Variants in <i>WFS1</i> and Other Mendelian Deafness Genes Are Associated with Cisplatin-Associated Ototoxicity

Abstract

<b>Purpose:</b> Cisplatin is one of the most commonly used chemotherapy drugs worldwide and one of the most ototoxic. We sought to identify genetic variants that modulate cisplatin-associated ototoxicity (CAO).<b>Experimental Design:</b> We performed a genome-wide association study (GWAS) of CAO using quantitative audiometry (4-12 kHz) in 511 testicular cancer survivors of European genetic ancestry. We performed polygenic modeling and functional analyses using a variety of publicly available databases. We used an electronic health record cohort to replicate our top mechanistic finding.<b>Results:</b> One SNP, rs62283056, in the first intron of Mendelian deafness gene <i>WFS1</i> (wolframin ER transmembrane glycoprotein) and an expression quantitative trait locus (eQTL) for <i>WFS1</i> met genome-wide significance for association with CAO (<i>P</i> = 1.4 × 10^-8). A significant interaction between cumulative cisplatin dose and rs62283056 genotype was evident, indicating that higher cisplatin doses exacerbate hearing loss in patients with the minor allele (<i>P</i> = 0.035). The association between decreased <i>WFS1</i> expression and hearing loss was replicated in an independent BioVU cohort (<i>n</i> = 18,620 patients, Bonferroni adjusted <i>P</i> < 0.05). Beyond this top signal, we show CAO is a polygenic trait and that SNPs in and near 84 known Mendelian deafness genes are significantly enriched for low <i>P</i> values in the GWAS (<i>P</i> = 0.048).<b>Conclusions:</b> We show for the first time the role of <i>WFS1</i> in CAO and document a statistically significant interaction between increasing cumulative cisplatin dose and rs62283056 genotype. Our clinical translational results demonstrate that pretherapy patient genotyping to minimize ototoxicity could be useful when deciding between cisplatin-based chemotherapy regimens of comparable efficacy with different cumulative doses. <i>Clin Cancer Res; 23(13); 3325-33. ©2016 AACR</i>.