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.

Anthracyclines induce cardiotoxicity via DNA double-strand breaks (DSBs) and reactive oxygen species (ROS) formation, resulting in cardiomyocyte dysfunction. The role of DNA damage response/repair (DDR) genes in anthracycline-induced cardiomyopathy remains unstudied. We conducted a gene-based and pathway-based analysis to examine 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 COG-ALTE03N1 was replicated using a cohort of anthracycline-exposed non-Hispanic White childhood cancer survivors from the Childhood Cancer Survivor Study cohort. Functional analyses were performed by examining response to doxorubicin of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM) with CRISPR/Cas9-mediated knockout of candidate genes. Our findings provide evidence for the role of DDR genes and pathways in anthracycline-induced cardiomyopathy and provide a framework for targeted therapeutic targets.

Reference

Xuexia Wang^*, Purnima Singh^*, Romina Cejas, Liting Zhou, Noha Sharafeldin, Patrick Trainor, Wendy Landier, Changde Cheng, Lindsey Hageman, Fan Wang, Yadav Sapkota, Yutaka Yasui, Melissa Hudson, Eric Chow, Saro Armenian, Joseph Neglia, Douglas Hawkins, Jill Ginsberg, Paul Burridge, Gregory Armstrong, and Smita Bhatia.