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J Peripher Nerv Syst. 2015 Mar;20(1):15-23. doi: 10.1111/jns.12110.

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

Author information

1
Dipartimento di Scienze del Farmaco and Centro di Ricerca Interdipartimentale di Farmacogenetica e Farmacogenomica (CRIFF), Università del Piemonte Orientale "A. Avogadro", Novara, Italy.
2
Department of Neurology, "Saint Andrew's" General Hospital of Patras, Patras, Greece.
3
Laboratory of Molecular Oncology, Division of Oncology-Department of Medicine, University Hospital of Patras, Rion-Patras, Greece.
4
Department of Neurosciences, University of Padua, Padua, Italy.
5
Unit of Neuro-Oncology, Bellvitge University Hospital-ICO Duran and Reynals, Barcelona, Spain.
6
Department of Surgery and Translational Medicine, University of Milan-Bicocca, Monza, Italy.
7
Unit of Medical Oncology, Veneto Oncology Institute, Padua, Italy.
8
Department of Oncology, S. Gerardo Hospital, Monza, Italy.
9
Unit of Colorectal Cancer, Bellvitge University Hospital-ICO Duran and Reynals, Barcelona, Spain.

Abstract

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.

KEYWORDS:

chemotherapy-induced peripheral neuropathy; meta-analysis; neurotoxicity; oxaliplatin; polymorphisms

PMID:
25858589
DOI:
10.1111/jns.12110
[Indexed for MEDLINE]

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