Mutations driving CLL and their evolution in progression and relapse.
Mutations driving CLL and their evolution in progression and relapse.
复制标题
推动CLL的突变及其在进展和复发中的演变。
DOI：
10.1038/nature15395
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发表时间：
2015-10-22
期刊：
影响因子：
64.8
通讯作者：
Wu CJ
中科院分区：
文献类型：
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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
哪些遗传改变驱动肿瘤发生以及它们在疾病和治疗过程中如何演变是癌症生物学中的核心问题。我们通过对538例慢性淋巴细胞白血病（CLL）和匹配的生殖系DNA样本进行全外显子组测序，确定了44个复发性突变基因和11个复发性体细胞拷贝数变异，其中278个样本是在前瞻性临床试验中收集的。这些包括以前未被识别的癌症驱动因子（RPS 15，IKZF 3），并共同鉴定RNA加工和输出，MYC活性和MAPK信号传导作为参与CLL的中心途径。这个大数据集的克隆性分析进一步使得能够重建驱动程序事件之间的时间关系。来自59名患者的匹配治疗前和复发样本之间的直接比较显示了高度频繁的克隆进化。因此，临床信息样本的大型测序数据集使得能够发现新的癌症基因以及驱动事件与其对疾病复发和临床结果的影响之间的关系网络。
Which genetic alterations drive tumorigenesis and how they evolve over the course of disease and therapy are central questions in cancer biology. We identify 44 recurrently mutated genes and 11 recurrent somatic copy number variations through whole-exome sequencing of 538 chronic lymphocytic leukemia (CLL) and matched germline DNA samples, 278 of which were collected in a prospective clinical trial. These include previously unrecognized cancer drivers (RPS15, IKZF3) and collectively identify RNA processing and export, MYC activity and MAPK signaling as central pathways involved in CLL. Clonality analysis of this large dataset further enabled reconstruction of temporal relationships between driver events. Direct comparison between matched pre-treatment and relapse samples from 59 patients demonstrated highly frequent clonal evolution. Thus, large sequencing datasets of clinically informative samples enable the discovery of novel cancer genes and the network of relationships between the driver events and their impact on disease relapse and clinical outcome.