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.
Highlights
Medulloblastoma is the most common brain malignancy among pediatric populations [1]
A total of 81 pediatric patients diagnosed with medulloblastoma (n = 76) or supratentorial primitive neuroectodermal tumors (PNET; n = 5), seen at Texas Children’s Cancer Center between 1987 and 2010, who received cisplatin-based chemotherapy, had peripheral blood samples available for genotyping, and had no documented hearing impairment at the time of tumor diagnosis were included in this study
Using a tagSNP approach, we identified five variants on the HumanOmni-1 Quad BeadChip which captured much of the genetic variation in SOD2 across diverse populations (Table 1)
Summary
Medulloblastoma is the most common brain malignancy among pediatric populations [1]. The optimal use of cisplatin chemotherapy, is often restricted by the clinical onset of serious dose-limiting side effects. One such side effect is ototoxicity, which can lead to permanent, bilateral hearing loss in up to 70% of patients treated with cisplatin [2,3,4]. Ototoxicity risk has been previously associated with young age at cancer diagnosis, cumulative cisplatin dose, and cranial irradiation [2, 5,6,7,8]. A recent genome-wide association study (GWAS) of ototoxicity among pediatric medulloblastoma patients identified common variants in ACYP2 associated with cisplatin-induced hearing loss [9]. Much work is needed to further characterize the role of inherited
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