GPCRs show widespread differential mRNA expression and frequent mutation and copy number variation in solid tumors

Abstract

G protein-coupled receptors (GPCRs) are the most widely targeted gene family for FDA-approved drugs. To assess possible roles for GPCRs in cancer, we analyzed Cancer Genome Atlas data for mRNA expression, mutations, and copy number variation (CNV) in 20 categories/45 sub-types of solid tumors and quantified differential expression of GPCRs by comparing tumors against normal tissue from the GTEx database. GPCRs are over-represented among coding genes with elevated expression in solid tumors; most tumor types differentially express >50 GPCRs, including many targets for approved drugs, hitherto largely unrecognized as targets of interest in cancer. GPCR mRNA signatures characterize specific tumor types, indicate survival and correlate with expression of cancer-related pathways. Tumor GPCR mRNA signatures have prognostic relevance for survival and correlate with expression of numerous cancer-related genes and pathways. GPCR expression in tumors is largely independent of staging/grading/metastasis/driver mutations and GPCRs expressed in cancer cell lines parallels that measured in tumors. Certain GPCRs are frequently mutated and appear to be hotspots, serving as bellwethers of accumulated genomic damage. CNV of GPCRs while common, does not generally correlate with mRNA expression. We suggest a previously under-appreciated role for GPCRs in cancer, perhaps as functional oncogenes, biomarkers, surface antigens and pharmacological targets.