Abstract 794: Pan-cancer proteogenomic analysis reveals functional mechanisms underlying DNA repair deficiencies

Abstract Emerging classifiers that leverage recent advances in the characterization of mutational signatures have identified a broader range of cancer patients with DNA repair deficiencies, many of whom do not harbor mutations or epigenetic silencing of canonical DNA repair genes. Investigating the various mechanisms underlying dysfunctional DNA damage response (DDR) and heterogeneity across patients will be crucial to understand disparate responses to therapy, including to PARP1 inhibitors and to immunotherapy. In this study, we integrate genomic, transcriptomic, proteomic, and post-translational modification (PTM) data across 11 cancer types to elucidate the diverse functional mechanisms of DNA repair deficiencies and their therapeutic implications through an in-depth proteogenomic analysis. We first characterized the landscape of mutational signatures in 1110 patients by applying SignatureAnalyzer, a tool that uses a Bayesian non-negative matrix factorization method to discover patterns of somatic mutations. Our analysis identified 144 homologous recombination-deficient (HRD) and 60 mismatch repair-deficient (MMRD) patients. Multi-omic (mRNA, protein, PTMs) signature based hierarchical clustering revealed two distinct clusters of HRD patients defined by either (i) acute or (ii) chronic hypoxic states. The acute hypoxia cluster exhibited typical HRD phenotypes, including a preference for non-homologous end joining (NHEJ) and enrichment in PARP1 activity, as well as phosphorylation patterns driven by DNA-PKcs, ATM, and ATR. In contrast, tumors under chronic hypoxia exhibited a halting of replication and silencing of DDR, suggesting that patients with these tumors may respond poorly to common HRD treatments that exploit alternative error-prone repair and PARP1 activation. Notably, these tumors were enriched in signatures representative of highly active kinases involved in cellular stress responses, potentially providing additional avenues for therapy. Additional analysis of both HRD and MMRD tumors revealed groups of highly immunogenic DNA repair-deficient tumors that may respond well to some types of immunotherapy given their increased mutagenesis. Moreover, differences in inflammation-related kinase activities offer further insight into the interaction between faulty DDR and the innate immune response (e.g., alterations in the cGAS-STING DNA sensing pathway). Overall, our multi-omic signature analysis provides insights into the mechanisms underlying DDR and its crosstalk with other cancer-related pathways that remain unexplained by evaluating genomic and transcriptomic data alone. Our characterization of the heterogeneity within the population of patients with DNA repair deficiency shows promise for improved prediction of treatment response, as well as identifying additional potential therapeutic targets. Citation Format: Yo Akiyama, Yifat Geffen, Shankara Anand, Tomer Yaron, Jared L. Johnson, Emily Huntsman, David Heiman, Chet Birger, Karl Clauser, Özgün Babur, Mendy Miller, Karsten Krug, D R Mani, Lewis C. Cantley, Steven A. Carr, PanCancer Oncogenic Drivers and Pathways Group, Clinical Proteomic Tumor Analysis Consortium (CPTAC), Francois Aguet, Li Ding, Gad Getz. Pan-cancer proteogenomic analysis reveals functional mechanisms underlying DNA repair deficiencies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 794.