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.