Document Type
Article
Publication Date
12-30-2016
Publication Title
Clinical Cancer Research
Pages
1-20
Abstract
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=1.4x10-8). 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 pre-therapy patient genotyping to minimize ototoxicity could be useful when deciding between cisplatin-based chemotherapy regimens of comparable efficacy with different cumulative doses.
Recommended Citation
Wheeler, Heather E.; Gamazon, Eric R.; Frisina, Robert; Perez-Cervantes, Carlos; Charif, Omar El; Mapes, Brandon; Fossa, Sophie D.; Feldman, Darren; Hamilton, Robert; Vaughn, David J.; Beard, Clair; Fung, Chunkit; Kollmannsberger, Chiristian; Kim, Jeri; Mushiroda, Taisei; Kubo, Michiaki; Ardeshir-Rouhani-Fard, Shirin; Einhorn, Lawrence H.; Cox, Nancy; Dolan, M. Eileen; and Travis, Lois. Variants in WFS1 and Other Mendelian Deafness Genes are Associated with Cisplatin-Associated Ototoxicity. Clinical Cancer Research, , : 1-20, 2016. Retrieved from Loyola eCommons, Bioinformatics Faculty Publications, http://dx.doi.org/10.1158/1078-0432.CCR-16-2809
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.
Copyright Statement
© American Association for Cancer Research 2016
Comments
Author Posting. © American Association for Cancer Research 2016. This article is posted here by permission of the AARC for personal use, not for redistribution. The article was published in Clinical Cancer Research, 2016, http://doi.org/10.1158/1078-0432.CCR-16-2809