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Genetic determinants of chronic oxaliplatin‐induced peripheral neurotoxicity: a genome‐wide study replication and meta‐analysis

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We aimed at validating the role of genetic variants identified by a recent genome‐wide association study (GWAS) as determinants of chronic oxaliplatin‐induced peripheral neurotoxicity (OXAIPN). Eight polymorphisms (rs10486003, rs2338, rs843748, rs797519, rs4936453, rs12023000, rs17140129, and rs6924717) were genotyped in a total of 150 colorectal cancer patients of Caucasian origin receiving oxaliplatin‐based chemotherapy. The severity grade of chronic OXAIPN was assessed by NCI‐CTC criteria and the clinical version of the Total Neuropathy Score© (TNSc©). None of the polymorphisms investigated was found associated with grade ≥ 2 chronic OXAIPN (NCI‐CTC criteria), while a nominal association emerged for ACYP2 rs843748 when using the TNSc© scale (dominant model: odds ratio [OR]: 0.27, 95% confidence interval [CI]: 0.10–0.75, P = 0.008). In the combined analysis of this results with data of the two previously published studies which assessed chronic OXAIPN by NCI‐CTC criteria, evidence suggestive of association with chronic OXAIPN (NCI‐CTC criteria) was found for ACYP2 rs843748 (dominant model: OR: 2.40, 95%CI: 1.40–5.24, P = 0.027), which, however, did not remain significant after correction for multiple testing (threshold P‐value <0.00625). These findings suggest a minor role of the single nucleotide polymorphisms (SNPs) investigated as genetic determinants of chronic OXAIPN. These results also highlight the importance of replication studies with meta‐analysis for validation of GWAS findings.
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Keywords: chemotherapy‐induced peripheral neuropathy; meta‐analysis; neurotoxicity; oxaliplatin; polymorphisms

Document Type: Research Article

Publication date: March 1, 2015

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