Replication of TPMT and ABCC3 genetic variants highly associated with cisplatin-induced hearing loss in children

Abstract

Cisplatin is a widely used chemotherapeutic agent for the treatment of solid tumors. A serious complication of cisplatin treatment is permanent hearing loss. The aim of this study was to replicate previous genetic findings in an 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 (patient age, vincristine treatment, germ-cell tumor, and cranial irradiation) significantly improved the prediction of hearing-loss development as compared with using clinical risk factors alone (area under the curve (AUC) 0.786 vs. 0.708, P = 0.00048). The novel combination of genetic and clinical factors predicted the risk of hearing loss with a sensitivity of 50.3% and a specificity of 92.7%. These findings provide evidence to support the importance of TPMT, COMT, and ABCC3 in the prediction of cisplatin-induced hearing loss in children.

Figure 1

Receiver operating characteristic curves of clinical and genetic variables for the prediction of cisplatin-induced hearing loss in the combined cohort (n = 317). (a) Clinical variables are age, vincristine treatment, germ-cell tumor, and cranial irradiation, whereas genetic variables combine the effect of TPMT rs12201199, COMT rs4646316, and ABCC3 rs1051640. (b) The area under the curve for the combined cohort for each model. The P-values indicate the statistical significance between the curves for the combination of genetic and clinical variables as compared with clinical variables alone. CI, confidence interval; SNP, single-nucleotide polymorphism.

Figure 2

Kaplan–Meier curve of cisplatin-induced hearing loss in three different risk groups (Table 3) combining genetic factors (TPMT rs12201199, ABCC3 rs1051640, and COMT rs4646316). The curves show that the incidence of hearing loss increases with increasing risk group status. Hazard ratios (HRs) were used to compare curves with that of the lower risk group and were adjusted for clinical variables (P_trend = 5.3 × 10⁻⁹). CI, confidence interval.

Figure 3

Kaplan–Meier curve of cisplatin-induced hearing loss in three different risk groups (Table 3) combining clinical and genetic information. Clinical variables are age, vincristine treatment, germ-cell tumor, and cranial irradiation, whereas genetic variables combine the effect of TPMT rs12201199, COMT rs4646316, and ABCC3 rs1051640. The curves show that the incidence of hearing loss increases with increasing risk group status. Hazard ratios (HRs) were used to compare curves with that of the lower risk group and were adjusted for clinical variables (P_trend = 3.4 × 10⁻¹⁹). CI, confidence interval.