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Updated: Jul 26, 2025
Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
Whole genome sequencing across clinical trials identifies rare coding variants in GPR68 associated with
Zia Khan1, Min Jung2, Megan Crow2
1Genentech, 1 DNA Way, South San Francisco, 94080, USA. khanz12@gene.com.
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.
Insights
Genetic analysis of 4900 cancer patients reveals novel variants in GRID2 and GPR68 associated with chemotherapy-induced peripheral neuropathy (CIPN). This discovery opens new avenues for preventing this common, dose-limiting toxicity.
Area of Science:
- Genomics
- Pharmacogenomics
- Neuroscience
Background:
- Dose-limiting toxicities significantly affect drug benefit/risk.
- Chemotherapy-induced peripheral neuropathy (CIPN) is a common, dose-limiting neurological toxicity.
- Effective prevention strategies for CIPN are lacking.
Purpose of the Study:
- To identify genetic variants associated with the risk of developing CIPN.
- To explore therapeutic hypotheses for preventing CIPN using whole genome sequencing (WGS).
Main Methods:
- Conducted a genetic study using germline WGS data from 4900 European-ancestry cancer patients across 14 randomized controlled trials.
- Analyzed time-to-first peripheral neuropathy event in patients receiving taxane and platinum-based chemotherapies.
- Performed gene-level burden analysis and analyzed snRNA-seq data from human dorsal root ganglia.
Main Results:
- Identified a locus with low-frequency variants in GRID2 associated with CIPN onset (rs17020773, p=2.03×10⁻⁸).
- Discovered rare coding variants in GPR68 associated with increased CIPN risk (p=1.59×10⁻⁶).
- Found GPR68 variants alter predicted arrestin binding motifs and GPR68 is highly expressed in sensory nociceptors.
Conclusions:
- Genetic variation in GRID2 and GPR68 impacts CIPN risk.
- GPR68 in sensory neurons presents a potential therapeutic target for CIPN prevention.
- Further research into GPR68 may yield novel strategies to mitigate chemotherapy-induced nerve damage.
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