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Developing Mutation Signature Extraction (MSE) for human tissues

Award Number: R61CA309676
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/03/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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Developing Mutation Signature Extraction (MSE) for human tissues - PROJECT SUMMARY/ABSTRACT (PUBLIC) Mutation signatures characteristic of human cancers are a product of mutagenic events leading to cancer- causing mutations that initiate or promote tumorigenesis. Therefore, screening for these signatures in normal tissues could aid in cancer early detection, prevention, and interception. These signatures have been captured by sequencing the genomes of multiple clones derived from adapting bronchial brushings to grow in tissue culture, or more recently, from surveying large portions of the genome from a variety of tissues by error-corrected sequencing. Unfortunately, the first approach is limited to those very few human tissues that can be cultured and is completely impractical in a clinical setting while the second approach does not provide genome privacy to the patient and is limited to the western European genome to differentiate bona fide mutations from naturally occurring single nucleotide polymorphisms. Thus, a new method is needed to detect mutation signatures that neither requires establishing tissues to grow in culture nor relies on sequencing large portions of the genome. In this regard, we demonstrate that deeply sequencing a single short region of genomic DNA by the novel mammalian Maximum Depth Sequencing (mMDS) assay can detect a mutation signature in the normal tissues of mice following a carcinogen exposure. Further, by increasing the amount of genomic DNA sequenced, we propose that mMDS could also identify the rarer mutation signatures in normal human tissues. To achieve this goal, we propose to develop Mutation Signature Extraction (MSE) for normal human tissues based on mMDS in four aims. In AIM 1 we will determine which region of the genome yields sufficient independent (barcoded) DNA fragments for MSE to capture enough mutations to derive a mutation signature. In AIM 2, we will test and optimize as needed MSE to reach a detection limit required to detect the rare mutations of a mutation signature. In AIM 3, we will test and optimize as needed MSE to detect the mutations comprising the mutation signature in cultured human bronchial epithelial cells exposed to a tobacco smoke carcinogen. Finally, in AIM 4 we will evaluate the ability of MSE to detect the mutations of the signature characteristic of tobacco smoking in actual human bronchial brushings isolated from patients that smoke tobacco. Completion of these four aims will develop MSE to identify the mutations defining mutation signatures in human tissues, ultimately for use in cancer early detection, prevention, and interception.


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 = $232,297 )
2026	2026	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cancer Detection and Diagnosis Research	000	1	9/3/2026	NEW	$232,297
														Subtotal = $232,297

Grand Total All Awards = $232,297

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Developing Mutation Signature Extraction (MSE) for human tissues

Award Number: R61CA309676

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/03/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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