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

Cisplatin is one of the most effective chemotherapeutic agents for children with solid tumors, including hepatoblastoma, brain tumors, and germ-cell tumors, and has contributed to a dramatic increase in the survival rate. Cisplatin has shown efficacy in standard-risk hepatoblastoma and can be used as monotherapy with a >80% 3-year event-free survival.1 A major complication that limits the use of cisplatin is the risk of drug-induced ototoxicity,2 which manifests as permanent, bilateral hearing loss in about 10–25% of adults and 26–90% of children depending on dose and treatment regimen.3–8 In children, even mild losses in hearing can significantly influence speech and language development and increase the risk of learning difficulties.9,10 In adults, the rate of hearing loss may be higher than reported due to a lack of baseline and follow-up audiometry in cisplatin protocols. Interindividual variability of cisplatin-induced effects on hearing in patients receiving the same dose of cisplatin is considerable, from no hearing loss to high-frequency hearing loss often progressing to severe hearing impairment in the speech frequencies.10–12 Furthermore, patients show no improvement in hearing and often the progression of hearing loss continues long after the end of therapy.13 Higher cumulative cisplatin dose,3,14,15 younger age,3,14,16 cranial irradiation,15,17 and concomitant use of aminoglycosides and vincristine14,18,19 are known to influence cisplatin-induced ototoxicity.11 However, the debate over ototoxicity of vincristine continues; case reports suggest that vincristine may be ototoxic20,21 or transiently ototoxic at high doses14 whereas larger systematic clinical trials have reported that vincristine, alone, is not ototoxic.22,23 Because of the limited number of large studies, there is insufficient evidence to either support or refute the hypothesis that vincristine is an ototoxic agent. The interindividual variability in hearing loss suggests that clinical factors alone are insufficient predictors of safety. At present, no standard methods exist to identify individuals who are at increased risk of developing hearing loss. Genetic factors involved in drug biotransformation, transport, and receptors have been recognized to influence patient drug response and susceptibility to adverse drug events, including ototoxicity.24–26 The identification of genetic markers that increase susceptibility to cisplatin-induced ototoxicity has important implications for improving patient care during cisplatin treatment. Recently, a candidate gene study in children receiving cispl-atin identified genetic variants in thiopurine S-methyltransferase (TPMT) (rs12201199, rs1800460, rs1142345), catechol O-methyltransferase (COMT) (rs9332377, rs4646316), and several other variants, including the ATP-binding cassette transporter C3 (ABCC3) (rs1051640) as conferring increased risk of developing cisplatin-induced hearing loss.9 For clinical application, it is essential to replicate these genetic findings in independent cohorts of patients so as to reduce the number of false-positive results and to ensure that the genetic risk prediction is consistent.27 It is now well recognized that replication of genetic associations is required before any causal inferences can be drawn.27 However, several studies have reported that consistent replication is challenging and difficult to achieve. The aim of this study was to investigate replication of genetic risk factors for cisplatin-induced hearing loss in an independent cohort of patients recruited from across Canada, as well as to evaluate a predictive multi-SNP (single-nucleotide polymorphism) model.