Abstract 5576: MnSOD polymorphism is associated with ototoxicity in pediatric medulloblastoma patients

Purpose: The SOD2 gene encodes manganese superoxide dismutase (MnSOD) and is critical for superoxide anion detoxification. Variants in SOD2 have been associated with noise-induced hearing loss, and animal models suggest MnSOD expression is up-regulated in the cochlea after treatment with platinum-based chemotherapeutic agents. Therefore, we examined the role of SOD2 variants on ototoxicity among cisplatin-treated childhood medulloblastoma patients. Methods: Peripheral blood samples were obtained from 100 patients treated for pediatric medulloblastoma or supratentorial primitive neuroectodermal tumor at Texas Children9s Cancer Center or MD Anderson Cancer Center between 1982 and 2009. Demographic, clinical, and treatment information was abstracted from patient medical records. A diagnosis of ototoxicity was assigned to patients whose medical records indicated they had received cisplatin chemotherapy and required the use of a hearing aid ≥1 year following the completion of primary therapy. DNA was genotyped on the Illumina HumanOmni-1 Quad BeadChip (San Diego, CA). A linkage disequilibrium-based single nucleotide polymorphism (SNP) selection strategy was used to identify a minimal set of informative common variants (minor allele frequency ≥5%). The association between each SNP and ototoxicity was assessed using multivariable logistic regression, assuming a log-additive model. Adjusted models included confounders (age at diagnosis, gender, craniospinal radiotherapy dose, cisplatin dose, amifostine therapy, and ethnicity) selected using a change in estimate approach. Results: Study participants were primarily male (73.2%) and non-Hispanic white (42.3%) with a mean age at diagnosis of 7.3 years. Of the 71 eligible patients with available information, 26 (36.6%) suffered from cisplatin-related ototoxicity. Five SOD2 variants (rs7855, rs5746151, rs5746136, rs2758331, rs4880) identified by the LD-based selection strategy were available in the genotyped data. After correcting for multiple comparisons, the C allele of the rs4880 variant was significantly associated with ototoxicity (OR = 3.00; 95% CI: 1.32-6.82) in adjusted models. Conclusions: In this study, the SOD2 rs4880 variant was associated with ototoxicity. The rs4880 T>C substitution results in a Val>Ala amino acid change at position 16 of the MnSOD mitochondrial targeting sequence. Specifically, 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. Characterizing genetic predictors of ototoxicity susceptibility may aid in prevention strategies and potentially identify novel antioxidant therapeutic targets. Citation Format: Austin L. Brown, Philip J. Lupo, Mehmet F. Okcu, Ching C. Lau, Surya P. Rednam, Michael E. Scheurer. MnSOD polymorphism is associated with ototoxicity in pediatric medulloblastoma patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5576. doi:10.1158/1538-7445.AM2015-5576