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

Kexin Chen, Da Yang, Xiangchun Li, Baocun Sun, Fengju Song, Wenfeng Cao, Daniel J. Brat, Zhibo Gao, Haixin Li, Han Liang, Yanrui Zhao, Hong Zheng, Miao Li, Jan Buckner, Scott D. Patterson, Xiang Ye, Christoph Reinhard, Anahita Bhathena, Deepa Joshi, Paul S. MischelCarlo M. Croce, Yi Michael Wang, Sreekumar Raghavakaimal, Hui Li, Xin Lu, Yang Pan, Han Chang, Sujuan Ba, Longhai Luo, Webster K. Cavenee, Wei Zhang, Xishan Hao

Research output: Contribution to journalArticle

81 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1107-1112
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number4
DOIs
StatePublished - Jan 27 2015

Keywords

  • BRCA2
  • Clonality
  • ERBB
  • Exome sequencing
  • Mutation

ASJC Scopus subject areas

  • General

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  • Cite this

    Chen, K., Yang, D., Li, X., Sun, B., Song, F., Cao, W., Brat, D. J., Gao, Z., Li, H., Liang, H., Zhao, Y., Zheng, H., Li, M., Buckner, J., Patterson, S. D., Ye, X., Reinhard, C., Bhathena, A., Joshi, D., ... Hao, X. (2015). Mutational landscape of gastric adenocarcinoma in Chinese: Implications for prognosis and therapy. Proceedings of the National Academy of Sciences of the United States of America, 112(4), 1107-1112. https://doi.org/10.1073/pnas.1422640112