Abstract 3293: Solid tumors have frequent mutation, copy number variation and differential mRNA expression of GPCRs: Are such GPCRs functional oncogenes

Abstract

G protein-coupled receptors (GPCRs), the largest family of membrane receptors, regulate numerous cellular functions and are drug targets for many disorders but not generally in cancer. We analyzed The Cancer Genome Atlas (TCGA) for GPCR mutations, copy number variation (CNV) and mRNA expression in 20 categories of solid tumors. We found that numerous GPCRs are frequently mutated, in particular, certain adhesion GPCRs (e.g.,GPR98 and GPR112), which appear to have a higher density of mutation events than other genes of similar length. Tumors with high mutational burden show a high frequency of such GPCR mutations that may result from DNA damage. CNV (especially amplifications and single-copy deletions) of GPCRs is widespread. In certain tumor types, particular GPCRs (e. g., GPR160) show high-level amplification in >30% of tumors. However, CNV does not appear to be a major factor in determining differential expression (DE) of GPCRs in tumors. Compared to RNA expression in normal tissues (GTEX database), most solid tumor types (including those accounting for the most annual deaths) differentially express >50 GPCRs, including 77 GPCRs with increased expression in at least one tumor type that are targets for approved drugs, providing opportunities for drug repurposing. DE of GPCRs is largely independent of tumor stage/grade, largely insensitive to specific driver mutations, and similar in primary and metastatic tumors, which both have high expression of numerous GPCRs in nearly all members within tumor populations. Cancer cells highly express most GPCRs overexpressed in tumors, making such GPCRs (especially those that are druggable) attractive candidates for further validation and functional studies. Multiple published studies provide functional data for certain such GPCRs. These findings imply a previously unappreciated role for GPCRs in solid tumors. Overexpressed GPCRs in tumors may regulate tumor biology as “functional oncogenes” and are potentially novel biomarkers and therapeutic targets, including for approved drugs. Citation Format: Krishna Sriram, Kevin Moyung, Ross Corriden, Paul Insel. Solid tumors have frequent mutation, copy number variation and differential mRNA expression of GPCRs: Are such GPCRs functional oncogenes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3293.