Comparative Molecular Analysis of Gastrointestinal Adenocarcinomas

Cancer Cell. 2018 Apr 9;33(4):721-735.e8. doi: 10.1016/j.ccell.2018.03.010. Epub 2018 Apr 2.

Abstract

We analyzed 921 adenocarcinomas of the esophagus, stomach, colon, and rectum to examine shared and distinguishing molecular characteristics of gastrointestinal tract adenocarcinomas (GIACs). Hypermutated tumors were distinct regardless of cancer type and comprised those enriched for insertions/deletions, representing microsatellite instability cases with epigenetic silencing of MLH1 in the context of CpG island methylator phenotype, plus tumors with elevated single-nucleotide variants associated with mutations in POLE. Tumors with chromosomal instability were diverse, with gastroesophageal adenocarcinomas harboring fragmented genomes associated with genomic doubling and distinct mutational signatures. We identified a group of tumors in the colon and rectum lacking hypermutation and aneuploidy termed genome stable and enriched in DNA hypermethylation and mutations in KRAS, SOX9, and PCBP1.

Keywords: cancer; colon; colorectal; epigenetic; esophagus; genomic; methylation; rectum; stomach; tumor.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenocarcinoma / classification
  • Adenocarcinoma / genetics*
  • Aneuploidy
  • Chromosomal Instability*
  • DNA Methylation*
  • DNA Polymerase II / genetics*
  • DNA-Binding Proteins
  • Epigenesis, Genetic
  • Female
  • Gastrointestinal Neoplasms / classification
  • Gastrointestinal Neoplasms / genetics*
  • Gene Regulatory Networks
  • Heterogeneous-Nuclear Ribonucleoproteins / genetics
  • Humans
  • Male
  • Microsatellite Instability
  • MutL Protein Homolog 1 / genetics*
  • Mutation
  • Poly-ADP-Ribose Binding Proteins / genetics*
  • Polymorphism, Single Nucleotide
  • Proto-Oncogene Proteins p21(ras) / genetics
  • RNA-Binding Proteins
  • SOX9 Transcription Factor / genetics

Substances

  • DNA-Binding Proteins
  • Heterogeneous-Nuclear Ribonucleoproteins
  • KRAS protein, human
  • MLH1 protein, human
  • PCBP1 protein, human
  • Poly-ADP-Ribose Binding Proteins
  • RNA-Binding Proteins
  • SOX9 Transcription Factor
  • SOX9 protein, human
  • DNA Polymerase II
  • POLE protein, human
  • MutL Protein Homolog 1
  • Proto-Oncogene Proteins p21(ras)