title: Genome-wide association study identifies ephrin type A receptors implicated in paclitaxel induced peripheral sensory neuropathy.
abstract: 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.affiliation: Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Madrid, Spain.
authors.forename: Luis J
authors.initials: LJ
authors.lastname: Leandro-García
authors.forename: Lucía
authors.initials: L
authors.lastname: Inglada-Pérez
authors.forename: Guillermo
authors.initials: G
authors.lastname: Pita
authors.forename: Elisabet
authors.initials: E
authors.lastname: Hjerpe
authors.forename: Susanna
authors.initials: S
authors.lastname: Leskelä
authors.forename: Carlos
authors.initials: C
authors.lastname: Jara
authors.forename: Xabier
authors.initials: X
authors.lastname: Mielgo
authors.forename: Anna
authors.initials: A
authors.lastname: González-Neira
authors.forename: Mercedes
authors.initials: M
authors.lastname: Robledo
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Avall-Lundqvist
authors.forename: Henrik
authors.initials: H
authors.lastname: Gréen
authors.forename: Cristina
authors.initials: C
authors.lastname: Rodríguez-Antona
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D017239:Paclitaxel / Q000009:adverse effects* / Q000627:therapeutic use; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D036081:Receptors, Eph Family / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D036081:Receptors, Eph Family; D017239:Paclitaxel
keywords: Genetics; Genome-wide; Molecular genetics; Oncology; Peripheral nerve disease