The mutational landscape underlying the late effects of anthracyclines on tumor, blood, and heart genomes

Motivation : Anthracyclines, an essential chemotherapy, disproportionately contributes to several late effects burdening survivors of cancer, including cancer relapse, therapy-related blood cancers, and fatal cardiotoxicity. Despite decades of clinical use, the mechanisms underlying these late effects - particularly how anthracyclines damage the genome of neoplastic and non-neoplastic tissues (blood and heart) - remain poorly understood. A deeper understanding of the tissue-specific mutational outcomes of anthracyclines could yield promising biomarkers to improve survivorship care for survivors of cancer. Methods : We assembled a cohort of untreated or anthracycline-treated tumor, blood, and heart samples. Tumors and blood were leveraged from childhood cancer patients enrolled in the SickKids Cancer Sequencing Program. Heart samples were obtained from cancer survivors who received anthracyclines and later developed severe cardiotoxicity that required a heart transplant. We sequenced the DNA of each tissue type to identify anthracycline-induced somatic mutations. Results: Our initial results revealed minimal genome-wide mutational differences between anthracycline-treated versus untreated samples across all tissue types. We hypothesized that anthracyclines may cause localized mutagenesis in unique genomic topographies. Indeed, we found that anthracycline-treated tissues had a strong enrichment of somatic mutations in open chromatin of their respective cell of origin but differed based on the mutation type. Anthracycline-treated tumors had an enrichment of single nucleotide variants in promoters and introns, but depletion of deletions in exonic regions. However, leveraging matched blood samples from these cancer patients demonstrated that anthracycline-treated blood samples had an enrichment for deletions in open chromatin of various blood cell types. Despite the heart's non-proliferative capacity, anthracycline-treated hearts had a significant enrichment of insertion-deletions in fetal cardiomyocyte open chromatin and non-B DNA regions. Lastly, comparative analysis of the somatic mutational profiles of anthracycline-exposed hearts, tumors, and blood samples, we uncovered previously underappreciated tissue-specific mutational signatures. Significance: This study is the first to characterize the tissue-specific genomic consequences of anthracyclines on tumors, blood, and heart. The early identification of high-risk patients will transform survivorship care, ensuring children with cancer do not merely survive their diagnosis - they thrive beyond it.