全基因组测序揭示了胃癌中新的串联重复热点和预后突变特征。

Whole-genome sequencing reveals novel tandem-duplication hotspots and a prognostic mutational signature in gastric cancer.

机构信息

Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, 100142, Beijing, China.

Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, Shenzhen, 518000, China.

出版信息

Nat Commun. 2019 May 2;10(1):2037. doi: 10.1038/s41467-019-09644-6.

Genome-wide analysis of genomic signatures might reveal novel mechanisms for gastric cancer (GC) tumorigenesis. Here, we analysis structural variations (SVs) and mutational signatures via whole-genome sequencing of 168 GCs. Our data demonstrates diverse models of complex SVs operative in GC, which lead to high-level amplification of oncogenes. We find varying proportion of tandem-duplications (TDs) among individuals and identify 24 TD hotspots involving well-established cancer genes such as CCND1, ERBB2 and MYC. Specifically, we nominate a novel hotspot involving the super-enhancer of ZFP36L2 presents in approximately 10% GCs from different cohorts, the oncogenic role of which is further confirmed by experimental data. In addition, our data reveal a mutational signature, specifically occurring in noncoding region, significantly enriched in tumors with cadherin 1 mutations, and associated with poor prognoses. Collectively, our data suggest that TDs might serve as an important mechanism for cancer gene activation and provide a novel signature for stratification.

全基因组分析基因组特征可能揭示胃癌（GC）发生的新机制。在这里，我们通过对 168 个 GC 进行全基因组测序来分析结构变异（SV）和突变特征。我们的数据表明，GC 中存在多种复杂 SV 作用模式，导致癌基因高水平扩增。我们发现个体之间存在不同比例的串联重复（TD），并确定了 24 个涉及 CCND1、ERBB2 和 MYC 等已确立癌症基因的 TD 热点。具体来说，我们提名了一个涉及 ZFP36L2 超级增强子的新热点，该热点大约存在于来自不同队列的 10% GC 中，其致癌作用通过实验数据进一步得到证实。此外，我们的数据还揭示了一个突变特征，特别是在非编码区域中显著富集，与钙粘蛋白 1 突变的肿瘤相关，并与不良预后相关。总的来说，我们的数据表明 TD 可能是癌症基因激活的一个重要机制，并提供了一个新的分层特征。