Data from Variants in WFS1 and Other Mendelian Deafness Genes Are Associated with Cisplatin-Associated Ototoxicity
Year: 2023
Type: other
Abstract: Purpose: 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. Clin Cancer Res; 23(13); 3325–33. ©2016 AACR.
Authors: Heather E. Wheeler, Eric R. Gamazon, Robert D. Frisina, Carlos Perez-Cervantes, Omar El Charif, Brandon Mapes, Sophie D. Fossa, Darren R. Feldman, Robert J. Hamilton, David J. Vaughn, Clair J. Beard, Chunkit Fung, Christian Kollmannsberger, Jeri Kim, Taisei Mushiroda, Michiaki Kubo, Shirin Ardeshir-Rouhani-Fard, Lawrence H. Einhorn, Nancy J. Cox, M. Eileen Dolan, Lois B. Travis
Language: English
Subfield: Sensory Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4361945483