title: Proteogenomic characterization of human colon and rectal cancer.
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.
authors.affiliation: 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.
authors.forename: Bing
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Zhiao
authors.initials: Z
authors.lastname: Shi
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Chambers
authors.affiliation: 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.
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Zimmerman
authors.affiliation: Jim Ayers Institute for Precancer Detection and Diagnosis, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee 37232, USA.
authors.forename: Kent F
authors.initials: KF
authors.lastname: Shaddox
authors.affiliation: Directorate of Fundamental and Computational Sciences, Pacific Northwest National Laboratory, Richland, Washington 99352, USA.
authors.forename: Sangtae
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Sherri R
authors.initials: SR
authors.lastname: Davies
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, M2-B500, Seattle, Washington 98109, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Pei
authors.initials: P
authors.lastname: Wang
authors.affiliation: Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Kinsinger
authors.affiliation: Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Rivers
authors.affiliation: Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: Henry
authors.initials: H
authors.lastname: Rodriguez
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: R Reid
authors.initials: RR
authors.lastname: Townsend
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Matthew J C
authors.initials: MJ
authors.lastname: Ellis
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Maryland 02142, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Carr
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Tabb
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Coffey
authors.affiliation: 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.
authors.forename: Robbert J C
authors.initials: RJ
authors.lastname: Slebos
authors.affiliation: 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.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Liebler
mesh_terms: D002890:Chromosomes, Human, Pair 20 / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D018899:CpG Islands / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics; D019175:DNA Methylation; D023281:Genomics; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D020125:Mutation, Missense / Q000235:genetics; D009363:Neoplasm Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation / Q000235:genetics; D020543:Proteome / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics; D000090063:Proto-Oncogene Mas; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D012004:Rectal Neoplasms / Q000235:genetics* / Q000378:metabolism*; D059467:Transcriptome / Q000235:genetics*
chemical_list: C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; C000715470:MAS1 protein, human; D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D009363:Neoplasm Proteins; D020543:Proteome; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C108485:TOMM34 protein, human; D016392:Proto-Oncogene Proteins pp60(c-src)