Academic Journal
Genome-wide association study identifies ephrin type A receptors implicated in paclitaxel induced peripheral sensory neuropathy.
| العنوان: | Genome-wide association study identifies ephrin type A receptors implicated in paclitaxel induced peripheral sensory neuropathy. |
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| المؤلفون: | Leandro-García, Luis J, Inglada-Pérez, Lucía, Pita, Guillermo, Hjerpe, Elisabet, Leskelä, Susanna, Jara, Carlos, Mielgo, Xabier, Gonzalez-Neira, Anna, Robledo Batanero, Mercedes, Avall-Lundqvist, Elisabeth, Gréen, Henrik, Rodriguez Antona, Cristina |
| المساهمون: | Ministerio de Ciencia y Competitividad (España), Swedish Cancer Society (Cancerfonden), Swedish Research Council |
| بيانات النشر: | BMJ Publishing Group |
| سنة النشر: | 2013 |
| المجموعة: | REPISALUD (REPositorio Institucional en SALUD del Instituto de Salud Carlos III - ISCIII) |
| مصطلحات موضوعية: | Genome-Wide Association Study, Adult, Aged, 80 and over, Antineoplastic Agents, Female, Genetic Predisposition to Disease, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Neoplasms, Paclitaxel, Peripheral Nervous System Diseases, Polymorphism, Single Nucleotide, Receptors, Eph Family |
| الوصف: | 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. ; This work was supported by projects from the Spanish Ministry of Science and Innovation (grant numbers SAF2006-01139 and SAF2009-08307), the Spanish Ministry of Economy and Competiveness (grant number SAF2012-35779), the Swedish ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 1468-6244 |
| Relation: | https://doi.org/10.1136/jmedgenet-2012-101466.; info:eu-repo/grantAgreement/SAF2006-01139; info:eu-repo/grantAgreement/SAF2009-08307; info:eu-repo/grantAgreement/SAF2012-35779; J Med Genet . 2013;50(9):599-605.; http://hdl.handle.net/20.500.12105/17504; Journal of medical genetics |
| DOI: | 10.1136/jmedgenet-2012-101466 |
| الاتاحة: | https://hdl.handle.net/20.500.12105/17504 https://doi.org/10.1136/jmedgenet-2012-101466 |
| Rights: | http://creativecommons.org/licenses/by-nc-nd/4.0/ ; Attribution-NonCommercial-NoDerivatives 4.0 Internacional ; open access |
| رقم الانضمام: | edsbas.9956F1A2 |
| قاعدة البيانات: | BASE |
| تدمد: | 14686244 |
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| DOI: | 10.1136/jmedgenet-2012-101466 |