RT Journal Article
T1 Targeted Sequencing Reveals Low-Frequency Variants in EPHA Genes as Markers of Paclitaxel-Induced Peripheral Neuropathy
A1 Apellániz Ruiz, María
A1 Tejero Franco, Héctor
A1 Inglada Pérez, Lucía Silvia
A1 Sánchez Barroso, Lara
A1 Gutiérrez Gutiérrez, Gerardo
A1 Calvo, Isabel
A1 Castelo, Beatriz
A1 Redondo, Andrés
A1 García Donás, Jesús
A1 Romero Laorden, Nuria
A1 Sereno, María
A1 Merino, María
A1 Currás Freixes, María
A1 Montero Conde, Cristina
A1 Mancikova, Veronika
A1 Åvall Lundqvist, Elisabeth
A1 Green, Henrik
A1 Al-Shahrour, Fátima
A1 Cascón, Alberto
A1 Robledo, Mercedes
A1 Rodríguez Antona, Cristina
AB 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.
SN 1078-0432
YR 2017
FD 2017
LK https://hdl.handle.net/20.500.14352/96185
UL https://hdl.handle.net/20.500.14352/96185
LA eng
NO María Apellániz-Ruiz, Héctor Tejero, Lucía Inglada-Pérez, Lara Sánchez-Barroso, Gerardo Gutiérrez-Gutiérrez, Isabel Calvo, Beatriz Castelo, Andrés Redondo, Jesús García-Donás, Nuria Romero-Laorden, María Sereno, María Merino, María Currás-Freixes, Cristina Montero-Conde, Veronika Mancikova, Elisabeth Åvall-Lundqvist, Henrik Green, Fátima Al-Shahrour, Alberto Cascón, Mercedes Robledo, Cristina Rodríguez-Antona; Targeted Sequencing Reveals Low-Frequency Variants in EPHA Genes as Markers of Paclitaxel-Induced Peripheral Neuropathy. Clin Cancer Res 1 March 2017; 23 (5): 1227–1235. https://doi.org/10.1158/1078-0432.CCR-16-0694
DS Docta Complutense
RD 6 abr 2025