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

Rui Xing (), Yong Zhou, Jun Yu, Yingyan Yu, Yongzhan Nie, Wen Luo, Chao Yang, Teng Xiong, William K. K. Wu, Zhongwu Li, Yang Bing, Shuye Lin, Yaping Zhang, Yingqi Hu, Lin Li, Lijuan Han, Chen Yang, Shaogang Huang, Suiping Huang, Rui Zhou, Jing Li, Kaichun Wu, Daiming Fan, Guangbo Tang, Jianhua Dou, Zhenggang Zhu, Jiafu Ji (), Xiaodong Fang () and Youyong Lu ()
Additional contact information
Rui Xing: Peking University Cancer Hospital & Institute
Yong Zhou: Peking University Cancer Hospital & Institute
Jun Yu: CUHK Shenzhen Research Institute
Yingyan Yu: Shanghai Jiaotong University School of Medicine
Yongzhan Nie: Fourth Military Medical University
Wen Luo: Peking University Cancer Hospital & Institute
Chao Yang: Peking University Cancer Hospital & Institute
Teng Xiong: Peking University Cancer Hospital & Institute
William K. K. Wu: CUHK Shenzhen Research Institute
Zhongwu Li: Peking University Cancer Hospital & Institute
Yang Bing: Peking University Cancer Hospital & Institute
Shuye Lin: Peking University Cancer Hospital & Institute
Yaping Zhang: Peking University Cancer Hospital & Institute
Yingqi Hu: Peking University Cancer Hospital & Institute
Lin Li: Shanghai Jiao-Tong University School of Medicine
Lijuan Han: The Second Affiliated Hospital of Guangzhou University of Chinese Medicine
Chen Yang: The Second Affiliated Hospital of Guangzhou University of Chinese Medicine
Shaogang Huang: The Second Affiliated Hospital of Guangzhou University of Chinese Medicine
Suiping Huang: The Second Affiliated Hospital of Guangzhou University of Chinese Medicine
Rui Zhou: Huazhong Agricultural University
Jing Li: Huazhong Agricultural University
Kaichun Wu: Fourth Military Medical University
Daiming Fan: Fourth Military Medical University
Guangbo Tang: Fourth Military Medical University
Jianhua Dou: Fourth Military Medical University
Zhenggang Zhu: Shanghai Jiaotong University School of Medicine
Jiafu Ji: Peking University Cancer Hospital & Institute
Xiaodong Fang: The Second Affiliated Hospital of Guangzhou University of Chinese Medicine
Youyong Lu: Peking University Cancer Hospital & Institute

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-09644-6

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