Abstract 2262: Comprehensive characterization of cancer drivers and therapeutic targets

Abstract

Abstract Cancer is a family of diseases caused primarily by genetic “driver” mutations. Building upon a large-scale Pan-cancer study of ours, we expand our investigation to the proteogenomic level (including global proteome and phosphoproteome data) drawing >1,000 cases over 10 cancer types (BR, ccRCC, CO, EC, GBM, HNSCC, LSCC, LUAD, OV, PDAC) from the Clinical Proteomic Tumor Analysis Consortium (CPTAC). We concentrate on 6 aspects of drivers: (1) We identify genomic & epigenomic drivers (mutations, SVs, CNVs, fusions, etc.), estimate their frequencies, and investigate their exclusivities & co-occurrences. (2) We investigate the proteogenomic impact of drivers, especially recurrent ones, e.g. cis/trans effects, on miRNA, RNA, and protein expression. (3) We investigate their impact on Post Transcriptional Modifications (PTMs), comparing levels of protein and PTM, e.g. for one- and two-hit events. For example, we found upregulation of PTPN11 phosphorylation sites in EGFR-altered LUAD, GBM, and HNSCC samples, suggesting a pan-cancer effect, and observed high NRF2 phosphorylation and activation of antioxidant pathways in KEAP1 or NRF2-altered samples in lung cancer (LSCC and LUAD); (4) We compare tumors and normal adjacent tissues (NATs) to identify key protein level changes and regulations for oncogenic pathways and further examine cell type composition, proteomic variation, and association with driver mutations. For instance, we found VHL mutations often signify enrichment of endothelial cells. (5) We capture potential Significant Protein Drivers (SPRDs), independent of DNA level changes, to uncover hidden drivers in cause-ambiguous tumors. (6) We examine actionable driver alterations and expression changes across proteogenomic levels and associations with immune infiltration and immunogenic peptides to understand targeting, therapeutic implications and, influence on tumor micro-environment. We comment upon the clinical utility of comprehensive proteogenomics, especially in cases where a strictly genomic assessment is inconclusive. Proteomics can further prioritize gene targets with additional layers of evidence for differential expression among features such as cell-type composition, anatomical location, disease stage, and immune infiltration. Our approach has the potential for identifying cancer-type-specific and non-specific novel druggable targets, which would provide new biological and clinical insights into cancer. Citation Format: Yize Li, Oncogenic Drivers and Pathways GroupClinical Proteomic Tumor Analysis Consortium. Comprehensive characterization of cancer drivers and therapeutic targets [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 2262.