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

Genome Med. 2023 Jun 21;15(1):45. doi: 10.1186/s13073-023-01193-4.

Abstract

Background: 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. Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting neurological toxicity of chemotherapies with no effective approach for prevention.

Methods: We conducted a genetic study of time-to-first peripheral neuropathy event using 30× germline WGS data from whole blood samples from 4900 European-ancestry cancer patients in 14 randomized controlled trials. A substantial number of patients in these trials received taxane and platinum-based chemotherapies as part of their treatment regimen, either standard of care or in combination with the PD-L1 inhibitor atezolizumab. The trials spanned several cancers including renal cell carcinoma, triple negative breast cancer, non-small cell lung cancer, small cell lung cancer, bladder cancer, ovarian cancer, and melanoma.

Results: We identified a locus consisting of low-frequency variants in intron 13 of GRID2 associated with time-to-onset of first peripheral neuropathy (PN) indexed by rs17020773 (p = 2.03 × 10-8, all patients, p = 6.36 × 10-9, taxane treated). Gene-level burden analysis identified rare coding variants associated with increased PN risk in the C-terminus of GPR68 (p = 1.59 × 10-6, all patients, p = 3.47 × 10-8, taxane treated), a pH-sensitive G-protein coupled receptor (GPCR). The variants driving this signal were found to alter predicted arrestin binding motifs in the C-terminus of GPR68. Analysis of snRNA-seq from human dorsal root ganglia (DRG) indicated that expression of GPR68 was highest in mechano-thermo-sensitive nociceptors.

Conclusions: Our genetic study provides insight into the impact of low-frequency and rare coding genetic variation on PN risk and suggests that further study of GPR68 in sensory neurons may yield a therapeutic hypothesis for prevention of CIPN.

Keywords: CIPN; Cancer; Chemotherapy-induced peripheral neuropathy; GPR68; GRID2; Neurological toxicity; Paclitaxel; Pharmacogenomics; Rare coding variants; Taxane; Whole genome sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents* / adverse effects
  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • Female
  • Humans
  • Lung Neoplasms* / drug therapy
  • Paclitaxel / adverse effects
  • Peripheral Nervous System Diseases* / chemically induced
  • Peripheral Nervous System Diseases* / drug therapy
  • Peripheral Nervous System Diseases* / genetics
  • Randomized Controlled Trials as Topic
  • Receptors, G-Protein-Coupled / genetics
  • Taxoids / adverse effects

Substances

  • Antineoplastic Agents
  • GPR68 protein, human
  • Paclitaxel
  • Receptors, G-Protein-Coupled
  • taxane
  • Taxoids