| 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. ©2014 Macmillan Publishers Limited. All rights reserved. |
| Keywords: |
carrier protein; gene mutation; human cell; genetics; missense mutation; mutation, missense; cancer patient; quality control; proteome; phenotype; metabolism; proto oncogene; gene expression; neoplasm proteins; protein; colonic neoplasms; tumor xenograft; peptide; proteomics; microsatellite dna; dna methylation; rna; dna; messenger rna; rna, messenger; cpg island; cpg islands; colon cancer; colon tumor; breast tumor; amplicon; tumor protein; genomics; amino acid; tumor; point mutation; mitochondrial membrane; rectal neoplasms; rectum cancer; rectum tumor; rna, neoplasm; transcriptome; chromosome 20q; microsatellite repeats; rna sequence; dna copy number variations; proto-oncogene proteins pp60(c-src); database; copy number variation; chromosome 20; data set; chromosomes, human, pair 20; protein kinase p60; mitochondrial membrane transport proteins; cancer; humans; human; priority journal; article; hepatocyte nuclear factor 4; hnf4a protein, human; tomm34 protein, human
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