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The authors sought to identify clinical determinants and genetic risk factors for ototoxicity among adult survivors of pediatric cancer treated with CRT.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>Logistic regression evaluated associations of tinnitus (n\u00a0=\u00a01991) and hearing loss (n\u00a0=\u00a02198) with nongenetic risk factors and comorbidities among CRT\u2010treated survivors in the Childhood Cancer Survivor Study. Genome\u2010wide association studies (GWASs) of CRT\u2010related tinnitus and hearing loss were also performed.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>Males were more likely to report CRT\u2010related tinnitus (9.4% vs 5.4%; <jats:italic>P<\/jats:italic>\u00a0=\u00a05.1\u00a0\u00d7\u00a010<jats:sup>\u22124<\/jats:sup>) and hearing loss (14.0% vs 10.7%; <jats:italic>P<\/jats:italic>\u00a0=\u00a0.02) than females. Survivors with tinnitus or hearing loss were more likely to experience persistent dizziness or vertigo (tinnitus: <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a02\u00a0\u00d7\u00a010<jats:sup>\u221216<\/jats:sup>; hearing loss: <jats:italic>P<\/jats:italic>\u00a0=\u00a06.4\u00a0\u00d7\u00a010<jats:sup>\u22129<\/jats:sup>), take antidepressants (tinnitus: <jats:italic>P<\/jats:italic>\u00a0=\u00a0.02; hearing loss: <jats:italic>P<\/jats:italic>\u00a0=\u00a0.01), and report poorer overall health (tinnitus: <jats:italic>P<\/jats:italic>\u00a0=\u00a01.5\u00a0\u00d7\u00a010<jats:sup>\u22126<\/jats:sup>; hearing loss: <jats:italic>P<\/jats:italic>\u00a0=\u00a01.7\u00a0\u00d7\u00a010<jats:sup>\u22126<\/jats:sup>) in comparison with controls. GWAS of CRT\u2010related tinnitus revealed a genome\u2010wide significant signal in chromosome 1 led by rs203248 (<jats:italic>P<\/jats:italic>\u00a0=\u00a01.5\u00a0\u00d7\u00a010<jats:sup>\u22129<\/jats:sup>), whereas GWAS of CRT\u2010related hearing loss identified rs332013 (<jats:italic>P<\/jats:italic>\u00a0=\u00a05.8\u00a0\u00d7\u00a010<jats:sup>\u22127<\/jats:sup>) in chromosome 8 and rs67522722 (<jats:italic>P<\/jats:italic>\u00a0=\u00a07.8\u00a0\u00d7\u00a010<jats:sup>\u22127<\/jats:sup>) in chromosome 6 as nearly genome\u2010wide significant. A replication analysis identified rs67522722, intronic to <jats:italic>ATXN1<\/jats:italic>, as being significantly associated with CRT\u2010related hearing loss (<jats:italic>P<\/jats:italic>\u00a0=\u00a0.03) and de novo hearing loss (<jats:italic>P<\/jats:italic>\u00a0=\u00a03.6\u00a0\u00d7\u00a010<jats:sup>\u22124<\/jats:sup>).<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>CRT\u2010associated ototoxicity was associated with sex, several neuro\u2010otological symptoms, increased antidepressant use, and poorer self\u2010reported health. GWAS of CRT\u2010related hearing loss identified rs67522722, which was supported in an independent cohort of survivors.<\/jats:p><\/jats:sec><jats:sec><jats:title>LAY SUMMARY<\/jats:title><jats:p>\n<jats:list list-type=\"bullet\">\n\n<jats:list-item><jats:p>Hearing loss and subjective tinnitus (the perception of noise or ringing in the ear) are long\u2010term side effects of cancer treatment and are common in children treated with radiation to the brain.<\/jats:p><\/jats:list-item>\n\n<jats:list-item><jats:p>These toxicities can affect childhood development and potentially contribute to serious learning and behavioral difficulties.<\/jats:p><\/jats:list-item>\n\n<jats:list-item><jats:p>This study's data indicate that males are at greater risk for hearing loss and tinnitus than females after radiation therapy to the brain.<\/jats:p><\/jats:list-item>\n\n<jats:list-item><jats:p>Those who develop these toxicities are more likely to use antidepressants and report poorer overall health.<\/jats:p><\/jats:list-item>\n\n<jats:list-item><jats:p>Health care providers can improve the management of survivors by informing patients and\/or their parents of these risks.<\/jats:p><\/jats:list-item>\n<\/jats:list>\n<\/jats:p><\/jats:sec>","DOI":"10.1002\/cncr.33775","type":"journal-article","created":{"date-parts":[[2021,7,19]],"date-time":"2021-07-19T09:59:38Z","timestamp":1626688778000},"page":"4091-4102","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Clinical and genetic risk factors for radiation\u2010associated ototoxicity: A report from the Childhood Cancer Survivor Study and the St. Jude Lifetime Cohort"],"prefix":"10.1002","volume":"127","author":[{"given":"Matthew R.","family":"Trendowski","sequence":"first","affiliation":[{"name":"Department of Medicine University of Chicago Chicago 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