Proteogenomic characterization of human colon and rectal cancer

Bing Zhang, Jing Wang, Xiaojing Wang, Jing Zhu, Qi Liu, Zhiao Shi, Matthew C. Chambers, Lisa J. Zimmerman, Kent F. Shaddox, Sangtae Kim, Sherri R. Davies, Sean Wang, Pei Wang, Christopher R. Kinsinger, Robert C. Rivers, Henry Rodriguez, R. Reid Townsend, Matthew J. C. Ellis, Steven A. Carr, David L. Tabb, Robert J. Coffey, Robbert J. C. Slebos and Daniel C. Liebler ()
Additional contact information
Bing Zhang: Vanderbilt University School of Medicine
Jing Wang: Vanderbilt University School of Medicine
Xiaojing Wang: Vanderbilt University School of Medicine
Jing Zhu: Vanderbilt University School of Medicine
Qi Liu: Vanderbilt University School of Medicine
Zhiao Shi: Advanced Computing Center for Research and Education, Vanderbilt University
Matthew C. Chambers: Vanderbilt University School of Medicine
Lisa J. Zimmerman: Vanderbilt University School of Medicine
Kent F. Shaddox: Jim Ayers Institute for Precancer Detection and Diagnosis, Vanderbilt-Ingram Cancer Center
Sangtae Kim: Directorate of Fundamental and Computational Sciences, Pacific Northwest National Laboratory
Sherri R. Davies: Washington University School of Medicine
Sean Wang: Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, M2-B500, Seattle, Washington 98109, USA
Pei Wang: Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1498, New York, New York 10029, USA
Christopher R. Kinsinger: Office of Cancer Clinical Proteomics Research, National Cancer Institute
Robert C. Rivers: Office of Cancer Clinical Proteomics Research, National Cancer Institute
Henry Rodriguez: Office of Cancer Clinical Proteomics Research, National Cancer Institute
R. Reid Townsend: Washington University School of Medicine
Matthew J. C. Ellis: Washington University School of Medicine
Steven A. Carr: Broad Institute of MIT and Harvard
David L. Tabb: Vanderbilt University School of Medicine
Robert J. Coffey: Vanderbilt University School of Medicine
Robbert J. C. Slebos: Vanderbilt University School of Medicine
Daniel C. Liebler: Vanderbilt University School of Medicine

Nature, 2014, vol. 513, issue 7518, 382-387

Abstract: 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.

Date: 2014
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DOI: 10.1038/nature13438

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