Pan-cancer proteogenomics connects oncogenic drivers to functional states

• DOI: 10.1016/j.cell.2023.07.014
• Publication Date: 2023-08-14T14:33:35Z
• Authors: Yize Li; Eduard Porta-Pardo; Collin Tokheim; Matthew H. Bailey; Tomer M. Yaron; Vasileios Stathias; Yifat Geffen; Kathleen J. Imbach; Song Cao; Shankara Anand; Yo Akiyama; Wenke Liu; Matthew A. Wyczal...; Yizhe Song; Erik P. Storrs; Michael C. Wendl; Wubing Zhang; Mustafa Sibai; Victoria Ruiz-Serra; Wen-Wei Liang; Nadezhda V. Terek...; Fernanda Martins ...; Karl R. Clauser; David I. Heiman; Qing Zhang; Francois Aguet; Anna P. Calinawan; Saravana M. Dhana...; Chet Birger; Shankha Satpathy; Daniel Cui Zhou; Liang-Bo Wang; Jessika Baral; Jared L. Johnson; Emily M. Huntsman; Pietro Pugliese; Antonio Colaprico; Antonio Iavarone; Milan G. Chheda; Christopher J. Ri...; David Fenyö; Samuel H. Payne; Henry Rodriguez; Ana I. Robles; Michael A. Gillette; Chandan Kumar-Sinha; Alexander J. Lazar; Lewis C. Cantley; Gad Getz; Li Ding; Eunkyung An; Meenakshi Anurag; Jasmin Bavarva; Michael J. Birrer; Anna Calinawan; Michele Ceccarelli; Daniel W. Chan; Arul M. Chinnaiyan; Hanbyul Cho; Shrabanti Chowdhury; Marcin P. Cieslik; Felipe da Veiga L...; Corbin Day; Marcin J. Domagalski; Yongchao Dou; Brian J. Druker; Nathan Edwards; Matthew J. Ellis; Myvizhi Esai Selvan; Steven M. Foltz; Alicia Francis; Tania J. Gonzalez...; Sara J.C. Gosline; Zeynep H. Gümüş; Tara Hiltke; Runyu Hong; Galen Hostetter; Yingwei Hu; Chen Huang; Emily Huntsman; Eric J. Jaehnig; Scott D. Jewel; Jiayi Ji; Wen Jiang; Lizabeth Katsnelson; Karen A. Ketchum; Iga Kolodziejczak; Jonathan T. Lei; Yuxing Liao; Caleb M. Lindgren; Tao Liu; Weiping Ma; Wilson McKerrow; Alexey I. Nesvizh...; Chelsea Newton; Robert Oldroyd; Gilbert S. Omenn; Amanda G. Paulovich; Francesca Petralia; Boris Reva; Karin D. Rodland; Kelly V. Ruggles; Dmitry Rykunov; Sara R. Savage; Eric E. Schadt; Michael Schnaubelt; Tobias Schraink; Zhiao Shi; Richard D. Smith; Xiaoyu Song; Jimin Tan; Ratna R. Thangudu; Nicole Tignor; Joshua M. Wang; Pei Wang; Ying (Cindy) Wang; Bo Wen; Maciej Wiznerowicz; Xinpei Yi; Bing Zhang; Hui Zhang; Xu Zhang; Zhen Zhang
• Keywords: Proteomics; Neoplastic; CPTAC; Phosphoproteomics; DNA Copy Number Variations; Therapeutic target; ICTS (Institute of Clinical and Translational Sciences); Protein complex; Pan-cancer; 612; Oncogenes; Cell Transformation; 3. Good health; Oncogenic driver; Cell Transformation, Neoplastic; Cancer hallmark; Neoplasms; Medicine and Health Sciences; Humans; Proteogenomics

Cancer driver events refer to key genetic aberrations that drive oncogenesis; however, their exact molecular mechanisms remain insufficiently understood. Here, our multi-omics pan-cancer analysis uncovers insights into the impacts of cancer drivers by identifying their significant cis-effects and distal trans-effects quantified at the RNA, protein, and phosphoprotein levels. Salient observations include the association of point mutations and copy-number alterations with the rewiring of protein interaction networks, and notably, most cancer genes converge toward similar molecular states denoted by sequence-based kinase activity profiles. A correlation between predicted neoantigen burden and measured T cell infiltration suggests potential vulnerabilities for immunotherapies. Patterns of cancer hallmarks vary by polygenic protein abundance ranging from uniform to heterogeneous. Overall, our work demonstrates the value of comprehensive proteogenomics in understanding the functional states of oncogenic drivers and their links to cancer development, surpassing the limitations of studying individual cancer types.