Journal Article

Proteogenomic characterization of human colon and rectal cancer

Coffey, Robert J., Zhang, Bing, Shaddox, Kent F., Liebler, Daniel C., Zimmerman, Lisa J., Rivers, Robert C., Davies, Sherri R., Rodriguez, Henry, Shi, Zhiao, Tabb, David L., Wang, Jing, Zhu, Jing, Liu, Qi, Wang, Sean, Ellis, Matthew J. C., Carr, Steven A., Slebos, Robbert J. C., Townsend, R. Reid, Wang, Xiaojing, Wang, Pei, Kim, Sangtae, Chambers, Matthew C., Kinsinger, Christopher R.

2014

Overview

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. Proteome analysis of The Cancer Genome Atlas (TCGA) colorectal cancer specimens reveals that DNA- or RNA-level measurements cannot reliably predict protein abundance, colorectal tumours can be separated into distinct proteotypes, and that copy number alterations drive mRNA abundance changes but few extend to protein-level changes. Proteomics/genomics of colorectal tumours A team from the Clinical Proteomics Tumor Analysis Consortium has now analysed the proteomes of 95 colon and rectal tumours previously characterized by the Cancer Genome Atlas project. Integration of the proteomics with the original genomic data demonstrates that protein abundance cannot be reliably predicted from DNA- or RNA-level measurements, and that mRNA and protein levels are modestly correlated. Proteomics identified five colorectal cancer subtypes that reflect known biological characteristics, yet capture differences that are not evident at the transcriptome level. Integrated proteogenomic analysis of this type can provide functional context to interpret genomic abnormalities in terms of cancer biology.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/1647/2067 / 631/208/69 / 692/699/67/1504/1885/1393 / 82/58 / Analysis / Cancer / Care and treatment / Chemical properties / Chromosomes, Human, Pair 20 - genetics / Colon / Colon cancer / Colonic Neoplasms - genetics / Colonic Neoplasms - metabolism / Colorectal cancer / Comparative analysis / CpG Islands - genetics / DNA Copy Number Variations - genetics / DNA Methylation / Genes / Genetic aspects / Genomics / Hepatocyte Nuclear Factor 4 - genetics / Humanities and Social Sciences / Humans / Mass spectrometry / Methylation / Microsatellite Repeats - genetics / Mitochondrial Membrane Transport Proteins - genetics / multidisciplinary / Mutation, Missense - genetics / Neoplasm Proteins - analysis / Neoplasm Proteins - genetics / Neoplasm Proteins - metabolism / Peptides / Point Mutation - genetics / Proteins / Proteome - analysis / Proteome - genetics / Proteome - metabolism / Proteomics / Proto-Oncogene Proteins pp60(c-src) - genetics / Rectal Neoplasms - genetics / Rectal Neoplasms - metabolism / RNA / RNA, Messenger - analysis / RNA, Messenger - genetics / RNA, Messenger - metabolism / RNA, Neoplasm - analysis / RNA, Neoplasm - genetics / RNA, Neoplasm - metabolism / Science / Transcriptome - genetics / Tumors