Abstract LB-232: Deep integrated proteogenomic characterization of clear cell renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC) is the predominant histology of renal cell carcinoma (RCC), representing 75% of all cases and accounting for the majority of associated deaths. Towards understanding the impact of genomic alterations on the functional modules that drive ccRCC tumorigenesis, the Clinical Proteomics Tumor Analysis Consortium (CPTAC) leveraged a proteogenomic approach to characterize 110 RCC tumors and 84 paired normal adjacent tissue (NAT) samples. Pairing state-of-the-art mass spectrometry based proteomic and phosphoproteomic strategies with comprehensive genomic and transcriptomic analyses, we integrated global and phosphoproteomic measurements with genomic and transcriptomic data to elucidate the dysregulated cellular mechanism resulting from genomic alterations. In addition to delineating chromosomal translocations involving chromosome 3p as a possible mechanism for 3p loss in ccRCC and the altered cellular pathways between tumors and NATs, we also identified several novel proteomic, phosphoproteomic, and immune ccRCC subtypes for personalized, precision-based care. Investigation of the phosphoproteome in our cohort revealed the activation of cell signaling pathways associated with ERK/MAPK, PI3K/AKT, metabolic reprogramming, and G2/M cell cycle regulation. Leveraging FDA-approved kinase inhibitors, prioritized by our phosphoproteomic results, allowed for the examination of the functional consequences of these therapies respective to mechanisms of action in ccRCC cells. Independently, the immunogenicity of ccRCC tumors prompted our exploration of the degree of immune infiltration in our cohort, wherein we identified four subtypes based on immune and stromal tumor microenvironment cell compositions: CD8+ Inflamed, CD8- Inflamed, VEGF Immune Desert, and Metabolic Immune Desert. These subtypes were further discriminated by proteomic and transcriptomic features, as well as displaying distinct predicted outcomes related to patient survival and response to targeted therapeutic intervention. We verified the protein features of these subtypes via orthogonal methodologies, including data-independent acquisition (DIA) and selective reaction monitoring (SRM) mass spectrometry, finding a high degree of correlation between the datasets. Further examination of these proteomic features in an independent cohort found the subtypes robustly identified; providing further evidence of ccRCC inter-tumor heterogeneity and rationale to stratify ccRCC patients for treatment selection. Overall, our study highlights the unique insight that can be gained when integrating multi-level “omics” analyses to broaden our understanding of ccRCC biology, as well as leading to the identification of several new hypothesis-driven investigations for therapeutic intervention in ccRCC. Citation Format: David J. Clark, Clinical Proteomic Tumor Analysis Consortium. Deep integrated proteogenomic characterization of clear cell renal cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-232.