{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T21:09:10Z","timestamp":1753736950733,"version":"3.41.0"},"reference-count":34,"publisher":"American Medical Association (AMA)","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"Importance<\/jats:title>Cancer therapy\u2013related cardiomyopathy (CCM) is an important concern for childhood cancer survivors. In the general population, rare variants in TTN<\/jats:italic> and BAG3<\/jats:italic> are associated with an increased risk of familial dilated cardiomyopathy, and common variants are associated with a decreased risk of sporadic dilated cardiomyopathy.<\/jats:p><\/jats:sec>Objectives<\/jats:title>To examine associations of common and rare protein-altering variants (PAVs) in TTN<\/jats:italic> and BAG3<\/jats:italic> with late-onset CCM risk in childhood cancer survivors.<\/jats:p><\/jats:sec>Design, Setting, and Participants<\/jats:title>This retrospective cohort study with a prospective follow-up included childhood cancer survivors from the St Jude Lifetime Cohort (SJLIFE) and the Childhood Cancer Survivor Study (CCSS) with prior exposure to anthracyclines and\/or chest-directed radiation. Cancer therapy\u2013related cardiomyopathy was clinically assessed in SJLIFE and self-reported in CCSS, with severity graded using Common Terminology Criteria for Adverse Events, version 4.03. The data analysis was conducted from January 4, 2023, to March 6, 2025.<\/jats:p><\/jats:sec>Exposure<\/jats:title>Late-onset CCM.<\/jats:p><\/jats:sec>Main Outcome and Measures<\/jats:title>Multivariable logistic regression was used to evaluate the association of common variants in TTN<\/jats:italic> and BAG3<\/jats:italic> with late-onset CCM risk, adjusting for relevant demographic and cancer treatment exposures. In SJLIFE alone, 7 echocardiographic parameters were assessed. Rare PAVs were examined using Fisher exact test. Cohort-specific results were combined using meta-analytic approaches.<\/jats:p><\/jats:sec>Results<\/jats:title>The cohort included 1843 childhood cancer survivors from SJLIFE (median [IQR] age at CCM diagnosis, 34.9 [28.0-42.3] years; 53.2% male) and 4577 from CCSS (median [IQR] age at CCM diagnosis, 32.0 [23.0-41.0] years; 51.6% female). In the combined sample of European ancestry survivors from SJLIFE (205 with CCM grade \u22652) and CCSS (248 with CCM grade \u22652), common variants rs3829746-C in TTN<\/jats:italic> (odds ratio,\u20090.81; 95% CI, 0.68-0.97) and rs2234962-C in BAG3<\/jats:italic> (odds ratio,\u20090.79; 95% CI, 0.65-0.95) were associated with a decreased risk of late-onset CCM. In SJLIFE African ancestry survivors, no association was observed with either of the common variants. Rare PAVs were not associated with late-onset CCM in European or African ancestry survivors. In European ancestry survivors, both rs3829746-C and rs2234962-C were also associated with reduced left ventricular end-systolic volume (\u03b2\u2009[SE],\u2009\u22121.90 [0.65] and \u22122.68 [0.64], respectively) and global longitudinal peak strain (\u03b2\u2009[SE], \u22120.31 [0.13] and \u22120.30 [0.12]) and with increased left ventricular ejection fraction (\u03b2\u2009[SE],\u20090.62 [0.27] and 0.86 [0.27], respectively).<\/jats:p><\/jats:sec>Conclusions and Relevance<\/jats:title>The findings of this cohort study show that common variants in TTN<\/jats:italic> and BAG3<\/jats:italic> are associated with a decreased risk of late-onset CCM among childhood cancer survivors, while rare PAVs showed no association.<\/jats:p><\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2025.15793","type":"journal-article","created":{"date-parts":[[2025,6,20]],"date-time":"2025-06-20T15:00:21Z","timestamp":1750431621000},"page":"e2515793","source":"Crossref","is-referenced-by-count":1,"title":["TTN<\/i> and BAG3<\/i> in Cancer Therapy\u2013Related Cardiomyopathy Among Long-Term Survivors of Childhood Cancer"],"prefix":"10.1001","volume":"8","author":[{"given":"Achal","family":"Neupane","sequence":"first","affiliation":[{"name":"Department of Epidemiology and Cancer Control, St Jude Children\u2019s Research Hospital, Memphis, Tennessee"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kateryna","family":"Petrykey","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Cancer Control, St Jude Children\u2019s Research Hospital, Memphis, Tennessee"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kendrick","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, St Jude Children\u2019s Research Hospital, Memphis, Tennessee"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer","family":"French","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Cancer Control, St Jude Children\u2019s Research Hospital, Memphis, Tennessee"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Computational Biology, St Jude Children\u2019s Research Hospital, Memphis, Tennessee"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Computational Biology, St Jude Children\u2019s Research Hospital, Memphis, Tennessee"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cindy","family":"Im","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Minnesota, Minneapolis"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie B.","family":"Dixon","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Cancer Control, St Jude Children\u2019s Research Hospital, Memphis, Tennessee"},{"name":"Department of Oncology, St Jude Children\u2019s Research Hospital, Memphis, Tennessee"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew J.","family":"Ehrhardt","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Cancer Control, St Jude Children\u2019s Research Hospital, Memphis, Tennessee"},{"name":"Department of Oncology, St Jude Children\u2019s Research Hospital, Memphis, Tennessee"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel A.","family":"Mulrooney","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Cancer Control, St Jude Children\u2019s Research Hospital, Memphis, Tennessee"},{"name":"Department of Oncology, St Jude Children\u2019s Research Hospital, Memphis, Tennessee"},{"name":"School of Public Health, University of Memphis, Memphis, Tennessee"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John L.","family":"Jefferies","sequence":"additional","affiliation":[{"name":"School of Public Health, University of Memphis, Memphis, Tennessee"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. 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