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.

  • Review
  • Published:

ERIC recommendations on TP53 mutation analysis in chronic lymphocytic leukemia

Leukemia volume 26, pages 1458–1461 (2012)Cite this article

Subjects

Abstract

Recent evidence suggests that – in addition to 17p deletion – TP53 mutation is an independent prognostic factor in chronic lymphocytic leukemia (CLL). Data from retrospective analyses and prospective clinical trials show that ∼5% of untreated CLL patients with treatment indication have a TP53 mutation in the absence of 17p deletion. These patients have a poor response and reduced progression-free survival and overall survival with standard treatment approaches. These data suggest that TP53 mutation testing warrants integration into current diagnostic work up of patients with CLL. There are a number of assays to detect TP53 mutations, which have respective advantages and shortcomings. Direct Sanger sequencing of exons 4–9 can be recommended as a suitable test to identify TP53 mutations for centers with limited experience with alternative screening methods. Recommendations are provided on standard operating procedures, quality control, reporting and interpretation. Patients with treatment indications should be investigated for TP53 mutations in addition to the work-up recommended by the International workshop on CLL guidelines. Patients with TP53 mutation may be considered for allogeneic stem cell transplantation in first remission. Alemtuzumab-based regimens can yield a substantial proportion of complete responses, although of short duration. Ideally, patients should be treated within clinical trials exploring new therapeutic agents.

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

Similar content being viewed by others

References

  1. Levine AJ, Oren M . The first 30 years of p53: growing ever more complex. Nat Rev Cancer 2009; 9: 749–758.

    Article  CAS  Google Scholar 

  2. Zenz T, Krober A, Scherer K, Habe S, Buhler A, Benner A et al. Monoallelic TP53 inactivation is associated with poor prognosis in chronic lymphocytic leukemia: results from a detailed genetic characterization with long-term follow-up. Blood 2008; 112: 3322–3329.

    Article  CAS  Google Scholar 

  3. Zenz T, Eichhorst B, Busch R, Denzel T, Habe S, Winkler D et al. TP53 mutation and survival in chronic lymphocytic leukemia. J Clin Oncol 2010; 28: 4473–4479.

    Article  Google Scholar 

  4. Rossi D, Cerri M, Deambrogi C, Sozzi E, Cresta S, Rasi S et al. The prognostic value of TP53 mutations in chronic lymphocytic leukemia is independent of Del17p13: implications for overall survival and chemorefractoriness. Clin Cancer Res 2009; 15: 995–1004.

    Article  CAS  Google Scholar 

  5. Gonzalez D, Martinez P, Wade R, Hockley S, Oscier D, Matutes E et al. Mutational status of the TP53 gene as a predictor of response and survival in patients with chronic lymphocytic leukemia: results from the LRF CLL4 trial. J Clin Oncol 2011; 29: 2223–2229.

    Article  Google Scholar 

  6. Dicker F, Herholz H, Schnittger S, Nakao A, Patten N, Wu L et al. The detection of TP53 mutations in chronic lymphocytic leukemia independently predicts rapid disease progression and is highly correlated with a complex aberrant karyotype. Leukemia 2009; 23: 117–124.

    Article  CAS  Google Scholar 

  7. Malcikova J, Smardova J, Rocnova L, Tichy B, Kuglik P, Vranova V et al. Monoallelic and biallelic inactivation of TP53 gene in chronic lymphocytic leukemia: selection, impact on survival, and response to DNA damage. Blood 2009; 114: 5307–5314.

    Article  CAS  Google Scholar 

  8. Zenz T, Mertens D, Kuppers R, Dohner H, Stilgenbauer S . From pathogenesis to treatment of chronic lymphocytic leukaemia. Nat Rev Cancer 2010; 10: 37–50.

    Article  CAS  Google Scholar 

  9. Zenz T, Habe S, Denzel T, Mohr J, Winkler D, Buhler A et al. Detailed analysis of p53 pathway defects in fludarabine-refractory chronic lymphocytic leukemia (CLL): dissecting the contribution of 17p deletion, TP53 mutation, p53-p21 dysfunction, and miR34a in a prospective clinical trial. Blood 2009; 114: 2589–2597.

    Article  CAS  Google Scholar 

  10. Dohner H, Fischer K, Bentz M, Hansen K, Benner A, Cabot G et al. p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias. Blood 1995; 85: 1580–1589.

    CAS  PubMed  Google Scholar 

  11. el Rouby S, Thomas A, Costin D, Rosenberg CR, Potmesil M, Silber R et al. p53 gene mutation in B-cell chronic lymphocytic leukemia is associated with drug resistance and is independent of MDR1/MDR3 gene expression. Blood 1993; 82: 3452–3459.

    CAS  PubMed  Google Scholar 

  12. Fenaux P, Preudhomme C, Lai JL, Quiquandon I, Jonveaux P, Vanrumbeke M et al. Mutations of the p53 gene in B-cell chronic lymphocytic leukemia: a report on 39 cases with cytogenetic analysis. Leukemia 1992; 6: 246–250.

    CAS  PubMed  Google Scholar 

  13. Zenz T, Vollmer D, Trbusek M, Smardova J, Benner A, Soussi T et al. TP53 mutation profile in chronic lymphocytic leukemia: evidence for a disease specific profile from a comprehensive analysis of 268 mutations. Leukemia 2010; 24: 2072–2079.

    Article  CAS  Google Scholar 

  14. Joerger AC, Fersht AR . Structural biology of the tumor suppressor p53. Annu Rev Biochem 2008; 77: 557–582.

    Article  CAS  Google Scholar 

  15. Oren M, Rotter V . Mutant p53 gain-of-function in cancer. Cold Spring Harb Perspect Biol 2010; 2: a001107.

    Article  Google Scholar 

  16. Petitjean A, Mathe E, Kato S, Ishioka C, Tavtigian SV, Hainaut P et al. Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum Mutat 2007; 28: 622–629.

    Article  CAS  Google Scholar 

  17. Malcikova J, Tichy B, Damborsky J, Kabathova J, Trbusek M, Mayer J et al. Analysis of the DNA-binding activity of p53 mutants using functional protein microarrays and its relationship to transcriptional activation. Biol Chem 2010; 391: 197–205.

    Article  CAS  Google Scholar 

  18. Trbusek M, Smardova J, Malcikova J, Sebejova L, Dobes P, Svitakova M et al. Missense mutations located in structural p53 DNA-binding motifs are associated with extremely poor survival in chronic lymphocytic leukemia. J Clin Oncol 2011; 29: 2703–2708.

    Article  CAS  Google Scholar 

  19. Silva AL, Romao L . The mammalian nonsense-mediated mRNA decay pathway: to decay or not to decay! Which players make the decision? FEBS Lett 2009; 583: 499–505.

    Article  CAS  Google Scholar 

  20. Kringen P, Bergamaschi A, Due EU, Wang Y, Tagliabue E, Nesland JM et al. Evaluation of arrayed primer extension for TP53 mutation detection in breast and ovarian carcinomas. Biotechniques 2005; 39: 755–761.

    Article  CAS  Google Scholar 

  21. Tonisson N, Zernant J, Kurg A, Pavel H, Slavin G, Roomere H et al. Evaluating the arrayed primer extension resequencing assay of TP53 tumor suppressor gene. Proc Natl Acad Sci USA 2002; 99: 5503–5508.

    Article  CAS  Google Scholar 

  22. Best OG, Gardiner AC, Majid A, Walewska R, Austen B, Skowronska A et al. A novel functional assay using etoposide plus nutlin-3a detects and distinguishes between ATM and TP53 mutations in CLL. Leukemia 2008; 22: 1456–1459.

    Article  CAS  Google Scholar 

  23. Mohr J, Helfrich H, Fuge M, Eldering E, Buhler A, Winkler D et al. DNA damage-induced transcriptional program in CLL: biological and diagnostic implications for functional p53 testing. Blood 2011; 117: 1622–1632.

    Article  CAS  Google Scholar 

  24. Pettitt AR, Sherrington PD, Stewart G, Cawley JC, Taylor AM, Stankovic T . p53 dysfunction in B-cell chronic lymphocytic leukemia: inactivation of ATM as an alternative to TP53 mutation. Blood 2001; 98: 814–822.

    Article  CAS  Google Scholar 

  25. Zainuddin N, Murray F, Kanduri M, Gunnarsson R, Smedby KE, Enblad G et al. TP53 Mutations are infrequent in newly diagnosed chronic lymphocytic leukemia. Leuk Res 2011; 35: 272–274.

    Article  CAS  Google Scholar 

  26. Best OG, Gardiner AC, Davis ZA, Tracy I, Ibbotson RE, Majid A et al. A subset of Binet stage A CLL patients with TP53 abnormalities and mutated IGHV genes have stable disease. Leukemia 2009; 23: 212–214.

    Article  CAS  Google Scholar 

  27. Tam CS, Shanafelt TD, Wierda WG, Abruzzo LV, Van Dyke DL, O’Brien S et al. De novo deletion 17p13.1 chronic lymphocytic leukemia shows significant clinical heterogeneity: the MD Anderson and Mayo Clinic experience. Blood 2009; 114: 957–964.

    Article  CAS  Google Scholar 

  28. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 2008; 111: 5446–5456.

    Article  CAS  Google Scholar 

  29. Zenz T, Hoth P, Busch R, Helfrich H, Winkler D, Buhler A et al. TP53 mutations and outcome after fludarabine and cyclophosphamide (FC) or FC plus rituximab (FCR) in the CLL8 Trial of the GCLLSG. ASH Annu Meeting Abstr 2009; 114: 1267.

    Google Scholar 

  30. Grever MR, Lucas DM, Dewald GW, Neuberg DS, Reed JC, Kitada S et al. Comprehensive assessment of genetic and molecular features predicting outcome in patients with chronic lymphocytic leukemia: results from the US Intergroup Phase III Trial E2997. J Clin Oncol 2007; 25: 799–804.

    Article  CAS  Google Scholar 

Download references

Author information

Author notes

  1. S Pospisilova and D Gonzalez: These authors contributed equally to this work.

Authors and Affiliations

  1. Masaryk University and Department of Hematology and Oncology, Central European Institute of Technology, University Hospital Brno, Brno, Czech Republic

    S Pospisilova, J Malcikova & M Trbusek

  2. Division of Molecular Pathology, The Institute of Cancer Research, London, UK

    D Gonzalez

  3. Department of Translational Medicine, Division of Hematology, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy

    D Rossi

  4. Department of Hematology, Academic Medical Center, Amsterdam, The Netherlands

    A P Kater & M van Oers

  5. Hôpital Avicenne, Université Paris XIII, Laboratoire d’hématologie, Bobigny, France

    F Cymbalista

  6. Department of Internal Medicine I, Center for Integrated Oncology Köln-Bonn, University of Cologne, Cologne, Germany

    B Eichhorst & M Hallek

  7. Department of Internal Medicine III, University of Ulm, Ulm, Germany

    H Döhner & S Stilgenbauer

  8. Leeds Teaching Hospitals NHS Trust, St James's University Hospital, Leeds, UK

    P Hillmen

  9. Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK

    J Gribben

  10. Division of Molecular Oncology, Laboratory of B-cell Neoplasia, San Raffaele Scientific Institute, Milan, Italy

    P Ghia

  11. Department of Hematology, Institute of Hematology and Oncology, Hospital Clinic, Barcelona, IDIBAP, University of Barcelona, Barcelona, Spain

    E Montserrat

  12. Department of Translational Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany

    T Zenz

  13. Department of Internal Medicine V, University Hospital Heidelberg, Heidelberg, Germany

    T Zenz

Authors
  1. S Pospisilova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D Gonzalez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Malcikova
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Trbusek
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D Rossi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A P Kater
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. F Cymbalista
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. B Eichhorst
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M Hallek
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. H Döhner
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. P Hillmen
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. M van Oers
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. J Gribben
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. P Ghia
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. E Montserrat
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. S Stilgenbauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. T Zenz
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

on behalf of the European Research Initiative on CLL (ERIC)

Corresponding author

Correspondence to T Zenz.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pospisilova, S., Gonzalez, D., Malcikova, J. et al. ERIC recommendations on TP53 mutation analysis in chronic lymphocytic leukemia. Leukemia 26, 1458–1461 (2012). https://doi.org/10.1038/leu.2012.25

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2012.25

Keywords

This article is cited by

Search

Advanced search

Quick links