Proteogenomic characterization of human colon and rectal cancer.

Nature
Authors
Keywords
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.

Year of Publication
2014
Journal
Nature
Volume
513
Issue
7518
Pages
382-7
Date Published
2014 Sep 18
ISSN
1476-4687
URL
DOI
10.1038/nature13438
PubMed ID
25043054
PubMed Central ID
PMC4249766
Links
Grant list
R01 GM088822 / GM / NIGMS NIH HHS / United States
U24 CA160034 / CA / NCI NIH HHS / United States
P50CA095103 / CA / NCI NIH HHS / United States
U24 CA159988 / CA / NCI NIH HHS / United States
P50 CA095103 / CA / NCI NIH HHS / United States
P30 DK058404 / DK / NIDDK NIH HHS / United States
U24CA159988 / CA / NCI NIH HHS / United States
GM088822 / GM / NIGMS NIH HHS / United States
P30 CA068485 / CA / NCI NIH HHS / United States
U24 CA160019 / CA / NCI NIH HHS / United States
U54 HG003079 / HG / NHGRI NIH HHS / United States
UL1 TR000448 / TR / NCATS NIH HHS / United States
U24 CA160035 / CA / NCI NIH HHS / United States
U24CA160034 / CA / NCI NIH HHS / United States
P30CA068485 / CA / NCI NIH HHS / United States
U24CA160035 / CA / NCI NIH HHS / United States