RT Journal Article
SR Electronic
T1 Genome-wide association study identifies ephrin type A receptors implicated in paclitaxel induced peripheral sensory neuropathy
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 599
OP 605
DO 10.1136/jmedgenet-2012-101466
VO 50
IS 9
A1 Luis J Leandro-García
A1 Lucía Inglada-Pérez
A1 Guillermo Pita
A1 Elisabet Hjerpe
A1 Susanna Leskelä
A1 Carlos Jara
A1 Xabier Mielgo
A1 Anna González-Neira
A1 Mercedes Robledo
A1 Elisabeth Åvall-Lundqvist
A1 Henrik Gréen
A1 Cristina Rodríguez-Antona
YR 2013
UL http://jmg.bmj.com/content/50/9/599.abstract
AB 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 (r2=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.