Abstract 15: Confirmatory integrated proteogenomic characterization of clear cell renal cell carcinoma

Abstract

Abstract Clear cell renal cell carcinoma (ccRCC) is the most predominant histology of renal cell carcinoma (RCC), representing 75% of all RCC cases and accounting for the majority of associated deaths. Previously, the Clinical Proteomics Tumor Analysis Consortium (CPTAC) leveraged a proteogenomic approach to characterize a cohort of 103 ccRCC tumors and 80 paired normal adjacent tissue (NAT) samples to better understand the impact of genomic alterations on the functional modules that drive ccRCC tumorigenesis. Results of our report included delineating chromosomal translocations as a possible mechanism for 3p loss in ccRCC, detecting phospho-substrate targets for FDA-approved kinase inhibitors, and identifying four immune-based subtypes of ccRCC. In this report, we sought to verify these initial findings in an independent cohort comprised of 112 RCC tumors and 87 paired NAT samples. Leveraging data-independent acquisition mass spectrometry based proteomic strategies with comprehensive genomic and transcriptomic analyses, we integrated proteomic and phosphoproteomic analyses with genomic, epigenomic, microRNA, and transcriptomic data for tumor and NAT samples in a confirmatory cohort to elucidate the dysregulated cellular mechanism resulting from genomic alterations. We observed a high degree of concordance of genomic and transcriptomic signatures, as well as comparable tumor microenvironment cell compositions in this confirmatory cohort with our previous discovery cohort, indicating that many of the molecular characteristics defined in our first report are robustly maintained. Proteomic characterization identified protein profiles associated with disparate genomic alterations associated with ccRCC, as well as protein features specific to the four immune-based subtypes of ccRCC: CD8+ Inflamed, CD8- Inflamed, VEGF Immune Desert, and Metabolic Immune Desert. Investigation of the impact of FDA-approved kinase inhibitors, prioritized by our phosphoproteomic results, allowed for the examination of the functional consequences of these therapies respective to their mechanisms of action in ccRCC cells via the targeting of ERK/MAPK and PI3K/AKT signaling pathways, and G2/M cell cycle regulation. Finally, we explored the degree of intratumor heterogeneity of ccRCC at the genomic, transcriptomic, and proteomic levels, revealing molecular profiles that were maintained or altered in distinct regions of tumors, and further linked these molecular signatures to observed histopathological features. Overall, our study advances our understanding of functional consequences of the genomic alterations on gene and protein expression as well as subsequent cell signaling pathways related to targets for potential new therapeutic intervention, while further supporting the rationale for integrating multi-level “omics” analyses to characterize the proteogenomic landscape of ccRCC pathobiology. Citation Format: David J. Clark, Yize Li, Clinical Proteomic Tumor Analysis Consortium. Confirmatory integrated proteogenomic characterization of clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 15.