4.7 Article

Recurrent mutations refine prognosis in chronic lymphocytic leukemia

Journal

LEUKEMIA
Volume 29, Issue 2, Pages 329-336

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2014.196

Keywords

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Funding

  1. European Research Initiative in CLL steering board
  2. Nordic Cancer Union
  3. Swedish Cancer Society
  4. Swedish Research Council
  5. Lion's Cancer Research Foundation, Uppsala
  6. Cancer Research UK, Leukaemia
  7. Lymphoma Research, Kay Kendall Leukaemia Fund, United Kingdom
  8. Associazione Italiana per la Ricerca sul Cancro (AIRC) (Investigator grant and Molecular Clinical Oncology Program 5xMille), Milano, Italy [9965, 10007]
  9. Ricerca Finalizzata, Ministero della Salute, Roma, Italy
  10. ENosAI project [09SYN-13-880]
  11. EU
  12. Hellenic General Secretariat for Research and Technology, Greece
  13. MSMT-CR VaVPI [CZ.1.05/1.1.00/02.0068, IGA-MZ-CR NT13493-4/2012]
  14. 7th FP Health project NGS-PTL of European Commission [306242]
  15. MSMT-CR [7E13008]
  16. ICGC-CLL Genome Project from the Spanish Ministry of Economy and Competitivity (MINECO) through the Instituto de Salud Carlos III, Spain [RTICC RD12/0036/0023, PIE PI043043]
  17. Associazione Italiana per la Ricerca sul Cancro AIRC (Triennial fellowship 'Guglielmina Lucatello e Gino Mazzega')

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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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