title: Distinct Subtypes of Gastric Cancer Defined by Molecular Characterization Include Novel Mutational Signatures with Prognostic Capability.
abstract: Gastric cancer is not a single disease, and its subtype classification is still evolving. Next-generation sequencing studies have identified novel genetic drivers of gastric cancer, but their use as molecular classifiers or prognostic markers of disease outcome has yet to be established. In this study, we integrated somatic mutational profiles and clinicopathologic information from 544 gastric cancer patients from previous genomic studies to identify significantly mutated genes (SMG) with prognostic relevance. Gastric cancer patients were classified into regular (86.8%) and hypermutated (13.2%) subtypes based on mutation burden. Notably, TpCpW mutations occurred significantly more frequently in regular, but not hypermutated, gastric cancers, where they were associated with APOBEC expression. In the former group, six previously unreported (XIRP2, NBEA, COL14A1, CNBD1, ITGAV, and AKAP6) and 12 recurrent mutated genes exhibited high mutation prevalence (≥3.0%) and an unexpectedly higher incidence of nonsynonymous mutations. We also identified two molecular subtypes of regular-mutated gastric cancer that were associated with distinct prognostic outcomes, independently of disease staging, as confirmed in a distinct patient cohort by targeted capture sequencing. Finally, in diffuse-type gastric cancer, CDH1 mutation was found to be associated with shortened patient survival, independently of disease staging. Overall, our work identified previously unreported SMGs and a mutation signature predictive of patient survival in newly classified subtypes of gastric cancer, offering opportunities to stratify patients into optimal treatment plans based on molecular subtyping. Cancer Res; 76(7); 1724-32. ©2016 AACR.
authors: Institute of Digestive Disease and Department of Medicine & Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, Hong Kong. Beijing Genomics Institute, Shenzhen, Guangdong, P.R. China.
authors: Xiangchun
authors: X
authors: Li
authors: Institute of Digestive Disease and Department of Medicine & Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, Hong Kong. Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, Hong Kong. junyu@cuhk.edu.hk wukakei@cuhk.edu.hk.
authors: William K K
authors: WK
authors: Wu
authors: Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China.
authors: Rui
authors: R
authors: Xing
authors: Institute of Digestive Disease and Department of Medicine & Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
authors: Sunny H
authors: SH
authors: Wong
authors: Department of Epidemiology and Biostatistics, Tianjin Medical University Cancer Institute and Hospital, Tianjin, P.R. China.
authors: Yuexin
authors: Y
authors: Liu
authors: Beijing Genomics Institute, Shenzhen, Guangdong, P.R. China.
authors: Xiaodong
authors: X
authors: Fang
authors: Department of Computer Science, City University of Hong Kong, Hong Kong, Hong Kong.
authors: Yanlin
authors: Y
authors: Zhang
authors: Beijing Genomics Institute, Shenzhen, Guangdong, P.R. China.
authors: Mengyao
authors: M
authors: Wang
authors: Beijing Genomics Institute, Shenzhen, Guangdong, P.R. China.
authors: Jiaqian
authors: J
authors: Wang
authors: Beijing Genomics Institute, Shenzhen, Guangdong, P.R. China.
authors: Lin
authors: L
authors: Li
authors: Beijing Genomics Institute, Shenzhen, Guangdong, P.R. China.
authors: Yong
authors: Y
authors: Zhou
authors: Institute of Digestive Disease and Department of Medicine & Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
authors: Senwei
authors: S
authors: Tang
authors: School of Computer Science, National University of Defense Technology, Changsha, Hunan, P.R. China.
authors: Shaoliang
authors: S
authors: Peng
authors: Beijing Genomics Institute, Shenzhen, Guangdong, P.R. China.
authors: Kunlong
authors: K
authors: Qiu
authors: Beijing Genomics Institute, Shenzhen, Guangdong, P.R. China.
authors: Longyun
authors: L
authors: Chen
authors: Department of Epidemiology and Biostatistics, Tianjin Medical University Cancer Institute and Hospital, Tianjin, P.R. China.
authors: Kexin
authors: K
authors: Chen
authors: Beijing Genomics Institute, Shenzhen, Guangdong, P.R. China.
authors: Huanming
authors: H
authors: Yang
authors: Department of Pathology, University of Texas MD Anderson Cancer Center Informatics Center, Houston, Texas.
authors: Wei
authors: W
authors: Zhang
authors: Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
authors: Matthew T V
authors: MT
authors: Chan
authors: Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China.
authors: Youyong
authors: Y
authors: Lu
authors: Institute of Digestive Disease and Department of Medicine & Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
authors: Joseph J Y
authors: JJ
authors: Sung
authors: Institute of Digestive Disease and Department of Medicine & Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, Hong Kong. junyu@cuhk.edu.hk wukakei@cuhk.edu.hk.
authors: Jun
authors: J
authors: Yu
mesh_terms: D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D009154:Mutation; D011379:Prognosis; D013274:Stomach Neoplasms / Q000235:genetics* / Q000401:mortality