Mutational landscape of gastric adenocarcinoma in Chinese: Implications for prognosis and therapy

• Type of Material: Article
• Authors: Kexin Chen, Tianjin Medical University; Da Yang, University of Texas MD Anderson Cancer Center; Xiangchun Li, Beijing Genomics Institute-Shenzhen; Baocun Sun, Tianjin Medical University; Fengju Song, Tianjin Medical University; Wenfeng Cao, Tianjin Medical University; Daniel Brat, Emory University; Zhibo Gao, Beijing Genomics Institute-Shenzhen; Haixin Li, Tianjin Medical University; Han Liang, Tianjin Medical University
• Language: English
• Date: 2015-01-27
• Publisher: National Academy of Sciences
• Publication Version: Final Published Version
• Copyright Statement: 2015bNational Academy of Sciences
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1422640112
• Title of Journal or Parent Work: Proceedings of the National Academy of Sciences
• Volume: 112
• Issue: 4
• Start Page: 1107
• End Page: 1112
• Grant/Funding Information: This research was funded by the grants from The National Foundation for Cancer Research and the Asian Fund for Cancer Research.
• Keywords: Multidisciplinary Sciences; exome sequencing; Science & Technology; clonality; SENSITIVITY; SUBTYPE; mutation; Science & Technology - Other Topics; GENOME; BRCA2; CANCER; IDENTIFY; ERBB
• Research Categories: Health Sciences, Pathology; Health Sciences, Epidemiology; Health Sciences, Oncology

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.