Large-scale efforts to identify breast cancer (BC) risk alleles have historically taken place among women of European ancestry. Recently, there are new efforts to verify if these alleles increase risk in African American (AA) women as well. We investigated the effect of previously reported AA breast cancer and triple-negative breast cancer (TNBC) risk alleles in our African-enriched International Center for the Study of Breast Cancer Subtypes (ICSBCS) cohort. Using case–control, case-series and race-nested approaches, we report that the Duffy-null allele (rs2814778) is associated with TNBC risk (OR = 3.814, p = 0.001), specifically among AA individuals, after adjusting for self-indicated race and west African ancestry (OR = 3.368, p = 0.007). We have also validated the protective effect of the minor allele of the ANKLE1 missense variant rs2363956 among AA for TNBC (OR = 0.420, p = 0.005). Our results suggest that an ancestry-specific Duffy-null allele and differential prevalence of a polymorphic gene variant of ANKLE1 may play a role in TNBC breast cancer outcomes. These findings present opportunities for therapeutic potential and future studies to address race-specific differences in TNBC risk and disease outcome.
Large-scale efforts to identify breast cancer risk alleles have historically taken place among women on European ancestry, with recent efforts to validate these alleles or identify risk alleles applicable to women of African descent. We investigated the effect of previously reported breast cancer and triple-negative breast cancer (TNBC) risk alleles in our African enriched International Center for the Study of Breast Cancer Subtypes (ICSBCS) cohort. Using case-control and nested case-series approaches, we report that the Duffy-null allele (rs2814778) is associated with TNBC risk (OR = 3.814, p = 0.001), specifically among AA individuals, after adjusting for self-indicated race and west African ancestry (OR = 3.368, p = 0.007). We have also validated the protective effect of the minor allele of the ANKLE1 missense variant rs2363956 among AA for TNBC (OR = 0.4204, p = 0.005). We have shown that differential prevalence of the protective allele may reflect a polymorphic function of ANKLE1 in TNBC breast cancer outcomes. These AA specific risk alleles present opportunities for future studies of therapeutic potential that address race-specific differences in BC and TNBC risk and disease outcome.
Introduction: AL amyloidosis is widely regarded as a rare disease, but characterization of its epidemiology has scarcely been reported. The purpose of this systematic review is to estimate the incidence rate of AL amyloidosis and examine population differences. Methods: MEDLINE, PubMed, and Google Scholar were searched from their inception until November 13, 2021 using search terms AL amyloidosis or immunoglobulin light-chain amyloidosis or light-chain amyloidosis or primary amyloidosis and incidence or epidemiology. Random-effects meta analysis of all cohort studies reporting an incidence rates for AL amyloidosis was performed. The quality of each study was assessed using a modified Newcastle-Ottawa scale. Subgroup analysis was performed based on geographical region. Results: Six studies with data from 2502 diagnosed cases of AL amyloidosis from 5 countries were included. The pooled incidence rate for AL amyloidosis was 10.48 per one-million person years (95% CI, 8.99 to 11.96). There was moderate heterogeneity in the data, which was eliminated with a subgroup analysis according to geographical region. AL amyloidosis was found to be more common in the Americas (incidence rate 11.52 per one-million person years, 95% CI 11.04 to 12.00) than in the Europe (9.10 per one-million person years, 95% CI, 7.62 to 10.58). Conclusion: There is a low worldwide incidence rate for AL amyloidosis, supporting the characterization of AL amyloidosis as a rare disease. The incidence of AL amyloidosis appears to vary in different populations, which suggests further well-designed studies are needed to elucidate underlying etiological factors and better inform clinical suspicion for AL amyloidosis.
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. Citation Format: Solange Bayard, Rachel Martini, Yalei Chen, Brittany Jenkins, Isra Elhussin, Esther Cheng, Syed Hoda, Paula Ginter, Jeffrey Hanover, Rozina Zeidan, Joseph Oppong, Kofi Gyan, Clayton Yates, Rick Kittles, Engida Abebe, Ishmael Kyei, Frances Aitpillah, Michael Adinky, Lisa Newman, Melissa Davis. BRCA sequence variants in breast cancer patients with African ancestry [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-139.
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