Related Experiment Video
Updated: May 10, 2026
Partial Sciatic Nerve Ligation: A Mouse Model of Chronic Neuropathic Pain to Study the Antinociceptive Effect of Novel Therapies
Published on: October 6, 2022
Genome-wide association study identifies ephrin type A receptors implicated in paclitaxel induced peripheral sensory
Luis J Leandro-García1, Lucía Inglada-Pérez, Guillermo Pita
1Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Madrid, Spain.
Background:
Peripheral neuropathy is the dose limiting toxicity of paclitaxel, a chemotherapeutic drug widely used to treat solid tumours. This toxicity exhibits great inter-individual variability of unknown origin. The present study aimed to identify genetic variants associated with paclitaxel induced neuropathy via a whole genome approach.
Methods:
A genome-wide association study (GWAS) was performed in 144 white European patients uniformly treated with paclitaxel/carboplatin and for whom detailed data on neuropathy was available. Per allele single nucleotide polymorphism (SNP) associations were assessed by Cox regression, modelling the cumulative dose of paclitaxel up to the development of grade 2 sensory neuropathy.
Results:
The strongest evidence of association was observed for the ephrin type A receptor 4 (EPHA4) locus (rs17348202, p=1.0×10(-6)), and EPHA6 and EPHA5 were among the top 25 and 50 hits (rs301927, p=3.4×10(-5) and rs1159057, p=6.8×10(-5)), respectively. A meta-analysis of EPHA5-rs7349683, the top marker for paclitaxel induced neuropathy in a previous GWAS (r(2)=0.79 with rs1159057), gave a hazard ratio (HR) estimate of 1.68 (p=1.4×10(-9)). Meta-analysis of the second hit of this GWAS, XKR4-rs4737264, gave a HR of 1.71 (p=3.1×10(-8)). Imputed SNPs at LIMK2 locus were also strongly associated with this toxicity (HR=2.78, p=2.0×10(-7)).
Conclusions:
This study provides independent support of EPHA5-rs7349683 and XKR4-rs4737264 as the first markers of risk of paclitaxel induced neuropathy. In addition, it suggests that other EPHA genes also involved in axonal guidance and repair following neural injury, as well as LIMK2 locus, may play an important role in the development of this toxicity. The identified SNPs could form the basis for individualised paclitaxel chemotherapy.
Insights
Genetic variants in EPHA genes and LIMK2 are associated with paclitaxel-induced peripheral neuropathy. These findings may help personalize chemotherapy by identifying patients at higher risk for this common side effect.
Area of Science:
- Genetics
- Oncology
- Neuroscience
Background:
- Peripheral neuropathy is a common, dose-limiting toxicity of paclitaxel chemotherapy.
- Significant inter-individual variability in paclitaxel-induced neuropathy exists, with unknown genetic causes.
Purpose of the Study:
- To identify genetic variants associated with paclitaxel-induced neuropathy using a whole-genome approach.
Main Methods:
- Genome-wide association study (GWAS) in 144 European patients treated with paclitaxel/carboplatin.
- Cox regression analysis of single nucleotide polymorphism (SNP) associations with neuropathy development.
Main Results:
- Strongest association found at the EPHA4 locus (rs17348202).
- EPHA5-rs7349683 and XKR4-rs4737264 showed significant associations (HR 1.68, p=1.4×10(-9) and HR 1.71, p=3.1×10(-8), respectively).
- LIMK2 locus SNPs also strongly associated with neuropathy risk (HR=2.78, p=2.0×10(-7)).
Conclusions:
- EPHA5-rs7349683 and XKR4-rs4737264 are validated markers for paclitaxel-induced neuropathy risk.
- Other EPHA genes and the LIMK2 locus may play roles in neuropathy development.
- Identified SNPs could enable personalized paclitaxel chemotherapy regimens.
Related Concept Videos
01:24Local Anesthetics: Differential Sensitivity of Nerve Fibers
01:22Role of Ephrin-Eph Signalling in Intestinal Stem Cell Renewal
01:28Chemotherapy-Induced Nausea and Vomiting: Neurokinin-1 Receptor Antagonists