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Chronic Lymphocytic Leukemia

Recurrent mutations refine prognosis in chronic lymphocytic leukemia

Leukemia volume 29, pages 329–336 (2015)Cite this article

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Abstract

Through the European Research Initiative on chronic lymphocytic leukemia (CLL) (ERIC), we screened 3490 patients with CLL for mutations within the NOTCH1 (n=3334), SF3B1 (n=2322), TP53 (n=2309), MYD88 (n=1080) and BIRC3 (n=919) genes, mainly at diagnosis (75%) and before treatment (>90%). BIRC3 mutations (2.5%) were associated with unmutated IGHV genes (U-CLL), del(11q) and trisomy 12, whereas MYD88 mutations (2.2%) were exclusively found among M-CLL. NOTCH1, SF3B1 and TP53 exhibited variable frequencies and were mostly enriched within clinically aggressive cases. Interestingly, as the timespan between diagnosis and mutational screening increased, so too did the incidence of SF3B1 mutations; no such increase was observed for NOTCH1 mutations. Regarding the clinical impact, NOTCH1 mutations, SF3B1 mutations and TP53 aberrations (deletion/mutation, TP53ab) correlated with shorter time-to-first-treatment (P<0.0001) in 889 treatment-naive Binet stage A cases. In multivariate analysis (n=774), SF3B1 mutations and TP53ab along with del(11q) and U-CLL, but not NOTCH1 mutations, retained independent significance. Importantly, TP53ab and SF3B1 mutations had an adverse impact even in U-CLL. In conclusion, we support the clinical relevance of novel recurrent mutations in CLL, highlighting the adverse impact of SF3B1 and TP53 mutations, even independent of IGHV mutational status, thus underscoring the need for urgent standardization/harmonization of the detection methods.

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Acknowledgements

We are grateful to the European Research Initiative in CLL steering board for all their support during this project. We thank Jitka Malcikova and Karla Plevova for their valuable comments and help in sample management and to Jana Smardova for FASAY analysis. This research was funded by the Nordic Cancer Union, the Swedish Cancer Society, the Swedish Research Council and Lion’s Cancer Research Foundation, Uppsala; Cancer Research UK, Leukaemia and Lymphoma Research, Kay Kendall Leukaemia Fund, United Kingdom; Associazione Italiana per la Ricerca sul Cancro (AIRC) (Investigator grant and Molecular Clinical Oncology Program 5xMille no. 9965, no. 10007), Milano, Italy; Ricerca Finalizzata 2010, Ministero della Salute, Roma, Italy; the ENosAI project (code 09SYN-13-880) co-funded by the EU and the Hellenic General Secretariat for Research and Technology, Greece; by project MSMT-CR VaVPI CZ.1.05/1.1.00/02.0068 (CEITEC), research grant IGA-MZ-CR NT13493-4/2012 and 7th FP Health project NGS-PTL/2012-2015/no. 306242 of European Commission and MSMT-CR (2013-2015, no. 7E13008), and the ICGC-CLL Genome Project from the Spanish Ministry of Economy and Competitivity (MINECO) through the Instituto de Salud Carlos III (RTICC RD12/0036/0023 and PIE PI043043), Spain. Andreas Agathangelidis is a recipient of a fellowship by Associazione Italiana per la Ricerca sul Cancro AIRC (Triennial fellowship ‘Guglielmina Lucatello é Gino Mazzega’).

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Author notes

  1. J C Strefford, K Stamatopoulos and R Rosenquist: The last three authors contributed equally to this work.

Authors and Affiliations

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

    P Baliakas, A Hadzidimitriou, L-A Sutton, L Mansouri, D Cortese, K Stamatopoulos & R Rosenquist

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

    P Baliakas, E Stalika, A Anagnostopoulos & K Stamatopoulos

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

    A Hadzidimitriou, E Minga, A M Makris & K Stamatopoulos

  4. Division of Haematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy

    D Rossi & G Gaidano

  5. Hematopathology Unit and Department of Hematology, Hospital Clinic, University of Barcelona, Institut d’Investigacions Biomèdiques August Pi iSunyer (IDIBAPS), Barcelona, Spain

    N Villamor, A Navarro, J Delgado & E Campo

  6. Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK

    M Larrayoz, M J J Rose-Zerilli & J C Strefford

  7. Central European Institute of Technology, Masaryk University and University Hospital Brno, Brno, Czech Republic

    J Kminkova, B Kantorova, V Navrkalova & S Pospisilova

  8. Università Vita-Salute San Raffaele, Milan, Italy

    A Agathangelidis, L Scarfò & P Ghia

  9. Division of Molecular Oncology and Department of Onco-Hematology, San Raffaele Scientific Institute, Milan, Italy

    A Agathangelidis, L Scarfò & P Ghia

  10. Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK

    Z Davis & D Oscier

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

    E Tausch & S Stilgenbauer

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

    K E Smedby

  13. Lund University and Hospital Department of Hematology, Lund Stem Cell Center, Lund, Sweden

    G Juliusson

  14. Hematology Department, Nikea General Hospital, Pireaus, Greece

    C Belessi

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

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Correspondence to R Rosenquist.

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Competing interests

KS receives research support from Roche SA. JCS has financial support from Hoffman La Roche.

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Baliakas, P., Hadzidimitriou, A., Sutton, LA. et al. Recurrent mutations refine prognosis in chronic lymphocytic leukemia. Leukemia 29, 329–336 (2015). https://doi.org/10.1038/leu.2014.196

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