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.