Proteogenomic Characterization of Human Colon and Rectal Cancer

Nature. 2014 Sep 18;513(7518):382-7. doi: 10.1038/nature13438. Epub 2014 Jul 20.

Abstract

Extensive genomic characterization of human cancers presents the problem of inference from genomic abnormalities to cancer phenotypes. To address this problem, we analysed proteomes of colon and rectal tumours characterized previously by The Cancer Genome Atlas (TCGA) and perform integrated proteogenomic analyses. Somatic variants displayed reduced protein abundance compared to germline variants. Messenger RNA transcript abundance did not reliably predict protein abundance differences between tumours. Proteomics identified five proteomic subtypes in the TCGA cohort, two of which overlapped with the TCGA 'microsatellite instability/CpG island methylation phenotype' transcriptomic subtype, but had distinct mutation, methylation and protein expression patterns associated with different clinical outcomes. Although copy number alterations showed strong cis- and trans-effects on mRNA abundance, relatively few of these extend to the protein level. Thus, proteomics data enabled prioritization of candidate driver genes. The chromosome 20q amplicon was associated with the largest global changes at both mRNA and protein levels; proteomics data highlighted potential 20q candidates, including HNF4A (hepatocyte nuclear factor 4, alpha), TOMM34 (translocase of outer mitochondrial membrane 34) and SRC (SRC proto-oncogene, non-receptor tyrosine kinase). Integrated proteogenomic analysis provides functional context to interpret genomic abnormalities and affords a new paradigm for understanding cancer biology.

Publication types

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

MeSH terms

  • Chromosomes, Human, Pair 20 / genetics
  • Colonic Neoplasms / genetics*
  • Colonic Neoplasms / metabolism*
  • CpG Islands / genetics
  • DNA Copy Number Variations / genetics
  • DNA Methylation
  • Genomics*
  • Hepatocyte Nuclear Factor 4 / genetics
  • Humans
  • Microsatellite Repeats / genetics
  • Mitochondrial Membrane Transport Proteins / genetics
  • Mutation, Missense / genetics
  • Neoplasm Proteins / analysis
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Point Mutation / genetics
  • Proteome / analysis
  • Proteome / genetics
  • Proteome / metabolism*
  • Proteomics
  • Proto-Oncogene Proteins pp60(c-src) / genetics
  • RNA, Messenger / analysis
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Neoplasm / analysis
  • RNA, Neoplasm / genetics
  • RNA, Neoplasm / metabolism
  • Rectal Neoplasms / genetics*
  • Rectal Neoplasms / metabolism*
  • Transcriptome / genetics*

Substances

  • HNF4A protein, human
  • Hepatocyte Nuclear Factor 4
  • Mitochondrial Membrane Transport Proteins
  • Neoplasm Proteins
  • Proteome
  • RNA, Messenger
  • RNA, Neoplasm
  • TOMM34 protein, human
  • Proto-Oncogene Proteins pp60(c-src)