BACKGROUND: Peripheral neuropathy is the dose limiting toxicity of paclitaxel, a chemotherapeutic drug widely used to treat solid tumours. This toxicity exhibits great inter-individual variability of unknown origin. The present study aimed to identify genetic variants associated with paclitaxel induced neuropathy via a whole genome approach. METHODS: A genome-wide association study (GWAS) was performed in 144 white European patients uniformly treated with paclitaxel/carboplatin and for whom detailed data on neuropathy was available. Per allele single nucleotide polymorphism (SNP) associations were assessed by Cox regression, modelling the cumulative dose of paclitaxel up to the development of grade 2 sensory neuropathy. RESULTS: The strongest evidence of association was observed for the ephrin type A receptor 4 (EPHA4) locus (rs17348202, p=1.0×10(-6)), and EPHA6 and EPHA5 were among the top 25 and 50 hits (rs301927, p=3.4×10(-5) and rs1159057, p=6.8×10(-5)), respectively. A meta-analysis of EPHA5-rs7349683, the top marker for paclitaxel induced neuropathy in a previous GWAS (r(2)=0.79 with rs1159057), gave a hazard ratio (HR) estimate of 1.68 (p=1.4×10(-9)). Meta-analysis of the second hit of this GWAS, XKR4-rs4737264, gave a HR of 1.71 (p=3.1×10(-8)). Imputed SNPs at LIMK2 locus were also strongly associated with this toxicity (HR=2.78, p=2.0×10(-7)). CONCLUSIONS: This study provides independent support of EPHA5-rs7349683 and XKR4-rs4737264 as the first markers of risk of paclitaxel induced neuropathy. In addition, it suggests that other EPHA genes also involved in axonal guidance and repair following neural injury, as well as LIMK2 locus, may play an important role in the development of this toxicity. The identified SNPs could form the basis for individualised paclitaxel chemotherapy.
BACKGROUND:Peripheral neuropathy is the dose limiting toxicity of paclitaxel, a chemotherapeutic drug widely used to treat solid tumours. This toxicity exhibits great inter-individual variability of unknown origin. The present study aimed to identify genetic variants associated with paclitaxel induced neuropathy via a whole genome approach. METHODS: A genome-wide association study (GWAS) was performed in 144 white European patients uniformly treated with paclitaxel/carboplatin and for whom detailed data on neuropathy was available. Per allele single nucleotide polymorphism (SNP) associations were assessed by Cox regression, modelling the cumulative dose of paclitaxel up to the development of grade 2 sensory neuropathy. RESULTS: The strongest evidence of association was observed for the ephrin type A receptor 4 (EPHA4) locus (rs17348202, p=1.0×10(-6)), and EPHA6 and EPHA5 were among the top 25 and 50 hits (rs301927, p=3.4×10(-5) and rs1159057, p=6.8×10(-5)), respectively. A meta-analysis of EPHA5-rs7349683, the top marker for paclitaxel induced neuropathy in a previous GWAS (r(2)=0.79 with rs1159057), gave a hazard ratio (HR) estimate of 1.68 (p=1.4×10(-9)). Meta-analysis of the second hit of this GWAS, XKR4-rs4737264, gave a HR of 1.71 (p=3.1×10(-8)). Imputed SNPs at LIMK2 locus were also strongly associated with this toxicity (HR=2.78, p=2.0×10(-7)). CONCLUSIONS: This study provides independent support of EPHA5-rs7349683 and XKR4-rs4737264 as the first markers of risk of paclitaxel induced neuropathy. In addition, it suggests that other EPHA genes also involved in axonal guidance and repair following neural injury, as well as LIMK2 locus, may play an important role in the development of this toxicity. The identified SNPs could form the basis for individualised paclitaxel chemotherapy.
Authors: Elizabeth M Jaffee; Chi Van Dang; David B Agus; Brian M Alexander; Kenneth C Anderson; Alan Ashworth; Anna D Barker; Roshan Bastani; Sangeeta Bhatia; Jeffrey A Bluestone; Otis Brawley; Atul J Butte; Daniel G Coit; Nancy E Davidson; Mark Davis; Ronald A DePinho; Robert B Diasio; Giulio Draetta; A Lindsay Frazier; Andrew Futreal; Sam S Gambhir; Patricia A Ganz; Levi Garraway; Stanton Gerson; Sumit Gupta; James Heath; Ruth I Hoffman; Cliff Hudis; Chanita Hughes-Halbert; Ramy Ibrahim; Hossein Jadvar; Brian Kavanagh; Rick Kittles; Quynh-Thu Le; Scott M Lippman; David Mankoff; Elaine R Mardis; Deborah K Mayer; Kelly McMasters; Neal J Meropol; Beverly Mitchell; Peter Naredi; Dean Ornish; Timothy M Pawlik; Jeffrey Peppercorn; Martin G Pomper; Derek Raghavan; Christine Ritchie; Sally W Schwarz; Richard Sullivan; Richard Wahl; Jedd D Wolchok; Sandra L Wong; Alfred Yung Journal: Lancet Oncol Date: 2017-10-31 Impact factor: 41.316
Authors: Bryan P Schneider; Lang Li; Milan Radovich; Tatiana Foroud; George W Sledge; Fei Shen; Kathy D Miller; David A Flockhart; Guanglong Jiang; Gail Vance; Laura Gardner; Matteo Vatta; Shaochun Bai; Dongbing Lai; Daniel Koller; Fengmin Zhao; Anne O'Neill; Mary Lou Smith; Elda Railey; Carol White; Ann Partridge; Joseph Sparano; Nancy E Davidson Journal: Clin Cancer Res Date: 2015-07-02 Impact factor: 12.531