Clinical Cancer Research
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.
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
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© American Association for Cancer Research 2016