Clinical and Genome-wide Analysis of Cisplatin-induced Tinnitus Implicates Novel Ototoxic Mechanisms

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 ¼ 762) were dichotomized to cases (moderate/severe tinnitus; n ¼ 154) and controls (none; n ¼ 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 ¼ 0.007) and cumulative cisplatin dose (P ¼ 0.007). CisIT prevalence was not significantly greater in 400 mg/m 2-treated TCS compared with 300 (P ¼ 0.41), but doses >400 mg/m 2 (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 ¼ 6.47; P < 0.0001) and problems hearing in a crowd (OR ¼ 8.22; P < 0.0001) than controls. Cases reported poorer health (P < 0.0001) and greater psychotropic medication use (OR ¼ 2.4; P ¼ 0.003). GWAS suggested a variant near OTOS (rs7606353, P ¼ 2 Â 10 À6) and OTOS eQTLs were significantly enriched independently of that SNP (P ¼ 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 ¼ 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.

Clinical and genetic risk factors for radiation‐associated ototoxicity: A report from the Childhood Cancer Survivor Study and the St. Jude Lifetime Cohort

“…Independently of the age at last observation and the maximum CRT dose, males were 1.7 and 1.3 times more likely than females to experience tinnitus and hearing loss, respectively. Survivors with CRT‐related tinnitus are more likely to experience hearing loss, persistent dizziness/vertigo, poorer self‐reported health, and greater use of antidepressants; this is similar to results found in studies of young adult cancer survivors treated with cisplatin 18 . This indicates deleterious effects of tinnitus on quality of life, regardless of etiology.…”

“…The medication history was discerned though a section of the questionnaire that asked patients to list all relevant medications that they had taken regularly during the 2‐year period before Follow‐Up 4 and Follow‐Up 5. The types of medications extracted from the questionnaires were classified into those for hypertension and depression because both hypertension status and psychotropic drug use have been previously associated with treatment‐related tinnitus and/or hearing loss 18,24 . Variables entered into the logistic regression model for medication use were indicators of any use versus no use.…”

“…However, the mechanisms remain poorly understood, and this has resulted in a lack of effective prophylactic and therapeutic options. Several genome‐wide association studies (GWASs) of cisplatin‐induced hearing loss/tinnitus have been reported, 16–19 but to our knowledge, there have been no GWASs of CRT‐related ototoxicity. In this study, we aimed to identify nongenetic and genetic risk factors associated with radiation‐related ototoxicity within the CCSS, which provides a longitudinal examination of long‐term treatment‐related toxicities.…”

Local Cisplatin Delivery in Mouse Reliably Models Sensorineural Ototoxicity Without Systemic Adverse Effects

“…In addition, the more recently discovered loss of synaptic connections between inner hair cells and auditory neurons can be reliably induced. This is of relevance for modeling another typical outcome in cisplatin-treated patients, the hidden HL phenomenon, cursing with tinnitus, and decreased speech perception in the presence of only mild, or absent, measurable HL ( El Charif et al, 2019 ). By reducing the dose of local cisplatin delivered, a hidden HL situation can be adequately modeled through local delivery ( Supplementary Figure 3 ).…”

Cisplatin Resistance in Testicular Germ Cell Tumors: Current Challenges from Various Perspectives

“…Currently, survival rates frequently surpass 95%, and even patients relapsing or presenting disseminated disease are effectively treated with this agent, given in several successive treatment courses, if needed [ 8 ]. Since, at present, 70% of patients will be diagnosed with the localized disease only [ 9 ], efforts should be directed towards uncovering biomarkers (like vascular invasion [ 10 ]) that discriminate patients that will relapse and thus deserve adjuvant systemic treatment after surgery from those that are cured by orchiectomy alone and can avoid the long-term side effects of this compound and that are already reported to impact the quality of life of young-adult cancer survivors [ 11 , 12 , 13 ]. In other words, avoiding overtreatment should be a major aim of current clinical research; however, on the other side of the spectrum, there are TGCT that develop resistance to cisplatin.…”