Whole genome sequencing across clinical trials identifies rare coding variants in GPR68 associated with chemotherapy induced peripheral neuropathy

Abstract Dose-limiting toxicities significantly impact the benefit/risk profile of many drugs. Whole genome sequencing (WGS) in patients receiving drugs with dose-limiting toxicities can identify therapeutic hypotheses to prevent these toxicities. Peripheral neuropathy (PN) is a common dose-limiting neurological toxicity of chemotherapies with no effective approach for prevention. We conducted a meta-analysis of time-to-PN using WGS data in 4,900 European-ancestry patients receiving chemotherapeutic agents in 14 randomized controlled trials. We identified two low frequency variants associated with PN risk: rs17020773 in intron 13 of GRID2 and rs115575220 downstream of SCG2. Rare coding variant burden analysis identified predicted gain of function variants associated with increased PN risk in the C-terminus of GPR68, a pH-sensitive G-protein coupled receptor (GPCR), that alter arrestin binding motifs. Analysis of snRNA-seq from human dorsal root ganglia indicated that expression of GPR68 was highest in mechano-thermo sensitive nociceptors. Inhibition of GPR68 signaling may provide a strategy to prevent PN in cancer patients.