Abstract 5686: Identifying rare microRNA risk variants for hereditary breast cancer in African American individuals

Abstract Background: In the United States, breast cancer is the most frequently diagnosed cancer in women. However, African American women tend to have a higher incidence of triple negative breast cancer cases, and an earlier age of disease onset, which are hallmark characteristics of heredity disease. Even with current breakthroughs in breast cancer research, limited research participation from women of African descent has led to a gap in our knowledge of heredity factors that are involved in disease in this population. Furthermore, most breast cancer research has focused on protein coding genes being the culprit of tumorigenesis; however, within the last three decades, research efforts have begun to focus on noncoding RNAs, like microRNAs (miRNAs), as potential factors to promote carcinogenesis. miRNAs are short, noncoding RNA molecules that control gene expression at the post-translational level. miRNAs have several mechanisms to affect gene expression of cellular processes like cell proliferation, apoptosis, invasion, and metastasis. However, the identification and functional role miRNA risk variants play in African American breast cancer is still not fully understood. Methods: 30X whole genome sequencing (WGS) was carried out on an Illumina platform on blood- or saliva-derived DNA from 120 African American breast cancer cases from the Alabama Hereditary Cancer Cohort. The WGS data was analyzed using our established bioinformatics pipeline, which has been adapted from the Genome Analysis Toolkit (GATK) Best Practice Pipeline. Focusing on miRNA variants as risk factors, a miRNA BED file was used to extract regions harboring miRNA genes. The resulting file was then filtered for rare miRNA variants (minor allele frequency 1%) in the African American population based on the Genome Aggregation Database (gnomAD) allele frequency. P-values for variants of interest were calculated using Fisher’s Exact tests. Results: Sequencing data have revealed three rare miRNA variants from our African American cohort that can be potentially associated with breast cancer risk. Upon statistical analysis comparing allele frequencies between the African American general population and the Alabama Hereditary Cancer Cohort, miR7850, miR3145, and miR8074 had p-values 5. 21E-05, 3. 58E-05, and 2. 19E-04, respectively. Conclusions: We have identified three rare miRNA variants that were not previously known to be associated with breast cancer risk. Interestingly, both miR7850 and miR8074 target TP53 and miR3145 targets GREM1 and PALB2, which these targets are known breast cancer susceptibility genes. Understanding the consequence of these variants is important to add to our knowledge of miRNAs that play critical roles in carcinogenesis leading to better treatment strategies. Citation Format: Sheniqua R. Glover, Troy LoBue, Nancy D. Merner. Identifying rare microRNA risk variants for hereditary breast cancer in African American individuals abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 5686.