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Thesis
Profiling DNA damage response in lymphocytes from BRCA2 heterozygote carriers
Master of Science (M.S.), Drexel University
Jun 2025
DOI:
https://doi.org/10.17918/00011110
Abstract
Germline pathogenic variants (gPVs) in DNA repair genes, including BRCA2, confer a significantly elevated lifetime risk of cancer. Early identification of these variants is essential for personalized cancer risk assessment and prevention strategies. This research measured DNA damage response (DDR) protein activity in peripheral blood mononuclear cells (PBMCs) from BRCA2 gPV carriers using a multiplex DDR protein immunoassay. Select markers of activated DDR and DD-related signaling events optimized in prior studies were included in the immunoassay. Clinically well-annotated peripheral blood mononuclear cells (PBMCs) specimens were obtained from BRCA2 gPV carriers with cancer, BRCA2 gPV carriers without cancer, and unaffected non-carrier controls through the Fox Chase Cancer Center's Risk Assessment Program and Biosample Repository Facility. Next, EBV-transformed B-cell lines were generated from PBMCs of BRCA2 gPV carriers with and without cancer, and from the controls. Cellular viability post-DNA damage was assessed using multiple DNA damaging agents. We found that even at baseline several DDR proteins were significantly elevated in PBMCs from all gPV carriers compared to PBMCs from the controls. Cellular viability experiments revealed unique patterns of response to DNA damage suggesting that specific gPVs differ in their DNA repair capacity. Intriguingly, baseline cellular viability was significantly elevated in B-cells from BRCA2 gPV carriers with cancer compared to B-cells from unaffected gPV carriers and the controls. Overall, these findings provide preliminary evidence that DDR profiling may serve as a functional approach to detect altered DDRs and could be developed further to evaluate variants of uncertain significance to guide cancer risk assessment.
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Details
- Title
- Profiling DNA damage response in lymphocytes from BRCA2 heterozygote carriers
- Creators
- Khushi Amish Patel
- Contributors
- Sanjeevani Arora (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Master of Science (M.S.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- 60 pages
- Resource Type
- Thesis
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 991022064242004721