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.

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Acknowledgements

This work was supported by National Cancer Institute (NCI) CPTAC awards U24CA159988, U24CA160035, and U24CA160034; by NCI SPORE award P50CA095103 and NCI Cancer Center Support Grant P30CA068485; by National Institutes of Health grant GM088822; and by contract 13XS029 from Leidos Biomedical Research, Inc. Genomics data for this study were generated by The Cancer Genome Atlas pilot project established by the NCI and the National Human Genome Research Institute. Information about TCGA and the investigators and institutions comprising the TCGA research network can be found at http://cancergenome.nih.gov/.

Author information

Affiliations

  1. Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA

    • Bing Zhang
    • , Jing Wang
    • , Xiaojing Wang
    • , Jing Zhu
    • , Qi Liu
    • , Matthew C. Chambers
    •  & David L. Tabb
  2. Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA

    • Bing Zhang
    •  & Robbert J. C. Slebos
  3. Advanced Computing Center for Research and Education, Vanderbilt University, Nashville, Tennessee 37232, USA

    • Zhiao Shi
  4. Department of Electrical Engineering and Computer Science, Vanderbilt University, Tennessee 37232, USA

    • Zhiao Shi
  5. Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA

    • Lisa J. Zimmerman
    •  & Daniel C. Liebler
  6. Jim Ayers Institute for Precancer Detection and Diagnosis, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee 37232, USA

    • Lisa J. Zimmerman
    • , Kent F. Shaddox
    • , Robbert J. C. Slebos
    •  & Daniel C. Liebler
  7. Directorate of Fundamental and Computational Sciences, Pacific Northwest National Laboratory, Richland, Washington 99352, USA

    • Sangtae Kim
  8. Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA

    • Sherri R. Davies
    • , R. Reid Townsend
    •  & Matthew J. C. Ellis
  9. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, M2-B500, Seattle, Washington 98109, USA

    • Sean Wang
  10. 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

    • Pei Wang
  11. Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, Maryland 20892, USA

    • Christopher R. Kinsinger
    • , Robert C. Rivers
    •  & Henry Rodriguez
  12. Broad Institute of MIT and Harvard, Cambridge, Maryland 02142, USA

    • Steven A. Carr
  13. Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA

    • Robert J. Coffey
  14. The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Massachusetts 02142, USA.

    • Steven A. Carr
    • , Michael A. Gillette
    • , Karl R. Klauser
    • , Eric Kuhn
    • , D. R. Mani
    •  & Philipp Mertins
  15. Enterprise Science and Computing, Inc., 155 Gibbs St, Suite 420, Rockville, Maryland 20850, USA.

    • Karen A. Ketchum
  16. Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Eastlake Avenue East, Seattle, Washington 98109, USA.

    • Amanda G. Paulovich
    •  & Jeffrey R. Whiteaker
  17. Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, 3900 Reservoir Rd NW, Washington, DC 20057, USA.

    • Nathan J. Edwards
    •  & Peter B. McGarvey
  18. Innovation Center for Biomedical Informatics, Georgetown University Medical Center, 2115 Wisconsin Ave NW, Suite 110, Washington, DC 20057, USA.

    • Subha Madhavan
  19. Icahn Institute and Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, Hess CSM Building, Room S8-102, 1470 Madison Avenue, New York, New York 10029, USA.

    • Pei Wang
  20. Department of Pathology, The Johns Hopkins University, 600 North Wolfe Street, Baltimore, Maryland 21287, USA.

    • Daniel Chan
    • , Akhilesh Pandey
    • , Ie-Ming Shih
    • , Hui Zhang
    •  & Zhen Zhang
  21. Department of Pharmacology and Molecular Science, the Johns Hopkins University, 733 N. Broadway, Baltimore, Maryland 21287, USA.

    • Heng Zhu
  22. Antibody Characterization Laboratory, Advanced Technology Program, Leidos, Inc., 1050 Boyles Street, Frederick, Maryland 21701, USA.

    • Gordon A. Whiteley
  23. Biostatistics Center, Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, Massachusetts 02114, USA.

    • Steven J. Skates
  24. Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.

    • Forest M. White
  25. Gynecology Service/Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.

    • Douglas A. Levine
  26. Office of Cancer Clinical Proteomics Research, National Cancer Institute, 31 Center Drive, MS 2580 Bethesda, Maryland 20892, USA.

    • Emily S. Boja
    • , Christopher R. Kinsinger
    • , Tara Hiltke
    • , Mehdi Mesri
    • , Robert C. Rivers
    • , Henry Rodriguez
    •  & Kenna M. Shaw
  27. Biomolecular Measurement Division, Material Measurement Laboratory, National Institute of Standards and Technology, 100 Bureau Drive, M/S 8300, Gaithersburg, Maryland 20899, USA.

    • Stephen E. Stein
  28. Department of Biochemistry and Molecular Pharmacology, Smilow Research Building, Room 201, 522 First Avenue, New York University Langone Medical Center, New York, New York 10016, USA.

    • David Fenyo
  29. Biological Sciences Division, Pacific Northwest National Laboratory, 902 Battelle Boulevard, Richland, Washington 99352, USA.

    • Tao Liu
    • , Jason E. McDermott
    • , Samuel H. Payne
    • , Karin D. Rodland
    •  & Richard D. Smith
  30. Spectragen-Informatics, Rockville, Maryland 20850, USA.

    • Paul Rudnick
  31. Department of Genetics, Stanford University, Stanford, California 94305, USA.

    • Michael Snyder
  32. The Ben May Department for Cancer Research, University of Chicago, 929 East 57th Street, W421 Chicago, Illinois 60637, USA.

    • Yingming Zhao
  33. University of North Carolina at Chapel Hill, 130 Mason Farm Road, Chapel Hill, North Carolina 27599, USA.

    • Xian Chen
    •  & David F. Ransohoff
  34. Department of Lab Medicine, University of Washington, Campus Box 357110, Seattle, Washington 98195, USA.

    • Andrew N. Hoofnagle
  35. Vanderbilt University School of Medicine, 1161 21st Avenue South, Nashville, Tennessee 37232, USA.

    • Daniel C. Liebler
    • , Melinda E. Sanders
    • , Zhiao Shi
    • , Robbert J. C. Slebos
    • , David L. Tabb
    • , Bing Zhang
    •  & Lisa J. Zimmerman
  36. Bradley Department of Electrical and Computer Engineering, Virginia Tech, 900 N. Glebe Road, Arlington, Virginia 22203, USA.

    • Yue Wang
  37. Department of Medicine, Washington University in St. Louis, 660 S. Euclid Avenue, St. Louis, Missouri 063110, USA.

    • Sherri R. Davies
    • , Li Ding
    • , Matthew J. C. Ellis
    •  & R. Reid Townsend

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    National Cancer Institute Clinical Proteomics Tumor Analysis Consortium (NCI CPTAC)

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Contributions

B.Z., R.J.C.S., D.L.T., L.J.Z. and D.C.L. designed the proteomic analysis experiments, data analysis workflow, and proteomic–genomic data comparisons. K.F.S., L.J.Z., R.J.C.S. and D.C.L. directed and performed proteomic analysis of colon tumour and quality control samples. J.W., X.W., J.Z., Q.L., Z.S., P.W., S.W., R.J.C.S. and B.Z. performed proteomic-genomic data analyses. M.C.C., S.K., R.J.C.S. and D.L.T. performed analyses of mass spectrometry data and adapted algorithms and software for data analysis. S.R.D., R.R.T. and M.J.C.E. developed and prepared breast xenografts used as quality control samples. S.A.C., K.F.S. and D.C.L. designed strategy for quality control analyses. R.J.C.S., C.R.K, R.C.R. and H.R. coordinated acquisition, distribution and quality control evaluation of TCGA tumor samples. B.Z., J.W., R.J.C.S., R.J.C. and D.C.L. interpreted data in context of colon cancer biology. B.Z., R.J.C.S. and D.C.L. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Daniel C. Liebler.

All of the primary mass spectrometry data on TCGA tumour samples are deposited at the CPTAC Data Coordinating Center as raw and mzML files for public access (https://cptac-data-portal.georgetown.edu).

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