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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 4091-4102 |
| Number of pages | 12 |
| Journal | Cancer |
| Volume | 127 |
| Issue number | 21 |
| DOIs | |
| State | Published - Nov 1 2021 |
Keywords
- genome-wide
- ototoxicity
- pediatric oncology
- radiation
ASJC Scopus subject areas
- Oncology
- Cancer Research
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In: Cancer, Vol. 127, No. 21, 01.11.2021, p. 4091-4102.
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}
TY - JOUR
T1 - Clinical and genetic risk factors for radiation-associated ototoxicity
T2 - A report from the Childhood Cancer Survivor Study and the St. Jude Lifetime Cohort
AU - Trendowski, Matthew R.
AU - Baedke, Jessica L.
AU - Sapkota, Yadav
AU - Travis, Lois B.
AU - Zhang, Xindi
AU - El Charif, Omar
AU - Wheeler, Heather E.
AU - Leisenring, Wendy M.
AU - Robison, Leslie L.
AU - Hudson, Melissa M.
AU - Morton, Lindsay M.
AU - Oeffinger, Kevin C.
AU - Howell, Rebecca M.
AU - Armstrong, Gregory T.
AU - Bhatia, Smita
AU - Dolan, M. Eileen
N1 - Funding Information: This work was supported by the National Cancer Institute (CA55727 [Gregory T. Armstrong, principal investigator] and CA195547 [Melissa M. Hudson and Leslie L. Robison, principal investigators]). Support for St. Jude Children's Research Hospital was also provided by Cancer Center Support (CORE) Grant CA21765 (C. Roberts, principal investigator) and by the American Lebanese Syrian Associated Charities. This work was also supported by grant R01 CA157823 (Lois B. Travis, principal investigator) and the University of Chicago Comprehensive Cancer Center Women's Board (M. Eileen Dolan). The Genotype‐Tissue Expression (GTEx) project was supported by the Common Fund of the Office of the Director of the National Institutes of Health and by the National Cancer Institute, the National Human Genome Research Institute, the National Heart, Lung, and Blood Institute, the National Institute on Drug Abuse, the National Institute of Mental Health, and the National Institute of Neurological Disorders and Stroke. The data used for the analyses described in this article were obtained from the GTEx portal on November 25, 2019. The Database of Genotypes and Phenotypes study accession for the Childhood Cancer Survivor Study is phs001327.v1.p1. Funding Information: This work was supported by the National Cancer Institute (CA55727 [Gregory T. Armstrong, principal investigator] and CA195547 [Melissa M. Hudson and Leslie L. Robison, principal investigators]). Support for St. Jude Children's Research Hospital was also provided by Cancer Center Support (CORE) Grant CA21765 (C. Roberts, principal investigator) and by the American Lebanese Syrian Associated Charities. This work was also supported by grant R01 CA157823 (Lois B. Travis, principal investigator) and the University of Chicago Comprehensive Cancer Center Women's Board (M. Eileen Dolan). The Genotype-Tissue Expression (GTEx) project was supported by the Common Fund of the Office of the Director of the National Institutes of Health and by the National Cancer Institute, the National Human Genome Research Institute, the National Heart, Lung, and Blood Institute, the National Institute on Drug Abuse, the National Institute of Mental Health, and the National Institute of Neurological Disorders and Stroke. The data used for the analyses described in this article were obtained from the GTEx portal on November 25, 2019. The Database of Genotypes and Phenotypes study accession for the Childhood Cancer Survivor Study is phs001327.v1.p1. All patients were enrolled in CCSS, a large, multi-institutional collaboration of 31 participating centers in the United States and Canada coordinated through St. Jude Children's Research Hospital.20 CCSS has characterized demographic-, disease-, and treatment-related variables in 14,631 survivors of childhood/adolescent cancer (diagnosed in 1970-1986) by using medical record abstraction and self-reported surveys. Our analyses were performed on a subset of genotyped patients (n?=?4938) and was limited to 4483 survivors not treated with cisplatin or carboplatin. Human investigations were performed after approval by a local human investigations committee and in accordance with an assurance filed with and approved by the US Department of Health and Human Services. Dataset access (Database of Genotypes and Phenotypes study accession phs001327.v1.p1) was granted by CCSS through an approved protocol. All patients were enrolled in CCSS, a large, multi-institutional collaboration of 31 participating centers in the United States and Canada coordinated through St. Jude Children's Research Hospital.20 CCSS has characterized demographic-, disease-, and treatment-related variables in 14,631 survivors of childhood/adolescent cancer (diagnosed in 1970-1986) by using medical record abstraction and self-reported surveys. Our analyses were performed on a subset of genotyped patients (n?=?4938) and was limited to 4483 survivors not treated with cisplatin or carboplatin. Human investigations were performed after approval by a local human investigations committee and in accordance with an assurance filed with and approved by the US Department of Health and Human Services. Dataset access (Database of Genotypes and Phenotypes study accession phs001327.v1.p1) was granted by CCSS through an approved protocol. On the basis of responses from 2 successive longitudinal follow-up CCSS surveys (Follow-Up 4 and Follow-Up 5), survivors were dichotomized to tinnitus cases/controls on the basis of the following question: ?Have you ever been told by a doctor or other health care professional that you have, or have had: tinnitus or ringing in the ears?? Cases responded ?yes, and condition is still present? on both questionnaires or ?yes, and condition is still present? on one with a missing response on the other. Controls responded ?no? on both questionnaires or ?no? on one with a missing response on the other. Patients who responded ?yes, no longer present? or ?not sure? on either survey were excluded to ensure a well-defined phenotype. The hearing loss status was derived from the following questions: ?Have you ever been told by a doctor or other health care professional that you have, or have had: 1) Problems hearing sounds not requiring a hearing aid? 2) Hearing loss that requires a hearing aid or hearing loss not completely corrected by a hearing aid? 3) Deafness in both ears not completely corrected by a hearing aid?? Cases responded ?yes, and condition is still present? on both questionnaires or on one questionnaire with a missing response on the other. Controls responded ?no? on both questionnaires or ?no? on one with a missing response on the other. Patients indicating different severities of hearing loss on both questionnaires were designated as cases. Although these criteria may have excluded a few patients with ?late-onset? hearing loss (ie, no impairment on Follow-Up 4 and some impairment on Follow-Up 5), this was a conservative approach to establish a clearly defined phenotype. A Consolidated Standards of Reporting Trials diagram describing the exclusion criteria for the CRT-related tinnitus and hearing loss cohorts is provided in Supporting Figure?1. There were 146 cases and 1845 controls for CRT-related tinnitus and 270 cases and 1928 controls for CRT-related hearing loss. All patients in the CRT-related hearing loss and tinnitus cohorts received cranial radiation. The CRT doses were based on a detailed abstraction of individuals' radiotherapy records.21 The maximum prescribed dose (maximum treatment dose) within the brain was taken as the sum of the prescribed doses from all overlapping fields within the brain. For individuals who received radiotherapy to regions other than the brain, the stray dose (from scatter and leakage radiation) was estimated on the basis of proximity to the brain; regions directly adjacent to the brain were assigned stray high and more distant regions were assigned stray low, which were approximated as 2 and 0.2?Gy, respectively. Diagnoses of primary brain tumors were not excluded from CRT-related tinnitus or hearing loss analyses. All patients in this study were of European ancestry according to a genetic principal components analysis as previously described.22,23 Patients completed self-report surveys to ascertain their age at last observation, neurotoxic and other symptoms, lifestyle habits, comorbidities, and medication use. Because the cohort included patients who did not report their tinnitus or hearing loss status at Follow-Up 5, we generated an age at last observation variable reflecting the age of the patient at the last time point the tinnitus or hearing loss status was reported (Follow-Up 4 or Follow-Up 5). Age at last observation was used for age adjustment in both the phenotype association analyses and the GWASs. Age at diagnosis and age at last CRT dose were not significantly associated with tinnitus or hearing loss after adjustments for age at last observation (P?>.05), and they were not considered in the logistic regression models. Persistent dizziness or vertigo was based on responses to the following question: ?Have you ever been told by a doctor or other health care professional that you have, or have had: persistent dizziness or vertigo?? Cases and controls were established on the basis of the same criteria used for tinnitus and hearing loss (cases: ?yes, and condition is still present?; controls: ?no?), with responses being consistent for both surveys or present on one but absent on the other. For self-reported health, patients were asked the following question in relationship to their experience over the preceding 4?weeks: ?In general, would you say your health is: 1) excellent; 2) very good; 3) good; 4) fair; 5) poor?? Because this question was intended to determine patients' current self-reported health, only responses from the most recently completed questionnaire were considered. Responses to the question were used to create an ordinal variable of self-reported health ranging from 1 (excellent) to 5 (poor). 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. To investigate phenotypic correlations between tinnitus/hearing loss and relevant patient characteristics collected from CCSS follow-up questionnaires, univariate and multivariable logistic regressions evaluated statistical significance. Both age9 and cumulative cranial radiation dose25,26 were selected as covariates a priori because of their previous association with CRT-related hearing loss in the pediatric population. Sex was not included as a covariate because it did not significantly improve the fit of the model for the phenotype association analysis. Except as indicated, phenotypes were defined on the basis of patient responses from the Follow-Up 4 and 5 questionnaires, with data from patients with inconsistent answers eliminated from the analysis. Analyses were performed in R 3.3.2, with statistical significance set at P?<.05. GWASs of CRT-related tinnitus and hearing loss were performed in PLINK v1.927,28 with logistic regression assuming additive effects. The maximum CRT dose, age at last observation, and first 20 European genetic principal components22 were included as covariates. Imputation was performed on the basis of 1000 Genomes Project release version 3 reference haplotypes (National Center for Biotechnology Information genome build 37 [hg19]) with IMPUTE (version 2.3.0), as previously described.23,29 Exclusion criteria for samples included ?8% missingness, per-sample heterozygosity <0.11 or >0.16, and sex discordance (X chromosome heterozygosity >5.0% for males or 20.0% for females) and survivors with cryptic relatedness (PI_HAT???0.2) and >5% missingness across samples (tinnitus: n?=?21; hearing loss: n?=?23), as previously described,23 whereas exclusion criteria for single-nucleotide polymorphisms (SNPs) included variants with a minor allele frequency <1% and a Hardy-Weinberg equilibrium test with P?<?1???10?10, as previously described.23,29 Genome-wide significance was set to P?<?5???10?8. Summary GWAS statistics were uploaded to FUMA30 to run a gene-based association analysis and to generate a regional plot surrounding the SNPs most significantly associated with CRT-related tinnitus or hearing loss. SNPs (P?<.05) inputted to FUMA were mapped to 18,991 and 18,897 protein coding genes for tinnitus and hearing loss, respectively, and this produced a significance threshold of P?=?2.63???10?6 or P?=?2.65???10?6. For the gene-based association analysis, the aggregated effect of all SNPs within a gene was analyzed simultaneously in FUMA via MAGMA based on a multiple linear principal components regression.31 FUMA was also used to determine whether SNPs were expression quantitative trait loci (eQTLs) on the basis of 48 tissues in GTEx v6-832 and PsychENCODE33 or whether they affected transcription factor binding on the basis of RegulomeDB.34 The overall deleteriousness of identified SNPs was evaluated in FUMA through Combined Annotation Dependent Depletion (CADD), a tool that evaluates the deleteriousness of single nucleotide variants as well as insertion and deletion variants in the human genome through the integration of annotations from more than 60 different databases into 1 metric.35,36 CADD scores are evaluated on the basis of a scaled metric in which single nucleotide variants within the top 10% of CADD scores are assigned to CADD-10, those within the top 1% are assigned to CADD-20, those with the top 0.1% are assigned to CADD-30, and so forth. Summary statistics for both SNP-based GWASs of CRT-related hearing loss and tinnitus and MAGMA-based gene analysis of CRT-related hearing loss and tinnitus can be found at https://ccss.stjude.org/summa rysta tistics. To validate SNP-ototoxicity associations reaching or approaching genome-wide significance in GWASs of either CRT-related tinnitus or hearing loss, we performed a replication analysis in an independent cohort of childhood cancer survivors of European ancestry from the St. Jude Lifetime Cohort Study (SJLIFE), a clinically assessed, retrospective cohort study with prospective, longitudinal follow-up to characterize health outcomes of adult survivors of pediatric cancer.4 As with the CCSS discovery cohort, patients who received any form of CRT, including stray-low or stray-high cranial radiation, were included in the analysis, whereas patients who received cisplatin or carboplatin were excluded (Supporting Fig.?2). Patients who were present in both the CCSS discovery cohort and the SJLIFE replication cohort were removed from the analysis to ensure the validity of the replication analysis. To establish a comparable CRT-related tinnitus phenotype, the tinnitus status in the SJLIFE cohort was based on the same question used for the CCSS cohort: ?Have you ever been told by a doctor or other health care professional that you have, or have had: tinnitus or ringing in the ears?? Cases were defined as those who responded ?yes, and condition is still present,? and controls were those who responded ?no.? This produced a cohort of 952 patients (cases: 106; controls: 846). Only consistent responses were taken across surveys for the case/control definition, and this allowed for missing responses. For hearing loss, SJLIFE cases and controls were based on the Chang ototoxicity scale, as previously described.37 Patients who developed hearing loss due to other etiologies (congenital, M?ni?re's disease, or noise exposure) were excluded before the analysis. Patients with hearing loss defined as a Chang grade of 1a-4 in their worse ear were designated as cases, whereas patients with a Chang grade of 0 in both ears were designated as controls; this produced a cohort of 331 patients (cases: 156; controls: 175). SNPs were evaluated for statistical significance with logistic regression. Covariates included the maximum radiation dose received to any 1 of the 4 brain segments, the age at last observation, and 20 European genetic principal components accounting for population substructure. Using UK Biobank, a large-scale biomedical database from UK participants with a publicly available GWAS database for 3144 brain function?related phenotypes, including de novo tinnitus and hearing loss in 8148 individuals,38 we performed replication analyses for SNPs reaching or approaching genome-wide significance in GWASs of either CRT-related tinnitus or hearing loss. The UK Biobank tinnitus phenotypes included the following: 1) ?tinnitus: yes, now most or all of the time?; 2) ?non-cancer illness code, self-reported tinnitus?; and 3) ?tinnitus severity/nuisance.? The hearing phenotypes included the following: 1) ?hearing difficulty/problems: yes?; 2) ?hearing difficulty/problems with background noise?; and 3) ?hearing difficulty/problems: I am completely deaf.? Gene expression data in CNS tumor cell lines were obtained from the Cancer Cell Line Encyclopedia.39 Radiosensitivity, measured as the area under the survival curve derived from a linear-quadratic model to fit 9-day viability assay data, was obtained from the RadioGx package in R.40 Spearman correlations and linear regressions were performed between the expression and sensitivity of cancer cell lines with nonmissing expression data in R 3.3.2. Publisher Copyright: © 2021 American Cancer Society
PY - 2021/11/1
Y1 - 2021/11/1
N2 - 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.
AB - 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.
KW - genome-wide
KW - ototoxicity
KW - pediatric oncology
KW - radiation
UR - http://www.scopus.com/inward/record.url?scp=85110459378&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85110459378&partnerID=8YFLogxK
U2 - 10.1002/cncr.33775
DO - 10.1002/cncr.33775
M3 - Article
C2 - 34286861
AN - SCOPUS:85110459378
SN - 0008-543X
VL - 127
SP - 4091
EP - 4102
JO - Cancer
JF - Cancer
IS - 21
ER -