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Mechanisms Underlying Replication Stress And Genome Instability Upon BRCA2 Deficiency

Award Number: R01CA273696
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Mechanisms Underlying Replication Stress And Genome Instability Upon BRCA2 Deficiency - PROJECT SUMMARY BRCA2 mutation carriers are highly predisposed to breast and ovarian cancer (60% risk for breast cancer and 30-40% for ovarian cancer), and also have increased risk for other cancers like prostate and pancreatic. However, the mechanisms underlying these phenomena are still poorly understood. The molecular pathogenic steps, especially the earliest ones that drive the transition of normal cells (BRCA2mut/+) in a BRCA2 mutation carrier to tumor cells are largely unknown. Experiments detailed in this proposal will provide valuable clues to what those early steps could be. The knowledge and understanding of the way a normal, presumably healthy cell in BRCA2 mutation carrying individual starts becoming a tumor cell, will give us a much-needed early advantage to help design preventive strategies and contribute towards decreasing B2 mutant cancer incidence. The experimental strategy described in this proposal is based on our recently published work that shows increased single stranded DNA (ssDNA) accumulation in BRCA2 deficient cells, and on our preliminary data that shows high abasic site and uracil accumulation in BRCA2 deficient cells. Our preliminary data also shows defective nucleotide excision repair (NER) pathway in BRCA2 deficient cells. Based on our strong preliminary data, we propose to study the role of APOBEC/AID family of cytosine deaminases in generating abasic sites in BRCA2 deficient cells. We will also use BRCA2 patient derived tissue to design new ways to classify variants of unknown significance and also learn how increased abasic site and uracil in B2 heterozygous cells could contribute to genomic instability and tumorigenesis. Finally, we will also study whether BRCA2 deficient cells are defective in NER when undergoing replication stress, and if this weakness in BRCA2 mutant tumors could be targeted by combination drug therapy. This study provides an opportunity to address the question of early DNA damaging events that drive BRCA2 mutant tumorigenesis, and has the potential to provide the much needed, critical information that will help with the design of effective cancer prevention and therapeutic strategies for BRCA2 mutation bearing women.


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: 2025 ( Subtotal = $712,077 )
2025	2025	UNIVERSITY OF MASS AT BOSTON	100 WILLIAM T MORRISSEY BLVD	DORCHESTER	MA	02125	SUFFOLK	USA	Cancer Cause and Prevention Research	000	4	9/1/2025	EXTENSION WITH OR WITHOUT FUNDS	$712,077
2025	2024	UNIVERSITY OF MASS AT BOSTON	100 WILLIAM T MORRISSEY BLVD	DORCHESTER	MA	02125	SUFFOLK	USA	Cancer Cause and Prevention Research	001	3	9/2/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $712,077

Issue Date FY: 2024 ( Subtotal = $336,543 )
2024	2024	UNIVERSITY OF MASS AT BOSTON	100 WILLIAM T MORRISSEY BLVD	DORCHESTER	MA	02125	SUFFOLK	USA	Cancer Cause and Prevention Research	001	3	8/8/2024	NON-COMPETING CONTINUATION	$48,773
2024	2024	UNIVERSITY OF MASS AT BOSTON	100 WILLIAM T MORRISSEY BLVD	DORCHESTER	MA	02125	SUFFOLK	USA	Cancer Cause and Prevention Research	000	3	7/31/2024	NON-COMPETING CONTINUATION	$287,770
														Subtotal = $336,543

Issue Date FY: 2023 ( Subtotal = $358,941 )
2023	2023	UNIVERSITY OF MASSACHUSETTS	100 MORRISSEY BLVD RM 80	BOSTON	MA	02125	SUFFOLK	USA	Cancer Cause and Prevention Research	000	2	8/8/2023	NON-COMPETING CONTINUATION	$358,941
														Subtotal = $358,941

Issue Date FY: 2022 ( Subtotal = $348,844 )
2022	2022	UNIVERSITY OF MASSACHUSETTS	100 MORRISSEY BLVD RM 80	BOSTON	MA	02125	SUFFOLK	USA	Cancer Cause and Prevention Research	000	1	9/1/2022	NEW	$291,799
2022	2022	UNIVERSITY OF MASSACHUSETTS	100 MORRISSEY BLVD RM 80	BOSTON	MA	02125	SUFFOLK	USA	Cancer Cause and Prevention Research	001	1	9/13/2022	NEW	$57,045
														Subtotal = $348,844

Grand Total All Awards = $1,756,405

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Mechanisms Underlying Replication Stress And Genome Instability Upon BRCA2 Deficiency

Award Number: R01CA273696

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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