Functional analysis of genetic variants in African Americans with Breast Cancer - Abstract: African American (AA) women are more likely receive an inconclusive genetics test diminishing
the utility and impact of genetics and precision medicine technologies on cancer management and prevention.
In fact, actionable mutations are found less frequently in women of African descent. “Actionable” mutations are
mutations whose phenotype would result in specific, defined medical recommendation(s) and allow the proper
deployment of risk reduction strategies such as early detection, prophylactic surgery, chemoprevention, and
lifestyle modifications. Additionally, with the high prevalence of variants of unknown significance (VUSs) in the
population, additional research is warranted to determine the functional consequences of VUSs. Through this
R15 mechanism, we seek to expand our previous research which identified 29 BRCA VUSs in 30 high-risk
families thought to have meaningful clinical significance in treatment strategies. Using CRISPR methods will
allow us to determine the functional significance of novel variants comparing wild-type parental cell lines to
genetically edited, derived cell lines. The functionalization of VUSs using CRISPR will allow for improved risk
prediction, improved tumor targeting and thus, improved outcomes in a population not well represented in
genomic studies and disproportionately affected by VUSs. Our overall hypothesis is that African American breast
cancer patients have a unique genetic profile not currently represented in commercially available genetic tests
that could be readily discovered in our distinctive family-case-control study. We also hypothesize that VUSs in
actionable genes, especially those that hypothetically alter the function of the gene leading to changes in tumor
cell behavior, could be characterized using novel tools such as CRISPR. We plan to test our hypothesis and
accomplish the overall goals of this application by pursuing the following specific aims: 1) to prioritize,
characterize, and validate novel and genetic variants of unknown significance and determine their association
with BCA risk in AAs; 2) to use CRISPR-Cas9 editing to determine the functional consequences of VUSs in
actionable DNA-repair pathways overrepresented in African American breast cancer cases. The lack of research
in under-represented health disparity populations, such as AAs, hampers efforts to reduce and eliminate BCa
disparities. This proposal will allow us to better understand the genotypic indicators that may confer risk for
developing BCa and allow us to generate knowledge related to the biological indicators of the disease. This grant
mechanism will also help promote the development of burgeroning nurse scientists within an interdisciplinary
team of scientists committed to the development of precision medicine strategies to reduce BCa disease burden
in African Americans.
