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.

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.; Davis, Z.; Tausch, E.; Stalika, E.; Kantorova, B.; Mansouri, L.; Scarfo', L.; Cortese, D.; Navrkalova, V.; Rose-Zerilli, M. J. J.; Smedby, K. E.; Juliusson, G.; Anagnostopoulos, A.; Makris, A. M.; Navarro, A.; Delgado, J.; Oscier, D.; Belessi, C.; Stilgenbauer, S.; Ghia, P.; Pospisilova, S.; Gaidano, G.; Campo, E.; Strefford, J. C.; Stamatopoulos, K.; Rosenquist, R.. - In: LEUKEMIA. - ISSN 0887-6924. - 29:2(2015), pp. 329-336. [10.1038/leu.2014.196]

Recurrent mutations refine prognosis in chronic lymphocytic leukemia

Scarfo' L.;Ghia P.;
2015-01-01

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.
2015
Aged
Cytogenetics
DNA Mutational Analysis
Europe
Female
Gene Deletion
Humans
Leukemia, Lymphocytic, Chronic, B-Cell
Male
Middle Aged
Multivariate Analysis
Phosphoproteins
Polymorphism, Single Nucleotide
Prognosis
RNA Splicing Factors
Receptor, Notch1
Recurrence
Ribonucleoprotein, U2 Small Nuclear
Time Factors
Tumor Suppressor Protein p53
Mutation
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11768/106403
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