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

Award Number: R01CA290112
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/03/2024
PERIOD OF PERFORMANCE END DATE: 04/30/2026
AWARD TERMINATION DATE: 03/04/2026

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $0 )
2026	2025	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Cause and Prevention Research	001	2	3/4/2026	TERMINATION	$0
2026	2025	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Cause and Prevention Research	000	2	1/26/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $689,693 )
2025	2025	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Cause and Prevention Research	001	2	5/22/2025	NON-COMPETING CONTINUATION	$68,969
2025	2025	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Cause and Prevention Research	000	2	4/25/2025	NON-COMPETING CONTINUATION	$620,724
														Subtotal = $689,693

Issue Date FY: 2024 ( Subtotal = $683,650 )
2024	2024	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Cause and Prevention Research	000	1	5/3/2024	NEW	$683,650
														Subtotal = $683,650

Grand Total All Awards = $1,373,343

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

Award Number: R01CA290112

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/03/2024

PERIOD OF PERFORMANCE END DATE: 04/30/2026

AWARD TERMINATION DATE: 03/04/2026

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