Distinct subtypes of gastric cancer defined by molecular characterization include novel mutational signatures with prognostic capability

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review

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Author(s)

  • Xiangchun Li
  • William K.K. Wu
  • Rui Xing
  • Sunny Hwong
  • Yuexin Liu
  • And 17 others
  • Xiaodong Fang
  • Yanlin Zhang
  • Mengyao Wang
  • Jiaqian Wang
  • Lin Li
  • Yong Zhou
  • Senwei Tang
  • Shaoliang Peng
  • Kunlong Qiu
  • Longyun Chen
  • Kexin Chen
  • Huanming Yang
  • Wei Zhang
  • Matthew T.V. Chan
  • Youyong Lu
  • Joseph J.Y. Sung
  • Jun Yu

Related Research Unit(s)

Detail(s)

Original languageEnglish
Pages (from-to)1724-1732
Journal / PublicationCancer Research
Volume76
Issue number7
Publication statusPublished - 1 Apr 2016

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.

Citation Format(s)

Distinct subtypes of gastric cancer defined by molecular characterization include novel mutational signatures with prognostic capability. / Li, Xiangchun; Wu, William K.K.; Xing, Rui; Hwong, Sunny; Liu, Yuexin; Fang, Xiaodong; Zhang, Yanlin; Wang, Mengyao; Wang, Jiaqian; Li, Lin; Zhou, Yong; Tang, Senwei; Peng, Shaoliang; Qiu, Kunlong; Chen, Longyun; Chen, Kexin; Yang, Huanming; Zhang, Wei; Chan, Matthew T.V.; Lu, Youyong; Sung, Joseph J.Y.; Yu, Jun.

In: Cancer Research, Vol. 76, No. 7, 01.04.2016, p. 1724-1732.

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review