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

作者：Rui Xing, Yong Zhou, Jun Yu, Yingyan Yu, Yongzhan Nie, Wen Luo, Chao Yang, Teng Xiong, William Ka Kei Wu, Zhongwu Li, Bing Yang, Shuye Lin, Yaping Zhang, Yingqi Hu, Lin Li, Lijuan Han, Yang Chen, Shaogang Huang, Suiping Huang, Rui Zhou, Jing Li, Kaichun Wu, Daiming Fan, Guangbo Tang, Jianhua Dou, Zhenggang Zhu, Jiafu Ji, Xiaodong Fang, Youyong Lu · 发表于：Nature Communications · 年份：2019 · DOI：10.1038/s41467-019-09644-6 · 被引用次数：90 · 研究领域：Genetic factors in colorectal cancer、Cancer Genomics and Diagnostics、Cholangiocarcinoma and Gallbladder Cancer Studies

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.