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

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 The Cancer Genome Atlas (TCGA) 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. This analysis reveals that 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 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. GPCRs expressed in cancer cell lines largely parallels GPCR expression in tumors. Certain GPCRs are frequently mutated and appear to be hotspots, serving as bellwethers of accumulated genomic damage. CNV of GPCRs is common but does not generally correlate with mRNA expression. Our results suggest a previously under-appreciated role for GPCRs in cancer, perhaps as functional oncogenes, biomarkers, surface antigens and pharmacological targets. List of abbreviations/acronyms CAFs: Cancer associated fibroblasts; CCLE: Cancer Cell Line Encyclopedia; CNV/CNA: Copy number variation/ amplification; DE: Differential Expression; GPCR: G protein-coupled receptor; GTEx: Gene Tissue Expression Project [1]; GtoPdb: IUPHAR/BPS Guide to Pharmacology [2]; MDS: Multi-dimensional Scaling; Nmut: Number of genes with somatic non-silent mutations per tumor genome; OE: Overexpression; TCGA: The Cancer Genome Atlas; Table 1 lists abbreviated cancer names.

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