title: Targeted Sequencing Reveals Low-Frequency Variants inEPHAGenes as Markers of Paclitaxel-Induced Peripheral Neuropathy.
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 4EPHAgenes, 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 identifiedEPHA6as the gene most significantly associated with paclitaxel-induced neuropathy. Low-frequency nonsynonymous variants inEPHA6were 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 forEPHA5/6/8low-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 sequencingEPHAgenes revealed that low-frequency variants inEPHA6, EPHA5, andEPHA8contribute 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.
authors: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors: María
authors: M
authors: Apellániz-Ruiz
authors: Translational Bioinformatics Unit, Spanish National Cancer Research Centre, Madrid, Spain.
authors: Héctor
authors: H
authors: Tejero
authors: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.|ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain.
authors: Lucía
authors: L
authors: Inglada-Pérez
authors: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors: Lara
authors: L
authors: Sánchez-Barroso
authors: Neurology Section, Hospital Universitario Infanta Sofía, Madrid, Spain.
authors: Gerardo
authors: G
authors: Gutiérrez-Gutiérrez
authors: Medical Oncology Department, Hospital Montepríncipe, Madrid, Spain.|Medical Oncology Department, Centro Integral Oncológico Clara Campal, Madrid, Spain.
authors: Isabel
authors: I
authors: Calvo
authors: Medical Oncology Department, Hospital Universitario La Paz, Madrid, Spain.
authors: Beatriz
authors: B
authors: Castelo
authors: Medical Oncology Department, Hospital Universitario La Paz, Madrid, Spain.
authors: Andrés
authors: A
authors: Redondo
authors: Gynecological and Genitourinary Tumors Programme, Centro Integral Oncológico Clara Campal, Madrid, Spain.
authors: Jesús
authors: J
authors: García-Donás
authors: Gynecological and Genitourinary Tumors Programme, Centro Integral Oncológico Clara Campal, Madrid, Spain.
authors: Nuria
authors: N
authors: Romero-Laorden
authors: Medical Oncology Department, Hospital Universitario Infanta Sofía, Madrid, Spain.
authors: María
authors: M
authors: Sereno
authors: Medical Oncology Department, Hospital Universitario Infanta Sofía, Madrid, Spain.
authors: María
authors: M
authors: Merino
authors: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors: María
authors: M
authors: Currás-Freixes
authors: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors: Cristina
authors: C
authors: Montero-Conde
authors: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors: Veronika
authors: V
authors: Mancikova
authors: Department of Oncology and Department of Clinical and Experimental Medicine, Linköpings Universitet, Linköping, Sweden.
authors: Elisabeth
authors: E
authors: Åvall-Lundqvist
authors: 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.
authors: Henrik
authors: H
authors: Green
authors: Translational Bioinformatics Unit, Spanish National Cancer Research Centre, Madrid, Spain.
authors: Fátima
authors: F
authors: Al-Shahrour
authors: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.|ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain.
authors: Alberto
authors: A
authors: Cascón
authors: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.|ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain.
authors: Mercedes
authors: M
authors: Robledo
authors: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. crodriguez@cnio.es.|ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain.
authors: Cristina
authors: C
authors: Rodríguez-Antona
mesh_terms: D000328:Adult; D000368:Aged; D054316:Biomarkers, Pharmacological / Q000032:analysis; D001943:Breast Neoplasms / Q000150:complications / Q000188:drug therapy; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000150:complications / Q000188:drug therapy; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D011788:Quality of Life; D036123:Receptor, EphA5 / Q000235:genetics*; D036124:Receptor, EphA6 / Q000235:genetics*; D036143:Receptor, EphA8 / Q000235:genetics*
chemical_list: D054316:Biomarkers, Pharmacological; C484173:EPHA5 protein, human; D036123:Receptor, EphA5; D036124:Receptor, EphA6; D036143:Receptor, EphA8; D017239:Paclitaxel