Genomic characterization of high-count MBL cases indicates that early detection of driver mutations and subclonal expansion are predictors of adverse clinical outcome.
Genomic characterization of high-count MBL cases indicates that early detection of driver mutations and subclonal expansion are predictors of adverse clinical outcome.
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作者：
高计数单克隆b细胞淋巴细胞增多症（MBL）是一种在外周血中无症状的克隆b细胞扩增，无其他慢性淋巴细胞白血病（CLL）的表现。每年，1%的mbl发展为需要治疗的CLL；因此，了解决定哪些mbl进展为中/晚期CLL的生物学事件至关重要。在本研究中，我们对48个高计数MBLs进行了靶向深度测序，其中47个进行了2-4个序列样本分析，探索了21个驱动基因的突变状态，并评估了克隆进化。在分析的初始时间点，我们发现25例MBLs（52%）存在体细胞非同义突变，其中13例（27%）存在bbb1突变基因。在随后进展为CLL的病例中，在进展前41个月（中位数）检测到突变。除了NOTCH1、TP53和XPO1在MBL中的发生率较低外，其他基因的突变发生率与CLL相似，这表明MBL/CLL连续体中大多数驱动突变的早期起源。在分析的初始时间点发生突变的MBLs与较短的治疗时间（TTT）相关。此外，序列评估显示驱动突变亚克隆扩增的MBLs进展到CLL的时间更短，TTT时间更短。这些发现支持克隆进化在恶性前MBL阶段已经具有预后意义，预测哪些个体将更早发展为CLL。
High-count monoclonal B-cell lymphocytosis (MBL) is an asymptomatic expansion of clonal B-cells in the peripheral blood without other manifestations of chronic lymphocytic leukemia (CLL). Yearly, 1% of MBLs evolve to CLL requiring therapy; thus being critical to understand the biologic events that determine which MBLs progress to intermediate/advanced CLL. In this study, we performed targeted deep-sequencing on 48 high-count MBLs, 47 of them with 2-4 sequential samples analyzed, exploring the mutation status of 21 driver genes and evaluating clonal evolution. We found somatic non-synonymous mutations in 25 MBLs(52%) at the initial time-point analyzed, including 13(27%) with >1 mutated gene. In cases that subsequently progressed to CLL, mutations were detected 41 months (median) prior to progression. Excepting NOTCH1, TP53 and XPO1, which showed a lower incidence in MBL, genes were mutated with a similar prevalence to CLL, indicating the early origin of most driver mutations in the MBL/CLL continuum. MBLs with mutations at the initial time-point analyzed were associated with shorter time-to-treatment (TTT). Furthermore, MBLs showing subclonal expansion of driver mutations on sequential evaluation had shorter progression time to CLL and shorter TTT. These findings support that clonal evolution have prognostic implications already at the pre-malignant MBL stage, anticipating which individuals will progress earlier to CLL.
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DOI：
10.1093/bioinformatics/btu137
发表时间：
2014-07-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Kocher JP;Quest DJ;Duffy P;Meiners MA;Moore RM;Rider D;Hossain A;Hart SN;Dinu V
通讯作者：
Dinu V
影响因子：
64.8
作者：
Puente, Xose S.;Bea, Silvia;Campo, Elias
通讯作者：
Campo, Elias
推动CLL的突变及其在进展和复发中的演变。
影响因子：
64.8
作者：
Landau DA;Tausch E;Taylor-Weiner AN;Stewart C;Reiter JG;Bahlo J;Kluth S;Bozic I;Lawrence M;Böttcher S;Carter SL;Cibulskis K;Mertens D;Sougnez CL;Rosenberg M;Hess JM;Edelmann J;Kless S;Kneba M;Ritgen M;Fink A;Fischer K;Gabriel S;Lander ES;Nowak MA;Döhner H;Hallek M;Neuberg D;Getz G;Stilgenbauer S;Wu CJ
通讯作者：
Wu CJ
影响因子：
20.3
作者：
Rossi, Davide;Khiabanian, Hossein;Gaidano, Gianluca
通讯作者：
Gaidano, Gianluca
影响因子：
11.4
作者：
Baliakas, P.;Hadzidimitriou, A.;Rosenquist, R.
通讯作者：
Rosenquist, R.