Publication Date:
2014-07-22
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4249766/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4249766/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 R -- Wang, Sean -- Wang, Pei -- Kinsinger, Christopher R -- Rivers, Robert C -- Rodriguez, Henry -- Townsend, R Reid -- Ellis, Matthew J C -- Carr, Steven A -- Tabb, David L -- Coffey, Robert J -- Slebos, Robbert J C -- Liebler, Daniel C -- NCI CPTAC -- GM088822/GM/NIGMS NIH HHS/ -- P30 CA068485/CA/NCI NIH HHS/ -- P30 DK058404/DK/NIDDK NIH HHS/ -- P30CA068485/CA/NCI NIH HHS/ -- P50 CA095103/CA/NCI NIH HHS/ -- P50CA095103/CA/NCI NIH HHS/ -- R01 GM088822/GM/NIGMS NIH HHS/ -- U24 CA159988/CA/NCI NIH HHS/ -- U24 CA160019/CA/NCI NIH HHS/ -- U24 CA160034/CA/NCI NIH HHS/ -- U24 CA160035/CA/NCI NIH HHS/ -- U24CA159988/CA/NCI NIH HHS/ -- U24CA160034/CA/NCI NIH HHS/ -- U24CA160035/CA/NCI NIH HHS/ -- U54 HG003079/HG/NHGRI NIH HHS/ -- UL1 TR000448/TR/NCATS NIH HHS/ -- England -- Nature. 2014 Sep 18;513(7518):382-7. doi: 10.1038/nature13438. Epub 2014 Jul 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA [2] Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA. ; Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA. ; 1] Advanced Computing Center for Research and Education, Vanderbilt University, Nashville, Tennessee 37232, USA [2] Department of Electrical Engineering and Computer Science, Vanderbilt University, Tennessee 37232, USA. ; 1] Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA [2] Jim Ayers Institute for Precancer Detection and Diagnosis, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee 37232, USA. ; Jim Ayers Institute for Precancer Detection and Diagnosis, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee 37232, USA. ; Directorate of Fundamental and Computational Sciences, Pacific Northwest National Laboratory, Richland, Washington 99352, USA. ; Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA. ; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, M2-B500, Seattle, Washington 98109, USA. ; Department of Genetics and Genomic Sciences, 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. ; Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, Maryland 20892, USA. ; Broad Institute of MIT and Harvard, Cambridge, Maryland 02142, USA. ; Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA. ; 1] Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA [2] Jim Ayers Institute for Precancer Detection and Diagnosis, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee 37232, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043054" target="_blank"〉PubMed〈/a〉
Keywords:
Chromosomes, Human, Pair 20/genetics
;
Colonic Neoplasms/*genetics/*metabolism
;
CpG Islands/genetics
;
DNA Copy Number Variations/genetics
;
DNA Methylation
;
*Genomics
;
Hepatocyte Nuclear Factor 4/genetics
;
Humans
;
Microsatellite Repeats/genetics
;
Mitochondrial Membrane Transport Proteins/genetics
;
Mutation, Missense/genetics
;
Neoplasm Proteins/analysis/genetics/metabolism
;
Point Mutation/genetics
;
Proteome/analysis/genetics/*metabolism
;
Proteomics
;
Proto-Oncogene Proteins pp60(c-src)/genetics
;
RNA, Messenger/analysis/genetics/metabolism
;
RNA, Neoplasm/analysis/genetics/metabolism
;
Rectal Neoplasms/*genetics/*metabolism
;
Transcriptome/*genetics
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
Permalink
