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

Heather E. Wheeler, Eric R. Gamazon, Robert D. Frisina, Carlos Perez-Cervantes, Omar El Charif, Brandon Mapes, Sophie D. Fossa, Darren R. Feldman, Robert J. Hamilton, David J. Vaughn, Clair J. Beard, Chunkit Fung, Christian Kollmannsberger, Jeri Kim, Taisei Mushiroda, Michiaki Kubo, Shirin Ardeshir-Rouhani-Fard, Lawrence H. Einhorn, Nancy J. Cox, M. Eileen Dolan & 1 others Lois B. Travis

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Purpose: Cisplatin is one of the most commonly used chemo-genotype was evident, indicating that higher cisplatin doses therapy drugs worldwide and one of the most ototoxic. We sought exacerbate hearing loss in patients with the minor allele to identify genetic variants that modulate cisplatin-associated (P ¼ 0.035). The association between decreased WFS1 ototoxicity (CAO). expression and hearing loss was replicated in an indepen-Experimental Design: We performed a genome-wide associa-dent BioVU cohort (n ¼ 18,620 patients, Bonferroni adjusted tion study (GWAS) of CAO using quantitative audiometry (4–12 P < 0.05). Beyond this top signal, we show CAO is a poly-kHz) in 511 testicular cancer survivors of European genetic genic trait and that SNPs in and near 84 known Mendelian ancestry. We performed polygenic modeling and functional anal-deafness genes are significantly enriched for low P values in yses using a variety of publicly available databases. We used an the GWAS (P ¼ 0.048). electronic health record cohort to replicate our top mechanistic Conclusions: We show for the first time the role of WFS1 finding. in CAO and document a statistically significant interaction Results: One SNP, rs62283056, in the first intron of between increasing cumulative cisplatin dose and rs62283056 Mendelian deafness gene WFS1 (wolframin ER transmem-genotype. Our clinical translational results demonstrate that brane glycoprotein) and an expression quantitative trait pretherapy patient genotyping to minimize ototoxicity could locus (eQTL) for WFS1 met genome-wide significance for be useful when deciding between cisplatin-based chemother-association with CAO (P ¼ 1.4 108). A significant inter-apy regimens of comparable efficacy with different cumulative action between cumulative cisplatin dose and rs62283056 doses.

Original languageEnglish
Pages (from-to)3325-3333
Number of pages9
JournalClinical Cancer Research
Volume23
Issue number13
DOIs
Publication statusPublished - 01-07-2017

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Deafness
Cisplatin
Genes
Genome-Wide Association Study
Hearing Loss
Single Nucleotide Polymorphism
Genotype
Genome
Audiometry
Electronic Health Records
Testicular Neoplasms
Introns
Survivors
Glycoproteins
Research Design
Alleles
Databases
Drug Therapy

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Wheeler, H. E., Gamazon, E. R., Frisina, R. D., Perez-Cervantes, C., Charif, O. E., Mapes, B., ... Travis, L. B. (2017). Variants in WFS1 and other mendelian deafness genes are associated with cisplatin-associated ototoxicity. Clinical Cancer Research, 23(13), 3325-3333. https://doi.org/10.1158/1078-0432.CCR-16-2809
Wheeler, Heather E. ; Gamazon, Eric R. ; Frisina, Robert D. ; Perez-Cervantes, Carlos ; Charif, Omar El ; Mapes, Brandon ; Fossa, Sophie D. ; Feldman, Darren R. ; Hamilton, Robert J. ; Vaughn, David J. ; Beard, Clair J. ; Fung, Chunkit ; Kollmannsberger, Christian ; Kim, Jeri ; Mushiroda, Taisei ; Kubo, Michiaki ; Ardeshir-Rouhani-Fard, Shirin ; Einhorn, Lawrence H. ; Cox, Nancy J. ; Dolan, M. Eileen ; Travis, Lois B. / Variants in WFS1 and other mendelian deafness genes are associated with cisplatin-associated ototoxicity. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 13. pp. 3325-3333.
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abstract = "Purpose: Cisplatin is one of the most commonly used chemo-genotype was evident, indicating that higher cisplatin doses therapy drugs worldwide and one of the most ototoxic. We sought exacerbate hearing loss in patients with the minor allele to identify genetic variants that modulate cisplatin-associated (P ¼ 0.035). The association between decreased WFS1 ototoxicity (CAO). expression and hearing loss was replicated in an indepen-Experimental Design: We performed a genome-wide associa-dent BioVU cohort (n ¼ 18,620 patients, Bonferroni adjusted tion study (GWAS) of CAO using quantitative audiometry (4–12 P < 0.05). Beyond this top signal, we show CAO is a poly-kHz) in 511 testicular cancer survivors of European genetic genic trait and that SNPs in and near 84 known Mendelian ancestry. We performed polygenic modeling and functional anal-deafness genes are significantly enriched for low P values in yses using a variety of publicly available databases. We used an the GWAS (P ¼ 0.048). electronic health record cohort to replicate our top mechanistic Conclusions: We show for the first time the role of WFS1 finding. in CAO and document a statistically significant interaction Results: One SNP, rs62283056, in the first intron of between increasing cumulative cisplatin dose and rs62283056 Mendelian deafness gene WFS1 (wolframin ER transmem-genotype. Our clinical translational results demonstrate that brane glycoprotein) and an expression quantitative trait pretherapy patient genotyping to minimize ototoxicity could locus (eQTL) for WFS1 met genome-wide significance for be useful when deciding between cisplatin-based chemother-association with CAO (P ¼ 1.4 108). A significant inter-apy regimens of comparable efficacy with different cumulative action between cumulative cisplatin dose and rs62283056 doses.",
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Wheeler, HE, Gamazon, ER, Frisina, RD, Perez-Cervantes, C, Charif, OE, Mapes, B, Fossa, SD, Feldman, DR, Hamilton, RJ, Vaughn, DJ, Beard, CJ, Fung, C, Kollmannsberger, C, Kim, J, Mushiroda, T, Kubo, M, Ardeshir-Rouhani-Fard, S, Einhorn, LH, Cox, NJ, Dolan, ME & Travis, LB 2017, 'Variants in WFS1 and other mendelian deafness genes are associated with cisplatin-associated ototoxicity', Clinical Cancer Research, vol. 23, no. 13, pp. 3325-3333. https://doi.org/10.1158/1078-0432.CCR-16-2809

Variants in WFS1 and other mendelian deafness genes are associated with cisplatin-associated ototoxicity. / Wheeler, Heather E.; Gamazon, Eric R.; Frisina, Robert D.; Perez-Cervantes, Carlos; Charif, Omar El; Mapes, Brandon; Fossa, Sophie D.; Feldman, Darren R.; Hamilton, Robert J.; Vaughn, David J.; Beard, Clair J.; Fung, Chunkit; Kollmannsberger, Christian; Kim, Jeri; Mushiroda, Taisei; Kubo, Michiaki; Ardeshir-Rouhani-Fard, Shirin; Einhorn, Lawrence H.; Cox, Nancy J.; Dolan, M. Eileen; Travis, Lois B.

In: Clinical Cancer Research, Vol. 23, No. 13, 01.07.2017, p. 3325-3333.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Variants in WFS1 and other mendelian deafness genes are associated with cisplatin-associated ototoxicity

AU - Wheeler, Heather E.

AU - Gamazon, Eric R.

AU - Frisina, Robert D.

AU - Perez-Cervantes, Carlos

AU - Charif, Omar El

AU - Mapes, Brandon

AU - Fossa, Sophie D.

AU - Feldman, Darren R.

AU - Hamilton, Robert J.

AU - Vaughn, David J.

AU - Beard, Clair J.

AU - Fung, Chunkit

AU - Kollmannsberger, Christian

AU - Kim, Jeri

AU - Mushiroda, Taisei

AU - Kubo, Michiaki

AU - Ardeshir-Rouhani-Fard, Shirin

AU - Einhorn, Lawrence H.

AU - Cox, Nancy J.

AU - Dolan, M. Eileen

AU - Travis, Lois B.

PY - 2017/7/1

Y1 - 2017/7/1

N2 - Purpose: Cisplatin is one of the most commonly used chemo-genotype was evident, indicating that higher cisplatin doses therapy drugs worldwide and one of the most ototoxic. We sought exacerbate hearing loss in patients with the minor allele to identify genetic variants that modulate cisplatin-associated (P ¼ 0.035). The association between decreased WFS1 ototoxicity (CAO). expression and hearing loss was replicated in an indepen-Experimental Design: We performed a genome-wide associa-dent BioVU cohort (n ¼ 18,620 patients, Bonferroni adjusted tion study (GWAS) of CAO using quantitative audiometry (4–12 P < 0.05). Beyond this top signal, we show CAO is a poly-kHz) in 511 testicular cancer survivors of European genetic genic trait and that SNPs in and near 84 known Mendelian ancestry. We performed polygenic modeling and functional anal-deafness genes are significantly enriched for low P values in yses using a variety of publicly available databases. We used an the GWAS (P ¼ 0.048). electronic health record cohort to replicate our top mechanistic Conclusions: We show for the first time the role of WFS1 finding. in CAO and document a statistically significant interaction Results: One SNP, rs62283056, in the first intron of between increasing cumulative cisplatin dose and rs62283056 Mendelian deafness gene WFS1 (wolframin ER transmem-genotype. Our clinical translational results demonstrate that brane glycoprotein) and an expression quantitative trait pretherapy patient genotyping to minimize ototoxicity could locus (eQTL) for WFS1 met genome-wide significance for be useful when deciding between cisplatin-based chemother-association with CAO (P ¼ 1.4 108). A significant inter-apy regimens of comparable efficacy with different cumulative action between cumulative cisplatin dose and rs62283056 doses.

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