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Genome-wide association study identifies ephrin type A receptors implicated in paclitaxel induced peripheral sensory neuropathy
  1. Luis J Leandro-García1,
  2. Lucía Inglada-Pérez1,2,
  3. Guillermo Pita3,
  4. Elisabet Hjerpe4,
  5. Susanna Leskelä1,
  6. Carlos Jara5,
  7. Xabier Mielgo5,
  8. Anna González-Neira3,
  9. Mercedes Robledo1,2,
  10. Elisabeth Åvall-Lundqvist4,
  11. Henrik Gréen6,7,8,
  12. Cristina Rodríguez-Antona1,2
  1. 1Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Madrid, Spain
  2. 2Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain
  3. 3Human Genotyping-CEGEN Unit, Spanish National Cancer Research Centre, Madrid, Spain
  4. 4Department of Gynecologic Oncology, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden
  5. 5Unidad de Oncología Médica, Fundación Hospital Alcorcón, Madrid, Spain
  6. 6Clinical Pharmacology, Division of Drug Research, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköpings Universitet, Linköping, Sweden
  7. 7Science for Life Laboratory, Division of Gene Technology, School of Biotechnology, Royal Institute of Technology, Solna, Sweden
  8. 8Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden
  1. Correspondence to Dr Cristina Rodríguez-Antona, Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), E-28029 Madrid, Spain; crodriguez{at}cnio.es

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 (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.

  • Genetics
  • Genome-wide
  • Molecular genetics
  • Peripheral nerve disease
  • Oncology

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