A genome-wide association study of cisplatin-induced hearing loss in children

Cisplatin is an effective chemotherapeutic agent used for a variety of solid organ malignancies in children and adults. However, its clinical use is limited by the high incidence of cisplatin-induced ototoxicity (CIO), which can affect up to 40-60% of children treated. To date, the genetic basis for CIO has been studied with only focused candidate-gene approaches. Here we report the findings of the first genome-wide association study (GWAS) of cisplatin-induced ototoxicity in children. We examined 738,432 genetics markers in a discovery cohort of 282 Canadian paediatric patients treated with cisplatin, followed by a replication study in an independent Canadian cohort of 82 children. In addition, clinical, therapeutic, and demographic characteristics of cases and controls were analysed to identify clinical factors that may also contribute to the susceptibility to CIO. The genome-wide analyses identified a significant association within the toll-like receptor 4 (TLR4) gene on chromosome 9. The most highly associated single nucleotide polymorphism (SNP) rs960312 conferred a highly protective effect against cisplatin-induced hearing loss (P = 1.19x10-⁸ , odds ratio = 0.22). This variant was subsequently replicated in an independent paediatric cohort (P = 0.018, odds ratio = 0.25). This variant is a tag SNP for a TLR4 promoter haplotype reported to have significantly altered transcriptional efficiency of TLR4. In both cohorts, CIO is significantly associated with younger age (P = 3.41x10-⁶), concomitant vincristine use (P = 2.03x10-¹²), and germ-cell tumour type (P = 4.50x10-⁶). After correcting for these clinical factors, TLR4 rs960312 remains highly associated (Uncorrected P = 1.16x10-⁹ ; Corrected P = 1.01x10-⁹). Several lines of evidence from in vitro and in vivo studies have implicated TLR4 in cisplatin-induced cochlear toxicity and hearing loss. Here we provide the first evidence linking TLR4 and CIO in human patients treated for cancer, leading to new insights into the mechanism underlying this pervasive and clinically limiting adverse drug reaction. The identification of additional markers that contribute to the susceptibility of CIO can be used to develop individualized patient treatments, which can potentially improve safety and treatment outcome of cisplatin.Medicine, Faculty ofMedical Genetics, Department ofGraduat