title: Variants inWFS1and 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 geneWFS1(wolframin ER transmembrane glycoprotein) and an expression quantitative trait locus (eQTL) forWFS1met 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 decreasedWFS1expression and hearing loss was replicated in an independent BioVU cohort (n= 18,620 patients, Bonferroni adjustedP< 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 lowPvalues in the GWAS (P= 0.048).Conclusions:We show for the first time the role ofWFS1in 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.affiliation: Department of Biology, Loyola University Chicago, Chicago, Illinois.|Department of Computer Science, Loyola University Chicago, Chicago, Illinois.
authors.forename: Heather E
authors.initials: HE
authors.lastname: Wheeler
authors.affiliation: Division of Genetic Medicine, Vanderbilt University, Nashville, Tennessee.|Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Gamazon
authors.affiliation: Department of Chemical and Biomedical Engineering, University of South Florida, Tampa, Florida.|Department of Communication Sciences and Disorders, Global Center for Hearing and Speech Research, University of South Florida, Tampa, Florida.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Frisina
authors.affiliation: Department of Biology, Loyola University Chicago, Chicago, Illinois.|Department of Computer Science, Loyola University Chicago, Chicago, Illinois.
authors.forename: Carlos
authors.initials: C
authors.lastname: Perez-Cervantes
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Omar
authors.initials: O
authors.lastname: El Charif
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Brandon
authors.initials: B
authors.lastname: Mapes
authors.affiliation: Department of Oncology, Oslo University Hospital, Radiumhospital, Oslo, Norway.
authors.forename: Sophie D
authors.initials: SD
authors.lastname: Fossa
authors.affiliation: Department of Medical Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Darren R
authors.initials: DR
authors.lastname: Feldman
authors.affiliation: Department of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Hamilton
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: David J
authors.initials: DJ
authors.lastname: Vaughn
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Clair J
authors.initials: CJ
authors.lastname: Beard
authors.affiliation: J.P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York.
authors.forename: Chunkit
authors.initials: C
authors.lastname: Fung
authors.affiliation: Division of Medical Oncology, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Christian
authors.initials: C
authors.lastname: Kollmannsberger
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jeri
authors.initials: J
authors.lastname: Kim
authors.affiliation: RIKEN Center for Integrative Medical Science, Yokohama, Japan.
authors.forename: Taisei
authors.initials: T
authors.lastname: Mushiroda
authors.affiliation: RIKEN Center for Integrative Medical Science, Yokohama, Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.affiliation: Department of Medical Oncology, Indiana University, Indianapolis, Indiana.
authors.forename: Shirin
authors.initials: S
authors.lastname: Ardeshir-Rouhani-Fard
authors.affiliation: Department of Medical Oncology, Indiana University, Indianapolis, Indiana. leinhorn@iupui.edu.
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Einhorn
authors.affiliation: Division of Genetic Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Cox
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: M Eileen
authors.initials: ME
authors.lastname: Dolan
authors.affiliation: Department of Medical Oncology, Indiana University, Indianapolis, Indiana.
authors.forename: Lois B
authors.initials: LB
authors.lastname: Travis
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D034381:Hearing Loss / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D013736:Testicular Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology
chemical_list: D000970:Antineoplastic Agents; D008565:Membrane Proteins; C114987:wolframin protein; D002945:Cisplatin