Targeted sequencing reveals low-frequency variants in EPHA genes as markers of paclitaxel-induced peripheral neuropathy Articles uri icon


  • Apellániz Ruiz, María
  • Romero Laorden, Nuria
  • Sereno, María
  • Merino, María
  • Currás Freixes, María
  • Montero Conde, Cristina
  • Mancikova, Veronika
  • Avall-Lundqvist, Elisabeth
  • Green, Henrik
  • Cascón, Alberto
  • Tejero, Héctor
  • Robledo, Mercedes
  • Rodríguez-Antona, Cristina
  • Sánchez Barroso, Lara
  • Gutiérrez Gutiérrez, Gerardo
  • Calvo, Isabel
  • Castelo, Beatriz
  • García Donás, Jesús

publication date

  • March 2017


  • 5


  • 23

International Standard Serial Number (ISSN)

  • 1078-0432

Electronic International Standard Serial Number (EISSN)

  • 1557-3265


  • 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��).