title: Promoter region variation in NFE2L2 influences susceptibility to ototoxicity in patients exposed to high cumulative doses of cisplatin.
abstract: Ototoxicity is a disabling reaction to cisplatin chemotherapy. Much of the inter-individual variability in the development of hearing impairment among cisplatin-receiving patients has not been fully accounted for. In particular, little is known about the pharmacogenomics of cisplatin-induced ototoxicity. This study sought to investigate the role of variation in five candidate genes in a cohort of South African cancer patients. Five variants within the candidate genes were genotyped in 214 patients, of which SLC22A2 rs316019 and NFE2L2 rs6721961 associated with reduced rates of ototoxicity. In the patients who were exposed to cumulative cisplatin doses ⩾200 mg m-2(n=113), the variant rs6721961 associated with ototoxicity according to three different grading scales of hearing loss (ASHA, P=0.005; Chang, P=0.028; CTCAE, P=0.004). The NFE2L2 promotor variant rs6721961 may therefore be protective against hearing loss in cisplatin-receiving cancer patients.
authors.affiliation: MRC Human Genetics Research Unit, Division of Human Genetics, Institute for Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: T F
authors.initials: TF
authors.lastname: Spracklen
authors.affiliation: MRC Human Genetics Research Unit, Division of Human Genetics, Institute for Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: A A
authors.initials: AA
authors.lastname: Vorster
authors.affiliation: Division of Communication Sciences and Disorders, Groote Schuur Hospital, Cape Town, South Africa.
authors.forename: L
authors.initials: L
authors.lastname: Ramma
authors.affiliation: Department of Radiation Oncology, Groote Schuur Hospital, Cape Town, South Africa.
authors.forename: S
authors.initials: S
authors.lastname: Dalvie
authors.affiliation: MRC Human Genetics Research Unit, Division of Human Genetics, Institute for Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: R S
authors.initials: RS
authors.lastname: Ramesar
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D001299:Audiometry; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D034381:Hearing Loss / Q000139:chemically induced / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D000071184:Pharmacogenomic Variants; D011401:Promoter Regions, Genetic
chemical_list: D000970:Antineoplastic Agents; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D002945:Cisplatin