Variants in WFS1 and other mendelian deafness genes are associated with cisplatin-associated ototoxicity

Purpose: Cisplatin is one of the most commonly used chemo-genotype was evident, indicating that higher cisplatin doses therapy drugs worldwide and one of the most ototoxic. We sought exacerbate hearing loss in patients with the minor allele to identify genetic variants that modulate cisplatin-associated (P ¼ 0.035). The association between decreased WFS1 ototoxicity (CAO). expression and hearing loss was replicated in an indepen-Experimental Design: We performed a genome-wide associa-dent BioVU cohort (n ¼ 18,620 patients, Bonferroni adjusted tion study (GWAS) of CAO using quantitative audiometry (4–12 P < 0.05). Beyond this top signal, we show CAO is a poly-kHz) in 511 testicular cancer survivors of European genetic genic trait and that SNPs in and near 84 known Mendelian ancestry. We performed polygenic modeling and functional anal-deafness genes are significantly enriched for low P values in yses using a variety of publicly available databases. We used an the GWAS (P ¼ 0.048). electronic health record cohort to replicate our top mechanistic Conclusions: We show for the first time the role of WFS1 finding. in CAO and document a statistically significant interaction Results: One SNP, rs62283056, in the first intron of between increasing cumulative cisplatin dose and rs62283056 Mendelian deafness gene WFS1 (wolframin ER transmem-genotype. Our clinical translational results demonstrate that brane glycoprotein) and an expression quantitative trait pretherapy patient genotyping to minimize ototoxicity could locus (eQTL) for WFS1 met genome-wide significance for be useful when deciding between cisplatin-based chemother-association with CAO (P ¼ 1.4 10⁸). A significant inter-apy regimens of comparable efficacy with different cumulative action between cumulative cisplatin dose and rs62283056 doses.