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

Thiesen, Signe, Yin, Peng, Jorgensen, Andrea L ORCID: 0000-0002-6977-9337, Zhang, Jieying E ORCID: 0000-0003-1813-2207, Manzo, Valentina, McEvoy, Laurence ORCID: 0000-0002-2169-6735, Barton, Christopher, Picton, Susan, Bailey, Simon, Brock, Penelope
et al (show 7 more authors) (2017) <i>TPMT</i>, <i>COMT</i> and <i>ACYP2</i> genetic variants in paediatric cancer patients with cisplatin-induced ototoxicity. PHARMACOGENETICS AND GENOMICS, 27 (6). pp. 213-222.

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<h4>Objectives</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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).<h4>Conclusion</h4>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.

Item Type: Article
Uncontrolled Keywords: ACYP2, cancer, catechol-O-methyltransferase, cisplatin, ototoxicity, paediatric cancer, pharmacogenetics, thiopurine methyltransferase
Depositing User: Symplectic Admin
Date Deposited: 25 Apr 2017 06:33
Last Modified: 12 Oct 2023 15:53
DOI: 10.1097/FPC.0000000000000281
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3007119