Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Manuscript
  • Published:

Lymphoma

Genetic instability is associated with histological transformation of follicle center lymphoma

Leukemia volume 14, pages 2142–2148 (2000)Cite this article

Abstract

Follicle center lymphoma (FCL) is an indolent B cell non-Hodgkin's lymphoma (NHL) characterized genetically by the t(14;18) translocation. Histological transformation and clinical progression of FCLs are frequently associated with secondary genetic alterations at both nucleic acid and chromosomal levels. To determine the type and pattern of genomic instability occurring in histological transformation of FCLs and the role of DNA mismatch repair defects in this procedure, we have performed microsatellite analysis, comparative genomic hybridization (CGH) and mutational analysis of hMLH1 and hMSH2 genes on serial biopsy specimens from patients with FCL transformed to diffuse large cell lymphoma (DLCL). Paired biopsy samples of eight patients were analyzed for microsatellite instability and structural alterations for hMLH1 and hMSH2 genes, and tumor samples of five patients were subjected to CGH analysis. A high level of microsatellite instability was associated with histological transformation of two cases of FCL, but no mutations of the hMLH1 and hMSH2 genes were detected in any of the lymphoma samples. In the five cases subjected to CGH analysis, the histological transformation of FCLs was associated with genomic imbalances at 21 chromosomal regions. The genomic abnormalities found were rather heterogeneous and none of the genetic changes were overrepresented in the transformed DLCLs. These data suggest that histological transformation of FCLs to DLCL is frequently associated with genome wide instability at both nucleic acid and chromosomal levels, although mutations of the hMSH1 and hMLH2 genes are not involved in this process.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Ersbøll J, Schultz HB, Perdersen-Bjergaard J, Nissen NJ . Follicular low-grade non-Hodgkin lymphomas: long-term outcome with or without tumor progression Eur J Haematol 1989 42: 155–163

    PubMed  Google Scholar 

  2. Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, Delsol G, De Wolf-Peeters C, Falini B, Gatter KC, Grogan TM, Isaacson PG, Knowles DM, Mason DY, Muller-Hermelink HK, Pileri SA, Piris MA, Ralfkiaer E, Warnke RA . 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 

  3. Cullen MH, Lister TA, Brearley RI, Shand WS, Stansfeld AG . Histological transformation of non-Hodgkin's lymphoma: a prospective study Cancer 1979 44: 645–651

    CAS  PubMed  Google Scholar 

  4. Garvin AJ, Simon RM, Osborne CK, Merrill J, Young RC, Berard CW . An autopsy study of histological progression in non-Hodgkin's lymphomas: 192 cases from the National Cancer Institute Cancer 1983 52: 393–398

    CAS  PubMed  Google Scholar 

  5. Hubbard SM, Chabner BA, DeVita VT, Simon R, Berard CW, Jones RB, Garvin AJ, Canellos GP, Osborne CK, Young RC . Histologic progression in non-Hodgkin's lymphoma Blood 1982 59: 258–264

    CAS  PubMed  Google Scholar 

  6. Oviatt DL, Vousar JB, Collins RD, Flexner JM, Stein RS . Malignant lymphomas of follicular center cell origin in humans. V. Incidence, clinical features, and prognostic implications of transformation of small cleaved cell nodular lymphoma Cancer 1984 53: 1109–1114

    CAS  PubMed  Google Scholar 

  7. Weiss LM, Warnke RA, Sklar J, Cleary ML . Molecular analysis of the t(14;18) chromosomal translocation in malignant lymphomas New Engl J Med 1987 317: 1185–1189

    CAS  PubMed  Google Scholar 

  8. Chao DT, Korsmeyer SJ . Bcl-2 family: regulators of cell death Annu Rev Immunol 1998 16: 395–416

    CAS  PubMed  Google Scholar 

  9. Richardson ME, Chen QG, Filippa DA, Offit K, Hampton A, Koduru PR, Jhanwar SC, Lieberman PH, Clarkson BD, Chaganti RS . Intermediate- to high-grade histology of lymphomas carrying t(14;18) is associated with additional nonrandom chromosome changes Blood 1987 70: 444–447

    CAS  PubMed  Google Scholar 

  10. Armitage JO, Sanger WG, Weisenburger DD, Harrington DS, Linder J, Bierman PJ, Vose JM, Purtilo DT . Correlation of secondary cytogenetic abnormalities with histological appearance in non-Hodgkin's lymphomas bearing t(14; 18)(q32;q21) J Natl Cancer Inst 1988 80: 576–580

    CAS  PubMed  Google Scholar 

  11. Whang-Peng J, Knutsen T, Jaffe ES, Steinberg SM, Raffeld M, Zhao WP, Duffey P, Condron K, Yano T, Longo DL . Sequential analysis of 43 patients with non-Hodgkin's lymphoma: clinical correlations with cytogenetic, histological, immunophenotyping, and molecular studies Blood 1995 85: 203–216

    CAS  PubMed  Google Scholar 

  12. Bernell P, Jacobsson B, Liliemark J, Hjalmar V, Arvidsson I, Hast R . Gain of chromosome 7 marks the progression from indolent to aggressive follicle centre lymphoma and is a common finding in patients with diffuse large B-cell lymphoma: a study by FISH Br J Haematol 1998 101: 487–491

    CAS  PubMed  Google Scholar 

  13. Yano T, Jaffe ES, Longo DL, Raffeld M . MYC rearrangements in histologically progressed follicular lymphomas Blood 1992 80: 758–767

    CAS  PubMed  Google Scholar 

  14. Lo Coco F, Gaidano G, Louie DC, Offit K, Chaganti RSK, Dalla-Favera R . p53 mutations are associated with histological transformation of follicular lymphoma Blood 1993 82: 2289–2295

    CAS  PubMed  Google Scholar 

  15. Sander CA, Yano T, Clark HM, Harris C, Longo DL, Jaffe ES, Raffeld M . p53 mutation is associated with progression in follicular lymphomas Blood 1993 82: 1994–2004

    CAS  PubMed  Google Scholar 

  16. Clark HM, Yano T, Sander C, Jaffe ES, Raffeld M . Mutation of the ras genes is a rare genetic event in the histologic transformation of follicular lymphoma Leukemia 1996 10: 844–847

    CAS  PubMed  Google Scholar 

  17. Matolcsy A, Casali P, Warnke RA, Knowles DM . Morphologic transformation of follicular lymphoma is associated with somatic mutation of the translocated bcl-2 gene Blood 1996 88: 3937–3944

    CAS  PubMed  Google Scholar 

  18. Szereday Z, Csernus B, Nagy M, László T, Warnke RA, Matolcsy A . Somatic mutation of the 5′ noncoding region of the BCL-6 gene is associated with intraclonal diversity and clonal selection in histological transformation of follicular lymphoma Am J Pathol 2000 156: 1017–1024

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Elenitoba-Johnson KS, Gascoyne RD, Lim MS, Chhanabai M, Jaffe ES, Raffeld M . Homozygous deletions at chromosome 9p21 involving p16 and p15 are associated with histologic progression in follicle center lymphoma Blood 1998 91: 4677–4685

    CAS  PubMed  Google Scholar 

  20. Pinyol M, Cobo F, Bea S, Jares P, Nayach I, Fernandez PL, Montserrat E, Cardesa A, Campo E . p16INK4a gene inactivation by deletions, mutations, and hypermethylation is associated with transformed and aggressive variants of non-Hodgkin's lymphomas Blood 1998 91: 2977–2984

    CAS  PubMed  Google Scholar 

  21. Villuendas R, Sánchez-Beato M, Martínez JC, Saez AI, Martínez-Delgado B, García JF, Mateo MS, Sanchez-Verde L, Benítez J, Martínez P, Piris MA . Loss of p16/INK4A protein expression in non-Hodgkin's lymphomas is a frequent finding associated with tumor progression Am J Pathol 1998 153: 887–897

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Karran P . Microsatellite instability and DNA mismatch repair in human cancer Semin Cancer Biol 1996 7: 15–24

    CAS  PubMed  Google Scholar 

  23. Ramel C . Mini- and microsatellites Environ Health Perspect 1997 105: (Suppl. 4) 781–789

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Lengauer C, Kinzler KW, Vogelstein B . Genetic instabilities in human cancers Nature 1998 396: 643–649

    CAS  PubMed  Google Scholar 

  25. Miller SA, Dykes DD, Polesky HF . A simple salting out procedure for extracting DNA from human nucleated cells Nucleic Acids Res 1988 16: 1215

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Han HY, Maruyama M, Baba S, Park JG, Nakamura Y . Genomic structure of human mismatch repair gene, hMLH1, and its mutation analysis in patients with hereditary non-polyposis colorectal cancer (HNPCC) Hum Mol Genet 1995 4: 237–242

    CAS  PubMed  Google Scholar 

  27. Hangaishi A, Ogawa S, Mitani K, Hosoya N, Chiba S, Yazaki Y, Hirai H . Mutations and loss of expression of a mismatch repair gene, hMLH1, in leukemia and lymphoma cell lines Blood 1997 89: 1740–1747

    CAS  PubMed  Google Scholar 

  28. Fishel R, Lescoe MK, Rao MR, Copeland NG, Jenkins NA, Garber J, Kane M, Kolodner R . The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer Cell 1993 75: 1027–1038

    CAS  PubMed  Google Scholar 

  29. Kallioniemi OP, Kallioniemi A, Piper J, Isola J, Waldman FM, Gray JW, Pinkel D . Optimizing comparative genomic hybridization for analysis of DNA sequence copy number changes in solid tumors Genes Chromosomes Cancer 1994 10: 231–243

    CAS  PubMed  Google Scholar 

  30. Robledo M, Martinez B, Arranz E, Trujillo MJ, Gonzalez Ageitos A, Rivas C, Benitez J . Genetic instability of microsatellites in hematological neoplasms Leukemia 1995 9: 960–964

    CAS  PubMed  Google Scholar 

  31. Volpe G, Gamberi B, Pastore C, Roetto A, Pautasso M, Parvis G, Camaschella C, Mazza U, Saglio G, Gaidano G . Analysis of microsatellite instability in chronic lymphoproliferative disorders Ann Hematol 1996 72: 67–71

    CAS  PubMed  Google Scholar 

  32. Gamberi B, Gaidano G, Parsa N, Carbone A, Roncella S, Knowles DM, Louie DC, Shibata D, Chaganti RS, Dalla-Favera R . Microsatellite instability is rare in B-cell non-Hodgkin's lymphomas Blood 1997 89: 975–979

    CAS  PubMed  Google Scholar 

  33. Hodges KB, Vnencak-Jones CL, Larson RS, Kinney MC . Rarity of genomic instability in pathogenesis of systemic anaplastic large cell lymphoma (ALCL) in immunocompetent patients Hum Pathol 1999 30: 173–177

    CAS  PubMed  Google Scholar 

  34. Wada C, Shionoya S, Fujino Y, Tokuhiro H, Akahoshi T, Uchida T, Ohtani H . Genomic instability of microsatellite repeates and its association with the evolution of chronic myelogenous leukemia Blood 1994 83: 3449–3456

    CAS  PubMed  Google Scholar 

  35. Calvert R, Randerson J, Evans P, Cawkwell L, Lewis F, Dixon MF, Jack A, Owen R, Shiach C, Morgan GJ . Genetic abnormalities during transition from Helicobacter-pylori-associated gastritis to low-grade MALToma Lancet 1995 345: 26–27

    CAS  PubMed  Google Scholar 

  36. Tasaka T, Lee S, Spira S, Takeuchi S, Nagai M, Takahara J, Koeffler HP . Microsatellite instability during the progression of acute myelocytic leukaemia Br J Haematol 1997 98: 219–221

    CAS  PubMed  Google Scholar 

  37. Dietmaier W, Wallinger S, Bocker T, Kullmann F, Fishel R, Rüschoff J . Diagnostic microsatellite instability: definition and correlation with mismatch repair protein expression Cancer Res 1997 57: 4749–4756

    CAS  PubMed  Google Scholar 

  38. Chong JM, Fukayama M, Hayashi Y, Hishima T, Funata N, Koike M, Matsuya S, Konishi M, Miyaki M . Microsatellite instability and loss of heterozygosity in gastric lymphoma Lab Invest 1997 77: 639–645

    CAS  PubMed  Google Scholar 

  39. Herman JG, Umar A, Polyak K, Graff JR, Ahuja N, Issa JP, Markowitz S, Willson JK, Hamilton SR, Kinzler KW, Kane MF, Kolodner RD, Vogelstein B, Kunkel TA, Baylin SB . Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma Proc Natl Acad Sci USA 1998 95: 6870–6875

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Esteller M, Catasus L, Matias-Guiu X, Mutter GL, Prat J, Baylin SB, Herman JG . hMLH1 promoter hypermethylation is an early event in human endometrial tumorigenesis Am J Pathol 1999 155: 1767–1772

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Knuutila S, Aalto Y, Autio K, Björkqvist AM, El-Rifai W, Hemmer S, Huhta T, Kettunen E, Kiuru-Kuhlefelt S, Larramendy ML, Lushnikova T, Monni O, Pere H, Tapper J, Tarkkanen M, Varis A, Wasenius VM, Wolf M, Zhu Y . DNA copy number losses in human neoplasms Am J Pathol 1999 155: 683–694

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Yunis JJ, Frizzera G, Oken MM, McKenna J, Theologides A, Arnesen M . Multiple recurrent genomic defects in follicular lymphoma. A possible model for lymphoma New Engl J Med 1987 316: 79–84

    CAS  PubMed  Google Scholar 

  43. Tilly H, Rossi A, Stamatoullas A, Lenormand B, Bigorgne C, Kunlin A, Monconduit M, Bastard C . Prognostic value of chromosomal abnormalities in follicular lymphoma Blood 1994 84: 1043–1049

    CAS  PubMed  Google Scholar 

  44. Johansson B, Mertens F, Mitelman F . Cytogenetic evolution patterns in non-Hodgkin's lymphoma Blood 1995 86: 3905–3914

    CAS  PubMed  Google Scholar 

  45. Knuutila S, Björkqvist AM, Autio K, Tarkkanen M, Wolf M, Monni O, Szymanska J, Larramendy ML, Tapper J, Pere H, El-Rifai W, Hemmer S, Wasenius V-M, Vidgren V, Zhu Y . DNA copy number amplifications in human neoplasms: review of comparative genomic hybridization studies Am J Pathol 1998 152: 1107–1123

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Rao PH, Houldsworth J, Dyomina K, Parsa NZ, Cigudosa JC, Louie DC, Popplewell L, Offit K, Ihanwar SC, Chaganti RS . Chromosomal and gene amplification in diffuse large B-cell lymphoma Blood 1998 92: 234–240

    CAS  PubMed  Google Scholar 

  47. Bea S, Ribas M, Hernández JM, Bosch F, Pinyol M, Hernández L, García JL, Flores T, González M, López-Guillermo A, Piris MA, Cardesa A, Montserrat E, Miró R, Campo E . Increased number of chromosomal imbalances and high-level DNA amplifications in mantle cell lymphoma are associated with blastoid variants Blood 1999 93: 4365–4374

    CAS  PubMed  Google Scholar 

  48. Loeb KR, Loeb LA . Significance of multiple mutations in cancer Carcinogenesis 2000 21: 379–385

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Hungarian National Science Foundation OTKA T032572 (to AM), T022429 and T032587 (to MB), from the Hungarian Ministry of Health ETT 332/2000 (to AM) and from the National Institutes of Health CA34233 (to RAW).

Author information

Author notes

  1. M Nagy and M Balázs: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, Faculty of Medicine, Pécs University, Hungary

    M Nagy, B Tímár, Z Szereday, T László & A Matolcsy

  2. Department of Preventive Medicine, School of Public Health, University of Debrecen, Hungary

    M Balázs, Z Ádám & Z Petkó

  3. Department of Pathology, Stanford University Medical Center, Stanford, CA, USA

    RA Warnke

Authors
  1. M Nagy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Balázs
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Z Ádám
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Z Petkó
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. B Tímár
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Z Szereday
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. T László
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. RA Warnke
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A Matolcsy
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nagy, M., Balázs, M., Ádám, Z. et al. Genetic instability is associated with histological transformation of follicle center lymphoma. Leukemia 14, 2142–2148 (2000). https://doi.org/10.1038/sj.leu.2401978

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2401978

Keywords

This article is cited by

Search

Advanced search

Quick links