BRCA sequence variants in breast cancer patients with African ancestry
Recommended Citation
Bayard S, Martini R, Chen Y, Jenkins B, Elhussin I, Cheng E, Hoda S, Ginter P, Hanover J, Zeidan R, Oppong J, Gyan K, Yates C, Kittles R, Abebe E, Kyei I, Aitpillah F, Adinky M, Newman L, Davis M. BRCA sequence variants in breast cancer patients with African ancestry. Cancer Epidemiology Biomarkers and Prevention 2022; 31(1 SUPPL).
Document Type
Conference Proceeding
Publication Date
1-1-2022
Publication Title
Cancer Epidemiology Biomarkers and Prevention
Abstract
Introduction Breast cancer is the most common cause of cancer related deaths in women worldwide; however, significant disparities are evident in the epidemiology of breast cancer subtypes and clinical outcomes of different racial/ethnic groups. African Americans are 40% more likely to die from breast cancer-a disparity that is partially explained by genetic predisposition to early onset breast cancer and triple negative breast cancer (TNBC), an aggressive subtype linked to West African ancestry and associated with BRCA-1 germline mutations. Pathogenic BRCA mutations significantly alter breast cancer treatment, informing alternate screening, chemoprevention, prophylactic resections and use of PARB inhibitors; however, AAs have higher prevalence of BRCA variants of uncertain significance (VUS) secondary to underrepresentation of African ancestry in the reference genome. The aim of this study is therefore to further characterize BRCA mutations and BRCA VUS in breast cancer patients with African ancestry. Methods RNA Sequencing platforms were used to determine somatic mutation profiles from primary tumor samples of over 70 breast cancer patients from Ethiopia and Ghana, by identifying single nucleotide polymorphisms (SNPs) in BRCA 1 and 2. Each sequence variant was evaluated for consequence on the gene, previously reported clinical significance, and allele frequency by self-reported race in comparison to global allele frequencies. Results BRCA1: 10 BRCA1 SNPs were identified: Missense: Rs1799966, rs16942, rs16941, rs799917, rs4986850, rs1799950; synonymous: rs1060915, rs16940, rs1799949; variant of 3'UTR: rs3092995. Rs1799966, rs16942, rs16941 and rs1799950 cause deleterious missense mutations, and have been reported as uncertain clinical significance. No SNPs were previously reported pathogenic, 6 had uncertain significance, and 4 were classified as either benign or likely benign. Allele frequency of Rs799917 was high among Ethiopian, Ghanaian, and 1KG African subgroups. BRCA2: 13 BRCA2 SNPs were identified: Missense: rs766173, rs144848, rs1799944, rs169547; synonymous: rs1801439, rs1801499, rs1801406, rs543304, rs206075, rs1799955, rs9590940; downstream/missense: rs1801426; variant of 5'Prime UTR: rs1799943. Rs766173 caused a deleterious missense mutation, with conflicting interpretations of pathogenicity. No SNPs were previously reported pathogenic, 4 had uncertain significance, and 8 were either benign or likely benign. No SNPs had high allele frequency in African ancestry. Conclusions The BRCA-1 SNP Rs799917 has a high allele frequency rate among Ethiopian, Ghanaian, and 1KG African ancestry, suggesting this mutation is potentially unique to African ancestry. Further investigation with RNA seq or whole genome sequencing in larger cohorts is warranted.
Volume
31
Issue
1 SUPPL
