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Unlocking the Diagnostic and Prognostic Potential of 5hmC in Urine cfDNA: Characterization of Genome-wide Landscape in Healthy Urine and Biomarker Development in Localized Bladder Cancer

Award Number: F30CA288116
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Unlocking the Diagnostic and Prognostic Potential of 5hmC in Urine cfDNA: Characterization of Genome-wide Landscape in Healthy Urine and Biomarker Development in Localized Bladder Cancer - PROJECT SUMMARY/ABSTRACT Epigenetic modifications play a crucial role in mammalian development, cellular differentiation, and disease, with 5-methylcytosine (5mC) being the most well-studied epigenetic modification. 5mC globally represses gene expression and has significant gene-regulatory importance in various diseases. The ten-eleven translocation (TET) family of enzymes can oxidize 5mC to 5-hydroxymethylcytosine (5hmC), which is a stable marker of global transcriptional activation. While previous studies have characterized the role of 5hmC modifications in healthy human tissues and evaluated plasma cell-free DNA (cfDNA) for its biomarker potential in various malignancies, urine cfDNA has not yet been studied. Urine represents a non-invasive, easily collectible, and proximal biofluid to a number of GU diseases. At present, it is unclear how urine cell-free DNA (cfDNA) 5hmC profiles reflect normal physiological conditions and mirror the composition of neighboring tissues. Researchers wonder whether urine cfDNA 5hmC profiles might offer a superior alternative to plasma cfDNA, the current gold standard in liquid biopsy, in the diagnosis of GU cancers like bladder cancer. To address these questions, this proposal seeks to characterize the genome-wide 5hmC landscape of healthy urine and develop biomarkers in the setting of localized bladder cancer. The proposal aims to achieve these objectives through two specific aims. The first aim focuses on identifying sources of unwanted variation, characterizing the genomic and epigenomic 5hmC landscape, and inferring the tissue-of-origin of cell-free DNA (cfDNA) derived from healthy urine samples. To accomplish this aim, a bioinformatic pipeline will be optimized for processing 5hmC profiles from urine cfDNA. The 5hmC regulation in urine cfDNA will be characterized by analyzing its activity on gene bodies, promoters, enhancers, and various regulatory epigenomic regions. This aim also proposes the creation of tools to determine the tissue-of-origin of urine cfDNA and confirm its enrichment for GU tissues compared to plasma cfDNA, highlighting the applicability of urine cfDNA in GU contexts. The insights gained from Aim 1 will provide a reference for evaluating the deviations in 5hmC distribution in urine cfDNA in various cancer and non-cancer disease states. The second aim focuses on developing robust diagnostic and predictive biomarkers for localized bladder cancer. The study will demonstrate the utility of urine cfDNA 5hmC-profiles in bladder cancer diagnosis and treatment surveillance and compare its performance to plasma cfDNA 5hmC profiles. Additionally, a multi- omics classifier model incorporating 5hmC, copy number, and targeted mutational data will be created and validated for predicting minimal residual disease in bladder cancer patients who underwent curative-intent bladder removal surgery. The results from Aim 2 will generate 5hmC signatures that can be used to predict the onset of localized bladder cancer and to predict minimal residual disease. Ultimately, the data from Aim 2 could deliver a set of new gene and enhancer targets that maybe serve as exciting therapeutic targets for prevenation and treatment of bladder cancer.


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 = $55,114 )
2026	2026	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cancer Research Manpower	000	3	3/27/2026	NON-COMPETING CONTINUATION	$54,538
2026	2026	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cancer Research Manpower	001	3	4/16/2026	NON-COMPETING CONTINUATION	$576
														Subtotal = $55,114

Issue Date FY: 2025 ( Subtotal = $54,538 )
2025	2025	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cancer Research Manpower	000	2	6/2/2025	NON-COMPETING CONTINUATION	$54,538
														Subtotal = $54,538

Issue Date FY: 2024 ( Subtotal = $53,974 )
2024	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cancer Research Manpower	002	1	5/7/2024	NEW	$0
2024	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cancer Research Manpower	000	1	2/6/2024	NEW	$52,694
2024	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cancer Research Manpower	001	1	5/7/2024	NEW	$1,280
														Subtotal = $53,974

Grand Total All Awards = $163,626

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Unlocking the Diagnostic and Prognostic Potential of 5hmC in Urine cfDNA: Characterization of Genome-wide Landscape in Healthy Urine and Biomarker Development in Localized Bladder Cancer

Award Number: F30CA288116

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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