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

Abstract

BACKGROUND Cranial radiation therapy (CRT) is associated with ototoxicity, which manifests as hearing loss and tinnitus. The authors sought to identify clinical determinants and genetic risk factors for ototoxicity among adult survivors of pediatric cancer treated with CRT. METHODS Logistic regression evaluated associations of tinnitus (n = 1991) and hearing loss (n = 2198) with nongenetic risk factors and comorbidities among CRT‐treated survivors in the Childhood Cancer Survivor Study. Genome‐wide association studies (GWASs) of CRT‐related tinnitus and hearing loss were also performed. RESULTS Males were more likely to report CRT‐related tinnitus (9.4% vs 5.4%; P = 5.1 × 10−4) and hearing loss (14.0% vs 10.7%; P = .02) than females. Survivors with tinnitus or hearing loss were more likely to experience persistent dizziness or vertigo (tinnitus: P < 2 × 10−16; hearing loss: P = 6.4 × 10−9), take antidepressants (tinnitus: P = .02; hearing loss: P = .01), and report poorer overall health (tinnitus: P = 1.5 × 10−6; hearing loss: P = 1.7 × 10−6) in comparison with controls. GWAS of CRT‐related tinnitus revealed a genome‐wide significant signal in chromosome 1 led by rs203248 (P = 1.5 × 10−9), whereas GWAS of CRT‐related hearing loss identified rs332013 (P = 5.8 × 10−7) in chromosome 8 and rs67522722 (P = 7.8 × 10−7) in chromosome 6 as nearly genome‐wide significant. A replication analysis identified rs67522722, intronic to ATXN1, as being significantly associated with CRT‐related hearing loss (P = .03) and de novo hearing loss (P = 3.6 × 10−4). CONCLUSIONS CRT‐associated ototoxicity was associated with sex, several neuro‐otological symptoms, increased antidepressant use, and poorer self‐reported health. GWAS of CRT‐related hearing loss identified rs67522722, which was supported in an independent cohort of survivors. LAY SUMMARY Hearing loss and subjective tinnitus (the perception of noise or ringing in the ear) are long‐term side effects of cancer treatment and are common in children treated with radiation to the brain. These toxicities can affect childhood development and potentially contribute to serious learning and behavioral difficulties. This study's data indicate that males are at greater risk for hearing loss and tinnitus than females after radiation therapy to the brain. Those who develop these toxicities are more likely to use antidepressants and report poorer overall health. Health care providers can improve the management of survivors by informing patients and/or their parents of these risks.

Clinical and genome-wide association analysis of chemoradiation-induced hearing loss in nasopharyngeal carcinoma

“…A systematic review demonstrated that self-reported hearing loss based on questionnaires could accurately distinguish subjects with hearing difficulty from those without hearing difficulty (Chou et al 2011 ). Previous studies utilizing self-reported hearing status have also successfully identified several genetic variants for radiation-related hearing loss in childhood cancer survivors (Trendowski et al 2021 ), and age-related hearing impairment in UK Biobank populations (Wells et al 2019 ). Therefore, we think hearing evaluation based on subjective sensation may be a feasible and cost-effective measurement for alternative, when audiometry test is absent.…”

“…Similarly, we examined the correlations of gene expression with radiosensitivity in the cell line types mentioned above (Trendowski et al 2021 ). Radiosensitivity was measured by the surviving fraction after 2 Gy radiation (SF2) from the 9-days viability assay in tumor cell lines (Yard et al 2016 ).…”

“…Nevertheless, these clinical parameters could not fully account for inter-patient variability, suggesting there remain other potential factors playing roles in individual predisposition to treatment-induced hearing loss. Genome-wide association studies (GWASs) have reported that genetic variants were associated with cisplatin or radiation-induced ototoxicity in pediatric cancer survivors (mainly medulloblastoma, osteosarcoma, and acute lymphoblastic leukemia) or adult testicular patients (Xu et al 2015 ; Wheeler et al 2017 ; Meijer et al 2021 ; Trendowski et al 2021 ), indicating the underlying role of genetic variants in cisplatin or radiation-induced hearing loss. However, previous GWASs were mainly conducted in European populations of pediatric patients and those with certain cancer types, only focusing on the risk of hearing loss induced by cisplatin or radiotherapy alone.…”

Ranking Breast Cancer Drugs and Biomarkers Identification Using Machine Learning and Pharmacogenomics

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Neurobehavioral Impairment in Pediatric Brain Tumor Survivors: A Meta-Analysis

“…Given the increased survival in PBTS, there needs to be more efforts to understand and improve the long-term outcomes [28], particularly the risk of neurobehavioral impairments such as emotional, psychosocial, and attention problems. Such information will be useful to ensure that PBTS at risk of neurobehavioral impairment can receive early diagnosis and interventions.…”