Cisplatin is a widely used chemotherapeutic agent for the treatment of solid tumours. A serious complication of cisplatin treatment is permanent hearing loss. The study hypothesis is that genetic variants in genes involved in drug metabolism and transport can contribute to increased susceptibility to hearing loss in pediatric oncology patients treated with cisplatin. Patients were recruited from across Canada through the Canadian Pharmacogenomics Network for Drug Safety (CPNDS). Recently, our group identified several predictive genetic variants that were highly associated with cisplatin-induced hearing loss in children. We evaluated whether we could replicate these findings in a new independent cohort of 155 pediatric patients. Associations were replicated for genetic variants in TPMT (rs12201199, P=0.0013, Odds Ratio, OR 6.1) and ABCC3 (rs1051640, P=0.036, OR 1.8). A predictive model combining variants in TPMT, ABCC3 and COMT with clinical variables significantly improved the prediction of risk of developing hearing loss compared to clinical risk factors alone (P=0.00048). We next evaluated whether we could identify additional genetic variants that confer susceptibility to cisplatin-induced hearing loss. We identified novel variants in ABCB5 (rs10950831, P=1.06×10⁻⁶, OR 2.0) and DPYD (rs6667550, P=0.0047, OR 1.9) that were significantly associated with cisplatin-induced hearing loss. We included these variants into the initial genetic model that consists of variants in TPMT, ABCC3 and COMT to evaluate whether we could improve the prediction of risk. We demonstrate that the risk of prediction of hearing loss significantly improves by including genetic variants in ABCB5 and DPYD (P=0.0023). We also demonstrate that by combining the clinical and genetic factors we can significantly improve the prediction of risk of hearing loss compared to clinical factors alone (P=2.63x10⁻⁷). We were able to replicate previously described findings and also provide evidence for novel genetic variants in the prediction of cisplatin-induced hearing loss in children. Furthermore, this study demonstrates that predictive models can classify patients based on predicted risk of cisplatin-induced hearing loss. These findings have the potential to influence treatment modifications for cisplatin therapy and may improve safety in children.Medicine, Faculty ofMedical Genetics, Department ofGraduat
