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.