The Consensus Molecular Subtypes of Colorectal Cancer

Nat Med. 2015 Nov;21(11):1350-6. doi: 10.1038/nm.3967. Epub 2015 Oct 12.

Abstract

Colorectal cancer (CRC) is a frequently lethal disease with heterogeneous outcomes and drug responses. To resolve inconsistencies among the reported gene expression-based CRC classifications and facilitate clinical translation, we formed an international consortium dedicated to large-scale data sharing and analytics across expert groups. We show marked interconnectivity between six independent classification systems coalescing into four consensus molecular subtypes (CMSs) with distinguishing features: CMS1 (microsatellite instability immune, 14%), hypermutated, microsatellite unstable and strong immune activation; CMS2 (canonical, 37%), epithelial, marked WNT and MYC signaling activation; CMS3 (metabolic, 13%), epithelial and evident metabolic dysregulation; and CMS4 (mesenchymal, 23%), prominent transforming growth factor-β activation, stromal invasion and angiogenesis. Samples with mixed features (13%) possibly represent a transition phenotype or intratumoral heterogeneity. We consider the CMS groups the most robust classification system currently available for CRC-with clear biological interpretability-and the basis for future clinical stratification and subtype-based targeted interventions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma / classification
  • Carcinoma / genetics*
  • Carcinoma / pathology
  • Colorectal Neoplasms / classification
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • Consensus
  • CpG Islands
  • DNA Copy Number Variations / genetics
  • DNA Methylation
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Genes, myc / genetics
  • Humans
  • Information Dissemination
  • Microsatellite Instability
  • Mutation / genetics
  • Neovascularization, Pathologic / genetics*
  • Neovascularization, Pathologic / pathology
  • Phenotype
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins p21(ras)
  • Transforming Growth Factor beta / genetics*
  • Wnt Signaling Pathway / genetics
  • ras Proteins / genetics

Substances

  • KRAS protein, human
  • Proto-Oncogene Proteins
  • Transforming Growth Factor beta
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins