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http://purl.uniprot.org/citations/27582484http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/27582484http://www.w3.org/2000/01/rdf-schema#comment"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."xsd:string
http://purl.uniprot.org/citations/27582484http://purl.org/dc/terms/identifier"doi:10.1158/1078-0432.ccr-16-0694"xsd:string
http://purl.uniprot.org/citations/27582484http://purl.uniprot.org/core/author"Robledo M."xsd:string
http://purl.uniprot.org/citations/27582484http://purl.uniprot.org/core/author"Merino M."xsd:string
http://purl.uniprot.org/citations/27582484http://purl.uniprot.org/core/author"Green H."xsd:string
http://purl.uniprot.org/citations/27582484http://purl.uniprot.org/core/author"Rodriguez-Antona C."xsd:string
http://purl.uniprot.org/citations/27582484http://purl.uniprot.org/core/author"Cascon A."xsd:string
http://purl.uniprot.org/citations/27582484http://purl.uniprot.org/core/author"Apellaniz-Ruiz M."xsd:string
http://purl.uniprot.org/citations/27582484http://purl.uniprot.org/core/author"Curras-Freixes M."xsd:string
http://purl.uniprot.org/citations/27582484http://purl.uniprot.org/core/author"Inglada-Perez L."xsd:string
http://purl.uniprot.org/citations/27582484http://purl.uniprot.org/core/author"Mancikova V."xsd:string
http://purl.uniprot.org/citations/27582484http://purl.uniprot.org/core/author"Montero-Conde C."xsd:string
http://purl.uniprot.org/citations/27582484http://purl.uniprot.org/core/author"Sereno M."xsd:string
http://purl.uniprot.org/citations/27582484http://purl.uniprot.org/core/author"Calvo I."xsd:string
http://purl.uniprot.org/citations/27582484http://purl.uniprot.org/core/author"Redondo A."xsd:string
http://purl.uniprot.org/citations/27582484http://purl.uniprot.org/core/author"Avall-Lundqvist E."xsd:string
http://purl.uniprot.org/citations/27582484http://purl.uniprot.org/core/author"Al-Shahrour F."xsd:string
http://purl.uniprot.org/citations/27582484http://purl.uniprot.org/core/author"Garcia-Donas J."xsd:string
http://purl.uniprot.org/citations/27582484http://purl.uniprot.org/core/author"Castelo B."xsd:string
http://purl.uniprot.org/citations/27582484http://purl.uniprot.org/core/author"Romero-Laorden N."xsd:string
http://purl.uniprot.org/citations/27582484http://purl.uniprot.org/core/author"Tejero H."xsd:string
http://purl.uniprot.org/citations/27582484http://purl.uniprot.org/core/author"Gutierrez-Gutierrez G."xsd:string
http://purl.uniprot.org/citations/27582484http://purl.uniprot.org/core/author"Sanchez-Barroso L."xsd:string
http://purl.uniprot.org/citations/27582484http://purl.uniprot.org/core/date"2017"xsd:gYear
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