Dataset Information

The germline mutational landscape of BRCA1 and BRCA2 in Brazil.

ABSTRACT: The detection of germline mutations in BRCA1 and BRCA2 is essential to the formulation of clinical management strategies, and in Brazil, there is limited access to these services, mainly due to the costs/availability of genetic testing. Aiming at the identification of recurrent mutations that could be included in a low-cost mutation panel, used as a first screening approach, we compiled the testing reports of 649 probands with pathogenic/likely pathogenic variants referred to 28 public and private health care centers distributed across 11 Brazilian States. Overall, 126 and 103 distinct mutations were identified in BRCA1 and BRCA2, respectively. Twenty-six novel variants were reported from both genes, and BRCA2 showed higher mutational heterogeneity. Some recurrent mutations were reported exclusively in certain geographic regions, suggesting a founder effect. Our findings confirm that there is significant molecular heterogeneity in these genes among Brazilian carriers, while also suggesting that this heterogeneity precludes the use of screening protocols that include recurrent mutation testing only. This is the first study to show that profiles of recurrent mutations may be unique to different Brazilian regions. These data should be explored in larger regional cohorts to determine if screening with a panel of recurrent mutations would be effective.

SUBMITTER: Palmero EI

PROVIDER: S-EPMC6003960 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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The germline mutational landscape of BRCA1 and BRCA2 in Brazil.

Palmero Edenir Inêz EI Carraro Dirce Maria DM Alemar Barbara B Moreira Miguel Angelo Martins MAM Ribeiro-Dos-Santos Ândrea Â Abe-Sandes Kiyoko K Galvão Henrique Campos Reis HCR Reis Rui Manuel RM de Pádua Souza Cristiano C Campacci Natalia N Achatz Maria Isabel MI Brianese Rafael Canfield RC da Cruz Formiga Maria Nirvana MN Makdissi Fabiana Baroni FB Vargas Fernando Regla FR Evangelista Dos Santos Anna Cláudia AC Seuanez Hector N HN Lobo de Souza Kelly Rose KR Netto Cristina B O CBO Santos-Silva Patrícia P da Silva Gustavo Stumpf GS Burbano Rommel M R RMR Santos Sidney S Assumpção Paulo Pimentel PP Bernardes Izabel Maria Monteiro IMM Machado-Lopes Taisa Manuela Bonfim TMB Bomfim Thais Ferreira TF Toralles Maria Betânia Pereira MBP Nascimento Ivana I Garicochea Bernardo B Simon Sergio D SD Noronha Simone S de Lima Fernanda Teresa FT Chami Anisse Marques AM Bittar Camila Matzenbacher CM Bines Jose J Artigalas Osvaldo O Esteves-Diz Maria Del Pilar MDP Lajus Tirzah Braz Petta TBP Gifoni Ana Carolina Leite Vieira Costa ACLVC Guindalini Rodrigo S C RSC Cintra Terezinha Sarquis TS Schwartz Ida V D IVD Bernardi Pricila P Miguel Diego D Nogueira Sonia Tereza Dos Santos STDS Herzog Josef J Weitzel Jeffrey N JN Ashton-Prolla Patricia P

Scientific reports 20180615 1

The detection of germline mutations in BRCA1 and BRCA2 is essential to the formulation of clinical management strategies, and in Brazil, there is limited access to these services, mainly due to the costs/availability of genetic testing. Aiming at the identification of recurrent mutations that could be included in a low-cost mutation panel, used as a first screening approach, we compiled the testing reports of 649 probands with pathogenic/likely pathogenic variants referred to 28 public and priva ...[more]

PMID: 29907814

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Project description:BackgroundThere is an increasing amount of data from Latin America on the characterization of BRCA variants; however, there is limited information from Peru. We conducted a retrospective study to describe germline pathogenic/likely pathogenic(P/LP) variants and variants of uncertain/unknown significance (VUS) in the BRCA1 and BRCA2 genes in Peru, in patients with breast and ovarian cancer, candidates for treatment with poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors.MethodsThe patients were evaluated during the period 2019-2021. Genomic DNA was isolated from peripheral blood samples and targeted sequencing was performed using the Ampliseq BRCA panel. Genetic variant interpretation was carried out in accordance with the recommendations of the American College of Medical Genetics and ClinVar. During this period, 525 patients (143 with breast cancer and 382 with ovarian cancer) were studied.ResultsWe found that 14.7% (21/143) of breast cancer patients and 20.7% (79/382) of ovarian cancer patients were carriers of P/LP variants in BRCA1/2. The most frequent pathogenic variants detected in BRCA1 were c.2105dupT (BIC: 2224insT, n=12, 18.75%), c.68_69delAG (BIC: 185delAG, n=6, 9.38%), c.140G>T and c.815_824dupAGCCATGTGG (n=5, 7.81%), while in BRCA2 were c.8023A>G (n=6, 16.67%), c.6024dupG (BIC: 6252insG, n=4, 11.11%), and c.9235delG (BIC: 9463delG, n=3, 8.33%). Regarding VUS, we found that 6.99% (10/143) of breast cancer patients and 7.33% (28/382) of ovarian cancer patients were carriers of a VUS in BRCA1/2. For BRCA1, the most frequent VUS was c.93C>G (n=2), and for BRCA2, c.5465A>T (n=4), c.3101T>C (n=3), c.205C>A and c.437T>C (n=2).ConclusionWe found a frequency of 14.7% germline mutations in breast cancer patients and 20.7% in ovarian cancer patients. The most recurrent mutations were BRCA1 c.2105dupT and BRCA2 c.8023A>G. We found that BRCA2 c.8023A>G, c.6024dupG, and c.9235delG were not previously reported in Peruvian patients. BRCA1 c.2344dupA is a novel mutation that has not been previously reported in any database. The frequency of VUS in our cohort was 7.2%.

Project description:BACKGROUND:MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene expression regulation and have been described as key regulators of carcinogenesis. Aberrant miRNA expression has been frequently reported in sporadic breast cancers, but few studies have focused on profiling hereditary breast cancers. In this study, we aimed to identify specific miRNA signatures in hereditary breast tumors and to compare with sporadic breast cancer and normal breast tissues. METHODS:Global miRNA expression profiling using NanoString technology was performed on 43 hereditary breast tumors (15 BRCA1, 14 BRCA2, and 14 BRCAX), 23 sporadic breast tumors and 8 normal breast tissues. These normal breast tissues derived from BRCA1- and BRCA2- mutation carriers (n =?5) and non-mutation carriers (n =?3). Subsequently, we performed receiver operating characteristic (ROC) curve analyses to evaluate the diagnostic performance of differentially expressed miRNAs. Putative target genes of each miRNAs considered as potential biomarkers were identified using miRDIP platform and used for pathway enrichment analysis. RESULTS:miRNA expression analyses identified several profiles that were specific to hereditary breast cancers. A total of 25 miRNAs were found to be differentially expressed (fold change: >?2.0 and p <?0.05) and considered as potential biomarkers (area under the curve >?0.75) in hereditary breast tumors compared to normal breast tissues, with an expressive upregulation among BRCAX cases. Furthermore, bioinformatic analysis revealed that these miRNAs shared target genes involved in ErbB, FoxO, and PI3K-Akt signaling pathways. CONCLUSIONS:Our results showed that miRNA expression profiling can differentiate hereditary from sporadic breast tumors and normal breast tissues. These miRNAs were remarkably deregulated in BRCAX hereditary breast cancers. Therefore, miRNA signatures can be used as potential novel diagnostic biomarkers for the prediction of BRCA1/2- germline mutations and may be useful for future clinical management.

Project description:ObjectiveTo investigate the prevalence of BRCA1/2 gene variants and evaluate the clinical and pathological characteristics associated with these variants in Chinese Hakka breast cancer patients.MethodsA total of 409 breast cancer patients were analyzed based on next-generation sequencing results, with 337 categorized as non-carriers and 72 as carriers of BRCA1/2 variants. Data on the patients' BRCA1/2 gene mutation status, clinical and pathological characteristics, as well as menstrual and reproductive information, were collected, analyzed, compared, and tabulated. Logistic regression analysis was performed to explore the relationship between clinical characteristics and pathogenic variants.ResultsAmong the patients, 72 were identified as carriers of pathogenic or likely pathogenic variants in BRCA1/2, while 337 had likely benign or benign mutations. The BRCA1 c.2635G > T (p. Glu879*) variant was detected at a high frequency, accounting for 12.5% (4/32) of the BRCA1 mutations, while the c.5164_5165del (p.Ser1722Tyrfs*4) variant was common among the BRCA2 mutations, accounting for 17.5% (7/40). It was observed that a higher proportion of BRCA1 carriers had the triple-negative breast cancer subtype, whereas more BRCA2 carriers exhibited estrogen receptor (ER) + and progesterone receptor (PR) + subtypes. Multivariate logistic regression analysis revealed that a family history of cancer (OR = 2.36, 95% CI = 1.00-5.54), bilateral cancer (OR = 4.78, 95% CI 1.61-14.20), human epidermal growth factor receptor 2 (HER2)- (OR = 8.23, 95% CI 3.25-20.84), and Ki67 ≥ 15% (OR = 3.88, 95% CI 1.41-10.65) were associated with BRCA1/2 mutations, with the age at diagnosis, age at menarche, and premenopausal status serving as covariates.ConclusionsThe most common pathogenic variant of the BRCA1 and BRCA2 in breast cancer patients was c.2635G > T and c.5164_5165del, respectively. Additionally, a family history of cancer, bilateral cancer, HER2-, and Ki67 ≥ 15% were identified as independent predictors of BRCA1/2 pathogenic variants.

Dataset Information

The germline mutational landscape of BRCA1 and BRCA2 in Brazil.

Publications

The germline mutational landscape of BRCA1 and BRCA2 in Brazil.

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