1. Targeted Sequencing Reveals Low-Frequency Variants in EPHA Genes as Markers of Paclitaxel-Induced Peripheral Neuropathy.
- Author
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Apellániz-Ruiz M, Tejero H, Inglada-Pérez L, Sánchez-Barroso L, Gutiérrez-Gutiérrez G, Calvo I, Castelo B, Redondo A, García-Donás J, Romero-Laorden N, Sereno M, Merino M, Currás-Freixes M, Montero-Conde C, Mancikova V, Åvall-Lundqvist E, Green H, Al-Shahrour F, Cascón A, Robledo M, and Rodríguez-Antona C more...
- Subjects
- 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, Peripheral Nervous System Diseases chemically induced, Peripheral Nervous System Diseases pathology, Polymorphism, Single Nucleotide, Proportional Hazards Models, Quality of Life, Paclitaxel adverse effects, Peripheral Nervous System Diseases genetics, Receptor, EphA5 genetics, Receptor, EphA6 genetics, Receptor, EphA8 genetics
- Abstract
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 ., (©2016 American Association for Cancer Research.) more...- Published
- 2017
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