Pan-cancer analysis of whole genomes
Pan-cancer analysis of whole genomes
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DOI：
10.1038/s41586-020-1969-6
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发表时间：
2020-02-06
期刊：
影响因子：
64.8
通讯作者：
Zhang, Jiashan
中科院分区：
文献类型：
--
作者：
Campbell, Peter J.;Getz, Gad;Zhang, Jiashan
癌症是由基因变化驱动的，大规模平行测序的出现使得在全基因组尺度上系统地记录这种变异成为可能（1-3）。在这里，我们报告了来自国际癌症基因组联盟（ICGC）的全基因组泛癌症分析（PCAWG）联盟和癌症基因组图谱（TCGA）的38种肿瘤类型的2,658个全癌症基因组及其匹配的正常组织的综合分析。我们描述了通过使用计算云的国际数据共享促进的PCAWG资源的生成。当编码和非编码基因组元件结合时，癌症基因组平均包含4-5个驱动突变；然而，在大约5%的病例中，没有发现任何驱动因素，这表明癌症驱动因素的发现尚未完成。染色体断裂，在单个灾难性事件中出现许多簇状结构变异，通常是肿瘤进化的早期事件；例如，在肢端黑色素瘤中，这些事件先于大多数体细胞点突变，并同时影响几个与癌症相关的基因。端粒维持异常的癌症通常起源于低复制活性的组织，并显示出几种防止端粒磨损达到临界水平的机制。常见和罕见的种系变异影响体细胞突变的模式，包括点突变、结构变异和体细胞反转位。来自PCAWG联盟的一系列论文描述了除TERT启动子外驱动癌症的非编码突变(4)；识别导致碱基替换、小插入和删除以及结构变化的突变过程的新特征（5,6）；分析肿瘤进化的时间和模式(7)；描述了体细胞突变对剪接、表达水平、融合基因和启动子活性的多种转录后果（8,9）；并评估了一系列更专业的癌症基因组特征（8,10-18）。
Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).