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Point mutations of the BCL-6 gene: clinical and prognostic correlation in B-diffuse large cell lymphoma

Leukemia volume 16, pages 268–275 (2002)Cite this article

Abstract

Although point mutations of the 5′ noncoding regions of the BCL-6proto-oncogene are frequently detected in B-diffuse large cell lymphoma (B-DLCL), a thorough analysis of the clinical correlation of these mutations has not been performed to date. In this study, BCL-6 mutations were examined by DNA direct sequencing in 103 patients with B-DLCL. BCL-6 mutations were found in 53/103 patients, including 38/76 treated with standard chemotherapy and 15/27 treated with autologous stem cell transplantation (ASCT) up front. The presence of BCL-6 mutations was correlated with clinical features at diagnosis and outcome. Mutated patients had a significantly higher LDH level (66% vs 38%, P < 0.05), and bulky disease (51% vs 32%, P = 0.05). In the whole series of patients BCL-6 mutations did not affect CR and OS. Patients with BCL-6 mutations tended to have a prolonged 5-years DFS and FFS compared to those without mutations (DFS 82% vs 63%, FFS 63% vs 49%). Among B-DLCL treated with standard chemotherapy, mutated patients showed a significantly improved 5-year DFS (85% vs 61%, P < 0.05) and, notably, the only four relapses observed among mutated patients occurred in less than 8 months. The multivariate regression analysis (P < 0.01) with DFS as endpoint confirmed the independent prognostic value of BCL-6 mutations. There was a trend for 5-year failure-free survival to be better for patients with BCL-6 mutations (63% vs43%, P = 0.09). In the 27 patients treated with ASCT, BCL-6 mutations did not correlate with outcome. These results suggest that BCL-6mutations may predict a higher chance of being free of disease in B-DLCL treated with standard chemotherapy. Larger series of patients need to be analyzed to evaluate the clinical relevance of BCL-6 mutations properly.

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References

  1. Ye BH, Lista F, Lo Coco F, Knowles DM, Offit K, Chaganti RS, Dalla-Favera R . Alterations of a zinc finger-encoding gene, BCL-6, in diffuse large cell lymphoma Science 1993 262: 747–750

    Article  CAS  PubMed  Google Scholar 

  2. Kerckaert JP, Deweindt C, Tilly H, Quief S, Lecocq G, Bastard C . LAZ3, a novel zinc finger encoding gene, is disrupted by recurring chromosome 3q27 translocations in human lymphomas Nat Genet 1993 6: 66–70

    Article  Google Scholar 

  3. Offit K, Lo Coco F, Louie DC, Parsa NZ, Leung D, Portlock C, Ye BH, Lista F, Filippa DA, Rosenbaum A, Ladanyi M, Jhanwar S, Dalla-Favera R, Chaganti RSK . Rearrangement of the BCL-6 gene as a prognostic marker in diffuse large cell lymphoma N Engl J Med 1994 331: 71–80

    Article  Google Scholar 

  4. Bastard C, Deweindt C, Kerckaert JP, Lenormand B, Rossi A, Pezzella F, Frichart C, Duval C, Monconduit M, Tilly H . LAZ3 rearrangements in non Hodgkin's lymphoma: correlation with histology, immunophenotipe, karyotype and clinical outcome in 217 patients Blood 1994 83: 2423–2427

    CAS  PubMed  Google Scholar 

  5. Lo Coco F, Ye BH, Lista F, Corradini P, Offit K, Knowles DM, Chaganti RSK, Dalla-Favera R . Rearrangements of the BCL-6 gene in diffuse large cell non-Hodgkin's lymphomas Blood 1994 83: 1757–1759

    CAS  PubMed  Google Scholar 

  6. Volpe G, Vitolo U, Carbone A, Pastore C, Bertini M, Botto B, Audisio E, Freilone R, Novero D, Cappia S, De Giuli P, Mazza U, Resegotti L, Palestro G, Saglio G, Gaidano G . Molecular heterogeneity of B-lineage diffuse large cell lymphoma Genes Chromos Cancer 1996 16: 21–30

    Article  CAS  PubMed  Google Scholar 

  7. Pescarmona E, De Sanctis V, Pistilli A, Pacchiarotti A, Martelli M, Guglielmi C, Mandelli F, Baroni CD, Lo Coco F . Pathogenetic and clinical implications of BCL-6 and BCL-2 gene configuration in nodal diffuse large B-cell lymphomas J Pathol 1997 183: 281–286

    Article  CAS  PubMed  Google Scholar 

  8. Migliazza A, Martinotti S, Chen W, Fusco C, Ye BH, Knowles DM, Offit K, Chaganti RS, Dalla-Favera R . Frequent somatic hypermutation of the 5′ noncoding region of the BCL-6 gene in B-cell lymphoma Proc Natl Acad Sci USA 1995 92: 12520–12524

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Shen HM, Peters A, Baron B, Zhu X, Storb U . Mutation of BCL-6 gene in normal B-cells by the process of somatic hypermutation of Ig genes Science 1998 280: 1750–1752

    Article  CAS  PubMed  Google Scholar 

  10. Pasqualucci L, Migliazza A, Fracchiolla N, William C, Neri A, Baldini L, Chaganti RS, Klein U, Kuppers R, Rajewski K . BCL-6 mutations in normal germinal center B cells: evidence of somatic hypermutation acting outside Ig loci Proc Natl Acad Sci USA 1998 95: 11816–11821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Peng HZ, Du MQ, Koulis A, Aiello A, Dogan A, Pan LX, Isaacson PG . Nonimmunoglobulin gene hypermutation in germinal center B-cells Blood 1999 93: 2167–2172

    CAS  PubMed  Google Scholar 

  12. Gaidano G, Carbone A . MUM-1: a step ahead toward the understanding of lymphoma histogenesis Leukemia 2000 14: 563–566

    Article  CAS  PubMed  Google Scholar 

  13. Capello D, Vitolo U, Pasqualucci L, Quattrone S, Migliaretti G, Fassone L, Ariatti C, Vivenza D, Gloghini A, Pastore C, Lanza C, Nomdedeu J, Botto B, Freilone R, Buonaiuto D, Zagonel V, Gallo E, Palestro G, Saglio G, Dalla-Favera R, Carbone A, Gaidano G . Distribution and pattern of BCL-6 mutations throughout the spectrum of B-cell neoplasia Blood 2000 95: 651–659

    CAS  PubMed  Google Scholar 

  14. Vitolo U, Cortellazzo S, Liberati AM, Freilone R, Falda M, Bertini M, Botto B, Cinieri S, Levis A, Locatelli F, Lovisone E, Marmont F, Pizzuti M, Rossi A, Viero P, Barbui T, Grignani F, Resegotti L . Intensified and high-dose chemotherapy with granulocyte colony-stimulating factor and autologous stem-cell transplantation support as first-line therapy in high-risk diffuse large-cell lymphoma J Clin Oncol 1997 15: 491–498

    Article  CAS  PubMed  Google Scholar 

  15. Gianni AM, Bregni M, Siena S, Brambilla C, Di Nicola M, Lombardi F, Gandola L, Tarella C, Pileri A, Ravagnani F, Valagussa P, Bonadonna G . High dose chemotherapy and autologous bone marrow transplantation compared with MACOP-B in aggressive B-cell lymphoma N Engl J Med 1997 336: 1290–1297

    Article  CAS  PubMed  Google Scholar 

  16. Haioun C, Lepage E, Gisselbrecht C, Bastion Y, Coiffier B, Brice P, Bosly A, Dupriez B, Nouvel C, Tilly H, Lederlin P, Biron P, Briere J, Gaulard P, Reyes F . Benefit of autologous bone marrow transplatation over sequential chemotherapy in poor risk aggressive non Hogkin's lymphoma: updated results of the prospective study LNH87–2. Groupe d'Etudes des Lymphomes de l'Adulte J Clin Oncol 1997 15: 1131–1137

    Article  CAS  PubMed  Google Scholar 

  17. Shipp MA, Harrington DP . A predictive model for aggressive NHL: the International non-Hodgkin's lymphoma prognostic factors project N Engl J Med 1993 329: 987–994

    Article  Google Scholar 

  18. Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, Del Sol G, De Wolf Peteers C, Falini B, Gatter KC . A revised European–American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group Blood 1994 84: 1361–1392

    CAS  PubMed  Google Scholar 

  19. Tang SC, Visser L, Hepperle B, Hanson J, Poppema S . Clinical significance of the BCL-2 MBR gene rearrangement and protein expression in diffuse large cell lymphoma: an analysis of 83 cases J Clin Oncol 1994 12: 149–154

    Article  CAS  PubMed  Google Scholar 

  20. Gascoyne RD, Adomat SA, Krajewski S, Krajewska M, Horsman DE, Tolcher AW, O'Reilly SE, Hoskins P, Coldman AJ, Reed JC, Connors JM . Prognostic significance in BCL-2 protein expression and BCL-2 gene rearrangement in diffuse aggressive non-Hodgkin's lymphoma Blood 1997 90: 244–251

    CAS  PubMed  Google Scholar 

  21. Vitolo U, Gaidano G, Botto B, Volpe G, Audisio E, Bertini M, Calvi R, Freilone R, Novero D, Orsucci L, Pastore C, Capello D, Parvis G, Sacco C, Zagonel V, Carbone A, Mazza U, Palestro G, Saglio G, Resegotti L . Rearrangement of BCL-6, BCL-2, c-myc and 6q deletion in B-diffuse large cell lymphoma:clinical relevance in 71 patients Ann Oncol 1998 9: 55–61

    Article  CAS  PubMed  Google Scholar 

  22. Moller MB, Kania PW, Ino Y, Gerdes AM, Nielsen O, Lovis DN, Pedersen NT . Frequent disruption of the RB1 pathway in B-diffuse large cell lymphoma: prognostic significance of E2F! and p16INK4A Leukemia 2000 14: 898–904

    Article  CAS  PubMed  Google Scholar 

  23. Harada S, Suzuki R, Verika K, Yatabe Y, Kagami Y, Oguna M, Suzuki H, Oyoma A, Kodero Y, Uedo R, Morishima Y, Nakamura S, Seto Y . Molecular and immunogenetic dissection of diffuse large cell lymphoma: CD5+ and CD5− with CD10 groups may constitute clinical relevant subtypes Leukemia 1999 13: 1441–1447

    Article  CAS  PubMed  Google Scholar 

  24. Pasqualucci L, Migliazza A, Ye BH, Cattoretti G, Chaganti RSK, Dalla Favera R . Transcriptional deregulation of mutated BCL-6 alleles in diffuse large cell lymphoma Blood 1999 1 (Suppl. 1): Abstr. 247

  25. Carbone A, Cilia AM, Gloghini A, Capello D, Fassone L, Perin T, Rossi D, Canzonieri V, De Paoli P, Vaccher E, Tirelli U, Volpe R, Gaidano G . Characterization of a novel HHV-8-positive cell line reveals implications for the pathogenesis and cell cycle control of primary effusion lymphoma Leukemia 2000 14: 1301–1309

    Article  CAS  PubMed  Google Scholar 

  26. Carbone PP, Kaplan HS, Musshof K, Smithers DW, Tubiana M . Report of the committee on Hodgkin's disease staging classification Cancer Res 1971 31: 1860–1861

    CAS  PubMed  Google Scholar 

  27. Freilone R, Botto B, Vitolo U, Bertini M, Audisio E, Calvi R, Cucchi M, De Crescenzo A, Gallamini A, Ghio R, Griso L, Levis A, Massara G, Orsucci L, Ricardi U, Rota Scalabrini D, Salvi F, Secondo V, Resegotti L . Combined modality treatment with a brief chemotherapy (ACOP-B) followed by a locoregional radiotherapy in localized-stage intermediate to high-grade non-Hodgkin's lymphoma Ann Oncol 1996 7: 919–924

    Article  CAS  PubMed  Google Scholar 

  28. Coltman AC Jr, Dahlberg S, Jones ES . CHOP is curative in thirty per cent of patients with large cell lymphoma: a twelve year Southwest Oncology Group follow-up. In: Skarin AT (ed.) Update on Treatment for Diffuse Large cell Lymphoma Park Row: New York 1986 pp 71–77

    Google Scholar 

  29. Klimo P, Connors JM . MACOP-B chemotherapy for the treatment of advanced diffuse large cell lymphoma Ann Intern Med 1985 102: 596–602

    Article  CAS  PubMed  Google Scholar 

  30. O'Reilly SE, Hoskins P, Klimo P, Connors JM . MACOP-B and VACOP-B in diffuse large cell lymphomas and MOPP/ABV in Hodgkin's disease Ann Oncol 1991 2: 17–23

    Article  PubMed  Google Scholar 

  31. Bertini M, Freilone R, Vitolo U, Botto B, Pizzuti M, Gavarotti P, Levis A, Orlandi E, Orsucci L, Pini M . P-VEBEC: a new 8 weekly schedule with or without rG-CSF for elderly patients with aggressive non-Hodgkin's lymphoma (NHL) Ann Oncol 1994 5: 895–900

    Article  CAS  PubMed  Google Scholar 

  32. Salvagno L, Contu A, Bianco A, Endrizzi L, Schintu GM, Olmeo N, Aversa SM, Chiarion-Sileni V, Soraru M, Fiorentino MV . A combination of mitoxantrone, etoposide and prednisone in elderly patients with non-Hodgkin's lymphoma Ann Oncol 1992 3: 833–837

    Article  CAS  PubMed  Google Scholar 

  33. Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM, Lister TA, Vose J, Grillo-Lopez A, Hagenbeek A, Cabanillas F, Klippensten D, Hiddemann W, Castellino R, Harris NL, Aremitaje JO, Carter W, Hoppe R, Canellos GP . Report of an International Workshop to standardize response criteria for non-Hodgkin's lymphomas J Clin Oncol 1999 17: 1244–1253

    Article  CAS  PubMed  Google Scholar 

  34. Fassone L, Bhatia K, Gutierrez M, Capello D, Gloghini A, Dolcetti R, Vivenza D, Ascoli V, Lo Coco F, Pagani L, Dotti G, Rambaldi A, Raphael M, Tirelli U, Saglio G, Magrath IT, Carbone A, Gaidano G . Molecular profile of Epstein–Barr virus infection in HHV-8-positive primary effusion lymphoma Leukemia 2000 14: 271–277

    Article  CAS  PubMed  Google Scholar 

  35. Fais F, Gaidano G, Capello D, Gloghini A, Ghiotto F, Roncella S, Carbone A, Chiorazzi N, Ferrarini M . Immunoglobulin V region gene use and structure suggest antigen selection in AIDS-related primary effusion lymphomas Leukemia 1999 13: 1093–1099

    Article  CAS  PubMed  Google Scholar 

  36. Capello D, Fais F, Vivenza D, Migliaretti G, Chiorazzi N, Gaidano G, Ferrarini M . Identification of three distinct subgroups of B-cell chronic lymphocytic leukemia based upon mutations of BCL-6 and IgV genes Leukemia 2000 14: 811–815

    Article  CAS  PubMed  Google Scholar 

  37. Kaplan EL, Meier P . Nonparametric estimation from incomplete information J Am Stat Assoc 1958 53: 547–581

    Article  Google Scholar 

  38. Cox DR . Regression model and life tables (with discussion) JR Stat Soc 1972 34: 187–222

    Google Scholar 

  39. antini G, Salvagno L, Leoni P, Chisesi T, De Souza C, Sertoli MR, Rubagotti A, Congiu AM, Centurioni R, Olivieri A, Tedeschi L, Vespignani M, Nati S, Soracco M, Porcellini A, Contu A, Guarnaccia C, Pescosta N, Majolino I, Spriano M, Vimercati R, Rossi E, Zambaldi G, Mangoni L, Rizzoli V . VACOP-B versus VACOP-B plus autologous bone marrow transplatation for advanced diffuse non-Hodgkin's lymphoma: results of a prospective randomized trial by the non-Hodgkin's Lymphoma Cooperative Study Group J Clin Oncol 1998 16: 2796–2802

    Article  Google Scholar 

  40. Haioun C, Lepage E, Gisselbrecht C, Salles G, Coiffier B, Brice P, Bosly A, Morel P, Nouvel C, Tilly H, Lederlin P, Sebban C, Briere J, Gaulard P, Reyes F . Survival benefit of high dose therapy in poor risk non Hodgkin's lymphoma: final analysis of the prospective LNH87–2 protocol, a groupe d'Etude des lymphomes de l'Adulte study J Clin Oncol 2000 18: 3025–3030

    Article  CAS  PubMed  Google Scholar 

  41. Fisher RI, Gaynor ER, Dahlberg R, Oken MM, Grogan TM, Mize EM, Glick JH, Coltman CA Jr, Miller TP . Comparison of standard regimen (CHOP) with three intensive chemotherapy regimen for advanced non-Hodgkin's lymphoma N Engl J Med 1993 328: 1002–1006

    Article  CAS  PubMed  Google Scholar 

  42. Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, Boldrick JC, Sabet H, Tran T, Yu X, Powell JI, Yang L, Marti GE, Moore T, Hudson J Jr, Lu L, Lewis DB, Tibshirani R, Sherlock G, Chan WC, Greiner TC, Weisenburger DD, Armitage JO, Warnke R, Levy R, Wilson W, Grevers MR, Byrd JC, Botstein D, Brown PO, Staudt LM . Distinct types of diffuse B-large cell lymphoma identified by gene express profiling Nature 2000 403: 503–511

    Article  CAS  PubMed  Google Scholar 

  43. Shipp M, Tamajo P, Angelo M, Ray T, Riech M, Neuberg D, Last K, Aster J, Mesirow J, Lister A, Todol R . Diffuse large B-cell lymphoma outcome prediction by gene expression profiling Blood 2000 96: Abstr. 948

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Acknowledgements

This work has been supported by AIRC, Milan, Italy, Fondo ex-60% dell'Università del Piemonte Orientale Amedeo Avogadro, and Fondazione Piera Pietro e Giovanni Ferrero, Alba Italy. DC is being supported by a fellowship from FIRC, Milan, Italy.

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Author notes

  1. B Botto and D Capello: B Botto and D Capello contributed equally to this work.

Authors and Affiliations

  1. Dipartimento di Oncologia, UOA Ematologia, Azienda Ospedaliera S Giovanni Battista, Torino, Italy

    U Vitolo, B Botto, R Calvi, M Bertini, C Boccomini, R Freilone, P Pregno, L Orsucci & E Gallo

  2. Divisione di Medicina Interna, Dipartimento di Scienze Mediche, Università del Piemonte Orientale Amedeo Avogadro, Novara, Italy

    D Capello, D Vivenza, C Ariatti & G Gaidano

  3. Divisione di Oncologia Medica B Centro di Riferimento Oncologico-Instituto Nazionale Tumori, Aviano, Italy

    V Zagonel & I Milan

  4. Divisione di Anatomia Patologica, Centro di Riferimento Oncologico-Istituto Nazionale Tumori, Aviano, Italy

    A Gloghini & A Carbone

  5. Dipartimento di Oncologia, Anatomia Patologica, Azienda Ospedaliera S Giovanni Battista and Università, Torino, Italy

    D Novero & G Palestro

  6. Divisione di Medicina Interna ed Ematologia, Dipartimento di Scienze Cliniche e Biologiche, Azienda Ospedaliera S Luigi e Università di Torino, Orbassano-Torino, Italy

    G Parvis & G Saglio

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Vitolo, U., Botto, B., Capello, D. et al. Point mutations of the BCL-6 gene: clinical and prognostic correlation in B-diffuse large cell lymphoma. Leukemia 16, 268–275 (2002). https://doi.org/10.1038/sj.leu.2402349

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