Targeted Sequencing Reveals Low-Frequency Variants in EPHA Genes as Markers of Paclitaxel-Induced Peripheral Neuropathy

Clin Cancer Res. 2017 Mar 1;23(5):1227-1235. doi: 10.1158/1078-0432.CCR-16-0694. Epub 2016 Aug 31.


Purpose: Neuropathy is the dose-limiting toxicity of paclitaxel and a major cause for decreased quality of life. Genetic factors have been shown to contribute to paclitaxel neuropathy susceptibility; however, the major causes for interindividual differences remain unexplained. In this study, we identified genetic markers associated with paclitaxel-induced neuropathy through massive sequencing of candidate genes.Experimental Design: We sequenced the coding region of 4 EPHA genes, 5 genes involved in paclitaxel pharmacokinetics, and 30 Charcot-Marie-Tooth genes, in 228 cancer patients with no/low neuropathy or high-grade neuropathy during paclitaxel treatment. An independent validation series included 202 paclitaxel-treated patients. Variation-/gene-based analyses were used to compare variant frequencies among neuropathy groups, and Cox regression models were used to analyze neuropathy along treatment.Results: Gene-based analysis identified EPHA6 as the gene most significantly associated with paclitaxel-induced neuropathy. Low-frequency nonsynonymous variants in EPHA6 were present exclusively in patients with high neuropathy, and all affected the ligand-binding domain of the protein. Accumulated dose analysis in the discovery series showed a significantly higher neuropathy risk for EPHA5/6/8 low-frequency nonsynonymous variant carriers [HR, 14.60; 95% confidence interval (CI), 2.33-91.62; P = 0.0042], and an independent cohort confirmed an increased neuropathy risk (HR, 2.07; 95% CI, 1.14-3.77; P = 0.017). Combining the series gave an estimated 2.5-fold higher risk of neuropathy (95% CI, 1.46-4.31; P = 9.1 × 10-4).Conclusions: This first study sequencing EPHA genes revealed that low-frequency variants in EPHA6, EPHA5, and EPHA8 contribute to the susceptibility to paclitaxel-induced neuropathy. Furthermore, EPHA's neuronal injury repair function suggests that these genes might constitute important neuropathy markers for many neurotoxic drugs. Clin Cancer Res; 23(5); 1227-35. ©2016 AACR.

MeSH terms

  • Adult
  • Aged
  • Biomarkers, Pharmacological / analysis
  • Breast Neoplasms / complications
  • Breast Neoplasms / drug therapy
  • Female
  • Genetic Association Studies
  • Humans
  • Middle Aged
  • Ovarian Neoplasms / complications
  • Ovarian Neoplasms / drug therapy
  • Paclitaxel / administration & dosage
  • Paclitaxel / adverse effects*
  • Peripheral Nervous System Diseases / chemically induced
  • Peripheral Nervous System Diseases / genetics*
  • Peripheral Nervous System Diseases / pathology
  • Polymorphism, Single Nucleotide
  • Proportional Hazards Models
  • Quality of Life
  • Receptor, EphA5 / genetics*
  • Receptor, EphA6 / genetics*
  • Receptor, EphA8 / genetics*


  • Biomarkers, Pharmacological
  • EPHA5 protein, human
  • Receptor, EphA5
  • Receptor, EphA6
  • Receptor, EphA8
  • Paclitaxel