Wheeler, Heather E.Gamazon, Eric R.Frisina, Robert D.Perez-Cervantes, CarlosEl Charif, OmarMapes, BrandonFossa, Sophie D.Feldman, Darren R.Hamilton, Robert J.Vaughn, David J.Beard, Clair J.Fung, ChunkitKollmannsberger, ChristianKim, JeriMushiroda, TaiseiKubo, MichiakiArdeshir-Rouhani-Fard, ShirinEinhorn, LawrenceCox, Nancy J.Dolan, M. EileenTravis, Lois B.2019-05-202019-05-202017-07-01Wheeler, H. E., Gamazon, E. R., Frisina, R. D., Perez-Cervantes, C., El Charif, O., Mapes, B., … Travis, L. B. (2017). Variants in WFS1 and Other Mendelian Deafness Genes Are Associated with Cisplatin-Associated Ototoxicity. Clinical cancer research : an official journal of the American Association for Cancer Research, 23(13), 3325–3333. doi:10.1158/1078-0432.CCR-16-2809https://hdl.handle.net/1805/19374Purpose: 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).Experimental Design: 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.Results: One SNP, rs62283056, in the first intron of Mendelian deafness gene WFS1 (wolframin ER transmembrane glycoprotein) and an expression quantitative trait locus (eQTL) for WFS1 met genome-wide significance for association with CAO (P = 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 (P = 0.035). The association between decreased WFS1 expression and hearing loss was replicated in an independent BioVU cohort (n = 18,620 patients, Bonferroni adjusted P < 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 P values in the GWAS (P = 0.048).Conclusions: We show for the first time the role of WFS1 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.en-USPublisher PolicyAntineoplastic AgentsCisplatinGenome-Wide Association StudyHearing LossMembrane ProteinsPolymorphism, Single NucleotideTesticular NeoplasmsArticle