Whole-genome Sequencing Reveals Novel Tandem-Duplication Hotspots and a Prognostic Mutational Signature in Gastric Cancer

Nat Commun. 2019 May 2;10(1):2037. doi: 10.1038/s41467-019-09644-6.

Abstract

Genome-wide analysis of genomic signatures might reveal novel mechanisms for gastric cancer (GC) tumorigenesis. Here, we analysis structural variations (SVs) and mutational signatures via whole-genome sequencing of 168 GCs. Our data demonstrates diverse models of complex SVs operative in GC, which lead to high-level amplification of oncogenes. We find varying proportion of tandem-duplications (TDs) among individuals and identify 24 TD hotspots involving well-established cancer genes such as CCND1, ERBB2 and MYC. Specifically, we nominate a novel hotspot involving the super-enhancer of ZFP36L2 presents in approximately 10% GCs from different cohorts, the oncogenic role of which is further confirmed by experimental data. In addition, our data reveal a mutational signature, specifically occurring in noncoding region, significantly enriched in tumors with cadherin 1 mutations, and associated with poor prognoses. Collectively, our data suggest that TDs might serve as an important mechanism for cancer gene activation and provide a novel signature for stratification.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antigens, CD / genetics
  • Cadherins / genetics
  • Carcinogenesis / genetics
  • Cell Line, Tumor
  • Enhancer Elements, Genetic / genetics
  • Exons / genetics
  • Female
  • Gene Duplication / genetics
  • Genomic Structural Variation
  • Humans
  • Male
  • Middle Aged
  • Oncogenes / genetics*
  • Prognosis
  • Stomach / pathology
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / mortality
  • Stomach Neoplasms / pathology
  • Survival Analysis
  • Transcription Factors / genetics*
  • Transcriptome / genetics*
  • Whole Genome Sequencing

Substances

  • Antigens, CD
  • CDH1 protein, human
  • Cadherins
  • Transcription Factors
  • ZFP36L2 protein, human