Daniel B Hawcutt1, Munir Pirmohamed1, Signe Thiesen1, Peng Yin2, Andrea L Jorgensen2, Jieying Eunice Zhang1, Valentina Manzo1,3, Laurence McEvoy1, Christopher Barton1,4, Susan Picton5, Simon Bailey6, Penelope Brock7, Harish Vyas8, David Walker8, Guy Makin9, Srinivas Bandi10, Barry Pizer1,4. 1. The Wolfson Centre for Personalised Medicine, Department of Molecular and Clinical, Pharmacology, Institute of Translational Medicine, University of Liverpool. 1-5 Brownlow Street, Liverpool L69 3GL, UK. 2. Department of Biostatistics, Institute of Translational Medicine, University of Liverpool. 1-5 Brownlow Street, Liverpool, L69 3GL, UK. 3. Dept. of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Salerno, Italy. 4. Department of Paediatric Oncology, Alder Hey Children's NHS Foundation Trust, Eaton Road Liverpool, L12 2AP, UK. 5. Paediatric Oncology & Haematology Department, Claredon Wing, Leeds General Infirmary, Great George St, Leeds LS1 3EX, UK. 6. Department of Paediatric and Adolescent Haematology and Oncology, Great North Children's Hospital NHS Trust, Victoria Wing, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK. 7. Haematology and Oncology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK, Great Ormond Street, London, WC1N 3JH. 8. Nottingham Children's Hospital, Queen's Medical Centre, Nottingham University Hospitals NHS Trust, Derby Road, Nottingham, NG7 2UH, UK. 9. Royal Manchester Children's Hospital NHS Trust, Oxford Rd, Manchester M13 9WL, UK. 10. Leicester Royal Infirmary, University Hospitals of Leicester NHS Trust, Infirmary Square, Leicester, Leicestershire, LE1 5WW, UK.
Abstract
OBJECTIVES: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.
OBJECTIVES: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.
Authors: Chiaho Hua; Johnnie K Bass; Raja Khan; Larry E Kun; Thomas E Merchant Journal: Int J Radiat Oncol Biol Phys Date: 2008-04-18 Impact factor: 7.038
Authors: Marelize Swart; Wesley M Stansberry; Victoria M Pratt; Elizabeth B Medeiros; Patrick J Kiel; Fei Shen; Bryan P Schneider; Todd C Skaar Journal: J Mol Diagn Date: 2019-02-20 Impact factor: 5.568
Authors: Matthew R Trendowski; Omar El Charif; Paul C Dinh; Lois B Travis; M Eileen Dolan Journal: Clin Cancer Res Date: 2018-10-10 Impact factor: 12.531
Authors: Barna Budai; Péter Prekopp; László Noszek; Erika R Kovács; Márta Szőnyi; Dániel J Erdélyi; Krisztina Bíró; Lajos Géczi Journal: J Mol Med (Berl) Date: 2020-05-20 Impact factor: 4.599
Authors: Evangelia Tserga; Tara Nandwani; Niklas K Edvall; Jan Bulla; Poulam Patel; Barbara Canlon; Christopher R Cederroth; David M Baguley Journal: Sci Rep Date: 2019-03-05 Impact factor: 4.379
Authors: Zulfan Zazuli; Naut J C B Duin; Katja Jansen; Susanne J H Vijverberg; Anke H Maitland-van der Zee; Rosalinde Masereeuw Journal: Int J Mol Sci Date: 2020-09-10 Impact factor: 5.923