title: Genetic determinants of chronic oxaliplatin-induced peripheral neurotoxicity: a genome-wide study replication and meta-analysis.
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.
authors: Dipartimento di Scienze del Farmaco and Centro di Ricerca Interdipartimentale di Farmacogenetica e Farmacogenomica (CRIFF), Università del Piemonte Orientale "A. Avogadro", Novara, Italy.
authors: Salvatore
authors: S
authors: Terrazzino
authors: Department of Neurology, "Saint Andrew's" General Hospital of Patras, Patras, Greece.|Laboratory of Molecular Oncology, Division of Oncology-Department of Medicine, University Hospital of Patras, Rion-Patras, Greece.
authors: Andreas A
authors: AA
authors: Argyriou
authors: Dipartimento di Scienze del Farmaco and Centro di Ricerca Interdipartimentale di Farmacogenetica e Farmacogenomica (CRIFF), Università del Piemonte Orientale "A. Avogadro", Novara, Italy.
authors: Sarah
authors: S
authors: Cargnin
authors: Laboratory of Molecular Oncology, Division of Oncology-Department of Medicine, University Hospital of Patras, Rion-Patras, Greece.
authors: Anna G
authors: AG
authors: Antonacopoulou
authors: Department of Neurosciences, University of Padua, Padua, Italy.
authors: Chiara
authors: C
authors: Briani
authors: Unit of Neuro-Oncology, Bellvitge University Hospital-ICO Duran and Reynals, Barcelona, Spain.
authors: Jordi
authors: J
authors: Bruna
authors: Unit of Neuro-Oncology, Bellvitge University Hospital-ICO Duran and Reynals, Barcelona, Spain.
authors: Roser
authors: R
authors: Velasco
authors: Department of Surgery and Translational Medicine, University of Milan-Bicocca, Monza, Italy.
authors: Paola
authors: P
authors: Alberti
authors: Department of Neurosciences, University of Padua, Padua, Italy.
authors: Marta
authors: M
authors: Campagnolo
authors: Unit of Medical Oncology, Veneto Oncology Institute, Padua, Italy.
authors: Sara
authors: S
authors: Lonardi
authors: Department of Oncology, S. Gerardo Hospital, Monza, Italy.
authors: Diego
authors: D
authors: Cortinovis
authors: Department of Oncology, S. Gerardo Hospital, Monza, Italy.
authors: Marina
authors: M
authors: Cazzaniga
authors: Unit of Colorectal Cancer, Bellvitge University Hospital-ICO Duran and Reynals, Barcelona, Spain.
authors: Cristina
authors: C
authors: Santos
authors: Laboratory of Molecular Oncology, Division of Oncology-Department of Medicine, University Hospital of Patras, Rion-Patras, Greece.
authors: Haralabos P
authors: HP
authors: Kalofonos
authors: Dipartimento di Scienze del Farmaco and Centro di Ricerca Interdipartimentale di Farmacogenetica e Farmacogenomica (CRIFF), Università del Piemonte Orientale "A. Avogadro", Novara, Italy.
authors: Pier Luigi
authors: PL
authors: Canonico
authors: Dipartimento di Scienze del Farmaco and Centro di Ricerca Interdipartimentale di Farmacogenetica e Farmacogenomica (CRIFF), Università del Piemonte Orientale "A. Avogadro", Novara, Italy.
authors: Armando A
authors: AA
authors: Genazzani
authors: Department of Surgery and Translational Medicine, University of Milan-Bicocca, Monza, Italy.
authors: Guido
authors: G
authors: Cavaletti
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects*; D015179:Colorectal Neoplasms / Q000188:drug therapy; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000009:adverse effects*; D000077150:Oxaliplatin; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D000097024:Acylphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000097024:Acylphosphatase
keywords: chemotherapy-induced peripheral neuropathy; meta-analysis; neurotoxicity; oxaliplatin; polymorphisms