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Bridging Racial Health Disparities: Advancing Health Equity Through the Incorporation of Functional Assay Insights [electronic resource].

The Ohio State University. Biomedical Sciences.

[S.l.] : The Ohio State University. 2024 Ann Arbor : ProQuest Dissertations & Theses , 2024

1 online resource(177 p.)

Source: Dissertations Abstracts International, Volume: 86-04, Section: B.
Includes supplementary digital materials.
Advisor: Parvin, Jeffrey.

Thesis (Ph.D.)--The Ohio State University, 2024.

BRCA1 pathogenic variants are well-established risk factors for hereditary breast and ovarian cancer (HBOC). The increasing accessibility and affordability of genetic testing have led to the identification of individuals with BRCA1 variants of uncertain significance (VUS), creating a clinical challenge due to the rarity of these variants. This issue disproportionately affects women from minority backgrounds, who often face a high prevalence of VUS in their genetic screening results. The American College of Medical Geneticists (ACMG) guidelines stipulate that clinical recommendations cannot be made until these VUS are reclassified, leaving many individuals stranded in the healthcare system without access to advancements in preventive medicine.To address this gap, ACMG has permitted the use of functional assays to experimentally assess the effects of BRCA1 variants. This dissertation aims to identify the genetic and environmental factors contributing to the gaps in care for minority women dealing with HBOC, redesign the analysis pipeline for multiplexed DNA repair assays, introduce a novel multiplexed repair assay based on cisplatin resistance (CR), and adapt this pipeline to functional limited datasets.Our research successfully functionally characterized 2271 variants from the carboxy terminus for homology-directed repair function (HDR) and 1427 variants for CR. Notably, we observed consistent results between the two multiplexed functional assays, especially for non-functional variants located within critical regions of the BRCA1 protein essential for tumor suppression. Variants classified in the multiplex HDR assay exhibited 81% specificity and 93% sensitivity, while those in the multiplex CR assay demonstrated 100% specificity and 86% sensitivity. Furthermore, the functional categorizations of the variants correlated with known clinical significance and other BRCA1 functional assays.Utilizing the redesigned analysis pipeline, we reanalyzed previously published multiplexed HDR results for amino-terminus variants, providing functional insights for 2172 variants. We also compared our functional classifications to clinical interpretations, enabling variants classified as functionally normal to be applied as BS3 strong and those classified as LOF as PS3 moderate.Applying our analysis pipeline to functionally classify the limited datapoints in the coiled-coil domain of BRCA1, we provided 330 functional classifications for variants in this region. Notably, when compared to ClinVar's designated benign or likely benign and pathogenic or likely pathogenic variants, our multiplexed assay demonstrated 100% specificity and 100% sensitivity.The functional classification of 4773 BRCA1 variants presented in this dissertation offers a valuable solution to bridge the diagnostic gap in the care cascade for the treatment of breast and ovarian cancer. It is our hope that clinicians can utilize this information to better inform all patients about the risks associated with HBOC variants, ultimately leading to an improved quality of life for those affected by these genetic variants.

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