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Title: Proteogenomic characterization of human colon and rectal cancer

Abstract

We analyzed proteomes of colon and rectal tumors previously characterized by the Cancer Genome Atlas (TCGA) and performed integrated proteogenomic analyses. Protein sequence variants encoded by somatic genomic variations displayed reduced expression compared to protein variants encoded by germline variations. mRNA transcript abundance did not reliably predict protein expression differences between tumors. Proteomics identified five protein expression subtypes, two of which were associated with the TCGA "MSI/CIMP" transcriptional subtype, but had distinct mutation and methylation patterns and associated with different clinical outcomes. Although CNAs showed strong cis- and trans-effects on mRNA expression, relatively few of these extend to the protein level. Thus, proteomics data enabled prioritization of candidate driver genes. Our analyses identified HNF4A, a novel candidate driver gene in tumors with chromosome 20q amplifications. Integrated proteogenomic analysis provides functional context to interpret genomic abnormalities and affords novel insights into cancer biology.

Authors:
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Publication Date:
Research Org.:
Pacific Northwest National Laboratory (PNNL), Richland, WA (US), Environmental Molecular Sciences Laboratory (EMSL)
Sponsoring Org.:
USDOE
OSTI Identifier:
1168928
Report Number(s):
PNNL-SA-98552
47418; KP1601010
DOE Contract Number:  
AC05-76RL01830
Resource Type:
Journal Article
Journal Name:
Nature, 513(7518):382-387
Additional Journal Information:
Journal Name: Nature, 513(7518):382-387
Country of Publication:
United States
Language:
English
Subject:
: colorectal cancer, shotgun proteomics, proteogenomics, proteomic subtypes; Environmental Molecular Sciences Laboratory

Citation Formats

Zhang, Bing, Wang, Jing, Wang, Xiaojing, Zhu, Jing, Liu, Qi, Shi, Zhiao, Chambers, Matthew C., Zimmerman, Lisa J., Shaddox, Kent F., Kim, Sangtae, Davies, Sherri, Wang, Sean, Wang, Pei, Kinsinger, Christopher, Rivers, Robert, Rodriguez, Henry, Townsend, Reid, Ellis, Matthew, Carr, Steven A., Tabb, David L., Coffey, Robert J., Slebos, Robbert, and Liebler, Daniel. Proteogenomic characterization of human colon and rectal cancer. United States: N. p., 2014. Web. doi:10.1038/nature13438.
Zhang, Bing, Wang, Jing, Wang, Xiaojing, Zhu, Jing, Liu, Qi, Shi, Zhiao, Chambers, Matthew C., Zimmerman, Lisa J., Shaddox, Kent F., Kim, Sangtae, Davies, Sherri, Wang, Sean, Wang, Pei, Kinsinger, Christopher, Rivers, Robert, Rodriguez, Henry, Townsend, Reid, Ellis, Matthew, Carr, Steven A., Tabb, David L., Coffey, Robert J., Slebos, Robbert, & Liebler, Daniel. Proteogenomic characterization of human colon and rectal cancer. United States. doi:10.1038/nature13438.
Zhang, Bing, Wang, Jing, Wang, Xiaojing, Zhu, Jing, Liu, Qi, Shi, Zhiao, Chambers, Matthew C., Zimmerman, Lisa J., Shaddox, Kent F., Kim, Sangtae, Davies, Sherri, Wang, Sean, Wang, Pei, Kinsinger, Christopher, Rivers, Robert, Rodriguez, Henry, Townsend, Reid, Ellis, Matthew, Carr, Steven A., Tabb, David L., Coffey, Robert J., Slebos, Robbert, and Liebler, Daniel. Thu . "Proteogenomic characterization of human colon and rectal cancer". United States. doi:10.1038/nature13438.
@article{osti_1168928,
title = {Proteogenomic characterization of human colon and rectal cancer},
author = {Zhang, Bing and Wang, Jing and Wang, Xiaojing and Zhu, Jing and Liu, Qi and Shi, Zhiao and Chambers, Matthew C. and Zimmerman, Lisa J. and Shaddox, Kent F. and Kim, Sangtae and Davies, Sherri and Wang, Sean and Wang, Pei and Kinsinger, Christopher and Rivers, Robert and Rodriguez, Henry and Townsend, Reid and Ellis, Matthew and Carr, Steven A. and Tabb, David L. and Coffey, Robert J. and Slebos, Robbert and Liebler, Daniel},
abstractNote = {We analyzed proteomes of colon and rectal tumors previously characterized by the Cancer Genome Atlas (TCGA) and performed integrated proteogenomic analyses. Protein sequence variants encoded by somatic genomic variations displayed reduced expression compared to protein variants encoded by germline variations. mRNA transcript abundance did not reliably predict protein expression differences between tumors. Proteomics identified five protein expression subtypes, two of which were associated with the TCGA "MSI/CIMP" transcriptional subtype, but had distinct mutation and methylation patterns and associated with different clinical outcomes. Although CNAs showed strong cis- and trans-effects on mRNA expression, relatively few of these extend to the protein level. Thus, proteomics data enabled prioritization of candidate driver genes. Our analyses identified HNF4A, a novel candidate driver gene in tumors with chromosome 20q amplifications. Integrated proteogenomic analysis provides functional context to interpret genomic abnormalities and affords novel insights into cancer biology.},
doi = {10.1038/nature13438},
journal = {Nature, 513(7518):382-387},
number = ,
volume = ,
place = {United States},
year = {2014},
month = {9}
}