Proteogenomic Analysis of Human Colon Cancer Reveals New Therapeutic Opportunities

作者：Suhas Vasaikar, Chen Huang, Xiaojing Wang, Vladislav Petyuk, Sara R. Savage, Bo Wen, Yongchao Dou, Yun Zhang, Zhiao Shi, Osama A. Arshad, Marina A. Gritsenko, Lisa J. Zimmerman, Jason McDermott, Therese RW Clauss, Ronald Moore, Rui Zhao, Matthew Monroe, Yi-Ting Wang, Matthew Chambers, Robbert J.C. Slebos, Ken S. Lau, Qianxing Mo, Li Ding, Matthew J. Ellis, Mathangi Thiagarajan, Christopher R. Kinsinger, Henry Rodriguez, Richard Smith, Karin Rodland, D.C. Liebler, Tao Liu, Bing Zhang, Akhilesh Pandey, Amanda G. Paulovich, Andrew N. Hoofnagle, D.R. Mani, Daniel W. Chan, David F. Ransohoff, David Fenyö, David L. Tabb, Douglas A. Levine, Emily S. Boja, Eric Kuhn, Forest M. White, Gordon A. Whiteley, Heng Zhu, Hui Zhang, Ie‐Ming Shih, Jasmin Bavarva, Jeffrey R. Whiteaker, Karen A. Ketchum, Karl R. Clauser, Kelly V. Ruggles, Kimberly Elburn, Linda I. Hannick, Mark A. Watson, Mauricio Oberti, Mehdi Mesri, Melinda E. Sanders, Melissa Borucki, Michael A. Gillette, M Snyder, Nathan Edwards, Negin Vatanian, Paul A. Rudnick, Peter B. McGarvey, Philip Mertins, R. Reid Townsend, Ratna R. Thangudu, Robert Rivers, Samuel Payne, Sherri R. Davies, Shuang Cai, Stephen E. Stein, Steven A. Carr, Steven J. Skates, Subha Madhavan, Tara Hiltke, Xian Chen, Yingming Zhao, Yue Wang, Zhen Zhang · 发表于：Cell · 年份：2019 · DOI：10.1016/j.cell.2019.03.030 · 被引用次数：865 · 研究领域：Cancer Genomics and Diagnostics、Cancer Research and Treatments、Colorectal Cancer Treatments and Studies

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.