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 pre-therapy patient genotyping to minimize ototoxicity could be useful when deciding between cisplatin-based chemotherapy regimens of comparable efficacy with different cumulative doses.

Clinical and Genome-Wide Analysis of Cisplatin-Induced Peripheral Neuropathy in Survivors of Adult-Onset Cancer

“…Autonomic items and the hearing loss item formed a distinct cluster on both plots. We have previously comprehensively evaluated hearing loss in this cohort with quantitative audiometry (37) and assessed genetic variants associated with cisplatin-induced ototoxicity (26). Therefore, we excluded hearing loss item from the sensory subscale.…”

“…Figure S2 illustrates the CONSORT flow diagram for the TCS. Quality control (QC) was performed as previously described (26). Individuals with pairwise identity by descent (IBD) > 0.125 and excess heterozygosity (F inbreeding coefficient >6 standard deviations from the mean) were excluded, leaving 827 individuals.…”

Pharmacogenomics of Cisplatin‐Induced Ototoxicity: Successes, Shortcomings, and Future Avenues of Research

“…For this reason, genetic variation is expected to play an important role in the development of CIO. Supporting this hypothesis, heritability studies have shown that 38–47% of the variability in cisplatin‐induced cytotoxicity can be attributed to genetics and that a large proportion (0.92 ± 0.62) of cisplatin‐associated ototoxicity can be attributed to common genetic variation …”

“…Following on from the GWAS of CIO in pediatric patients, Wheeler et al . performed a GWAS in 511 adult patients with testicular cancer of European genetic ancestry.…”

“…Hearing loss in this replication cohort could, therefore, have been caused by diverse factors, such as exposure to loud noise, ear infections, injuries to the ear, and genetic and congenital disorders. In addition to these analyses, Wheeler and colleagues tested for an interaction between rs62283056 WFS1 and cisplatin dose and showed that the effect of this variant on CIO was amplified at higher doses of cisplatin.…”