Clinical and genome-wide analysis of cisplatininduced tinnitus implicates novel ototoxic mechanisms

Omar El Charif, Brandon Mapes, Matthew R. Trendowski, Heather E. Wheeler, Claudia Wing, Paul C. Dinh, Robert D. Frisina, Darren R. Feldman, Robert J. Hamilton, David J. Vaughn, Chunkit Fung, Christian Kollmannsberger, Taisei Mushiroda, Michiaki Kubo, Eric R. Gamazon, Nancy J. Cox, Robert Huddart, Shirin Ardeshir-Rouhani-Fard, Patrick Monahan, Sophie D. Fossa & 3 others Lawrence Einhorn, Lois B. Travis, M. Eileen Dolan

Research output: Contribution to journalArticle

Abstract

Purpose: Cisplatin, a commonly used chemotherapeutic, results in tinnitus, the phantom perception of sound. Our purpose was to identify the clinical and genetic determinants of tinnitus among testicular cancer survivors (TCS) following cisplatin-based chemotherapy. Experimental Design: TCS (n = 762) were dichotomized to cases (moderate/severe tinnitus; n = 154) and controls (none; n = 608). Logistic regression was used to evaluate associations with comorbidities and SNP dosages in genome-wide association study (GWAS) following quality control and imputation (covariates: age, noise exposure, cisplatin dose, genetic principal components). Pathway over-representation tests and functional studies in mouse auditory cells were performed. Results: Cisplatin-induced tinnitus (CisIT) significantly associated with age at diagnosis (P = 0.007) and cumulative cisplatin dose (P = 0.007). CisIT prevalence was not significantly greater in 400 mg/m2-treated TCS compared with 300 (P = 0.41), but doses >400 mg/m2 (median 580, range 402-828) increased risk by 2.61-fold (P < 0.0001). CisIT cases had worse hearing at each frequency (0.25-12 kHz, P < 0.0001), and reported more vertigo (OR = 6.47; P < 0.0001) and problems hearing in a crowd (OR = 8.22; P < 0.0001) than controls. Cases reported poorer health (P < 0.0001) and greater psychotropic medication use (OR = 2.4; P = 0.003). GWAS suggested a variant near OTOS (rs7606353, P = 2 × 10-6) and OTOS eQTLs were significantly enriched independently of that SNP (P = 0.018). OTOS overexpression in HEI-OC1, a mouse auditory cell line, resulted in resistance to cisplatin-induced cytotoxicity. Pathway analysis implicated potassium ion transport (q = 0.007). Conclusions: CisIT associated with several neurootological symptoms, increased use of psychotropic medication, and poorer health. OTOS, expressed in the cochlear lateral wall, was implicated as protective. Future studies should investigate otoprotective targets in supporting cochlear cells.

Original languageEnglish (US)
Pages (from-to)4104-4116
Number of pages13
JournalClinical Cancer Research
Volume25
Issue number13
DOIs
StatePublished - Jan 1 2019
Externally publishedYes

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Tinnitus
Cisplatin
Genome
Testicular Neoplasms
Survivors
Genome-Wide Association Study
Cochlea
Hearing
Single Nucleotide Polymorphism
Vertigo
Ion Transport
Health
Quality Control
Noise
Comorbidity
Potassium
Research Design
Logistic Models
Drug Therapy
Cell Line

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

El Charif, O., Mapes, B., Trendowski, M. R., Wheeler, H. E., Wing, C., Dinh, P. C., ... Dolan, M. E. (2019). Clinical and genome-wide analysis of cisplatininduced tinnitus implicates novel ototoxic mechanisms. Clinical Cancer Research, 25(13), 4104-4116. https://doi.org/10.1158/1078-0432.CCR-18-3179

Clinical and genome-wide analysis of cisplatininduced tinnitus implicates novel ototoxic mechanisms. / El Charif, Omar; Mapes, Brandon; Trendowski, Matthew R.; Wheeler, Heather E.; Wing, Claudia; Dinh, Paul C.; Frisina, Robert D.; Feldman, Darren R.; Hamilton, Robert J.; Vaughn, David J.; Fung, Chunkit; Kollmannsberger, Christian; Mushiroda, Taisei; Kubo, Michiaki; Gamazon, Eric R.; Cox, Nancy J.; Huddart, Robert; Ardeshir-Rouhani-Fard, Shirin; Monahan, Patrick; Fossa, Sophie D.; Einhorn, Lawrence; Travis, Lois B.; Dolan, M. Eileen.

In: Clinical Cancer Research, Vol. 25, No. 13, 01.01.2019, p. 4104-4116.

Research output: Contribution to journalArticle

El Charif, O, Mapes, B, Trendowski, MR, Wheeler, HE, Wing, C, Dinh, PC, Frisina, RD, Feldman, DR, Hamilton, RJ, Vaughn, DJ, Fung, C, Kollmannsberger, C, Mushiroda, T, Kubo, M, Gamazon, ER, Cox, NJ, Huddart, R, Ardeshir-Rouhani-Fard, S, Monahan, P, Fossa, SD, Einhorn, L, Travis, LB & Dolan, ME 2019, 'Clinical and genome-wide analysis of cisplatininduced tinnitus implicates novel ototoxic mechanisms', Clinical Cancer Research, vol. 25, no. 13, pp. 4104-4116. https://doi.org/10.1158/1078-0432.CCR-18-3179
El Charif, Omar ; Mapes, Brandon ; Trendowski, Matthew R. ; Wheeler, Heather E. ; Wing, Claudia ; Dinh, Paul C. ; Frisina, Robert D. ; Feldman, Darren R. ; Hamilton, Robert J. ; Vaughn, David J. ; Fung, Chunkit ; Kollmannsberger, Christian ; Mushiroda, Taisei ; Kubo, Michiaki ; Gamazon, Eric R. ; Cox, Nancy J. ; Huddart, Robert ; Ardeshir-Rouhani-Fard, Shirin ; Monahan, Patrick ; Fossa, Sophie D. ; Einhorn, Lawrence ; Travis, Lois B. ; Dolan, M. Eileen. / Clinical and genome-wide analysis of cisplatininduced tinnitus implicates novel ototoxic mechanisms. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 13. pp. 4104-4116.
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abstract = "Purpose: Cisplatin, a commonly used chemotherapeutic, results in tinnitus, the phantom perception of sound. Our purpose was to identify the clinical and genetic determinants of tinnitus among testicular cancer survivors (TCS) following cisplatin-based chemotherapy. Experimental Design: TCS (n = 762) were dichotomized to cases (moderate/severe tinnitus; n = 154) and controls (none; n = 608). Logistic regression was used to evaluate associations with comorbidities and SNP dosages in genome-wide association study (GWAS) following quality control and imputation (covariates: age, noise exposure, cisplatin dose, genetic principal components). Pathway over-representation tests and functional studies in mouse auditory cells were performed. Results: Cisplatin-induced tinnitus (CisIT) significantly associated with age at diagnosis (P = 0.007) and cumulative cisplatin dose (P = 0.007). CisIT prevalence was not significantly greater in 400 mg/m2-treated TCS compared with 300 (P = 0.41), but doses >400 mg/m2 (median 580, range 402-828) increased risk by 2.61-fold (P < 0.0001). CisIT cases had worse hearing at each frequency (0.25-12 kHz, P < 0.0001), and reported more vertigo (OR = 6.47; P < 0.0001) and problems hearing in a crowd (OR = 8.22; P < 0.0001) than controls. Cases reported poorer health (P < 0.0001) and greater psychotropic medication use (OR = 2.4; P = 0.003). GWAS suggested a variant near OTOS (rs7606353, P = 2 × 10-6) and OTOS eQTLs were significantly enriched independently of that SNP (P = 0.018). OTOS overexpression in HEI-OC1, a mouse auditory cell line, resulted in resistance to cisplatin-induced cytotoxicity. Pathway analysis implicated potassium ion transport (q = 0.007). Conclusions: CisIT associated with several neurootological symptoms, increased use of psychotropic medication, and poorer health. OTOS, expressed in the cochlear lateral wall, was implicated as protective. Future studies should investigate otoprotective targets in supporting cochlear cells.",
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T1 - Clinical and genome-wide analysis of cisplatininduced tinnitus implicates novel ototoxic mechanisms

AU - El Charif, Omar

AU - Mapes, Brandon

AU - Trendowski, Matthew R.

AU - Wheeler, Heather E.

AU - Wing, Claudia

AU - Dinh, Paul C.

AU - Frisina, Robert D.

AU - Feldman, Darren R.

AU - Hamilton, Robert J.

AU - Vaughn, David J.

AU - Fung, Chunkit

AU - Kollmannsberger, Christian

AU - Mushiroda, Taisei

AU - Kubo, Michiaki

AU - Gamazon, Eric R.

AU - Cox, Nancy J.

AU - Huddart, Robert

AU - Ardeshir-Rouhani-Fard, Shirin

AU - Monahan, Patrick

AU - Fossa, Sophie D.

AU - Einhorn, Lawrence

AU - Travis, Lois B.

AU - Dolan, M. Eileen

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Purpose: Cisplatin, a commonly used chemotherapeutic, results in tinnitus, the phantom perception of sound. Our purpose was to identify the clinical and genetic determinants of tinnitus among testicular cancer survivors (TCS) following cisplatin-based chemotherapy. Experimental Design: TCS (n = 762) were dichotomized to cases (moderate/severe tinnitus; n = 154) and controls (none; n = 608). Logistic regression was used to evaluate associations with comorbidities and SNP dosages in genome-wide association study (GWAS) following quality control and imputation (covariates: age, noise exposure, cisplatin dose, genetic principal components). Pathway over-representation tests and functional studies in mouse auditory cells were performed. Results: Cisplatin-induced tinnitus (CisIT) significantly associated with age at diagnosis (P = 0.007) and cumulative cisplatin dose (P = 0.007). CisIT prevalence was not significantly greater in 400 mg/m2-treated TCS compared with 300 (P = 0.41), but doses >400 mg/m2 (median 580, range 402-828) increased risk by 2.61-fold (P < 0.0001). CisIT cases had worse hearing at each frequency (0.25-12 kHz, P < 0.0001), and reported more vertigo (OR = 6.47; P < 0.0001) and problems hearing in a crowd (OR = 8.22; P < 0.0001) than controls. Cases reported poorer health (P < 0.0001) and greater psychotropic medication use (OR = 2.4; P = 0.003). GWAS suggested a variant near OTOS (rs7606353, P = 2 × 10-6) and OTOS eQTLs were significantly enriched independently of that SNP (P = 0.018). OTOS overexpression in HEI-OC1, a mouse auditory cell line, resulted in resistance to cisplatin-induced cytotoxicity. Pathway analysis implicated potassium ion transport (q = 0.007). Conclusions: CisIT associated with several neurootological symptoms, increased use of psychotropic medication, and poorer health. OTOS, expressed in the cochlear lateral wall, was implicated as protective. Future studies should investigate otoprotective targets in supporting cochlear cells.

AB - Purpose: Cisplatin, a commonly used chemotherapeutic, results in tinnitus, the phantom perception of sound. Our purpose was to identify the clinical and genetic determinants of tinnitus among testicular cancer survivors (TCS) following cisplatin-based chemotherapy. Experimental Design: TCS (n = 762) were dichotomized to cases (moderate/severe tinnitus; n = 154) and controls (none; n = 608). Logistic regression was used to evaluate associations with comorbidities and SNP dosages in genome-wide association study (GWAS) following quality control and imputation (covariates: age, noise exposure, cisplatin dose, genetic principal components). Pathway over-representation tests and functional studies in mouse auditory cells were performed. Results: Cisplatin-induced tinnitus (CisIT) significantly associated with age at diagnosis (P = 0.007) and cumulative cisplatin dose (P = 0.007). CisIT prevalence was not significantly greater in 400 mg/m2-treated TCS compared with 300 (P = 0.41), but doses >400 mg/m2 (median 580, range 402-828) increased risk by 2.61-fold (P < 0.0001). CisIT cases had worse hearing at each frequency (0.25-12 kHz, P < 0.0001), and reported more vertigo (OR = 6.47; P < 0.0001) and problems hearing in a crowd (OR = 8.22; P < 0.0001) than controls. Cases reported poorer health (P < 0.0001) and greater psychotropic medication use (OR = 2.4; P = 0.003). GWAS suggested a variant near OTOS (rs7606353, P = 2 × 10-6) and OTOS eQTLs were significantly enriched independently of that SNP (P = 0.018). OTOS overexpression in HEI-OC1, a mouse auditory cell line, resulted in resistance to cisplatin-induced cytotoxicity. Pathway analysis implicated potassium ion transport (q = 0.007). Conclusions: CisIT associated with several neurootological symptoms, increased use of psychotropic medication, and poorer health. OTOS, expressed in the cochlear lateral wall, was implicated as protective. Future studies should investigate otoprotective targets in supporting cochlear cells.

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