Proteogenomic Analysis of Human Colon Cancer Reveals New Therapeutic Opportunities
Authors: Karen A Ketchum
Daniel W Chan
Mathangi Thiagarajan
Karin D Rodland
Bing Zhang
Shuang Cai
Emily S Boja
Karl R Clauser
Ken S Lau
Daniel C Liebler
Andrew Hoofnagle
Mark Watson
Ie-Ming Shih
Stephen E Stein
Sherri R Davies
Eric Kuhn
Michael A Gillette
Ronald J Moore
Peter B McGarvey
Zhen Zhang
Amanda Paulovich
Xian Chen
Douglas A Levine
Heng Zhu
Robbert J C Slebos
Tao Liu
Michael Snyder
Matthew C Chambers
Mehdi Mesri
Gordon A Whiteley
Therese R Clauss
Richard D Smith
Akhilesh Pandey
Jasmin Bavarva
Kelly Ruggles
Paul A Rudnick
Subha Madhavan
Bo Wen
Clinical Proteomic Tumor Analysis Consortium
Lisa J Zimmerman
Zhiao Shi
Sara R Savage
Yongchao Dou
Jason E McDermott
Henry Rodriguez
Philip Mertins
Chen Huang
Yingming Zhao
Hui Zhang
D R Mani
Kimberly Elburn
Tara Hiltke
Negin Vatanian
Marina A Gritsenko
Jeffrey Whiteaker
Steven J Skates
Matthew E Monroe
Qianxing Mo
Rui Zhao
Ratna R Thangudu
Christopher R Kinsinger
R Reid Townsend
David L Tabb
Li Ding
Xiaojing Wang
Yue Wang
Mauricio Oberti
Osama A Arshad
David Fenyo
Samuel H Payne
David F Ransohoff
Yun Zhang
Suhas Vasaikar
Forest M White
Steven A Carr
Melissa Borucki
Robert C Rivers
Matthew Ellis
Vladislav A Petyuk
Melinda E Sanders
Linda Hannick
Yi-Ting Wang
Nathan J Edwards
Journal: Cell (2019)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: RB1; SOX9; biomarkers; colon cancer; drug targets
Affiliations: 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., Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352, USA., Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA., Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA., Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232, USA., Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA., The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St. Louis, MO 63108, USA., 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., Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA., Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD 20892, USA., 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: ., Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: ., Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352, USA. Electronic address: ., 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: .

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. 

Retracted: No

PubPeer comments:
 There is no Figure 6F. However, the paper said it had. Although both the MSI and the Mesenchymal subtypes had higher immune infiltration than the CIN subtype, the MSI subtype was specifically enriched with cytotoxic immune cells, such as NK cells and activated CD8 T cells, whereas the Mesenchymal subtype was enriched with suppressor immune cells, such as myeloid-derived suppressor cells (MDSCs), macrophages, and Treg cells (Figure 6F). ,