Xuexia Wang, Purnima Singh, Romina B Cejas, Liting Zhou, Noha Sharafeldin, Patrick J Trainor, Wendy Landier, Changde Cheng, Lindsey Hageman, Fan Wang, Yadav Sapkota, Yutaka Yasui, Melissa M Hudson, Eric J Chow, Saro H Armenian, Joseph P Neglia, Douglas S Hawkins, Jill P Ginsberg, Paul W Burridge, Gregory T Armstrong, Smita Bhatia
{"title":"儿童癌症幸存者的 DNA 损伤反应和修复基因与蒽环类药物诱发的心肌病：儿童肿瘤学小组和儿童癌症幸存者研究报告》（Childhood's Oncology Group and the Childhood Cancer Survivor Study）。","authors":"Xuexia Wang, Purnima Singh, Romina B Cejas, Liting Zhou, Noha Sharafeldin, Patrick J Trainor, Wendy Landier, Changde Cheng, Lindsey Hageman, Fan Wang, Yadav Sapkota, Yutaka Yasui, Melissa M Hudson, Eric J Chow, Saro H Armenian, Joseph P Neglia, Douglas S Hawkins, Jill P Ginsberg, Paul W Burridge, Gregory T Armstrong, Smita Bhatia","doi":"10.1161/CIRCGEN.124.004813","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Anthracyclines induce cardiotoxicity via DNA double-strand breaks and reactive oxygen species formation, resulting in cardiomyocyte dysfunction. The role of DNA damage response/repair (DDR) genes in anthracycline-induced cardiomyopathy remains unstudied.</p><p><strong>Methods: </strong>We conducted a gene-based and pathway-based analysis to examine the main effect and gene-anthracycline interaction effect between DDR genes and anthracycline-induced cardiomyopathy. A discovery analysis performed with a matched case-control set of anthracycline-exposed non-Hispanic White childhood cancer survivors from Children's Oncology Group-ALTE03N1 (113 cases; 226 controls) was replicated using a cohort of anthracycline-exposed non-Hispanic White childhood cancer survivors from the Childhood Cancer Survivor Study cohort (n=1658; 97 cases). Functional analyses were performed by examining the response to doxorubicin of human-induced pluripotent stem cell-derived cardiomyocytes with CRISPR/Cas9-mediated knockout of prioritized genes.</p><p><strong>Results: </strong>Successfully replicated DDR genes demonstrating main-effect association included <i>FANCC</i> (<i>P</i>=0.037) and <i>XRCC5</i> (<i>P</i>=0.001) and demonstrated gene-anthracycline interaction included <i>MGMT</i> (<i>P</i>=0.041). Knockouts of <i>FANCC</i> and <i>MGMT</i> in human-induced pluripotent stem cell-derived cardiomyocytes demonstrated significant resistance to doxorubicin, suggesting that these genes play a role in anthracycline-induced cardiotoxicity. Successfully replicated DDR pathways demonstrating main-effect association included base excision repair (<i>P</i>=2.7×10<sup>-4</sup>); role of <i>BRCA1</i> in DDR (<i>P</i>=9.2×10<sup>-5</sup>); p53 signaling (<i>P</i><1×10<sup>-16</sup>); role of checkpoint kinases proteins in cell cycle checkpoint control (<i>P</i><1×10<sup>-16</sup>); mismatch repair (<i>P</i><10<sup>-16</sup>); and double-strand break repair by homologous recombination (<i>P</i><1×10<sup>-16</sup>). Successfully replicated DDR pathways demonstrating significant interaction effects included role of <i>BRCA1</i> in DDR (<i>P</i>=1.4×10<sup>-4</sup>); p53 signaling (<i>P<</i>1×10<sup>-16</sup>); the role of checkpoint kinases proteins in cell cycle checkpoint control (<i>P</i><1×10<sup>-16</sup>); mismatch repair (<i>P</i><1×10<sup>-16</sup>); cell cycle: G2/M DNA damage checkpoint regulation (<i>P</i>=0.002); double-strand break repair by homologous recombination (<i>P</i>=0.009); <i>GADD45</i> signaling (<i>P</i>=4.8×10<sup>-4</sup>); and cell cycle control of chromosomal replication (<i>P</i>=4.5×10<sup>-4</sup>).</p><p><strong>Conclusions: </strong>These findings provide evidence for the role of DDR genes and pathways in anthracycline-induced cardiomyopathy and provide a framework for targeted therapeutic interventions.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004813"},"PeriodicalIF":6.0000,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"DNA Damage Response and Repair Genes and Anthracycline-Induced Cardiomyopathy in Childhood Cancer Survivors: A Report From the Children's Oncology Group and the Childhood Cancer Survivor Study.\",\"authors\":\"Xuexia Wang, Purnima Singh, Romina B Cejas, Liting Zhou, Noha Sharafeldin, Patrick J Trainor, Wendy Landier, Changde Cheng, Lindsey Hageman, Fan Wang, Yadav Sapkota, Yutaka Yasui, Melissa M Hudson, Eric J Chow, Saro H Armenian, Joseph P Neglia, Douglas S Hawkins, Jill P Ginsberg, Paul W Burridge, Gregory T Armstrong, Smita Bhatia\",\"doi\":\"10.1161/CIRCGEN.124.004813\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Anthracyclines induce cardiotoxicity via DNA double-strand breaks and reactive oxygen species formation, resulting in cardiomyocyte dysfunction. The role of DNA damage response/repair (DDR) genes in anthracycline-induced cardiomyopathy remains unstudied.</p><p><strong>Methods: </strong>We conducted a gene-based and pathway-based analysis to examine the main effect and gene-anthracycline interaction effect between DDR genes and anthracycline-induced cardiomyopathy. A discovery analysis performed with a matched case-control set of anthracycline-exposed non-Hispanic White childhood cancer survivors from Children's Oncology Group-ALTE03N1 (113 cases; 226 controls) was replicated using a cohort of anthracycline-exposed non-Hispanic White childhood cancer survivors from the Childhood Cancer Survivor Study cohort (n=1658; 97 cases). Functional analyses were performed by examining the response to doxorubicin of human-induced pluripotent stem cell-derived cardiomyocytes with CRISPR/Cas9-mediated knockout of prioritized genes.</p><p><strong>Results: </strong>Successfully replicated DDR genes demonstrating main-effect association included <i>FANCC</i> (<i>P</i>=0.037) and <i>XRCC5</i> (<i>P</i>=0.001) and demonstrated gene-anthracycline interaction included <i>MGMT</i> (<i>P</i>=0.041). Knockouts of <i>FANCC</i> and <i>MGMT</i> in human-induced pluripotent stem cell-derived cardiomyocytes demonstrated significant resistance to doxorubicin, suggesting that these genes play a role in anthracycline-induced cardiotoxicity. Successfully replicated DDR pathways demonstrating main-effect association included base excision repair (<i>P</i>=2.7×10<sup>-4</sup>); role of <i>BRCA1</i> in DDR (<i>P</i>=9.2×10<sup>-5</sup>); p53 signaling (<i>P</i><1×10<sup>-16</sup>); role of checkpoint kinases proteins in cell cycle checkpoint control (<i>P</i><1×10<sup>-16</sup>); mismatch repair (<i>P</i><10<sup>-16</sup>); and double-strand break repair by homologous recombination (<i>P</i><1×10<sup>-16</sup>). Successfully replicated DDR pathways demonstrating significant interaction effects included role of <i>BRCA1</i> in DDR (<i>P</i>=1.4×10<sup>-4</sup>); p53 signaling (<i>P<</i>1×10<sup>-16</sup>); the role of checkpoint kinases proteins in cell cycle checkpoint control (<i>P</i><1×10<sup>-16</sup>); mismatch repair (<i>P</i><1×10<sup>-16</sup>); cell cycle: G2/M DNA damage checkpoint regulation (<i>P</i>=0.002); double-strand break repair by homologous recombination (<i>P</i>=0.009); <i>GADD45</i> signaling (<i>P</i>=4.8×10<sup>-4</sup>); and cell cycle control of chromosomal replication (<i>P</i>=4.5×10<sup>-4</sup>).</p><p><strong>Conclusions: </strong>These findings provide evidence for the role of DDR genes and pathways in anthracycline-induced cardiomyopathy and provide a framework for targeted therapeutic interventions.</p>\",\"PeriodicalId\":10326,\"journal\":{\"name\":\"Circulation: Genomic and Precision Medicine\",\"volume\":\" \",\"pages\":\"e004813\"},\"PeriodicalIF\":6.0000,\"publicationDate\":\"2025-03-28\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Circulation: Genomic and Precision Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1161/CIRCGEN.124.004813\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CARDIAC & CARDIOVASCULAR SYSTEMS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Circulation: Genomic and Precision Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1161/CIRCGEN.124.004813","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
DNA Damage Response and Repair Genes and Anthracycline-Induced Cardiomyopathy in Childhood Cancer Survivors: A Report From the Children's Oncology Group and the Childhood Cancer Survivor Study.
Background: Anthracyclines induce cardiotoxicity via DNA double-strand breaks and reactive oxygen species formation, resulting in cardiomyocyte dysfunction. The role of DNA damage response/repair (DDR) genes in anthracycline-induced cardiomyopathy remains unstudied.
Methods: We conducted a gene-based and pathway-based analysis to examine the main effect and gene-anthracycline interaction effect between DDR genes and anthracycline-induced cardiomyopathy. A discovery analysis performed with a matched case-control set of anthracycline-exposed non-Hispanic White childhood cancer survivors from Children's Oncology Group-ALTE03N1 (113 cases; 226 controls) was replicated using a cohort of anthracycline-exposed non-Hispanic White childhood cancer survivors from the Childhood Cancer Survivor Study cohort (n=1658; 97 cases). Functional analyses were performed by examining the response to doxorubicin of human-induced pluripotent stem cell-derived cardiomyocytes with CRISPR/Cas9-mediated knockout of prioritized genes.
Results: Successfully replicated DDR genes demonstrating main-effect association included FANCC (P=0.037) and XRCC5 (P=0.001) and demonstrated gene-anthracycline interaction included MGMT (P=0.041). Knockouts of FANCC and MGMT in human-induced pluripotent stem cell-derived cardiomyocytes demonstrated significant resistance to doxorubicin, suggesting that these genes play a role in anthracycline-induced cardiotoxicity. Successfully replicated DDR pathways demonstrating main-effect association included base excision repair (P=2.7×10-4); role of BRCA1 in DDR (P=9.2×10-5); p53 signaling (P<1×10-16); role of checkpoint kinases proteins in cell cycle checkpoint control (P<1×10-16); mismatch repair (P<10-16); and double-strand break repair by homologous recombination (P<1×10-16). Successfully replicated DDR pathways demonstrating significant interaction effects included role of BRCA1 in DDR (P=1.4×10-4); p53 signaling (P<1×10-16); the role of checkpoint kinases proteins in cell cycle checkpoint control (P<1×10-16); mismatch repair (P<1×10-16); cell cycle: G2/M DNA damage checkpoint regulation (P=0.002); double-strand break repair by homologous recombination (P=0.009); GADD45 signaling (P=4.8×10-4); and cell cycle control of chromosomal replication (P=4.5×10-4).
Conclusions: These findings provide evidence for the role of DDR genes and pathways in anthracycline-induced cardiomyopathy and provide a framework for targeted therapeutic interventions.
期刊介绍：
Circulation: Genomic and Precision Medicine is a distinguished journal dedicated to advancing the frontiers of cardiovascular genomics and precision medicine. It publishes a diverse array of original research articles that delve into the genetic and molecular underpinnings of cardiovascular diseases. The journal's scope is broad, encompassing studies from human subjects to laboratory models, and from in vitro experiments to computational simulations.
Circulation: Genomic and Precision Medicine is committed to publishing studies that have direct relevance to human cardiovascular biology and disease, with the ultimate goal of improving patient care and outcomes. The journal serves as a platform for researchers to share their groundbreaking work, fostering collaboration and innovation in the field of cardiovascular genomics and precision medicine.
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