Genomics-based Mechanistic Investigation of Cancer-treatment Related Cardiotoxicity among Survivors of Childhood Cancer

ABSTRACT Childhood cancer survivors (CCS) experience early onset and a higher burden of cardiovascular disease (CVD) compared to community controls. Such health disparity is largely attributable to cancer treatments at a young age. While the increased risk and high burden of CVD among CCS have been described extensively, there is

little information available from mechanistic investigations that illuminate causal pathways leading from cancer treatment exposures to development of CVD. To better understand the pathogenesis of CVD, there is an urgent need for research that employs an integrated approach to unravel the influence of, and complex interplay

between, prior therapeutic exposures, inherited genetic susceptibility and modifiable health behaviors. In the current grant proposal, we will focus on seven common cardiometabolic outcomes, including five modifiable CVD risk increasing conditions (abnormal glucose metabolism, obesity, hypertension, hypertriglyceridemia and

hypercholesterolemia), and two outcomes of end-organ damage (cardiomyopathy and myocardial infarction) among aging CCS. Our research framework will address the roles of genetic and epigenetic associations with cardiometabolic risk within the context of cancer treatment exposures and post-treatment health behaviors.

Specifically, we will characterize rare pathogenic/likely pathogenic germline variants (PGV) in genes of DNA repair, immune responses, especially inflammation response pathways, and drug metabolism, and evaluate the associations between PGV carriers and cardiometabolic conditions while adjusting for common genetic variants

expressed as a polygenic risk score (PRS). We will investigate variations of DNA methylation and hence altered gene expression as a mechanistic link between exposures (cancer treatments, and/or health behaviors) and cardiometabolic conditions. Furthermore, we will integrate multiple aging biomarkers (clonal hematopoiesis,

leukocyte telomere length and epigenetic age) and evaluate them as additional predictors for cardiometabolic risk. Our study will leverage the singular resource of the St. Jude Lifetime Cohort (SJLIFE) with a three time point longitudinal study design, and novel findings will be validated/replicated among survivors from the Childhood

Cancer Survivor (CCSS) cohort. Of note, multi-omics data generated from this study will not only fulfill the specific aims for this proposed project and will also allow us to generate a functional genomic database encompassing methylation quantitative trait loci, expression quantitative loci and expression quantitative trait methylation. This

reference database will have a meaningful impact on future genetic and genomic studies conducted on CCS. Taken together, we will investigate both “nature” (i.e., inherited genetics) and “nurture” (i.e., exposomes) to comprehensively evaluate the landscape of the cardiometabolic risk factors/predictors in CCS. The successful

completion of this project will provide translational pathways towards surveillance and intervention strategies for improvement of survivorship care as well as generate new hypotheses for future basic science research.