Variants in WFS1 and Other Mendelian Deafness Genes Are Associated with Cisplatin-Associated Ototoxicity.

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
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 23 Issue 13 Pg. 3325-3333 (07 01 2017) ISSN: 1557-3265 [Electronic] United States
• PMID: 28039263 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Membrane Proteins
• wolframin protein
• Cisplatin

Topics

• Antineoplastic Agents (adverse effects)
• Cisplatin (administration & dosage, adverse effects)
• Female
• Genome-Wide Association Study
• Genotype
• Hearing Loss (chemically induced, genetics, pathology)
• Humans
• Male
• Membrane Proteins (genetics)
• Polymorphism, Single Nucleotide (genetics)
• Testicular Neoplasms (drug therapy, genetics, physiopathology)