Date of Award
12-2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Healthcare Genetics
Committee Chair/Advisor
Luigi Boccuto
Committee Member
Diana Ivankovic
Committee Member
Christopher Farrell
Committee Member
Veronica Parker
Abstract
BRCA1-associated protein 1 (BAP1) is a tumor suppressor gene located on chromosome 3p21.3 and encodes a deubiquitinase enzyme (DUB) involved in DNA repair, cell cycle and metabolism, and apoptosis. BAP1 pathogenic germline variants are primarily associated with a familial cancer syndrome, Tumor Predisposition Syndrome 1 (TPDS1), but new missense variants have been linked to a neurodevelopmental disorder known as Kury-Isidor Syndrome (KURIS). Patients with TPDS1 variants have an increased risk for developing cancers, such as uveal and cutaneous melanomas, mesothelioma, and renal cell carcinoma, at an earlier age with lower thresholds for environmental exposures, mainly UV rays and asbestos, compared to the general population. The variants associated with TPDS1, and KURIS have not been seen in the same family and are considered to have a mutually exclusive genotype-phenotype correlation. Variants associated with the disorders that have conflicting classifications for pathogenicity had lab, clinical, and in silico evidence compiled from the literature where it was found that KURIS variants c.91G>A and c.271T>C could be reclassified as likely pathogenic along with TPDS1 variants c.535C>T, c.606G>T, and c.1991delA. Variant c.1891-1G>A was previously identified in multiple publications and could be reclassified as pathogenic for TPDS1. The clear classification is important for physicians treating patients with BAP1 germline variants because of the distinct genotype-phenotype correlations of TPDS1 and KURIS and the need for earlier and more stringent surveillance for those with pathogenic TPDS1 variants compared to benign or VUS. BAP1 interacts with multiple genes that currently have targeted therapies and may be effective for BAP1- patients. The EZH2 inhibitor tazemetostat showed efficacy for patients with BAP1- mesothelioma and was effective for patients with cancers potentially associated with BAP1, breast cancer and lymphoma.
Recommended Citation
Hobbs, Elizabeth, "BAP1: Genotype-Phenotype Correlation, Variant Classification, and Treatment Efficacy" (2024). All Dissertations. 3802.
https://open.clemson.edu/all_dissertations/3802
Author ORCID Identifier
0009-0008-6560-6800