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

A limited role for TP53 mutation in the transformation of follicular lymphoma to diffuse large B-cell lymphoma

Leukemia volume 19, pages 1459–1465 (2005)Cite this article

Abstract

The role of TP53 mutation in transformation of follicular lymphoma (FL) to diffuse large B-cell lymphoma (t-FL) was examined in a panel of 91 lymph node biopsies derived from 29 patients pre- and post-transformation. The entire TP53 coding sequence was screened and immunocytochemistry performed to determine expression of p53 and its key regulator MDM2. A total of 10 mutations were detected in eight patients (28%), although none were present at FL diagnosis. Mutations were not detected solely at the time of transformation; in three patients, mutated TP53 arose in at least one antecedent FL sample (6 months, 2.5 years and 4 years prior to transformation). Loss of heterozygosity at the TP53 locus occurred in 2/20 informative patients (only in t-FL samples). p53 staining was positive in 82% (9/11) of available biopsies with a missense mutation, and negative in 71% (45/63) with wtTP53. MDM2 expression was significantly higher in t-FL samples (mean 72% positive; 95% confidence interval (95% CI) 68–76%) than FL (mean 58% positive; 95% CI 54–62%) (P<0.001) but did not correlate with TP53 status. TP53 mutation has only a limited role in the transformation of FL, exerting a heterogeneous influence upon phenotypic change. In contrast, dysregulation of MDM2 is frequent and may provide a more rational therapeutic target.

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
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

Article 12 December 2019

Antonino Carbone, Sandrine Roulland, … Jude Fitzgibbon

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. The Non-Hodgkin's Lymphoma Classification Project. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. Blood 1997; 89: 3909–3918.

  2. Gallagher CJ, Gregory WM, Jones AE, Stansfeld AG, Richards MA, Dhaliwal HS et al. Follicular lymphoma: prognostic factors for response and survival. J Clin Oncol 1986; 4: 1470–1480.

    Article  CAS  Google Scholar 

  3. Horning SJ . Natural history of and therapy for the indolent non-Hodgkin's lymphomas. Semin Oncol 1993; 20: 75–88.

    CAS  PubMed  Google Scholar 

  4. 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.

    Article  CAS  Google Scholar 

  5. Hubbard SM, Chabner BA, DeVita Jr VT, Simon R, Berard CW, Jones RB et al. Histologic progression in non-Hodgkin's lymphoma. Blood 1982; 59: 258–264.

    CAS  PubMed  Google Scholar 

  6. Acker B, Hoppe RT, Colby TV, Cox RS, Kaplan HS, Rosenberg SA . Histologic conversion in the non-Hodgkin's lymphomas. J Clin Oncol 1983; 1: 11–16.

    Article  CAS  Google Scholar 

  7. Bastion Y, Sebban C, Berger F, Felman P, Salles G, Dumontet C et al. Incidence, predictive factors, and outcome of lymphoma transformation in follicular lymphoma patients. J Clin Oncol 1997; 15: 1587–1594.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  9. Foran JM, Apostolidis J, Papamichael D, Norton AJ, Matthews J, Amess JA et al. High-dose therapy with autologous haematopoietic support in patients with transformed follicular lymphoma: a study of 27 patients from a single centre. Ann Oncol 1998; 9: 865–869.

    Article  CAS  Google Scholar 

  10. Chen CI, Crump M, Tsang R, Stewart AK, Keating A . Autotransplants for histologically transformed follicular non-Hodgkin's lymphoma. Br J Haematol 2001; 113: 202–208.

    Article  CAS  Google Scholar 

  11. Hough RE, Goepel JR, Alcock HE, Hancock BW, Lorigan PC, Hammond DW . Copy number gain at 12q12–14 may be important in the transformation from follicular lymphoma to diffuse large B cell lymphoma. Br J Cancer 2001; 84: 499–503.

    Article  CAS  Google Scholar 

  12. Goff LK, Neat MJ, Crawley CR, Jones L, Jones E, Lister TA et al. The use of real-time quantitative polymerase chain reaction and comparative genomic hybridization to identify amplification of the REL gene in follicular lymphoma. Br J Haematol 2000; 111: 618–625.

    Article  CAS  Google Scholar 

  13. Martinez-Climent JA, Alizadeh AA, Segraves R, Blesa D, Rubio-Moscardo F, Albertson DG et al. Transformation of follicular lymphoma to diffuse large cell lymphoma is associated with a heterogeneous set of DNA copy number and gene expression alterations. Blood 2003; 101: 3109–3117.

    Article  CAS  Google Scholar 

  14. Hoglund M, Sehn L, Connors JM, Gascoyne RD, Siebert R, Sall T et al. Identification of cytogenetic subgroups and karyotypic pathways of clonal evolution in follicular lymphomas. Genes Chromosomes Cancer 2004; 39: 195–204.

    Article  Google Scholar 

  15. 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 

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

    CAS  PubMed  Google Scholar 

  17. Lossos IS, Alizadeh AA, Diehn M, Warnke R, Thorstenson Y, Oefner PJ et al. Transformation of follicular lymphoma to diffuse large-cell lymphoma: alternative patterns with increased or decreased expression of c-myc and its regulated genes. Proc Natl Acad Sci USA 2002; 99: 8886–8891.

    Article  CAS  Google Scholar 

  18. Akasaka T, Lossos IS, Levy R . BCL6 gene translocation in follicular lymphoma: a harbinger of eventual transformation to diffuse aggressive lymphoma. Blood 2003; 102: 1443–1448.

    Article  CAS  Google Scholar 

  19. Capello D, Vitolo U, Pasqualucci L, Quattrone S, Migliaretti G, Fassone L et al. Distribution and pattern of BCL-6 mutations throughout the spectrum of B-cell neoplasia. Blood 2000; 95: 651–659.

    CAS  PubMed  Google Scholar 

  20. Lossos IS, Levy R . Higher-grade transformation of follicle center lymphoma is associated with somatic mutation of the 5′ noncoding regulatory region of the BCL-6 gene. Blood 2000; 96: 635–639.

    CAS  PubMed  Google Scholar 

  21. Szereday Z, Csernus B, Nagy M, Laszlo 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.

    Article  CAS  Google Scholar 

  22. Guimaraes DP, Hainaut P . TP53: a key gene in human cancer. Biochimie 2002; 84: 83–93.

    Article  CAS  Google Scholar 

  23. Ryan KM, Phillips AC, Vousden KH . Regulation and function of the p53 tumor suppressor protein. Curr Opin Cell Biol 2001; 13: 332–337.

    Article  CAS  Google Scholar 

  24. Olivier M, Eeles R, Hollstein M, Khan MA, Harris CC, Hainaut P . The IARC TP53 database: new online mutation analysis and recommendations to users. Hum Mutat 2002; 19: 607–614.

    Article  CAS  Google Scholar 

  25. Prasad RK, Koduru PR, Raju K, Vadmal V, Menezes G, Shah S et al. Correlation between mutation in P53, p53 expression, cytogenetics, histologic type, and survival in patients with B-cell non-Hodgkin's lymphoma. Blood 1997; 90: 4078–4091.

    Google Scholar 

  26. Ichikawa A, Kinoshita T, Watanabe T, Kato H, Nagai H, Tsushita K et al. Mutations of the p53 gene as a prognostic factor in aggressive B-cell lymphoma. N Engl J Med 1997; 337: 529–534.

    Article  CAS  Google Scholar 

  27. Leroy K, Haioun C, Lepage E, Le Metayer N, Berger F, Labouyrie E et al. p53 gene mutations are associated with poor survival in low and low–intermediate risk diffuse large B-cell lymphomas. Ann Oncol 2002; 13: 1108–1115.

    Article  CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  30. Symmans WF, Katz RL, Ordonez NG, Dalton H, Romaguera JE, Cabanillas F . Transformation of follicular lymphoma. Expression of p53 and bcl-2 oncoprotein, apoptosis and cell proliferation. Acta Cytol 1995; 39: 673–682.

    CAS  PubMed  Google Scholar 

  31. Barrett MT, Sanchez CA, Prevo LJ, Wong DJ, Galipeau PC, Paulson TG et al. Evolution of neoplastic cell lineages in Barrett oesophagus. Nat Genet 1999; 22: 106–109.

    Article  CAS  Google Scholar 

  32. Soussi T, Beroud C . Assessing TP53 status in human tumours to evaluate clinical outcome. Nat Rev Cancer 2001; 1: 233–240.

    Article  CAS  Google Scholar 

  33. Jaffe ES, Harris NL, H S, (eds)., VJW. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press, 2001.

    Google Scholar 

  34. Buchonnet G, Lenain P, Ruminy P, Lepretre S, Stamatoullas A, Parmentier F et al. Characterisation of BCL2-JH rearrangements in follicular lymphoma: PCR detection of 3′ BCL2 breakpoints and evidence of a new cluster. Leukemia 2000; 14: 1563–1569.

    Article  CAS  Google Scholar 

  35. Norton AJ, Jordan S, Yeomans P . Brief, high-temperature heat denaturation (pressure cooking): a simple and effective method of antigen retrieval for routinely processed tissues. J Pathol 1994; 173: 371–379.

    Article  CAS  Google Scholar 

  36. Kaplan EL, Meier P . Nonparametric estimation form incomplete observations. J Am Stat Assoc 1958; 53: 457–481.

    Article  Google Scholar 

  37. Avigad S, Barel D, Blau O, Malka A, Zoldan M, Mor C et al. A novel germ line p53 mutation in intron 6 in diverse childhood malignancies. Oncogene 1997; 14: 1541–1545.

    Article  CAS  Google Scholar 

  38. Lossos IS, Levy R . Higher grade transformation of follicular lymphoma: phenotypic tumor progression associated with diverse genetic lesions. Semin Cancer Biol 2003; 13: 191–202.

    Article  CAS  Google Scholar 

  39. Elenitoba-Johnson KS, Jenson SD, Abbott RT, Palais RA, Bohling SD, Lin Z et al. Involvement of multiple signaling pathways in follicular lymphoma transformation: p38-mitogen-activated protein kinase as a target for therapy. Proc Natl Acad Sci USA 2003; 100: 7259–7264.

    Article  CAS  Google Scholar 

  40. Ichikawa A, Hotta T, Takagi N, Tsushita K, Kinoshita T, Nagai H et al. Mutations of p53 gene and their relation to disease progression in B-cell lymphoma. Blood 1992; 79: 2701–2707.

    CAS  PubMed  Google Scholar 

  41. Ory K, Legros Y, Auguin C, Soussi T . Analysis of the most representative tumour-derived p53 mutants reveals that changes in protein conformation are not correlated with loss of transactivation or inhibition of cell proliferation. EMBO J 1994; 13: 3496–3504.

    Article  CAS  Google Scholar 

  42. Varley JM, McGown G, Thorncroft M, James LA, Margison GP, Forster G et al. Are there low-penetrance TP53 alleles? Evidence from childhood adrenocortical tumors. Am J Hum Genet 1999; 65: 995–1006.

    Article  CAS  Google Scholar 

  43. Gronbaek K, Nedergaard T, Andersen MK, thor Straten P, Guldberg P, Moller P et al. Concurrent disruption of cell cycle associated genes in mantle cell lymphoma: a genotypic and phenotypic study of cyclin D1, p16, p15, p53 and pRb. Leukemia 1998; 12: 1266–1271.

    Article  CAS  Google Scholar 

  44. Moller MB, Ino Y, Gerdes AM, Skjodt K, Louis DN, Pedersen NT . Aberrations of the p53 pathway components p53, MDM2 and CDKN2A appear independent in diffuse large B cell lymphoma. Leukemia 1999; 13: 453–459.

    Article  CAS  Google Scholar 

  45. Gruszka-Westwood AM, Hamoudi RA, Matutes E, Tuset E, Catovsky D . p53 abnormalities in splenic lymphoma with villous lymphocytes. Blood 2001; 97: 3552–3558.

    Article  CAS  Google Scholar 

  46. Maestro R, Gloghini A, Doglioni C, Gasparotto D, Vukosavljevic T, De Re V et al. MDM2 overexpression does not account for stabilization of wild-type p53 protein in non-Hodgkin's lymphomas. Blood 1995; 85: 3239–3246.

    CAS  PubMed  Google Scholar 

  47. Lane DP, Lain S . Therapeutic exploitation of the p53 pathway. Trends Mol Med 2002; 8: S38–S42.

    Article  CAS  Google Scholar 

  48. Ott G, Katzenberger T, Lohr A, Kindelberger S, Rudiger T, Wilhelm M et al. Cytomorphologic, immunohistochemical, and cytogenetic profiles of follicular lymphoma: 2 types of follicular lymphoma grade 3. Blood 2002; 99: 3806–3812.

    Article  CAS  Google Scholar 

  49. Schmitt CA, McCurrach ME, de Stanchina E, Wallace-Brodeur RR, Lowe SW . INK4a/ARF mutations accelerate lymphomagenesis and promote chemoresistance by disabling p53. Genes Dev 1999; 13: 2670–2677.

    Article  CAS  Google Scholar 

  50. Schmitt CA, Fridman JS, Yang M, Baranov E, Hoffman RM, Lowe SW . Dissecting p53 tumor suppressor functions in vivo. Cancer Cell 2002; 1: 289–298.

    Article  CAS  Google Scholar 

  51. Watanabe T, Ichikawa A, Saito H, Hotta T . Overexpression of the MDM2 oncogene in leukemia and lymphoma. Leuk Lymphoma 1996; 21: 391–397.

    Article  CAS  Google Scholar 

  52. Eischen CM, Weber JD, Roussel MF, Sherr CJ, Cleveland JL . Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis. Genes Dev 1999; 13: 2658–2669.

    Article  CAS  Google Scholar 

  53. Moller MB, Nielsen O, Pedersen NT . Frequent alteration of MDM2 and p53 in the molecular progression of recurring non-Hodgkin's lymphoma. Histopathology 2002; 41: 322–330.

    Article  CAS  Google Scholar 

  54. Oliner JD, Kinzler KW, Meltzer PS, George DL, Vogelstein B . Amplification of a gene encoding a p53-associated protein in human sarcomas. Nature 1992; 358: 80–83.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are indebted to Louis M Staudt, Janet Matthews, Sylvia Bass and Clare Lynex for their assistance. This study was supported by grants from Cancer Research UK and The Research Advisory Board of St Bartholomew's and The Royal London Charitable Foundation (RAB03/PJ/07 and XMLQ).

Author information

Authors and Affiliations

  1. Cancer Research UK Medical Oncology Unit, Bart's and The Royal London School of Medicine and Dentistry, London, UK

    A J Davies, A M Lee, A J Clear, L K Goff, S Iqbal, T A Lister & J Fitzgibbon

  2. Cancer Research UK Mutation Detection Facility, St James's Hospital, Leeds, UK

    C Taylor & D Cuthbert-Heavens

  3. Department of Histopathology, St Bartholomew's Hospital, London, UK

    M Calaminici & A J Norton

Authors
  1. A J Davies
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A M Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C Taylor
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A J Clear
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. L K Goff
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S Iqbal
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. D Cuthbert-Heavens
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M Calaminici
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A J Norton
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. T A Lister
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. J Fitzgibbon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A J Davies.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Davies, A., Lee, A., Taylor, C. et al. A limited role for TP53 mutation in the transformation of follicular lymphoma to diffuse large B-cell lymphoma. Leukemia 19, 1459–1465 (2005). https://doi.org/10.1038/sj.leu.2403802

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2403802

Keywords

This article is cited by

Search

Advanced search

Quick links