PMID- 28039263 OWN - NLM STAT- MEDLINE DCOM- 20180503 LR - 20220414 IS - 1557-3265 (Electronic) IS - 1078-0432 (Print) IS - 1078-0432 (Linking) VI - 23 IP - 13 DP - 2017 Jul 1 TI - Variants in WFS1 and Other Mendelian Deafness Genes Are Associated with Cisplatin-Associated Ototoxicity. PG - 3325-3333 LID - 10.1158/1078-0432.CCR-16-2809 [doi] AB - 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 x 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. (c)2016 AACR. CI - (c)2016 American Association for Cancer Research. FAU - Wheeler, Heather E AU - Wheeler HE AD - Department of Biology, Loyola University Chicago, Chicago, Illinois. AD - Department of Computer Science, Loyola University Chicago, Chicago, Illinois. FAU - Gamazon, Eric R AU - Gamazon ER AD - Division of Genetic Medicine, Vanderbilt University, Nashville, Tennessee. AD - Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. FAU - Frisina, Robert D AU - Frisina RD AD - Department of Chemical and Biomedical Engineering, University of South Florida, Tampa, Florida. AD - Department of Communication Sciences and Disorders, Global Center for Hearing and Speech Research, University of South Florida, Tampa, Florida. FAU - Perez-Cervantes, Carlos AU - Perez-Cervantes C AD - Department of Biology, Loyola University Chicago, Chicago, Illinois. AD - Department of Computer Science, Loyola University Chicago, Chicago, Illinois. FAU - El Charif, Omar AU - El Charif O AD - Department of Medicine, University of Chicago, Chicago, Illinois. FAU - Mapes, Brandon AU - Mapes B AD - Department of Medicine, University of Chicago, Chicago, Illinois. FAU - Fossa, Sophie D AU - Fossa SD AD - Department of Oncology, Oslo University Hospital, Radiumhospital, Oslo, Norway. FAU - Feldman, Darren R AU - Feldman DR AD - Department of Medical Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York. FAU - Hamilton, Robert J AU - Hamilton RJ AD - Department of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. FAU - Vaughn, David J AU - Vaughn DJ AD - Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. FAU - Beard, Clair J AU - Beard CJ AD - Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. FAU - Fung, Chunkit AU - Fung C AD - J.P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York. FAU - Kollmannsberger, Christian AU - Kollmannsberger C AD - Division of Medical Oncology, University of British Columbia, Vancouver, British Columbia, Canada. FAU - Kim, Jeri AU - Kim J AD - Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. FAU - Mushiroda, Taisei AU - Mushiroda T AD - RIKEN Center for Integrative Medical Science, Yokohama, Japan. FAU - Kubo, Michiaki AU - Kubo M AD - RIKEN Center for Integrative Medical Science, Yokohama, Japan. FAU - Ardeshir-Rouhani-Fard, Shirin AU - Ardeshir-Rouhani-Fard S AD - Department of Medical Oncology, Indiana University, Indianapolis, Indiana. FAU - Einhorn, Lawrence H AU - Einhorn LH AD - Department of Medical Oncology, Indiana University, Indianapolis, Indiana. leinhorn@iupui.edu. FAU - Cox, Nancy J AU - Cox NJ AD - Division of Genetic Medicine, Vanderbilt University, Nashville, Tennessee. FAU - Dolan, M Eileen AU - Dolan ME AD - Department of Medicine, University of Chicago, Chicago, Illinois. FAU - Travis, Lois B AU - Travis LB AD - Department of Medical Oncology, Indiana University, Indianapolis, Indiana. LA - eng GR - P50 MH094267/MH/NIMH NIH HHS/United States GR - R01 CA157823/CA/NCI NIH HHS/United States GR - P30 CA008748/CA/NCI NIH HHS/United States GR - U19 GM061390/GM/NIGMS NIH HHS/United States GR - R01 MH101820/MH/NIMH NIH HHS/United States GR - R01 MH090937/MH/NIMH NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20161230 PL - United States TA - Clin Cancer Res JT - Clinical cancer research : an official journal of the American Association for Cancer Research JID - 9502500 RN - 0 (Antineoplastic Agents) RN - 0 (Membrane Proteins) RN - 0 (wolframin protein) RN - Q20Q21Q62J (Cisplatin) SB - IM MH - Antineoplastic Agents/adverse effects MH - Cisplatin/administration & dosage/*adverse effects MH - Female MH - Genome-Wide Association Study MH - Genotype MH - Hearing Loss/chemically induced/*genetics/pathology MH - Humans MH - Male MH - Membrane Proteins/*genetics MH - Polymorphism, Single Nucleotide/genetics MH - Testicular Neoplasms/drug therapy/*genetics/physiopathology PMC - PMC5493516 MID - NIHMS839776 COIS- Conflicts of Interest: The authors declare no potential conflicts of interest. EDAT- 2017/01/01 06:00 MHDA- 2018/05/04 06:00 PMCR- 2018/07/01 CRDT- 2017/01/01 06:00 PHST- 2016/11/08 00:00 [received] PHST- 2016/12/09 00:00 [revised] PHST- 2016/12/13 00:00 [accepted] PHST- 2017/01/01 06:00 [pubmed] PHST- 2018/05/04 06:00 [medline] PHST- 2017/01/01 06:00 [entrez] PHST- 2018/07/01 00:00 [pmc-release] AID - 1078-0432.CCR-16-2809 [pii] AID - 10.1158/1078-0432.CCR-16-2809 [doi] PST - ppublish SO - Clin Cancer Res. 2017 Jul 1;23(13):3325-3333. doi: 10.1158/1078-0432.CCR-16-2809. Epub 2016 Dec 30.