Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes

Nat Med. 2015 May;21(5):449-56. doi: 10.1038/nm.3850. Epub 2015 Apr 20.

Abstract

Gastric cancer, a leading cause of cancer-related deaths, is a heterogeneous disease. We aim to establish clinically relevant molecular subtypes that would encompass this heterogeneity and provide useful clinical information. We use gene expression data to describe four molecular subtypes linked to distinct patterns of molecular alterations, disease progression and prognosis. The mesenchymal-like type includes diffuse-subtype tumors with the worst prognosis, the tendency to occur at an earlier age and the highest recurrence frequency (63%) of the four subtypes. Microsatellite-unstable tumors are hyper-mutated intestinal-subtype tumors occurring in the antrum; these have the best overall prognosis and the lowest frequency of recurrence (22%) of the four subtypes. The tumor protein 53 (TP53)-active and TP53-inactive types include patients with intermediate prognosis and recurrence rates (with respect to the other two subtypes), with the TP53-active group showing better prognosis. We describe key molecular alterations in each of the four subtypes using targeted sequencing and genome-wide copy number microarrays. We validate these subtypes in independent cohorts in order to provide a consistent and unified framework for further clinical and preclinical translational research.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Cohort Studies
  • Disease Progression
  • Epithelial-Mesenchymal Transition
  • Female
  • Gene Dosage
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Helicobacter pylori / genetics
  • Humans
  • Male
  • Microsatellite Repeats / genetics
  • Middle Aged
  • Mutation
  • Oligonucleotide Array Sequence Analysis
  • Principal Component Analysis
  • Prognosis
  • Proportional Hazards Models
  • Recurrence
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / therapy
  • Tissue Array Analysis
  • Translational Medical Research
  • Treatment Outcome
  • Tumor Suppressor Protein p53 / genetics

Substances

  • TP53 protein, human
  • Tumor Suppressor Protein p53

Associated data

  • GEO/GSE62254
  • GEO/GSE62717