Open AccessSOD 2 genetic variant associated with treatment‐related ototoxicity in cisplatin‐treated pediatric medulloblastoma
Author(s) -
Brown Austin L.,
Lupo Philip J.,
Okcu Mehmet Fatih,
Lau Ching C.,
Rednam Surya,
Scheurer Michael E.
Publication year - 2015
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.516
Subject(s) - ototoxicity , sod2 , single nucleotide polymorphism , odds ratio , linkage disequilibrium , oncology , genetics , medicine , biology , genotype , superoxide dismutase , oxidative stress , cisplatin , gene , chemotherapy
Manganese superoxide dismutase (Mn SOD ), encoded by the SOD 2 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 SOD 2 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 SNP s 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 SOD 2 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 Mn SOD mitochondrial targeting sequence. The Ala variant, which has been associated with increased Mn SOD activity, was associated with hearing damage in this study. Platinum‐based therapies increase the expression of Mn SOD , 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.