Rein, Hayley
(2024)
Functional Characterization of RAD51 Paralog Cancer Associated Variants of Unknown Significance.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
This is the latest version of this item.
![[img]](https://d-scholarship.pitt.edu/style/images/fileicons/application_pdf.png) |
PDF (Biorender Publishing License)
Supplemental Material
Restricted to University of Pittsburgh users only until 16 September 2026.
Download (2MB)
| Request a Copy
|
|
PDF (Updated ETD)
Primary Text
Restricted to University of Pittsburgh users only until 16 September 2026.
Download (46MB)
| Request a Copy
|
Abstract
For many individuals harboring a variant of uncertain functional significance (VUS) in a homologous recombination (HR) gene, their risk of developing breast and ovarian cancer is unknown. Integral to the process of HR are BRCA1 and regulators of the central HR protein, RAD51, including BRCA2, PALB2, RAD51C and RAD51D. Due to advancements in sequencing technology and the continued expansion of cancer screening panels, the number of VUS identified in these genes has risen significantly. While variant analysis is improving, there remains a struggle to keep up with demand. Understanding the effects of an HR variant can aid in preventative care and is critical for developing an effective cancer treatment plan. In this dissertation, we functionally screened 27 RAD51C ovarian cancer VUS, identifying two HRD variants. Modeling these and other previously analyzed HRD RAD51C ovarian cancer variants in the newly published BCDX2 cryoEM structure, we found a functionally deficient cluster within the critical Walker B region. Our study of RAD51C also uncovered two active translational start sites located at amino acid 1 and amino acid 10. The resulting protein isoforms and the M1 and M10 patient derived VUS were assessed and found to be functionally similar in their HR capabilities but showed differences in expression and possible cell type specificity. In all, these studies broaden our understanding of RAD51C and how its dysfunction can promote disease progression and response to therapy. These data have the potential to aid in more efficacious pathogenicity classification and improve patient care.
Share
| Citation/Export: |
|
| Social Networking: |
|
Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
16 September 2024 |
| Date Type: |
Publication |
| Defense Date: |
29 August 2023 |
| Approval Date: |
16 September 2024 |
| Submission Date: |
2 October 2023 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
134 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Molecular Pharmacology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Homologous recombination deficient tumors; breast cancer; ovarian cancer; variant of unknown/uncertain significance; homologous recombination; BRCA1; BRCA2; PALB2; RAD51C; RAD51D; RAD51 |
| Date Deposited: |
16 Sep 2024 18:53 |
| Last Modified: |
16 Sep 2024 18:53 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/45677 |
Available Versions of this Item
-
Functional Characterization of RAD51 Paralog Cancer Associated Variants of Unknown Significance. (deposited 16 Sep 2024 18:53)
[Currently Displayed]
Metrics
Monthly Views for the past 3 years
Plum Analytics
Actions (login required)
 |
View Item |
![[feed]](/images/feed-icon-32x32.png){kind=icon}