Selective Analysis of Cancer-Cell Intrinsic Transcriptional Traits Defines Novel Clinically Relevant Subtypes of Colorectal Cancer

Nat Commun. 2017 May 31;8:15107. doi: 10.1038/ncomms15107.

Abstract

Stromal content heavily impacts the transcriptional classification of colorectal cancer (CRC), with clinical and biological implications. Lineage-dependent stromal transcriptional components could therefore dominate over more subtle expression traits inherent to cancer cells. Since in patient-derived xenografts (PDXs) stromal cells of the human tumour are substituted by murine counterparts, here we deploy human-specific expression profiling of CRC PDXs to assess cancer-cell intrinsic transcriptional features. Through this approach, we identify five CRC intrinsic subtypes (CRIS) endowed with distinctive molecular, functional and phenotypic peculiarities: (i) CRIS-A: mucinous, glycolytic, enriched for microsatellite instability or KRAS mutations; (ii) CRIS-B: TGF-β pathway activity, epithelial-mesenchymal transition, poor prognosis; (iii) CRIS-C: elevated EGFR signalling, sensitivity to EGFR inhibitors; (iv) CRIS-D: WNT activation, IGF2 gene overexpression and amplification; and (v) CRIS-E: Paneth cell-like phenotype, TP53 mutations. CRIS subtypes successfully categorize independent sets of primary and metastatic CRCs, with limited overlap on existing transcriptional classes and unprecedented predictive and prognostic performances.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Immunological / pharmacology
  • Cell Lineage
  • Cetuximab / pharmacology
  • Colorectal Neoplasms / classification*
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • Epithelial-Mesenchymal Transition
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / immunology
  • ErbB Receptors / metabolism
  • Female
  • Gene Expression Profiling
  • Genes, p53
  • Glycolysis
  • Heterografts
  • Humans
  • Insulin-Like Growth Factor II / genetics
  • Male
  • Mice
  • Microsatellite Instability
  • Mutation
  • Prognosis
  • Signal Transduction
  • Stromal Cells / metabolism*
  • Stromal Cells / pathology
  • Transcriptome*
  • Transforming Growth Factor beta / metabolism

Substances

  • Antineoplastic Agents, Immunological
  • IGF2 protein, human
  • Transforming Growth Factor beta
  • Insulin-Like Growth Factor II
  • ErbB Receptors
  • Cetuximab