U.S. Department of Energy

Pacific Northwest National Laboratory

Proteogenomic characterization of human colon and rectal cancer.

TitleProteogenomic characterization of human colon and rectal cancer.
Publication TypeJournal Article
Year of Publication2014
AuthorsZhang B, Wang J, Wang X, Zhu J, Liu Q, Shi Z, Chambers MC, Zimmerman LJ, Shaddox KF, Kim S, Davies SR, Wang S, Wang P, Kinsinger CR, Rivers RC, Rodriguez H, R Townsend R, Ellis MJC, Carr SA, Tabb DL, Coffey RJ, Slebos RJC, Liebler DC
Corporate Authorsthe NCI CPTAC, National Cancer Institute Clinical Proteomics Tumor Analysis Consortium(NCI CPTAC), National Cancer Institute Clinical Proteomics Tumor Analysis Consortium NCI CPTAC, National Cancer Institute Clinical Proteomics Tumor Analysis Consortium NCI CPTAC
JournalNature
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.

DOI10.1038/nature13438
Alternate JournalNature
PubMed ID25043054
Area of Research: 
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