Recurrent mutations refine prognosis in chronic lymphocytic leukemia

被引：226

作者：

Baliakas, P. ^{[1
,2
,3
]}

Hadzidimitriou, A. ^{[1
,4
]}

Sutton, L-A ^{[1
]}

Rossi, D. ^{[5
]}

Minga, E. ^{[4
]}

Villamor, N. ^{[6
,7
]}

Larrayoz, M. ^{[8
]}

Kminkova, J. ^{[9
,10
]}

Agathangelidis, A. ^{[11
,12
,13
]}

Davis, Z. ^{[14
]}

Tausch, E. ^{[15
]}

Stalika, E. ^{[2
,3
]}

Kantorova, B. ^{[9
,10
]}

Mansouri, L. ^{[1
]}

Scarfo, L. ^{[11
,12
,13
]}

Cortese, D. ^{[1
]}

Navrkalova, V. ^{[9
,10
]}

Rose-Zerilli, M. J. J. ^{[8
]}

Smedby, K. E. ^{[16
]}

Juliusson, G. ^{[17
,18
]}

Anagnostopoulos, A. ^{[2
,3
]}

Makris, A. M. ^{[4
]}

Navarro, A. ^{[6
,7
]}

Delgado, J. ^{[6
,7
]}

Oscier, D. ^{[14
]}

Belessi, C. ^{[19
]}

Stilgenbauer, S. ^{[15
]}

Ghia, P. ^{[11
,12
,13
]}

Pospisilova, S. ^{[9
,10
]}

Gaidano, G. ^{[5
]}

Campo, E. ^{[6
,7
]}

Strefford, J. C. ^{[8
]}

Stamatopoulos, K. ^{[1
,2
,3
,4
]}

Rosenquist, R. ^{[1
]}

机构：

[1] Uppsala Univ, Rudbeck Lab, Dept Immunol Genet & Pathol, Sci Life Lab, S-75185 Uppsala, Sweden

[2] G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece

[3] G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece

[4] CERTH, Inst Appl Biosci, Thessaloniki, Greece

[5] Amedeo Avogadro Univ Eastern Piedmont, Dept Translat Med, Div Haematol, Novara, Italy

[6] Univ Barcelona, Hosp Clin, Inst Invest Biomed August Pi ISunyer IDIBAPS, Hematopathol Unit, Barcelona, Spain

[7] Univ Barcelona, Hosp Clin, Inst Invest Biomed August Pi ISunyer IDIBAPS, Dept Hematol, Barcelona, Spain

[8] Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England

[9] Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic

[10] Univ Hosp Brno, Brno, Czech Republic

[11] Univ Vita Salute San Raffaele, Milan, Italy

[12] Ist Sci San Raffaele, Div Mol Oncol, I-20132 Milan, Italy

[13] Ist Sci San Raffaele, Dept Oncohematol, I-20132 Milan, Italy

[14] Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England

[15] Univ Ulm, Dept Internal Med 3, D-89069 Ulm, Germany

[16] Karolinska Inst, Clin Epidemiol Unit, Dept Med, Stockholm, Sweden

[17] Lund Univ, Lund, Sweden

[18] Lund Stem Cell Ctr, Hosp Dept Hematol, Lund, Sweden

[19] Nikea Gen Hosp, Hematol Dept, Piraeus, Greece

来源：

LEUKEMIA | 2015年 / 29卷 / 02期

基金：

瑞典研究理事会;

关键词：

NOTCH1; MUTATIONS; SF3B1; GENOMIC ABERRATIONS; HIGH-RISK; CLL; SURVIVAL; TP53; EVOLUTION; MYD88; BIRC3;

D O I：

10.1038/leu.2014.196

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：329 / 336

页数：8

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