Abstract
Ototoxicity is a debilitating side effect of platinating agents with substantial inter-patient variability. We sought to evaluate the association of TPMT and COMT genetic variations with cisplatin-related hearing damage in the context of frontline pediatric cancer treatment protocols. In 213 children from St. Jude Medulloblastoma-96 and -03 protocols, hearing loss was related to younger age (P=0.013) and craniospinal irradiation (P=0.001), but did not differ by TPMT or COMT variants. Results were similar in an independent cohort of 41 children from solid tumor frontline protocols. Functional hearing loss or hair cell damage was not different in TPMT knockout vs. wildtype mice following cisplatin treatment, and neither TPMT nor COMT variant was associated with cisplatin cytotoxicity in lymphoblastoid cell lines. In conclusion, our results indicated that TPMT or COMT genetic variation was not related to cisplatin ototoxicity in children with cancer and did not influence cisplatin-induced hearing damage in laboratory models.