Landau Dan A, Tausch Eugen, Taylor-Weiner Amaro N, Stewart Chip, Reiter Johannes G, Bahlo Jasmin, Kluth Sandra, Bozic Ivana, Lawrence Mike, Böttcher Sebastian, Carter Scott L, Cibulskis Kristian, Mertens Daniel, Sougnez Carrie L, Rosenberg Mara, Hess Julian M, Edelmann Jennifer, Kless Sabrina, Kneba Michael, Ritgen Matthias, Fink Anna, Fischer Kirsten, Gabriel Stacey, Lander Eric S, Nowak Martin A, Döhner Hartmut, Hallek Michael, Neuberg Donna, Getz Gad, Stilgenbauer Stephan, Wu Catherine J
Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Nature. 2015 Oct 22;526(7574):525-30. doi: 10.1038/nature15395. Epub 2015 Oct 14.
Which genetic alterations drive tumorigenesis and how they evolve over the course of disease and therapy are central questions in cancer biology. Here we identify 44 recurrently mutated genes and 11 recurrent somatic copy number variations through whole-exome sequencing of 538 chronic lymphocytic leukaemia (CLL) and matched germline DNA samples, 278 of which were collected in a prospective clinical trial. These include previously unrecognized putative cancer drivers (RPS15, IKZF3), and collectively identify RNA processing and export, MYC activity, and MAPK signalling as central pathways involved in CLL. Clonality analysis of this large data set 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 data sets of clinically informative samples enable the discovery of novel genes associated with cancer, the network of relationships between the driver events, and their impact on disease relapse and clinical outcome.
哪些基因改变驱动肿瘤发生，以及它们在疾病和治疗过程中如何演变，是癌症生物学的核心问题。在此，我们通过对538例慢性淋巴细胞白血病（CLL）及匹配的种系DNA样本进行全外显子组测序，鉴定出44个反复突变的基因和11个反复出现的体细胞拷贝数变异，其中278例样本是在前瞻性临床试验中收集的。这些基因包括先前未被识别的假定癌症驱动基因（RPS15、IKZF3），并共同确定RNA加工和输出、MYC活性以及MAPK信号传导是CLL涉及的核心途径。对这个大数据集的克隆性分析进一步实现了驱动事件之间时间关系的重建。对59例患者治疗前和复发样本的直接比较显示，克隆进化非常频繁。因此，具有临床信息的样本的大型测序数据集能够发现与癌症相关的新基因、驱动事件之间的关系网络，以及它们对疾病复发和临床结果的影响。
