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Recurrent mutations refine prognosis in chronic lymphocytic leukemia.

Baliakas, P; Hadzidimitriou, A; Sutton, L-A; Rossi, D; Minga, E; Villamor, N; Larrayoz, M; Kminkova, J; Agathangelidis, A and Davis, Z, et al. (2015) In Leukemia 29(2). p.329-336
Abstract
Through the European Research Initiative in CLL (ERIC), we screened 3490 patients with chronic lymphocytic leukemia (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 prior to 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... (More)
Through the European Research Initiative in CLL (ERIC), we screened 3490 patients with chronic lymphocytic leukemia (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 prior to 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-naïve Binet 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.Leukemia accepted article preview online, 19 June 2014; doi:10.1038/leu.2014.196. (Less)
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Leukemia
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29
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2
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329 - 336
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Nature Publishing Group
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  • pmid:24943832
  • wos:000349445000009
  • scopus:84922529491
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1476-5551
DOI
10.1038/leu.2014.196
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English
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2014-07-06 19:11:05
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@article{da3cc145-e26d-482d-af7e-8cc5a1cefa78,
  abstract     = {Through the European Research Initiative in CLL (ERIC), we screened 3490 patients with chronic lymphocytic leukemia (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 prior to treatment (&gt;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&lt;0.0001) in 889 treatment-naïve Binet 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.Leukemia accepted article preview online, 19 June 2014; doi:10.1038/leu.2014.196.},
  author       = {Baliakas, P and Hadzidimitriou, A and Sutton, L-A and Rossi, D and Minga, E and Villamor, N and Larrayoz, M and Kminkova, J and Agathangelidis, A and Davis, Z and Tausch, E and Stalika, E and Kantorova, B and Mansouri, L and Scarfò, L and Cortese, D and Navrkalova, V and Rose-Zerilli, M J J and Smedby, K E and Juliusson, Gunnar and Anagnostopoulos, A and Makris, A M and Navarro, A and Delgado, J and Oscier, D and Belessi, C and Stilgenbauer, S and Ghia, P and Pospisilova, S and Gaidano, G and Campo, E and Strefford, J C and Stamatopoulos, K and Rosenquist, R},
  issn         = {1476-5551},
  language     = {eng},
  number       = {2},
  pages        = {329--336},
  publisher    = {Nature Publishing Group},
  series       = {Leukemia},
  title        = {Recurrent mutations refine prognosis in chronic lymphocytic leukemia.},
  url          = {http://dx.doi.org/10.1038/leu.2014.196},
  volume       = {29},
  year         = {2015},
}