Targeted Sequencing Reveals Low-Frequency Variants in <i>EPHA</i> Genes as Markers of Paclitaxel-Induced Peripheral Neuropathy.

Abstract

<b>Purpose:</b> 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.<b>Experimental Design:</b> We sequenced the coding region of 4 <i>EPHA</i> 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.<b>Results:</b> Gene-based analysis identified <i>EPHA6</i> as the gene most significantly associated with paclitaxel-induced neuropathy. Low-frequency nonsynonymous variants in <i>EPHA6</i> 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 <i>EPHA5/6/8</i> low-frequency nonsynonymous variant carriers [HR, 14.60; 95% confidence interval (CI), 2.33-91.62; <i>P</i> = 0.0042], and an independent cohort confirmed an increased neuropathy risk (HR, 2.07; 95% CI, 1.14-3.77; <i>P</i> = 0.017). Combining the series gave an estimated 2.5-fold higher risk of neuropathy (95% CI, 1.46-4.31; <i>P</i> = 9.1 × 10^-4).<b>Conclusions:</b> This first study sequencing <i>EPHA</i> genes revealed that low-frequency variants in <i>EPHA6, EPHA5</i>, and <i>EPHA8</i> 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. <i>Clin Cancer Res; 23(5); 1227-35. ©2016 AACR</i>.