title: Influence of genetic variants in TPMT and COMT associated with cisplatin induced hearing loss in patients with cancer: two new cohorts and a meta-analysis reveal significant heterogeneity between cohorts.
abstract: Treatment with cisplatin-containing chemotherapy regimens causes hearing loss in 40-60% of cancer patients. It has been suggested that genetic variants in the genes encoding thiopurine S-methyltransferase (TPMT) and catechol O-methyltransferase (COMT) can predict the development of cisplatin-induced ototoxicity and may explain interindividual variability in sensitivity to cisplatin-induced hearing loss. Two recently published studies however, sought to validate these findings and showed inconsistent results. The aim of this study was to evaluate the role of polymorphisms in the TPMT and COMT genes in cisplatin-induced ototoxicity. Therefore we investigated two independent cohorts of 110 Dutch and 38 Spanish patients with osteosarcoma and performed a meta-analysis including all previously published studies resulting in a total population of 664 patients with cancer. With this largest meta-analysis performed to date, we show that the influence of TPMT and COMT on the development of cisplatin-induced hearing loss may be less important than previously suggested.
authors.affiliation: Department of Pediatric Hematology and Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Melanie M
authors.initials: MM
authors.lastname: Hagleitner
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Marieke J H
authors.initials: MJ
authors.lastname: Coenen
authors.affiliation: Department of Pediatrics, University of Navarra and University Clinic, Pamplona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Patino-Garcia
authors.affiliation: Department of Pediatric Hematology and Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Eveline S J M
authors.initials: ES
authors.lastname: de Bont
authors.affiliation: Human Genotyping Unit-CeGen, Spanish National Cancer Research Center, Madrid, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Gonzalez-Neira
authors.affiliation: Department of Pediatric Hematology and Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Hanneke I
authors.initials: HI
authors.lastname: Vos
authors.affiliation: Department of Pediatric Hematology and Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Frank N
authors.initials: FN
authors.lastname: van Leeuwen
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Gelderblom
authors.affiliation: Department of Pediatric Hematology and Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Hoogerbrugge
authors.affiliation: Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Guchelaar
authors.affiliation: Department of Pediatric Hematology and Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Maroeska W M
authors.initials: MW
authors.lastname: Te Loo
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000188:drug therapy; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002945:Cisplatin / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D005838:Genotype; D034381:Hearing Loss / Q000139:chemically induced* / Q000235:genetics*; D006801:Humans; D008297:Male; D008780:Methyltransferases / Q000235:genetics*; D009426:Netherlands; D012516:Osteosarcoma / Q000188:drug therapy; D020641:Polymorphism, Single Nucleotide; D013030:Spain; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D008780:Methyltransferases; C588010:COMT protein, human; D002394:Catechol O-Methyltransferase; C022745:thiopurine methyltransferase; D002945:Cisplatin