Proteogenomic Characterization of Ovarian HGSC Implicates Mitotic Kinases, Replication Stress in Observed Chromosomal Instability
Jason McDermott, Osama A. Arshad, Vladislav Petyuk, Yi Fu, Marina A. Gritsenko, Therese RW Clauss, Ronald Moore, Athena Schepmoes, Rui Zhao, Matthew Monroe, Michael Schnaubelt, Chia‐Feng Tsai, Samuel Payne, Chen Huang, Liang-Bo Wang, Steven M. Foltz, Matthew A. Wyczalkowski, Yige Wu, Ehwang Song, Molly Brewer, Mathangi Thiagarajan, Christopher R. Kinsinger, Ana I. Robles, Emily S. Boja, Henry Rodriguez, Daniel W. Chan, Bing Zhang, Zhen Zhang, Li Ding, Richard Smith, Tao Liu, Karin Rodland
Abstract
In the absence of a dominant driving mutation other than uniformly present TP53 mutations, deeper understanding of the biology driving ovarian high-grade serous cancer (HGSC) requires analysis at a functional level, including post-translational modifications. Comprehensive proteogenomic and phosphoproteomic characterization of 83 prospectively collected ovarian HGSC and appropriate normal precursor tissue samples (fallopian tube) under strict control of ischemia time reveals pathways that significantly differentiate between HGSC and relevant normal tissues in the context of homologous repair deficiency (HRD) status. In addition to confirming key features of HGSC from previous studies, including a potential survival-associated signature and histone acetylation as a marker of HRD, deep phosphoproteomics provides insights regarding the potential role of proliferation-induced replication stress in promoting the characteristic chromosomal instability of HGSC and suggests potential therapeutic targets for use in precision medicine trials.