Abstract 2458: Integrated proteogenomic characterization of clear cell renal cell carcinoma
Authors: David J. Clark
Journal: Cancer Research (2019)

Abstract Clear cell renal cell carcinoma (ccRCC) is the most predominant histology of renal cancer, representing 75% of all cases and accounting for the majority of associated deaths. Towards understanding the underlying molecular alterations that can drive renal oncogenesis, The Cancer Genome Atlas (TCGA) has performed extensive genomic and transcriptomic profiling, and comparative analyses. To gain insight into the impact of genomic alterations on the functional modules that drive ccRCC tumorigenesis, we leveraged comprehensive proteogenomic characterization of 110 ccRCC tumors and 84 corresponding normal adjacent tissue (NAT) samples. Pairing state-of-the-art mass spectrometry based proteomic and phosphoproteomic strategies with the comprehensive genomic analysis, we integrated global and phosphoproteomic measurements with genomic and transcriptomic data to elucidate the dysregulated cellular mechanism resulting from genomic alterations. Arm-level loss of 3p, involving genes VHL, SETD2, BAP1 and PBRM1 is a frequent event in ccRCC and investigation of chromosomal number variations (CNV), mutations, and methylation profiles of these genes, revealed a unique pattern of BAP1 regulated proteins relative to the other 3p loci genes. Comparative protein profiling of ccRCC tumors and NATs identified pathways associated with immune response and glycolysis to be regulated in ccRCC tumors, however correlating mRNA and protein revealed a non-linear relationship in cellular processes including Warburg Effect-related metabolism and protein translation. Employing unbiased consensus clustering identified three proteomic subtypes of ccRCC, discriminated by differential abundance of proteins involved in adaptive immune response, innate immunity, ribosome activity, and metabolic processes. Further evidence of tumor heterogeneity was observed in the phosphoproteome, with phosphopeptide co-expression modeling generating phospho-signaling modules that overlapped with global protein processes (i.e. adaptive and innate immunity), as well pathways only detected at the phosphoproteomic level (i.e. Notch signaling and DNA repair). The fact that ccRCC tumors are highly immunogenic prompted us to explore the degree of immune infiltration in our cohort. We deconvoluted immune, stromal, and microenvironment cell gene signatures, identifying 60 cell types in our cohort, and three immune-based subtypes of ccRCC: Inflamed, Immune-excluded, and Immune desert. These immune subtypes displayed unique patterns of PD-1, PD-L1, and CTLA4 expression, and could be discriminated by the up-regulation of distinct protein pathways including interferon-γ, HIF1, and EMT. Our results integrated multi-level “omics” analyses to provide greater depth and expand our understanding of ccRCC biology, while identifying novel proteomic, phosphoproteomic, and immune ccRCC subtypes for personalized, precision-based care. Citation Format: David J. Clark, The CPTAC Consortium. Integrated proteogenomic characterization of clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2458.