Variants in WFS1 and other Mendelian deafness genes are associated with cisplatin-associated ototoxicity.

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Variants in WFS1 and other Mendelian deafness genes are associated with cisplatin-associated ototoxicity.

Clin Cancer Res. 2016 Dec 30;:

Authors: Wheeler HE, Gamazon ER, Frisina R, Perez-Cervantes C, El Charif O, Mapes B, Fossa SD, Feldman D, Hamilton R, Vaughn DJ, Beard C, Fung C, Kollmannsberger C, Kim J, Mushiroda T, Kubo M, Ardeshir-Rouhani-Fard S, Einhorn LH, Cox N, Dolan ME, Travis L

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=1.4x10(-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.

PMID: 28039263 [PubMed - as supplied by publisher]

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