkin's lymphoma (NHL). Southern blot analysis showed LAZ3 rearrangement in 43 patients (19.8%).Rearrangement was found in 11 of the 84 patients (13%) with follicular lymphoma but was most frequent in aggressive lymphoma (diffuse mixed, diffuse large cell, and large cell immunoblastic subtypes), in which 31 of the 114 patients (27%) were affected. The highest proportion of LAZ3 alteration was observed in B-cell aggressive lymphoma (26 of 71 cases, 37%). Eleven of the 32 patients with 3q27 chromosomal abnormality hadno LAZ3 rearrangement, suggesting the possibility of LAZ3 involvement outside the MTC. On the other hand, 18 of the 39 patients with LAZ3 rearrangement and available cytogenetic results did nothave visible chromosomal break at 3q27, suggesting that almost a half of the rearrangements are not detectable by cytogenetic methods. No statistical association could be foundbetween LAZ3 status and initial features of thedisease or clinical outcomein either follicular oraggressive lymphomas. We conclude that LAZ3 alteration is a relativelyfrequent event in B-cell lymphoma, especially in those of aggressive histology. It could be used as a genomic marker of the disease, and further studies are needed t o clarify clinical implications of these alterations. 0 1994 by The American Society of Hematology. Tissue samples. Fresh lymph nodes were divided for morphoPECIFIC RECURRING chromosomal aberrations have logic, immunologic, and cytogenetic studies as previously debeen reported in most hematologic malignancies. In Bscribed." Cells were cryopreserved for various periods of time becell neoplasms, several translocations involve the Ig genes fore DNA extraction. All histologic material was reviewed by the at bands 14q32,2p12, and 22qll.I The most frequent defects same pathologist and classified according to the Working Formulain non-Hodgkin's lymphoma (NHL) are the (14; 18) translotion for Clinical Usage." cation, associated mainly with follicular lymphoma*; the DNA extraction and Southern blot analysis. DNA was extracted (8; 14) translocation and its variants found in Burkitt's by the sarkosyl-proteinase K-phenokhloroform method. After dil y m p h ~ m a ~and . ~ ; the (1 1 ;14) translocation associated with gestion with restriction endonucleases, DNA fragments were electrointermediate or "mantle zone" lymphoma.' The molecular phoresed on 0.8% agarose gels, transferred onto nylon N+ memanalysis of these chromosomal defects has shown that they lead branes, and hybridized according to the recommendations of the suppliers (Amersham). DNAs were digested using at least two of totheoncogenicconversion of genessuch as BCL-2,"' four restriction enzymes (EcoRI, BamHI, HindIII, Xba I). The genoa regulator of apoptotic cell death: or of proto-oncogenes mic probes F370, F372, and F381 (Fig 1) have been previously encoding transcription regulators such as MYC'03LLand described.18 CCND1/PRAD.'2"4 Cytogeneticanalysis. Cells (2 X 10b/mL) were cultured overWe have previously reported that translocations involving night in RPM1 1640 supplemented with 10% fetal calf serum in the chromosome 3q27 and Ig gene regions are the third most presence of colchicine (0.02 pg/mL). Cells were incubated for 25 common specific group of translocations in NHL, and are associated mainly with diffuse large cell lymphoma (DLCL)." In this subset of NHL, numerous chromosomal From the Department of Cytogenetics, CentreRkgional de Transdefects are found that affect the same region on chromosome fusion Sanguine et de Gdnne'tiqueHumaine, Bois Guillaume; INSERM 3 but not the Ig gene locations. We and others have shown U124, Institut de Recherche sur le Cancer, Lille; the Department of that most of these rearrangements involve the same major Biological Hematology and Cellular Immunology, Hbpital Charles Nicolle, Rouen; the Department of Clinical Hematology, Centre translocation cluster (MTC) on chromosome 3.'h"8 These Henri Becquerel, Rouen, France; and the Department of Hematoltranslocations result in the disruption and deregulation of a ogy, John Radcliffe Hospital, Oxford, UK. gene, LAZ3,I9 also named BCL-6," encoding a conserved Submitted January 25, 1994; accepted February 22, 1994. zinc finger protein that may act as a transcriptional regulator Supported in part by grants from la Ligue Nationale FranCaise involved in differentiation and development. To confirm the Contre le Cancer and la Fondation de France. prominent role of the LAZ3 gene in the pathogenesis of NHL, Address reprint requests to Christian Bastard, MD, Centre Re" weused genomic probes derived from the 3q27MTC to gional de Transfusion Sanguine, 609 Chemin de la Brett?que, BP study DNAs from a series of 217 patients with this disease. 58, 76232 Bois Guillaume Cedex, France. S MATERIALS AND METHODS Patients. High molecular weight DNA was obtained from biopsy specimens of 217 adult patients admitted to the Centre Henri Becquerel (Rouen, France) between September 1984 and April 1993 for the diagnosis and treatment of NHL. Blood, Vol 83, No 9 (May l), 1994: pp 2423-2427 The publication costsof this article were defrayedin part by page chargepayment. This article must therefore be hereby marked "adveaisement" in accordance with 18 U.S.C. section 1734 solely to indicate this fact. 0 1994 by The American Society of Hematology. 0006-4971/94/8309-07$3.00/0 2423 From www.bloodjournal.org by guest on June 14, 2017. For personal use only. 2424 BASTARD ET AL 1OKB 0 l MTC minutes at 37°C in 0.075 m o m potassium chloride, fixed in methanol-acetic acid (3: l), and spread on clean, dry slides. R-banding was obtained according toSehested?’ and karyotypes were described according to the International System for Human Cytogenetic Nomenclature.*’ Correlation with clinical presentation and outcome. For this retrospective study, we only considered patients who had a tumor sample studied at the time of primary diagnosis. Two patient populations were selected: patients with follicular lymphomas and patients with aggressive lymphomas as defined by the International Non-Hodgkin’s Lymphoma Prognostic Factor Proje~t,’~ namely diffuse mixed, diffuse large cell, and large cell immunoblastic subtypes. For each population, the association between LAW rearrangement and clinical features was studied. The clinical features studied were: age, sex, performance status, presence of B symptoms, Ann Arbor stage, bone marrow involvement, number of extranodal sites, presence of a mass greater than 10 cm, LDH level, serum albumin level, and overall survival. For aggressive lymphoma only, association with the International Prognostic Index,” response to treatment, and disease-free survival were also examined. Statistical methods. Associations between LA23 rearrangement and initial clinical features were analyzed with the two-sided chisquared test. Survival curves were plotted using the method of Kaplan and Meief’ and were compared by the log-rank test.26Analyses were performed with use of JPSI statistical software (developed by P. Kwiatkowski, Centre Jean Perrin, Clermont-Ferrand, France). RESULTS Fig 1. Partial map of the 3q27 rqion. Shadedboxesindicate tho locationof W e x o n r . MTC, 2 3 4 5 6 7 0 9 major trandocatlon cluster. Genomicprobes F370, F372,and F381 are indicated by black boxes. Restriction enzymes symbol are: E, € d l ; B, & d l ; X, Xba I; Xh, Xbo 1. patients with aggressive B-cell lymphoma, the LAZ3 gene was involved in 26patients (37%), mainly with diffuse large cell (14/46) and immunoblastic(6/12) lymphomas. Onlyone patient with T-cell lymphoma was found to have an LAZ3 rearrangement. In thiscase, the results of morphologic evaluation and immunostaining were confirmed by the absence ofIg gene rearrangement and the presence of a C@ rearrangement. The only anaplastic large cell lymphoma of B-cell phenotype included in this study had an M 3 rearrangement, whereas four T-anaplastic large cell lymphomas appeared to be unaffected. Good quality metaphases were obtained in 201 patients, 32 of which had adetectable abnormality of the 3q27 region (16%) (Table 3). LAZ3 rearrangement was found in 14 of the18 patients with translocations involving3q27andIg genes regions.Amongthe14 patients withchromosomal 3q27 defects (12 translocations, 2 deletions) that did not affect Ig gene regions, 7 showed LAB rearrangements, as did 18 patients with no evident cytogenetic involvement of the 3q27 region. Thirteen of these had a complex karyotype, whereas 5 displayed a more simple pattern: 47,xyy; 46,xx, t(2; 18)(p12;q21); 46,xx, t(14; 18)(q32;q21); 47,xy, +5; 46,xx, t( 15;2O)(q22;ql3)/46,xx,der(9)(~24). LAZ3 rearrangement was found to be associated, atthe cytogenetic level, with other specific abnormalities in 12 of 39 patients. These translocations were a t ( 14; 18) or a t(2; 18) LAZ3 rearrangements were detected in 43 of the 217 samples (19.8%). A common HindIII polymorphism was also noted in 15 patients. All histologic subtypes of the Working Table 1. Incidence of LAM Rearrangement Formulation were represented in thepatient population (TaAmong 217 Cases of NHL ble l ) and the involvement of LA23 was observed in all of Cases With L9z3 Rearrangement/ them, withthe exception of lymphocytic, lymphoblastic, and Total Cases Studied Histology diffuse small noncleaved cell lymphomas. Lymphocytic 014 Eleven of the 84 follicular lymphomas (13%) were found Follicular to be rearranged. M 3 alterations appeared to be more frecells Small 3/38 quent in large cell follicular lymphoma (4/10) than in small cells largeandsmall Mixed, 4/36 or mixed cell follicular lymphoma (7174). However, most of cells Large 4110 LAZ3 rearrangements were observed in aggressive Diffuse lymphoma (diffuse mixed, diffuse large cell, and large cell cells cleaved Small 115 cells largeand small Mixed, 5/24 immunoblastic), affecting 31 of the 114 patientsin these cells Large 14/51 subtypes (27%). lmmunoblastic 9/29 Immunophenotype could be determined in 204 tumors, Unclassifiable 3110 which comprised 163 B-cell and 41 T-cell lymphomas. Of Lymphoblastic 016 the 163 B-cell lymphomas (including follicular lymphomas), noncleaved cells small Diffuse 014 38 were rearranged (Table 2). Within the subgroup of 71 From www.bloodjournal.org by guest on June 14, 2017. For personal use only. 2425 LAZ3 REARRANGEMENTS IN NHL Table 2. Incidence of LAZ3 Rearrangemant Among 163 Cases of B-Cell NHL Cases With W 3 RearrangemenKases Studied Histology Lymphocytic Follicular Small cells Mixed, small and large cells Large cells Diffuse Small cleaved cells Mixed, small and large cells Large cells lrnmunoblastic Unclassifiable Diffuse small noncleaved cells Table 4. Correlations Between Main Clinical Characteristics and Presence or Absence of LAZ3 Rearrangement inthe 83 Patients W t h Aggressive Lymphoma Studied atthe Time of Diagnosis 013 All patients 3/35 4/35 4110 115 3/9 14/46 6112 314 014 in 8 cases, a t(8; 14) or a t(8;22) in 2 cases, and the association of a t(8; 14) and a t(14; 18) in 2 cases. The association of LAU rearrangement with clinical features could be studied in 55 patients with follicular lymphoma and in 83 patients with aggressive lymphoma (Table 4) examined at the time of diagnosis, but no statistical correlations were observed in either subgroup. LAZj rearrangement did not influence survival in patients with follicular lymphoma (Fig 2). The overall survival of patients with aggressive lymphoma and an LAU rearrangement appeared slightly better than those of patients without rearrangement, but the difference was not significant (P > .55) (Fig 3). DISCUSSION Molecular studies of the t(14; 18) and of the t(8; 14) have greatly improved our understanding of the pathogenesis of follicular and Burkitt's lymphoma. However, very little is known about the genes involved in DLCL, the most frequent subtype of lymphoma." We have previously shown that translocations involving Table 3. Incidence of LAZ3 Rearrangement in 32 Cases of NHL With Chromosomal Abnormalityat Band 3q27 Cases With W 3 Partial Karyotype RearrangernenUCases Studied t(3;14)(q27;q32) t(3;22)(q27;qlI) t(2;3)(p12:q27) t(2:3)(q22;q27) t(3;4)(q27;pl1) t(3;6)(q27;p21) t(3;6)(q27;q15) t(3;7)(q27;p12) t(3;8)(q27;q24) t(3;15)(q27;q21) der(3)t(3;?)(q27;7)* del(3)(q27) All 12114 112 112 011 112 111 011 111 111 1I2 113 112 21/32 * t(3;?) denotes a translocation with unidentified chromosomal material. Age s 6 0 yrs >60 yrs Sex M F Performance status 0-1 2-4 B symptoms No Yes Ann Arbor stage 1-11 Ill-IV Bone marrow involvement No Yes Number of extranodal sites 0-1 22 Largest mass < l 0 cm 210 cm Serum albumin level* S35 g/L >35 glL Serum LDH level* SN >N International Index (24)* 0-1 Risk factor 2-3 Risk factors 4-5 Risk factors LA13 LAZ3 Not Rearranged Rearranged 25 58 14 11 34 24 >.5 18 7 35 23 >.3 20 5 40 18 >.3 16 9 29 29 >.2 13 12 19 39 >.05 20 5 40 18 >.3 21 4 37 21 >.l 14 11 36 22 >.5 8 25 31 >.2 17 8 13 15 38 >.3 11 7 3 14 26 13 >.l PValue Some patients had missing data for serum albumin and LDH levels. the 3q27 region and Ig genes locations were frequently observed in NHL, mainly of large cell type.I5 Breakpoints on chromosome 3 are clustered into an MTC of 4 kb, together with those of several chromosome rearrangements of the same 3q27 region that do not affect Ig genes as partner." We have cloned a gene, L A Z 3 , encoding an evolutionary conserved zinc finger protein, that is disrupted and abnormally overexpressed in patients with3q27 molecular rearrangements, and postulated that the deregulation of this transcription factor (of unknown function) could be an important event in the pathogenesis of large cell lymphoma." The same breakpoint ~ l u s t e r ' ~and . ' ~ the same genez0have been cloned by others and named BCL-6. To assess the frequency and the significance of LA23 rearrangements, we studied a series of 2 17 patients and found that the 3q27 region was affected in 13% of follicular lymphomas and 27% of DLCL. M 3 rearrangements appeared to be nearly restricted to B-cell lymphoma because From www.bloodjournal.org by guest on June 14, 2017. For personal use only. 2426 BASTARD ET AL only 1 of 39 immunologically characterized positive samples was of T-cell phenotype. In the group of aggressive lymphoma of B-cell phenotype, the overall frequency of LAZ3 rearrangements reaches 37%, in accordance with the results reported by Ye et al.” As suspected from the cytogenetic analy~is,’~ LAZ3 rearrangement was found in a proportion of follicular lymphoma cases (13%). These results differs from those of Ye et a1’: who did not observe any BCL-6 alteration in a series of 28 patients with follicular lymphoma. The fact that LAZ3 rearrangement could be observed in some patients with follicular lymphoma at the time of diagnosis, and that it did not appear to influence survival, suggests that LAZ3 is not associated with clinical progression or histologic transformation. Correlation with cytogenetic data showed that 1 1 of the 32 patients displaying a chromosomal defect of the 3q27 region had no LAZ3 rearrangement. In these cases, the defect could either affect another gene or, more likely, affect the LAZ3 gene at a breakpoint located outside the MTC. Thus, the reported frequency of LAZ3 involvement could represent an underestimation of the real frequency. On the other hand, 18 of the 39 patients with LAZ3 rearrangement and available cytogenetic results did not exhibit visible chromosomal break of the 3q27 region. This result suggests that almost 50% of LAZ3 rearrangements may be invisible by cytogenetic methods. We were unable, in this series, to show any correlation between clinical characteristics and LAW rearrangement. Recently, Offit et alZ8described an association between BCL6 rearrangement and a subset of DLCL with high proportion of extranodal disease who enjoy a favorable outcome. Our study did not support this association. As both studies were retrospective, inclusion criteria might have been different. Our study included only patients with available cytogenetic data, and this fact probably discarded some patients with only extranodal localization at the time of diagnosis. In conclusion, this study confirms the importance of alterations of LAZ3 in NHL, involving a third of the patients with aggressive B-cell lymphoma. Further studies are now required to understand the mechanism of action of this new oncogene, and to define whether or not its alterations have ”.. U) C .- .B S v) c U g n OS8l 0.6 0.2- 0 -m+-mI 0 I 1 2 2 4 3 6 4 8 6 0 7 2 8 4 Months Fig 2. Survivalof the 55 patients with follicularlymphomaaccording to the presence (n = 8) or the absence In = 47) of LAZ3 rearrangement at diagnosis ( P = .96). 1 1 .-P .z 5 v) 0.2 0 1 2 2 4 3 6 4 8 6 0 7 2 8 4 Months Fig 3. Survival of the 83 patients with aggressive lymphoma according to the premnce (n = 251 or the absence of LAM (n = 5 8 ) rearrangement at diagnosis (P = 551. any prognostic significance in NHL. This genomic marker, allowing the identification and follow-up of a homogeneous group of patients, will probably represent an important new approach to the diagnosis and management of patients with B-cell lymphoma. We are currently developing a polymerase chain reaction assay to assess minimal residual disease in patients with a t(3; 14) translocation. ACKNOWLEDGMENT We are grateful to Dr David Y. Mason for his critical reading of the manuscript. REFERENCES I . Leder P, Battey J, Lenoir G, Moulding C, Murphy W, Potter H, Stewart T, Taub R Translocations among antibody genes in human cancer. Science 222:765, 1983 2. Fukuhara S, Rowley JD, Variakojis D, Golomb HM: Chromosome abnormalities in poorly differentiated lymphocytic lymphoma. Cancer Res 39:3119, 1979 3. Manolova Y, Manolov G, Kieler J, Levan A, Klein G: Genesis of the 14q+ marker in Burkitt’s lymphoma. Hereditas 90:5, 1979 4. 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Offit K, Lo Coco F, Louie D, Parsa NZ, Ye BH, Rosenbaum A, Siebert R, Dalla-Favera R, Chaganti RSK: BCL-6 rearrangement defines a clinical and prognostic subset of diffuse large cell lymphoma. Blood 82:133a, 1993 (abstr, suppl 1) From www.bloodjournal.org by guest on June 14, 2017. For personal use only. 1994 83: 2423-2427 LAZ3 rearrangements in non-Hodgkin's lymphoma: correlation with histology, immunophenotype, karyotype, and clinical outcome in 217 patients C Bastard, C Deweindt, JP Kerckaert, B Lenormand, A Rossi, F Pezzella, C Fruchart, C Duval, M Monconduit and H Tilly Updated information and services can be found at: http://www.bloodjournal.org/content/83/9/2423.full.html Articles on similar topics can be found in the following Blood collections Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. 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