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

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

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Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Translational Bioinformatics Unit, Spanish National Cancer Research Centre, Madrid, Spain.
ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain.
Neurology Section, Hospital Universitario Infanta Sofía, Madrid, Spain.
Medical Oncology Department, Hospital Montepríncipe, Madrid, Spain.
Medical Oncology Department, Centro Integral Oncológico Clara Campal, Madrid, Spain.
Medical Oncology Department, Hospital Universitario La Paz, Madrid, Spain.
Gynecological and Genitourinary Tumors Programme, Centro Integral Oncológico Clara Campal, Madrid, Spain.
Medical Oncology Department, Hospital Universitario Infanta Sofía, Madrid, Spain.
Department of Oncology and Department of Clinical and Experimental Medicine, Linköpings Universitet, Linköping, Sweden.
Clinical Pharmacology, Division of Drug Research, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköpings Universitet, Linköping, Sweden.
Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.


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.

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