%0 Journal Article
%A Apellániz Ruiz, María
%A Tejero Franco, Héctor
%A Inglada Pérez, Lucía Silvia
%A Sánchez Barroso, Lara
%A Gutiérrez Gutiérrez, Gerardo
%A Calvo, Isabel
%A Castelo, Beatriz
%A Redondo, Andrés
%A García Donás, Jesús
%A Romero Laorden, Nuria
%A Sereno, María
%A Merino, María
%A Currás Freixes, María
%A Montero Conde, Cristina
%A Mancikova, Veronika
%A Åvall Lundqvist, Elisabeth
%A Green, Henrik
%A Al-Shahrour, Fátima
%A Cascón, Alberto
%A Robledo, Mercedes
%A Rodríguez Antona, Cristina
%T Targeted Sequencing Reveals Low-Frequency Variants in EPHA Genes as Markers of Paclitaxel-Induced Peripheral Neuropathy
%D 2017
%@ 1078-0432
%U https://hdl.handle.net/20.500.14352/96185
%X 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 ¼ 0.0042], and an independent cohort confirmed an increased neuropathy risk (HR, 2.07; 95% CI, 1.14–3.77; P ¼ 0.017). Combining the series gave an estimated 2.5-fold higher risk of neuropathy (95% CI, 1.46–4.31; P ¼ 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-inducedneuropathy. Furthermore, EPHA's neuronal injury repair function suggests that these genes might constitute important neuropathy markers for many neurotoxic drugs.
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