African American breast cancer genetics is less understood compared to European American breast cancer susceptibility. Despite the many advantages of gene panel screening, studies investigating African American inherited breast cancer risk and comparing variant contributions between ethnicities are infrequent. Thus, 97 breast cancer-affected individuals of African and European descent from the Alabama Hereditary Cancer Cohort were screened using the research-based gene-panel, B.O.P. ( B reast, O varian, and P rostate cancer). Upon sequencing and bioinformatic processing, rare coding variants in 14 cancer susceptibility genes were categorized according to the American College of Medical Genetics guidelines and compared between ethnicities. Overall, 107 different variants were identified, the majority of which were benign/likely benign. A pathogenic/likely pathogenic variant was detected in 8.6% and 6.5% of African American and European American cases, respectively, which was not statistically significant. However, African Americans were more likely to have at least one variant of uncertain significance (VUS; p-value 0.006); they also had significantly more VUSs in BRCA1/2 compared to European Americans ( p-value 0.015). Additionally, 51.4% of African Americans and 32.3% of European Americans harbored multiple rare variants, and African Americans were more likely to have at least one VUS and one benign/likely benign variant ( p-value 0.032), as well as multiple benign/likely benign variants ( p-value 0.089). Moreover, of the 15 variants detected in multiple breast cancer cases, ATM c.2289T>C (p.F763L), a VUS, along with two likely benign variants, BRCA2 c.2926_2927delinsAT (p.S976I) and RAD51D c.251T>A (p.L84H), were determined to be associated with African American breast cancer risk when compared to ethnic-specific controls. Ultimately, B.O.P. screening provides essential insight towards the variant contributions in clinically relevant cancer susceptibility genes and differences between ethnicities, stressing the need for future research to elucidate inherited breast cancer risk.

Breast cancer (BC) is a very serious health concern being the second most commonly diagnosed cancer among American women. Although the overall incidence rate of BC in African American (AA) and European American women converged in 2012, AA women are reported to have a higher mortality rate at every age, and a higher incidence rate under the age of 45, which is a hallmark of hereditary BC. Characteristics of hereditary BC include a family history of the disease, early ages of onset, bilateral BC, male BC, as well as the occurrence of other associated cancers such as ovarian and prostate. Cancer incidences in these families are influenced by inherited risk factors; currently, mutations in known susceptibility genes, including BRCA1/2, explain ~20-30% of hereditary cases, leaving up to ~70% genetically unsolved. Despite the universal need to decipher the currently unexplained cases, it is important to note that these statistics are mainly the result of studying individuals of European descent. The mutational landscape that explains AA hereditary BC is more obscure since, comparatively, it has been vastly understudied. Recognizing this knowledge gap, our group is committed to adding to the current limited resources necessary to better understand AA BC genetics. We are doing this through a strategic community-based recruitment protocol to enroll underrepresented individuals in Alabama, adding to the Alabama Hereditary Cancer Cohort. With over 150 AAs enrolled to date, we have ascertained some impressive AA BC families. Of those families, Family 1CAD is one of the largest with over 15 family members enrolled. Their participation was fostered through an invitation to their family reunion. There, it was disclosed that a deceased family member had a pathogenic BRCA1 mutation (p.M1796R). Therefore, all participating family members were first screened for the BRCA1 mutation through polymerase chain reactions and Sanger sequencing; interestingly, not all cancer-affected individuals screened positive for this mutation. Therefore, five cancer-affected individuals (three mutation-positive and two mutation-negative) were selected and screened using an exploratory research-based gene panel that targets genes that have been suggested, predicted, or clinically proven to be associated with BC and associated cancers. Firstly, this screening confirmed each individual’s mutation status. It also provided additional insight; for example, all three cancer-affected individuals who have BRCA1 M1796R also share a truncation variant in a candidate gene on the panel, which plays an important role in cell cycle regulation (GeneX). A preliminary analysis using AA BC cases from The Cancer Genome Atlas and ethnic-specific controls from the Exome Variant Server, suggests that truncation variants in GeneX are associated with AA BC risk. We are in the process of validating these findings and determining how this truncation variant modifies risk in BRCA1 mutation carriers. Citation Format: Sophonie Omeler-Fenaud, Madison Bishop, Elizabeth Stallworth, Isaac McNeely, Nancy Merner. Complexities of hereditary breast cancer: Investigating a large African American family [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C041.

If there is any place to overcome research barriers it is Alabama. Known for being the site of one of the most unethical and inconceivable clinical studies - The Tuskegee Syphilis Study - and home of nearly double the national percentage of African Americans (AAs), history itself provides a substantial challenge. In Alabama, 85% of the counties are entirely medically underserved, most of which are rural, including the Alabama Black Belt, which is predominantly inhabited by AAs and associated with low economic status. Altogether, one can gather that getting proximate requires dedication, and considering all of the reported AA cancer health disparities, it is vital to address these barriers. Aiming to study hereditary breast cancer (BC) and other associated cancers in Alabama, we had to be adaptable and develop recruitment strategies appropriate for the community. In a recent publication, we described our initial efforts that were effective for recruiting AAs into the Alabama Hereditary Cancer Cohort (AHCC). A number of facets were key to this success, which included establishing community partners, educating and building trust in the community, and utilizing a recruitment bus, called the Gene Machine. As AA BC susceptibility is widely understudied, we realize the need to continue this effort; however, we recently went back to the drawing board and revamped our recruitment protocol in order to maximize our time and efficiency. We currently have over 150 AAs in the study and plan to bolster recruitment by implementing the protocol modifications. Ultimately, the goal of these rigorous efforts is to add to the limited, existing resources, i.e. biospecimens and genetic data, needed to better understand the science of cancer health disparities. When cancer-affected individuals enroll into our study, we carry out gene panel screening, initially searching for clinically significant variants in cancer susceptibility genes. Though our screening is currently research-based, through the development of our protocols, we felt it was important to offer the option to receive genetic research reports during the consent process. We had anticipated that many of our study participants would not have access to the care that provides such knowledge, and we have since confirmed that only ~20% of the cancer-affected AAs in the AHCC had previous clinical genetic screening. It was evident that most of those participants wanted such information with only 2% declining to be informed of the research results. Realizing that access to care is very limited in Alabama, we also established a collaborative telegenetic counseling project to provide services to mutation carriers in their local county health departments. Coupled together, these efforts attempt to provide study participants with a better understanding of disease risk and management, and allow integral genetic research to be carried out as we work towards reducing cancer health disparities. If there is any place to overcome barriers, it is here in Alabama and it is happening. Citation Format: Nancy Merner, Elizabeth Stallworth, Madison Bishop, Sophonie Omeler-Fenaud, Isaac McNeely, Anna Huskey. Getting proximate: Facing the truth about African American hereditary breast cancer research – insight from Alabama [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr B043.