Proteogenomic characterization of human colon and rectal cancer

Item Type:	Article
Title:	Proteogenomic characterization of human colon and rectal cancer
Creators Name:	Zhang, B. and Wang, J. and Wang, X. and Zhu, J. and Liu, Q. and Shi, Z. and Chambers, M.C. and Zimmerman, L.J. and Shaddox, K.F. and Kim, S. and Davies, S.R. and Wang, S. and Wang, P. and Kinsinger, C.R. and Rivers, R.C. and Rodriguez, H. and Townsend, R.R. and Ellis, M.J.C. and Carr, S.A. and Tabb, D.L. and Coffey, R.J. and Slebos, R.J.C. and Liebler, D.C.
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.
Keywords:	Colonic Neoplasms, CpG Islands, DNA Copy Number Variations, DNA Methylation, Genomics, Hepatocyte Nuclear Factor 4, Messenger RNA, Microsatellite Repeats, Missense Mutation, Mitochondrial Membrane Transport Proteins, Mitochondrial Precursor Protein Import Complex Proteins, Neoplasm Proteins, Neoplasm RNA, Pair 20 Human Chromosomes, Point Mutation, Proteome, Proteomics, Proto-Oncogene Mas, Proto-Oncogene Proteins pp60(c-src), Rectal Neoplasms, Transcriptome
Source:	Nature
ISSN:	0028-0836
Publisher:	Nature Publishing Group
Volume:	513
Number:	7518
Page Range:	382-387
Date:	18 September 2014
Additional Information:	Philipp Mertins is a member of the National Cancer Institute Clinical Proteomics Tumor Analysis Consortium (NCI CPTAC).
Official Publication:	https://doi.org/10.1038/nature13438
PubMed:	View item in PubMed

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