Abstract 754: Pan cancer analysis of germline variants in the CPTAC dataset highlights their significance and functional importance in cancer development
Authors: Rodrigues Fernanda Martins , Terekhanova Nadezhda V. ,   Oncogenic Drivers,   Pathways Group,   Clinical Proteomic Tumor Analysis Consortium, Getz Gad , Ding Li 
Published: June 2022

Germline variants play important roles in cancer susceptibility and development, but identification and interpretation of germline variation impacting cancer risk remains a challenge. There has been little research on the impact of germline variants on somatic global/phosphoproteomics landscapes, and even less so for their impact on other tumor characteristics. Here we use cross-cancer genomic, transcriptomic, and global/phosphoproteomics datasets from CPTAC (Clinical Proteomic Tumor Analysis Consortium) to study the global impact of germline variants (common and rare) and the differential impact of germline vs somatic mutations on oncogenic processes, the tumor microenvironment (TME), and treatment responses. We analyze data from 1,093 cases across 10 cancer types (BR, CO, OV, EC, HNSCC, PDAC, LSCC, LUAD, GBM, and ccRCC). We investigate the impact of rare pathogenic variants across cancer types, discerning cancer-gene associations enriched with predisposing variants. We find novel instances of cancer-gene associations not found using TCGA data alone. Loss of heterozygosity (LOH) analyses of germline variants show that BRCA2 may be involved in predisposition not only in BRCA and OV, but also in LUAD. We also see ATM LOH events in ccRCC, CO, and LSCC. Analyses of the effects of germline vs somatic mutations on gene, protein, and phosphoprotein expression revealed significantly different protein expression levels in carriers of pathogenic germline variants vs somatic mutations, notably within core MMR-genes (MSH2, MSH6, PMS2). We examine trans-effects of germline variants on interacting proteins using proteomic/phosphoproteomic data, finding multiple trans-effects of BRCA1 pathogenic variants on the phosphoprotein expression of genes known to interact with BRCA1. Finally, we explore associations of germline and somatic causal events, noting proteomic and mutational signatures indicative of mutational processes taking place in the cell. We see direct relationships between mutations in core gene members of key DNA-damage response pathways (mismatch repair, homologous recombination repair) and the respective signatures associated with those pathways’ deficiencies. Additional analyses include: quantitative trait locus (QTL) analyses to assess the impact of common germline variants on gene (eQTL), protein (pQTL), and phosphoprotein levels (phQTL); analyses of the impact of germline variants on protein signaling during oncogenesis by mapping germline variants to post-translational modification sites); impact of germline variants on the immune landscape and tumor microenvironment (TME); and analyses of paired tumor and Normal Adjacent Tissue (NAT) samples for the discovery of immunogenic germline variants. This study illustrates the broad influence of germline variants on mutational landscapes and their functional impact on cancer.

Citation Format: Fernanda Martins Rodrigues, Nadezhda V. Terekhanova, Oncogenic Drivers, Pathways Group, Clinical Proteomic Tumor Analysis Consortium, Gad Getz, Li Ding. Pan cancer analysis of germline variants in the CPTAC dataset highlights their significance and functional importance in cancer development [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 754.