RESUMO
PURPOSE: There is a paucity of data on the spectrum and prevalence of pathogenic variants among women of African ancestry in the Northeast region of Brazil. METHODS: We performed BROCA panel sequencing to identify inherited loss-of-function variants in breast cancer susceptibility genes among 292 Brazilian women referred to a single institution cancer risk assessment program. RESULTS: The study included a convenient cohort of 173 women with invasive breast cancer (cases) and 119 women who were cancer-free at the time of ascertainment. The majority of the women self-reported as African-descended (67% for cases and 90.8% for unaffected volunteers). Thirty-seven pathogenic variants were found in 36 (20.8%) patients. While the spectrum of pathogenic variants was heterogeneous, the majority (70.3%) of the pathogenic variants were detected in high-risk genes BRCA1, BRCA2, PALB2, and TP53. Pathogenic variants were also found in the ATM, BARD1, BRIP1, FAM175A, FANCM, NBN, and SLX4 genes in 6.4% of the affected women. Four recurrent pathogenic variants were detected in 11 patients of African ancestry. Only one unaffected woman had a pathogenic variant in the RAD51C gene. Different risk assessment models examined performed well in predicting risk of carrying germline loss-of-function variants in BRCA1 and/or BRCA2 in breast cancer cases. CONCLUSION: The high prevalence and heterogenous spectrum of pathogenic variants identified among self-reported African descendants in Northeast Brazil is consistent with studies in other African ancestry populations with a high burden of aggressive young onset breast cancer. It underscores the need to integrate comprehensive cancer risk assessment and genomic testing in the management of newly diagnosed Black women with breast cancer across the African Diaspora, enabling improved cancer control in admixed underserved and understudied populations.
Assuntos
Neoplasias da Mama , Proteína BRCA1/genética , Proteína BRCA2/genética , Brasil/epidemiologia , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , DNA Helicases/genética , Feminino , Genes BRCA2 , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , MutaçãoRESUMO
Genetic diversity of germline variants in breast cancer (BC) predisposition genes is unexplored in miscegenated populations, such those living in Latin America. We evaluated 1663 Brazilian BC patients, who underwent hereditary multigene panel testing (20-38 cancer susceptibility genes), to determine the spectrum and prevalence of pathogenic/likely pathogenic (P/LP) variants and variants of uncertain significance (VUS). Associations between P/LP variants and BC risk were estimated in a case-control analysis of BC patients and 18,919 Brazilian reference controls (RC). In total, 335 (20.1%) participants carried germline P/LP variants: 167 (10.0%) in BRCA1/2, 122 (7.3%) in BC actionable non-BRCA genes and 47 (2.8%) in candidate genes or other cancer predisposition genes. Overall, 354 distinctive P/LP variants were identified in 23 genes. The most commonly mutated genes were: BRCA1 (27.4%), BRCA2 (20.3%), TP53 (10.5%), monoallelic MUTYH (9.9%), ATM (8.8%), CHEK2 (6.2%) and PALB2 (5.1%). The Brazilian variant TP53 R337H (c.1010G>A, p.Arg337His), detected in 1.6% of BC patients and 0.1% of RC, was strongly associated with risk of BC, OR = 17.4 (95% CI: 9.4-32.1; p < 0.0001); monoallelic MUTYH variants c.1187G>A and c.536A>G, detected in 1.2% (0.9% RC) and 0.8% (0.4% RC) of the patients, respectively, were not associated with the odds of BC, the former with OR = 1.4 (95% CI: 0.8-2.4; p = 0.29) and the latter with OR = 1.9 (95% CI: 0.9-3.9; p = 0.09). The overall VUS rate was 46.1% for the entire patient population. Concluding, the use of multigene panel testing almost doubled the identification of germline P/LP variants in clinically actionable predisposition genes in BC patients. In Brazil, special attention should be given to TP53 P/LP variants.
Assuntos
Neoplasias da Mama , Brasil/epidemiologia , Neoplasias da Mama/patologia , Feminino , Genes BRCA2 , Predisposição Genética para Doença , Testes Genéticos , Células Germinativas/patologia , Mutação em Linhagem Germinativa , HumanosRESUMO
Introduction: Innovative interventions are needed to address the growing burden of breast cancer globally, especially among vulnerable patient populations. Given the success of Community Health Workers (CHWs) in addressing communicable diseases and non-communicable diseases, this scoping review will investigate the roles and impacts of CHWs in breast cancer screening programs. This paper also seeks to determine the effectiveness and feasibility of these programs, with particular attention paid to differences between CHW-led interventions in low- and middle-income countries (LMICs) and high-income countries (HICs).Methods: A scoping review was performed using six databases with dates ranging from 1978 to 2019. Comprehensive definitions and search terms were established for 'Community Health Workers' and 'breast cancer screening', and studies were extracted using the World Bank definition of LMIC. Screening and data extraction were protocolized using multiple independent reviewers. Chi-square test of independence was used for statistical analysis of the incidence of themes in HICs and LMICs.Results: Of the 1,551 papers screened, 33 were included based on inclusion and exclusion criteria. Study locations included the United States (n=27), Bangladesh (n=1), Peru (n=1), Malawi (n=2), Rwanda (n=1), and South Africa (n=1). Three primary roles for CHWs in breast cancer screening were identified: education (n=30), direct assistance or performance of breast cancer screening (n=7), and navigational services (n=6). In these roles, CHWs improved rates of breast cancer screening (n=23) and overall community member knowledge (n=21). Two studies performed cost-analyses of CHW-led interventions.Conclusion: This review extends our understanding of CHW effectiveness to breast cancer screening. It illustrates how CHW involvement in screening programs can have a significant impact in LMICs and HICs, and highlights the three CHW roles of education, direct performance of screening, and navigational services that emerge as useful pillars around which governments and NGOs can design effective programs in this area.
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Neoplasias da Mama , Agentes Comunitários de Saúde , Bangladesh , Neoplasias da Mama/diagnóstico , Detecção Precoce de Câncer , Promoção da Saúde , Humanos , Malaui , Peru , Ruanda , África do Sul , Estados UnidosRESUMO
Gene expression changes within the Hippo pathway were found to be associated with large tumor size and metastasis in breast cancer. The combined effect of genetic variants in genes of this pathway may have a causal role in breast cancer development. We examined 7086 SNPs that were not highly correlated (r2 < 0.8) in 35 Hippo pathway genes using data from the genome-wide association study of breast cancer from the Root Consortium, which includes 3686 participants of African ancestry from Nigeria, United States of America, and Barbados: 1657 cases (403 estrogen receptor-positive [ER+], 374 ER-) and 2029 controls. Gene-level analyses were conducted using improved AdaJoint test for large-scale genetic association studies adjusting for age, study site and the first four eigenvectors from the principal component analysis. SNP-level analyses were conducted with logistic regression. The Hippo pathway was significantly associated with risk of ER+ breast cancer (pathway-level P = 0.019), with WWC1 (Padj = 0.04) being the leading gene. The pathway-level significance was lost without WWC1 (P = 0.12). rs147106204 in the WWC1 gene was the most statistically significant SNP after gene-level adjustment for multiple comparisons (OR = 0.53, 95%CI = 0.41-0.70, Padj = 0.025). We found evidence of an association between genetic variations in the Hippo pathway and ER+ breast cancer. Moreover, WWC1 was identified as the most important genetic susceptibility locus highlighting the importance of genetic epidemiology studies of breast cancer in understudied populations.
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População Negra/genética , Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais/genética , Barbados , Neoplasias da Mama/etnologia , Neoplasias da Mama/metabolismo , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença/etnologia , Estudo de Associação Genômica Ampla , Genótipo , Via de Sinalização Hippo , Humanos , Pessoa de Meia-Idade , Nigéria , Receptores de Estrogênio/metabolismo , Estados UnidosRESUMO
Background: Germline genetic testing is standard practice in oncology. Outcomes of telephone disclosure of a wide range of cancer genetic test results, including multigene panel testing (MGPT) are unknown. Methods: Patients undergoing cancer genetic testing were recruited to a multicenter, randomized, noninferiority trial (NCT01736345) comparing telephone disclosure (TD) of genetic test results with usual care, in-person disclosure (IPD) after tiered-binned in-person pretest counseling. Primary noninferiority outcomes included change in knowledge, state anxiety, and general anxiety. Secondary outcomes included cancer-specific distress, depression, uncertainty, satisfaction, and screening and risk-reducing surgery intentions. To declare noninferiority, we calculated the 98.3% one-sided confidence interval of the standardized effect; t tests were used for secondary subgroup analyses. Only noninferiority tests were one-sided, others were two-sided. Results: A total of 1178 patients enrolled in the study. Two hundred eight (17.7%) participants declined random assignment due to a preference for in-person disclosure; 473 participants were randomly assigned to TD and 497 to IPD; 291 (30.0%) had MGPT. TD was noninferior to IPD for general and state anxiety and all secondary outcomes immediately postdisclosure. TD did not meet the noninferiority threshold for knowledge in the primary analysis, but it did meet the threshold in the multiple imputation analysis. In secondary analyses, there were no statistically significant differences between arms in screening and risk-reducing surgery intentions, and no statistically significant differences in outcomes by arm among those who had MGPT. In subgroup analyses, patients with a positive result had statistically significantly greater decreases in general anxiety with telephone disclosure (TD -0.37 vs IPD +0.87, P = .02). Conclusions: Even in the era of multigene panel testing, these data suggest that telephone disclosure of cancer genetic test results is as an alternative to in-person disclosure for interested patients after in-person pretest counseling with a genetic counselor.
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Predisposição Genética para Doença , Neoplasias Embrionárias de Células Germinativas/epidemiologia , Neoplasias Embrionárias de Células Germinativas/genética , Adulto , Afeto , Biomarcadores Tumorais , Cognição , Revelação , Feminino , Aconselhamento Genético , Testes Genéticos , Humanos , Entrevistas como Assunto , Masculino , Pessoa de Meia-Idade , Neoplasias Embrionárias de Células Germinativas/diagnóstico , TelefoneRESUMO
Recurrent mutations constituted nearly three quarters of all BRCA1 mutations and almost half of all BRCA2 mutations identified in the first cohort of the Nigerian Breast Cancer Study. To further characterize breast/ovarian cancer risks associated with BRCA1/BRCA2 mutations in the African diaspora, we genotyped recurrent mutations among Nigerian, African American, and Barbadian breast cancer patients. A replication cohort of 356 Nigerian breast cancer patients was genotyped for 12 recurrent BRCA1/2 mutant alleles (Y101X, 1742insG, 4241delTG, M1775R, 4359insC, C64Y, 1623delTTAAA, Q1090X, and 943ins10 from BRCA1, and 1538delAAGA, 2630del11, and 9045delGAAA from BRCA2) by means of SNaPshot followed by direct sequencing or by direct sequencing alone. In addition, 260 African Americans and 118 Barbadians were genotyped for six of the recurrent BRCA1 mutations by SNaPshot assay. Of all the BRCA1/2 recurrent mutations we identified in the first cohort, six were identified in 11 patients in the replication study. These mutation carriers constitute 3.1 % [95 % Confidence Interval (CI) 1.6-5.5 %] of the replication cohort. By comparison, 6.9 % (95 % CI 4.7-9.7 %) of the discovery cohort carried BRCA1/2 recurrent mutations. For the subset of recurrent mutations we tested in breast cancer cases from Barbados or the United States, only two 943ins10 carriers were identified in African Americans. Nigerian breast cancer patients from Ibadan carry a broad and unique spectrum of BRCA1/2 mutations. Our data suggest that BRCA1/2 mutation testing limited to recurrent mutations is not sufficient to understand the BRCA1/2-associated breast cancer risk in African populations in the diaspora. As the cost of Sanger sequencing is considerably reduced, deploying innovative technologies such as high throughput DNA sequencing of BRCA1/2 and other cancer susceptibility genes will be essential for identifying high-risk individuals and families to reduce the burden of aggressive early onset breast cancer in low-resource settings.