Abstract 1939: Discovery and proteogenomic investigation of genetic variants in human cancers

A significant fraction of cancers have a heritable component, and require an interplay between somatic and germline variants. Common and rare germline variants have been investigated by previous GWAS and family based studies. However, a comprehensive analysis of both somatic and germline variants in cancer using high throughput sequencing data to discover genetic variants of functional relevance is lacking. Herein, we investigated the potential role of somatic and germline variants from over 20 major cancer types from large-scale studies such as TCGA and ICGC and discovered thousands of somatic and germline variants in cancer genomes. To link these genetic variants to cancer phenotypes, we analyzed the proteomics data in breast, ovarian and colorectal cancers generated by the Clinical Proteomic Tumour Analysis Consortium (CPTAC) using a PepScan pipeline that can detect whether a genomic variant is observed at the peptide level. The pipeline incorporated QUILTS to construct patient-specific protein database and MS-GF+ to identify peptide sequences in the database from MS spectra. Our analysis validated roughly 2% of non-synonymous genetic variants in peptides with matched spectra. We correlated the effect of genetic mutations on proteomic subtypes based on global protein expression levels. Additionally, we assessed the role of genetic variations in kinase genes using phosphoproteome profiles, and identified downstream markers that may be candidate targets for diagnosis or treatment. This analysis also helped us prioritize kinase variants that are likely functional candidates for experimental validation. In conclusion, the comprehensive study of genetic variants utilizing an integrated proteogenomic approach revealed genetic variants with potential functional impacts in cancer. Citation Format: Kuan-lin Huang, Jaiyin Wang, Song Cao, Mingchao Xie, Reyka Jayasinghe, Jie Ning, Michael McLellan, Michael Wendl, Adam Scott, Kimberly Johnson, Sherri Davies, David Fenyo, Reid Townsend, Feng Chen, Jeffrey Parvin, Matthew Ellis, Li Ding. Discovery and proteogenomic investigation of genetic variants in human cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1939. doi:10.1158/1538-7445.AM2015-1939