Recurrent mutations refine prognosis in chronic lymphocytic leukemia
Recurrent mutations refine prognosis in chronic lymphocytic leukemia
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DOI：
10.1038/leu.2014.196
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发表时间：
2015-02-01
期刊：
影响因子：
11.4
通讯作者：
Rosenquist, R.
中科院分区：
文献类型：
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作者：
Baliakas, P.;Hadzidimitriou, A.;Rosenquist, R.
通过欧洲慢性淋巴细胞白血病（CLL）研究计划（ERIC），我们筛选了3490例CLL患者的NOTCH 1基因突变。（n = 3334）、SF 3B1（n = 2322）、TP 53（n = 2309）、MYD 88（n = 1080）和BIRC 3（n = 919）基因，主要在诊断时（75%）和治疗前（> 90%）。BIRC 3突变（2.5%）与未突变的IGHV基因（U-CLL）、del（11 q）和12三体相关，而MYD 88突变（2.2%）仅见于M-CLL。NOTCH1、SF3B1和TP53表现出可变的频率，并且大多在临床侵袭性病例中富集。有趣的是，随着诊断和突变筛查之间的时间间隔增加，SF3B1突变的发生率也增加;对于NOTCH1突变没有观察到这种增加。关于临床影响，在889例未经治疗的Binet A期病例中，NOTCH1突变、SF3B1突变和TP53畸变（缺失/突变，TP53ab）与首次治疗时间较短相关（P <0.0001）。在多变量分析（n = 774）中，SF 3 B1突变和TP 53 ab沿着del（11 q）和U-CLL，但不是NOTCH 1突变，保持独立的意义。重要的是，TP53ab和SF3B1突变即使在U-CLL中也有不利影响。总之，我们支持CLL中新复发突变的临床相关性，强调SF3B1和TP53突变的不利影响，即使独立于IGHV突变状态，因此强调迫切需要标准化/协调检测方法。
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.