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Nature DOI:10.1038/nature13438

Proteogenomic 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 AuthorsNCI CPTAC
Date Published2014 Sep 18
KeywordsChromosomes, Human, Pair 20, Colonic Neoplasms, CpG Islands, DNA Copy Number Variations, DNA Methylation, Genomics, Hepatocyte Nuclear Factor 4, Humans, Microsatellite Repeats, Mitochondrial Membrane Transport Proteins, Mutation, Missense, Neoplasm Proteins, Point Mutation, Proteome, Proteomics, Proto-Oncogene Proteins pp60(c-src), Rectal Neoplasms, RNA, Messenger, RNA, Neoplasm, Transcriptome

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.


Alternate JournalNature
PubMed ID25043054
PubMed Central IDPMC4249766
Grant ListR01 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