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Cell. 2019 May 2;177(4):1035-1049.e19. doi: 10.1016/j.cell.2019.03.030. Epub 2019 Apr 25.

Proteogenomic Analysis of Human Colon Cancer Reveals New Therapeutic Opportunities.

Author information

1
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
2
Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352, USA.
3
Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
4
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.
5
Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA.
6
Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232, USA.
7
Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
8
The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St. Louis, MO 63108, USA.
9
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
10
Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
11
Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD 20892, USA.
12
Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352, USA; Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, OR 97221, USA. Electronic address: karin.rodland@pnnl.gov.
13
Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: daniel.liebler@vanderbilt.edu.
14
Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352, USA. Electronic address: tao.liu@pnnl.gov.
15
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: bing.zhang@bcm.edu.

Abstract

We performed the first proteogenomic study on a prospectively collected colon cancer cohort. Comparative proteomic and phosphoproteomic analysis of paired tumor and normal adjacent tissues produced a catalog of colon cancer-associated proteins and phosphosites, including known and putative new biomarkers, drug targets, and cancer/testis antigens. Proteogenomic integration not only prioritized genomically inferred targets, such as copy-number drivers and mutation-derived neoantigens, but also yielded novel findings. Phosphoproteomics data associated Rb phosphorylation with increased proliferation and decreased apoptosis in colon cancer, which explains why this classical tumor suppressor is amplified in colon tumors and suggests a rationale for targeting Rb phosphorylation in colon cancer. Proteomics identified an association between decreased CD8 T cell infiltration and increased glycolysis in microsatellite instability-high (MSI-H) tumors, suggesting glycolysis as a potential target to overcome the resistance of MSI-H tumors to immune checkpoint blockade. Proteogenomics presents new avenues for biological discoveries and therapeutic development.

KEYWORDS:

RB1; SOX9; biomarkers; colon cancer; drug targets; glycolysis; immune evasion; proteogenomics; proteomics; tumor antigen

PMID:
31031003
DOI:
10.1016/j.cell.2019.03.030
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