Genome-wide association study identifies ephrin type A receptors implicated in paclitaxel induced peripheral sensory neuropathy

• Published in: Journal of medical genetics Vol. 50; no. 9; pp. 599 - 605
• Main Authors: Leandro-García, Luis J, Inglada-Pérez, Lucía, Pita, Guillermo, Hjerpe, Elisabet, Leskelä, Susanna, Jara, Carlos, Mielgo, Xabier, González-Neira, Anna, Robledo, Mercedes, Åvall-Lundqvist, Elisabeth, Gréen, Henrik, Rodríguez-Antona, Cristina
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd 01.09.2013; BMJ Publishing Group LTD
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Agents - adverse effects; Antineoplastic Agents - therapeutic use; Axon guidance; Cancer therapies; Carboplatin; Cell division; Chemotherapy; Drug dosages; EphA4 protein; Farmakologi och toxikologi; Female; Genetic diversity; Genetic Predisposition to Disease; Genetics; Genome-wide; Genome-wide association studies; Genome-Wide Association Study; Genome-wide studies; Genomes; Humans; Kaplan-Meier Estimate; Klinisk medicin; Male; MEDICIN; Medicin och hälsovetenskap; MEDICINE; Medicinska och farmaceutiska grundvetenskaper; Meta-analysis; Middle Aged; Molecular genetics; Neoplasms - drug therapy; Neurologi; Neurotoxicity; Oncology; Ovaries; Paclitaxel; Paclitaxel - adverse effects; Paclitaxel - therapeutic use; Peripheral nerve disease; Peripheral Nervous System Diseases - chemically induced; Peripheral Nervous System Diseases - genetics; Peripheral neuropathy; Polymorphism, Single Nucleotide; Receptors, Eph Family - genetics; Single-nucleotide polymorphism; Software; Solid tumors; Statistical analysis; Toxicity; United States > US; Genetics; Oncology; Genome-wide; Peripheral nerve disease; Molecular genetics
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmedgenet-2012-101466

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.