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.

Keywords: genome-wide; ototoxicity; pediatric oncology; radiation.

Figure 1.. Effects of Maximum Cranial Radiation Dose on Proportion of Patients with Radiation-Associated Ototoxicity.

The overall proportion of pediatric cancer survivors with A) tinnitus (p=4.82×10⁻¹⁴) or B) hearing loss (p<2×10⁻¹⁶) based on maximum cranial radiation dose is provided. Statistical significance is based on logistic regression, and sample sizes for each group are indicated within each panel on the x-axis.

Figure 2.. Genome-Wide Association Studies of Radiation-Associated Ototoxicity in Pediatric Cancer Survivors.

A) Manhattan plot of GWAS results for CRT-related tinnitus reveals a prominent signal in chromosome 1 exceeding genome-wide significance (p<5×10⁻⁸), with the most significant SNP being rs203248 (p=1.50×10⁻⁹). B) Quantile-Quantile plot of GWAS results for CRT-related tinnitus. C) Manhattan plot of GWAS results for CRT-related hearing loss reveals rs332013 in chromosome 8 (p=5.79×10⁻⁷) and rs67522722 (p=7.78×10⁻⁷) in chromosome 6 as nearly genome-wide significant. D) Quantile-Quantile plot of GWAS results for CRT-related hearing loss. Covariates in both GWAS include maximum cranial radiation dose, age at last observation, and 20 European genetic principal components accounting for population substructure.

Figure 3.. Scatter Plots of Radiosensitivity as a Function of Normalized NAV2 or MPC2 Expression.

Scatter plots of radiosensitivity as a function of normalized gene expression are provided for A) NAV2 (ρ=0.48, p=0.003; R²=0.18, p=0.01) and B) MPC2 (ρ=0.35, p=0.04; R²=0.08, p=0.10). Radiosensitivity, measured as the area under the survival curve derived from a linear-quadratic model to fit 9-day viability assay data, for all 36 CNS tumor cell lines, was obtained from the RadioGx package in R, and normalized gene expression data were downloaded from the Cancer Cell Line Encyclopedia. Correlation was assessed nonparametrically using the Spearman rank method, as well as by linear regression.