Format

Send to

Choose Destination
Clin Cancer Res. 2017 Jul 1;23(13):3325-3333. doi: 10.1158/1078-0432.CCR-16-2809. Epub 2016 Dec 30.

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

Author information

1
Department of Biology, Loyola University Chicago, Chicago, Illinois.
2
Department of Computer Science, Loyola University Chicago, Chicago, Illinois.
3
Division of Genetic Medicine, Vanderbilt University, Nashville, Tennessee.
4
Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
5
Department of Chemical and Biomedical Engineering, University of South Florida, Tampa, Florida.
6
Department of Communication Sciences and Disorders, Global Center for Hearing and Speech Research, University of South Florida, Tampa, Florida.
7
Department of Medicine, University of Chicago, Chicago, Illinois.
8
Department of Oncology, Oslo University Hospital, Radiumhospital, Oslo, Norway.
9
Department of Medical Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York.
10
Department of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
11
Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
12
Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
13
J.P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York.
14
Division of Medical Oncology, University of British Columbia, Vancouver, British Columbia, Canada.
15
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
16
RIKEN Center for Integrative Medical Science, Yokohama, Japan.
17
Department of Medical Oncology, Indiana University, Indianapolis, Indiana.
18
Department of Medical Oncology, Indiana University, Indianapolis, Indiana. leinhorn@iupui.edu.

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.

PMID:
28039263
PMCID:
PMC5493516
DOI:
10.1158/1078-0432.CCR-16-2809
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center