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.
