title: Mutational landscape of gastric adenocarcinoma in Chinese: implications for prognosis and therapy.
abstract: Gastric cancer (GC) is a highly heterogeneous disease. To identify potential clinically actionable therapeutic targets that may inform individualized treatment strategies, we performed whole-exome sequencing on 78 GCs of differing histologies and anatomic locations, as well as whole-genome sequencing on two GC cases, each with three primary tumors and two matching lymph node metastases. The data showed two distinct GC subtypes with either high-clonality (HiC) or low-clonality (LoC). The HiC subtype of intratumoral heterogeneity was associated with older age, TP53 (tumor protein P53) mutation, enriched C > G transition, and significantly shorter survival, whereas the LoC subtype was associated with younger age, ARID1A (AT rich interactive domain 1A) mutation, and significantly longer survival. Phylogenetic tree analysis of whole-genome sequencing data from multiple samples of two patients supported the clonal evolution of GC metastasis and revealed the accumulation of genetic defects that necessitate combination therapeutics. The most recurrently mutated genes, which were validated in a separate cohort of 216 cases by targeted sequencing, were members of the homologous recombination DNA repair, Wnt, and PI3K-ERBB pathways. Notably, the drugable NRG1 (neuregulin-1) and ERBB4 (V-Erb-B2 avian erythroblastic leukemia viral oncogene homolog 4) ligand-receptor pair were mutated in 10% of GC cases. Mutations of the BRCA2 (breast cancer 2, early onset) gene, found in 8% of our cohort and validated in The Cancer Genome Atlas GC cohort, were associated with significantly longer survivals. These data define distinct clinicogenetic forms of GC in the Chinese population that are characterized by specific mutation sets that can be investigated for efficacy of single and combination therapies.
authors.affiliation: Department of Epidemiology and Biostatistics.
authors.forename: Kexin
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center Informatics Center, Houston, TX 77030; Center of Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261;
authors.forename: Da
authors.initials: D
authors.lastname: Yang
authors.affiliation: Beijing Genomics Institute-Shenzhen, Shenzhen 518083, Guangdong, People's Republic of China; Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong 999077, People's Republic of China;
authors.forename: Xiangchun
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pathology, and.
authors.forename: Baocun
authors.initials: B
authors.lastname: Sun
authors.affiliation: Department of Epidemiology and Biostatistics.
authors.forename: Fengju
authors.initials: F
authors.lastname: Song
authors.affiliation: Department of Pathology, and.
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Cao
authors.affiliation: Department of Oncology Discovery, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322;
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Brat
authors.affiliation: Beijing Genomics Institute-Shenzhen, Shenzhen 518083, Guangdong, People's Republic of China;
authors.forename: Zhibo
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Department of Epidemiology and Biostatistics.
authors.forename: Haixin
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Gastrointestinal Surgery, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, People's Republic of China;
authors.forename: Han
authors.initials: H
authors.lastname: Liang
authors.affiliation: Department of Epidemiology and Biostatistics.
authors.forename: Yanrui
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Epidemiology and Biostatistics.
authors.forename: Hong
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Beijing Genomics Institute-Shenzhen, Shenzhen 518083, Guangdong, People's Republic of China;
authors.forename: Miao
authors.initials: M
authors.lastname: Li
authors.affiliation: Division of Medical Oncology, Mayo Clinic, Rochester, MN 55905;
authors.forename: Jan
authors.initials: J
authors.lastname: Buckner
authors.affiliation: Medical Sciences, Amgen Inc., Thousand Oaks, CA 91320;
authors.forename: Scott D
authors.initials: SD
authors.lastname: Patterson
authors.affiliation: Lilly China Research and Development Center and.
authors.forename: Xiang
authors.initials: X
authors.lastname: Ye
authors.affiliation: Translational Sciences Oncology, Eli Lilly and Company, Indianapolis, IN 46285;
authors.forename: Christoph
authors.initials: C
authors.lastname: Reinhard
authors.affiliation: Translational Oncology & Personalized Medicine, AbbVie Inc., North Chicago, IL 60064;
authors.forename: Anahita
authors.initials: A
authors.lastname: Bhathena
authors.affiliation: Exploratory Clinical & Translational Research, Bristol-Myers Squibb India, Mumbai 400013, India;
authors.forename: Deepa
authors.initials: D
authors.lastname: Joshi
authors.affiliation: Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093;
authors.forename: Paul S
authors.initials: PS
authors.lastname: Mischel
authors.affiliation: Human Cancer Genetics Program, Ohio State University, Columbus, OH 43210;
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.affiliation: The National Foundation for Cancer Research, Bethesda, MD 20814;
authors.forename: Yi Michael
authors.initials: YM
authors.lastname: Wang
authors.affiliation: The National Foundation for Cancer Research, Bethesda, MD 20814;
authors.forename: Sreekumar
authors.initials: S
authors.lastname: Raghavakaimal
authors.affiliation: Department of Epidemiology and Biostatistics, Department of Pathology, and Department of Gastrointestinal Surgery, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, People's Republic of China;
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Translational Oncology & Personalized Medicine, AbbVie Inc., North Chicago, IL 60064;
authors.forename: Xin
authors.initials: X
authors.lastname: Lu
authors.affiliation: Medical Sciences, Amgen Inc., Thousand Oaks, CA 91320;
authors.forename: Yang
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Applied Genomics and Bioinformatics, Bristol-Myers Squibb, Princeton, NJ 08540;
authors.forename: Han
authors.initials: H
authors.lastname: Chang
authors.affiliation: The National Foundation for Cancer Research, Bethesda, MD 20814; Asian Fund for Cancer Research, Hong Kong, People's Republic of China; and.
authors.forename: Sujuan
authors.initials: S
authors.lastname: Ba
authors.affiliation: Beijing Genomics Institute-Shenzhen, Shenzhen 518083, Guangdong, People's Republic of China; Department of Biology, University of Copenhagen, DK-1165 Copenhagen, Denmark.
authors.forename: Longhai
authors.initials: L
authors.lastname: Luo
authors.affiliation: Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093; wcavenee@ucsd.edu xishanhao@sina.com wzhang@mdanderson.org.
authors.forename: Webster K
authors.initials: WK
authors.lastname: Cavenee
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center Informatics Center, Houston, TX 77030; wcavenee@ucsd.edu xishanhao@sina.com wzhang@mdanderson.org.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Epidemiology and Biostatistics, Department of Pathology, and Department of Gastrointestinal Surgery, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, People's Republic of China; wcavenee@ucsd.edu xishanhao@sina.com wzhang@mdanderson.org.
authors.forename: Xishan
authors.initials: X
authors.lastname: Hao
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality* / Q000628:therapy; D000367:Age Factors; D044466:Asian People; D016022:Case-Control Studies; D002681:China / Q000453:epidemiology; D004252:DNA Mutational Analysis; D030561:Databases, Nucleic Acid; D018572:Disease-Free Survival; D005260:Female; D055106:Genome-Wide Association Study; D059765:Homologous Recombination; D006801:Humans; D008297:Male; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D013274:Stomach Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000628:therapy; D015996:Survival Rate
chemical_list: D009363:Neoplasm Proteins
keywords: BRCA2; ERBB; clonality; exome sequencing; mutation