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Feasibility of targeted next-generation sequencing of the TP53 and ATM genes in chronic lymphocytic leukemia

Leukemia volume 28, pages 694–696 (2014)Cite this article

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Chronic lymphocytic leukemia (CLL) comprises a very heterogeneous group of patients, where one-third of patients need treatment immediately upon diagnosis, one-third will never require treatment and the remainder will develop a more aggressive disease over time. In the last two decades, we have learned that detection of certain genomic aberrations (that is, 11q−, +12, 13q− and 17p−) by fluorescence in situ hybridization (FISH) can aid identification of high-risk patients and therefore is now recommended in clinical routine practice.1, 2, 3 In particular, CLL patients carrying 17p deletions (covering the TP53 gene; 5–10% of patients) have a short time to progression, are resistant to conventional therapy and display a significantly poorer overall survival.1, 3, 4 Similarly, patients with 11q deletions (covering the ATM gene; 10–15% of patients)1, 3, 4 are predicted to have a worse outcome, however, in contrast to 17p-deleted patients, medically fit patients with del(11q) appear to benefit from the current gold standard treatment regimen of fludarabine, cyclophosphamide and rituximab.5 Both of these aberrations are considered to be secondary aberrations and thus may evolve and/or emerge as the disease progresses.3, 6

In recent years, it has become evident that CLL patients with TP53 gene mutations, even in the absence of a 17p deletion (3–6% of patients),3 confer an equally poor prognosis as CLL patients with a 17p deletion, especially if the mutations are detected within the DNA-binding motifs of the TP53 gene.7 Therefore, in addition to FISH analysis for the common genomic aberrations, TP53 mutational screening using Sanger sequencing (or alternative methods) of hotspot exons (exons 4–9) is also recommended before the initiation of treatment aimed at achieving remission.2, 8 On the other hand, although ATM mutations have been convincingly associated with a worse clinical outcome in CLL, particularly in patients harboring biallelic mutations (that is, both 11q deletion and an ATM mutation),3, 9 few groups have attempted to investigate this gene primarily owing to the large size of the ATM gene (62 coding exons) and the absence of commonly mutated hotspot exons. Thus, ATM mutations have been virtually impossible to investigate in routine practice.

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References

  1. Dohner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger L et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 2000; 343: 1910–1916.

    Article  CAS  PubMed  Google Scholar 

  2. 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  PubMed  PubMed Central  Google Scholar 

  3. 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  PubMed  Google Scholar 

  4. Gunnarsson R, Isaksson A, Mansouri M, Goransson H, Jansson M, Cahill N et al. Large but not small copy-number alterations correlate to high-risk genomic aberrations and survival in chronic lymphocytic leukemia: a high-resolution genomic screening of newly diagnosed patients. Leukemia 2010; 24: 211–215.

    Article  CAS  PubMed  Google Scholar 

  5. Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 2010; 376: 1164–1174.

    Article  CAS  PubMed  Google Scholar 

  6. Landau DA, Carter SL, Stojanov P, McKenna A, Stevenson K, Lawrence MS et al. Evolution and impact of subclonal mutations in chronic lymphocytic leukemia. Cell 2013; 152: 714–726.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 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  PubMed  Google Scholar 

  8. Pospisilova S, Gonzalez D, Malcikova J, Trbusek M, Rossi D, Kater AP et al. ERIC recommendations on TP53 mutation analysis in chronic lymphocytic leukemia. Leukemia 2012; 26: 1458–1461.

    Article  CAS  PubMed  Google Scholar 

  9. Skowronska A, Parker A, Ahmed G, Oldreive C, Davis Z, Richards S et al. Biallelic ATM inactivation significantly reduces survival in patients treated on the United Kingdom Leukemia Research Fund Chronic Lymphocytic Leukemia 4 trial. J Clin Oncol 2012; 30: 4524–4532.

    Article  CAS  PubMed  Google Scholar 

  10. Johansson H, Isaksson M, Sorqvist EF, Roos F, Stenberg J, Sjoblom T et al. Targeted resequencing of candidate genes using selector probes. Nucleic Acids Res 2011; 39: e8.

    Article  CAS  PubMed  Google Scholar 

  11. de Miranda NF, Peng R, Georgiou K, Wu C, Sorqvist EF, Berglund M et al. DNA repair genes are selectively mutated in diffuse large B cell lymphomas. J Exp Med 2013; 210: 1729–1742.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Navrkalova V, Sebejova L, Zemanova J, Kminkova J, Kubesova B, Malcikova J et al. ATM mutations uniformly lead to ATM dysfunction in chronic lymphocytic leukemia: application of functional test using doxorubicin. Haematologica 2013; 98: 1124–1131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Trbusek M, Malcikova J . TP53 aberrations in chronic lymphocytic leukemia. Adv Exp Med Biol 2013; 792: 109–131.

    Article  CAS  PubMed  Google Scholar 

  14. Mansouri L, Cahill N, Gunnarsson R, Smedby KE, Tjonnfjord E, Hjalgrim H et al. NOTCH1 and SF3B1 mutations can be added to the hierarchical prognostic classification in chronic lymphocytic leukemia. Leukemia 2013; 27: 512–514.

    Article  CAS  PubMed  Google Scholar 

  15. Quesada V, Ramsay AJ, Rodriguez D, Puente XS, Campo E, Lopez-Otin C . The genomic landscape of chronic lymphocytic leukemia: clinical implications. BMC Med 2013; 11: 124.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Strefford JC, Sutton LA, Baliakas P, Agathangelidis A, Malcikova J, Plevova K et al. Distinct patterns of novel gene mutations in poor-prognostic stereotyped subsets of chronic lymphocytic leukemia: the case of SF3B1 and subset #2. Leukemia 2013; 27: 2196–2199.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This research project was supported by the Nordic Cancer Union, the Swedish Cancer Society, the Swedish Research Council, the Lion’s Cancer Research Foundation, Erik, Karin and Gösta Selanders' Foundation Uppsala and the European Community’s 7th Framework Program (FP7/2007–2013) under grant agreement no. 259796 (DiaTools). Sequencing was performed by the SNP&SEQ Technology Platform, Science for Life Laboratory at Uppsala University, a national infrastructure supported by the Swedish Research Council (VRRFI) and the Knut and Alice Wallenberg Foundation. The computations were performed on resources provided by SNIC through Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) under Project b2011080.

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Authors and Affiliations

  1. Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden

    L Mansouri, L-A Sutton, V Ljungström, E F Sörqvist, K Stamatopoulos, M Nilsson & R Rosenquist

  2. Department of Laboratory Medicine, Clinical Genetics, Lund University, Lund, Sweden

    R Gunnarsson

  3. Department of Medicine, Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, Sweden

    K E Smedby

  4. Department of Laboratory Medicine, Stem Cell Center, Hematology and Transplantation, Lund University, Lund, Sweden

    G Juliusson

  5. Institute of Applied Biosciences, CERTH, Thessaloniki, Greece

    K Stamatopoulos

  6. Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece

    K Stamatopoulos

  7. Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden

    M Nilsson

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  1. L Mansouri
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Correspondence to R Rosenquist.

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Mansouri, L., Sutton, LA., Ljungström, V. et al. Feasibility of targeted next-generation sequencing of the TP53 and ATM genes in chronic lymphocytic leukemia. Leukemia 28, 694–696 (2014). https://doi.org/10.1038/leu.2013.322

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