Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer

Kai Wang, Siu Tsan Yuen, Jiangchun Xu, Siu Po Lee, Helen H N Yan, Stephanie T Shi, Hoi Cheong Siu, Shibing Deng, Kent Man Chu, Simon Law, Kok Hoe Chan, Annie S Y Chan, Wai Yin Tsui, Siu Lun Ho, Anthony K W Chan, Jonathan L K Man, Valentina Foglizzo, Man Kin Ng, April S Chan, Yick Pang ChingGrace H W Cheng, Tao Xie, Julio Fernandez, Vivian S W Li, Hans Clevers, Paul A Rejto, Mao Mao, Suet Yi Leung

Research output: Contribution to journal/periodicalArticleScientificpeer-review

Abstract

Gastric cancer is a heterogeneous disease with diverse molecular and histological subtypes. We performed whole-genome sequencing in 100 tumor-normal pairs, along with DNA copy number, gene expression and methylation profiling, for integrative genomic analysis. We found subtype-specific genetic and epigenetic perturbations and unique mutational signatures. We identified previously known (TP53, ARID1A and CDH1) and new (MUC6, CTNNA2, GLI3, RNF43 and others) significantly mutated driver genes. Specifically, we found RHOA mutations in 14.3% of diffuse-type tumors but not in intestinal-type tumors (P < 0.001). The mutations clustered in recurrent hotspots affecting functional domains and caused defective RHOA signaling, promoting escape from anoikis in organoid cultures. The top perturbed pathways in gastric cancer included adherens junction and focal adhesion, in which RHOA and other mutated genes we identified participate as key players. These findings illustrate a multidimensional and comprehensive genomic landscape that highlights the molecular complexity of gastric cancer and provides a road map to facilitate genome-guided personalized therapy.

Original languageEnglish
Pages (from-to)573-82
Number of pages10
JournalNature Genetics
Volume46
Issue number6
DOIs
Publication statusPublished - Jun 2014

Keywords

  • Adherens Junctions
  • Algorithms
  • Animals
  • DNA Methylation
  • DNA Mutational Analysis
  • Epigenesis, Genetic
  • Female
  • Gene Dosage
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Genetic Variation
  • Genome, Human
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Oligonucleotide Array Sequence Analysis
  • Stomach Neoplasms
  • rhoA GTP-Binding Protein

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