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Access Type
WSU Access
Date of Award
January 2024
Degree Type
Dissertation
Degree Name
Ph.D.
Department
Molecular Biology and Genetics
First Advisor
Michael Tainsky
Abstract
Genes associated with the DNA repair pathway and cell cycle control have been the focus of many studies for their individual roles in hereditary cancer syndromes. Comprehensive genetic risk assessment provides the opportunity for early detection of hereditary cancer and improved survival. Multigene panels for hereditary cancer syndromes sequence genes to identify the presence of pathogenic (increased risk of cancer) mutations. Multigene sequencing panels result in large quantities of genetic data, much of which cannot be interpreted and are classified as variants of uncertain significance (VUS). VUSs provide no information regarding pathogenicity and hinder the ability of clinicians to classify these variants accurately and confidently. The inability to interpret variants leads to ambiguity in genetic counseling and has the potential to lead to inaccurate medical management. In the absence of variant segregation data, in vitro functional analyses can be used to clarify variant annotations, aiding in accurate clinical management of patient risk and treatment plan.The cell cycle checkpoint kinase 2 (CHEK2) is a tumor suppressor gene coding for a protein kinase with a role in the cell cycle and DNA repair pathways. Mutations within CHEK2 are associated with an increased risk of developing breast, colorectal, prostate and several other types of cancer. Databases of patient sequencing have identified over 1000 VUSs in CHEK2, and those that are pathogenic could be revealed through functional screens. We have established methods to evaluate the functional consequences of single nucleotide variants (SNVs) individually and comprehensively throughout the open reading frame (ORF) of CHEK2. In addition to the functional studies, we performed whole exome sequencing (WES) to investigate the prevalence of germline variants in 210 breast cancer patients and identified 16 individuals with CHEK2 variants and multiple variants within breast cancer susceptibility genes. Using these data, we evaluated the prevalence of these CHEK2 variants in African American (AA) and Caucasian (CA) populations, described their current clinical classifications, assembled available functional data, and computational functional prediction, as well as explored the role these variants may play in polygenic risk assessment. Functional analyses can expand the diagnostic impact of genetic testing and provide data that can be used to support and clarify variant annotation of CHEK2. With a more comprehensive analysis of VUSs in CHEK2, genetic counselors can identify more at-risk patients and improve patient care and surveillance.
Recommended Citation
Mccarthy-Leo, Claire, "Functional Evaluation Of Chek2 Single Nucleotide Variants In Hereditary Cancer Predisposition" (2024). Wayne State University Dissertations. 4056.
https://digitalcommons.wayne.edu/oa_dissertations/4056