TPMT, COMT and ACYP2 genetic variants in paediatric cancer patients with cisplatin-induced ototoxicity

Autor: David Walker, Daniel B Hawcutt, Chris Barton, Guy Makin, Munir Pirmohamed, Penelope Brock, Simon Bailey, Harish Vyas, Signe Thiesen, Jieying Eunice Zhang, Srinivas Bandi, Peng Yin, Valentina Manzo, Susan Picton, Andrea L. Jorgensen, Barry Pizer, Laurence McEvoy
Rok vydání: 2017
Předmět:
0301 basic medicine
Male
Adolescent
Antineoplastic Agents
Pharmacology
Catechol O-Methyltransferase
ACYP2
Polymorphism
Single Nucleotide
Article
03 medical and health sciences
0302 clinical medicine
Ototoxicity
Genetics
medicine
Odds Ratio
Humans
Polymorphism
General Pharmacology
Toxicology and Pharmaceutics
Preschool
Child
Hearing Loss
Molecular Biology
Genetics (clinical)
Genetic Association Studies
Retrospective Studies
Acid Anhydride Hydrolases
Child
Preschool
Cisplatin
Female
Infant
Methyltransferases
United Kingdom
Catechol-O-methyl transferase
Thiopurine methyltransferase
biology
business.industry
Genetic variants
Single Nucleotide
Odds ratio
medicine.disease
030104 developmental biology
030220 oncology & carcinogenesis
biology.protein
Molecular Medicine
business
Pharmacogenetics
medicine.drug
Zdroj: PHARMACOGENETICS AND GENOMICS
ISSN: 1744-6880
Popis: Cisplatin ototoxicity affects 42-88% of treated children. Catechol-O-methyltransferase (COMT), thiopurine methyltransferase (TPMT) and AYCP2 genetic variants have been associated with ototoxicity, but the findings have been contradictory. The aims of the study were as follows: (a) to investigate these associations in a carefully phenotyped cohort of UK children and (b) to perform a systematic review and meta-analysis.We recruited 149 children from seven UK centres using a retrospective cohort study design. All participants were clinically phenotyped carefully. Genotyping was performed for one ACYP2 (rs1872328), three TPMT (rs12201199, rs1142345 and rs1800460) and two COMT (rs4646316 and rs9332377) variants.For CTCAE grading, hearing loss was present in 91/120 (75.8%; worst ear) and 79/120 (65.8%; better ear). Using Chang grading, hearing loss was diagnosed in 85/119 (71.4%; worst ear) versus 75/119 (63.0%; better ear). No TPMT or COMT single-nucleotide polymorphisms (SNPs) were associated with ototoxicity. ACYP2 SNP rs1872328 was associated with ototoxicity (P=0.027; worst ear). Meta-analysis of our data with that reported in previous studies showed the pooled odds ratio (OR) to be statistically significant for both the COMT SNP rs4646316 (OR: 1.50; 95% confidence interval: 1.15-1.95) and the ACYP2 SNP rs1872328 (OR: 5.91; 95% confidence interval: 1.51-23.16).We showed an association between the ACYP2 polymorphism and cisplatin-induced ototoxicity, but not with the TPMT and COMT. A meta-analysis was statistically significant for both the COMT rs4646316 and the ACYP2 rs1872328 SNPs. Grading the hearing of children with asymmetric hearing loss requires additional clarification.
Databáze: OpenAIRE
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