title: SOD2 genetic variant associated with treatment-related ototoxicity in cisplatin-treated pediatric medulloblastoma.
abstract: Manganese superoxide dismutase (MnSOD), encoded by the SOD2 gene, is involved in the detoxification of superoxide anion. Superoxide is likely a source of oxidative stress in the cochlea following treatment with platinum agents and radiation. Therefore, we examined SOD2 variants in association with ototoxicity among cisplatin-treated childhood medulloblastoma patients. Blood samples were obtained from 71 eligible patients treated for pediatric medulloblastoma at Texas Children's Cancer Center (1987-2010). Ototoxicity was defined as requiring the use of a hearing aid sometime after the initiation of therapy. DNA was genotyped on the Illumina HumanOmni-1 Quad BeadChip. A linkage disequilibrium (LD)-based single-nucleotide polymorphism (SNP) selection strategy was used to identify a minimal set of informative variants. Associations between SNPs and ototoxicity were assessed using logistic regression. Of the 71 eligible patients, 26 (37%) suffered from cisplatin-related ototoxicity. Study participants were primarily male (73%) and non-Hispanic white (42%). Five SOD2 variants (rs7855, rs5746151, rs5746136, rs2758331, and rs4880) identified by the LD-based selection strategy were genotyped. After correcting for multiple comparisons, the C-allele of the rs4880 variant was significantly associated with ototoxicity (odds ratio = 3.06, 95% confidence interval: 1.30-7.20) in adjusted models. The rs4880 T > C substitution results in a Val > Ala amino acid change at position 16 of the MnSOD mitochondrial targeting sequence. The Ala variant, which has been associated with increased MnSOD activity, was associated with hearing damage in this study. Platinum-based therapies increase the expression of MnSOD, which may result in an abundance of hydrogen peroxide, a reactive oxygen species. Therefore, oxidative stress may be an important mechanism in therapy-related cochlear damage.
authors.affiliation: Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
authors.forename: Austin L
authors.initials: AL
authors.lastname: Brown
authors.affiliation: Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Lupo
authors.affiliation: Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Mehmet Fatih
authors.initials: MF
authors.lastname: Okcu
authors.affiliation: Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Ching C
authors.initials: CC
authors.lastname: Lau
authors.affiliation: Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Surya
authors.initials: S
authors.lastname: Rednam
authors.affiliation: Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Scheurer
mesh_terms: D000293:Adolescent; D000483:Alleles; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D016022:Case-Control Studies; D002528:Cerebellar Neoplasms / Q000150:complications* / Q000188:drug therapy / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002945:Cisplatin / Q000009:adverse effects / Q000627:therapeutic use; D004427:Ear Diseases / Q000209:etiology*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D008527:Medulloblastoma / Q000150:complications* / Q000188:drug therapy / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D013482:Superoxide Dismutase / Q000235:genetics*; D000099156:Superoxide Dismutase 2
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2
keywords: Cisplatin; genetics; hearing loss; ototoxicity; platinum chemotherapy; superoxide dismutase