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1.
Acta Biomed ; 93(4): e2022051, 2022 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-36043985

RESUMO

BACKGROUND AND AIM OF THE WORK: BRCA1/2 are tumour-suppressor genes involved in DNA homologous recombination and ovarian cancer development.  The study evaluated the risk of tumor cancer in women presenting the BRCA mutations. METHODS: Risk-reducing surgery (RRS) was performed in 100 patients carrying BRCA1 (aged between 30-73 years, median age was 51 years) and BRCA 2 mutation (aged between 36-70 years, median age was 53 years). Fifty-eight patients had previous history of breast cancer. RESULTS: Between the 100 patients, 82 women underwent risk-reducing salpingo-oophorectomy (RRSO) through a laparoscopic minimally invasive approach, 7 (7 %) underwent laparoscopic RRSO and contextual hysterectomy, 1 woman (1 %) underwent RRSO through a laparotomic approach and 10 women (10 %) laparotomic RRSO and hysterectomy. During 5 (5 %) laparoscopic RRSO, prophylactic bilateral mastectomy was also performed. Early and late complication occurred in 3 patients (3 %). Two patients (2 %) were found to have occult Serous Tubal Intraepithelial Carcinoma (STIC) and three patients (3 %) occult cancer. CONCLUSIONS: RRSO is safe and feasible in BRCA mutation carriers. The procedure is effective for genetic prevention of ovarian cancer.


Assuntos
Neoplasias da Mama , Neoplasias Ovarianas , Adulto , Idoso , Neoplasias da Mama/genética , Neoplasias da Mama/prevenção & controle , Neoplasias da Mama/cirurgia , Feminino , Genes BRCA1 , Genes BRCA2 , Humanos , Mastectomia , Pessoa de Meia-Idade , Mutação , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/prevenção & controle , Neoplasias Ovarianas/cirurgia , Ovariectomia , Estudos Prospectivos , Salpingo-Ooforectomia
2.
Ethiop J Health Sci ; 32(4): 699-708, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35950060

RESUMO

Background: The objective of this study is to search for mutations in the BRCA1 (c.5177_5180delGAAA and c.4986+6T>C) and BRCA2 genes (c.6445_6446delAT) in a population of women diagnosed with breast cancer. Methods: This is a case-control study that involved 140 participants, including 70 patients with histologically diagnosed breast cancer and 70 healthy women without breast cancer. Mutations in the BRCA1 (rs80357867, rs80358086) and BRCA2 (rs80359592) genes were tested by real-time PCR. The 95% confidence interval Odds Ratio (OR) was used to estimate the associations between specific genotypes and breast cancer. Results: The study revealed that no mutations were detected for rs80359592. Similarly, no reference allele (TTTC/TTTC) of rs80357867 was found in this study. However, the homozygous double mutant (-/) genotype of this rs80357867 was observed in 11.43% and 1.43% of patients and controls respectively, while 88.57% of patients and 98.57% of controls had a heterozygous deletion (TTTC/-). Concerning rs80358086, 8.57% of the patients had a heterozygous mutation (A/G) with no significantly risk association with occurrence of breast cancer (OR = 6.46; 95% CI: 0.75-55.21; p = 0.11). In addition, this heterozygous mutation was significantly associated with a family history of breast cancer (OR=128; 95% CI: 9.46-1730.93) and breast cancer risk in nonmultiparous women (OR=6; 95% CI: 1-35.90; p= 0.05) but no association with overweight/obesity (OR=1.66; 95% CI: 0.18-15.35; p=1). Conclusion: This study shows high frequencies of heterozygous mutation of rs80357867 and rs80358086 from patients. In Burkina Faso, these results could help with early diagnosis of breast cancer in patients.


Assuntos
Neoplasias da Mama , Genes BRCA2 , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Burkina Faso , Estudos de Casos e Controles , Detecção Precoce de Câncer , Feminino , Genes BRCA1 , Predisposição Genética para Doença , Humanos
3.
BMC Health Serv Res ; 22(1): 1007, 2022 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-35933387

RESUMO

BACKGROUND: BRCA1/2 alterations increase females' lifetime breast cancer risk to 40 - 90%, ovarian cancer to 10 - 60%, and males' lifetime prostate cancer risk to ~ 10 - 25%. Psychosocial issues such as heightened distress can, therefore, occur in this population. This study aimed to explore the subjective experiences and needs of the BRCA1/2 alteration population in navigating cancer risk reduction measures. METHOD: This study aimed to explore the experiences and identify the needs of 18 BRCA1/2 alteration carriers, recruited through strategic sampling. A public and patient panel (N = 6) collaborated on study development. Data were analysed using reflexive thematic analysis. RESULTS: Two themes were identified: (i) Healthcare Services as a Burden to Navigate, and (ii) Burden Experienced Through Interactions with Healthcare Professionals. Results indicated uncertainty regarding care pathways, alongside a lack of relevant information. Participants felt unsupported by healthcare professionals, and as though healthcare professionals often perceive them as a burden. CONCLUSIONS: These findings suggest that the quality of interactions in healthcare systems are of relevance to the BRCA1/2 alteration population, and that uncertainty surrounding access to services and information is prevalent. The establishment of specialist hereditary cancer clinics could reduce such burden.


Assuntos
Neoplasias da Mama , Neoplasias Ovarianas , Proteína BRCA1/genética , Neoplasias da Mama/genética , Feminino , Genes BRCA1 , Pessoal de Saúde , Humanos , Masculino , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/prevenção & controle , Incerteza
4.
Breast Cancer Res Treat ; 195(3): 453-459, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35930098

RESUMO

PURPOSE: The gene BRCA1 plays a key role in DNA repair in breast and ovarian cell lines and this is considered one of target tumor suppressor genes in same line of cancers. The 5382insC mutation is among the most frequently detected in patients (Eastern Europe) with triple-negative breast cancer (TNBC). In Ukraine, there is not enough awareness of necessity to test patients with TNBC for BRCA1 mutations. That is why this group of patients is not well-studied, even through is known the mutation may affect the course of disease. METHODS: The biological samples of 408 female patients were analyzed of the 5382insC mutation in BRCA1. We compared the frequency of the 5382insC mutation in BRCA1 gene observed in Ukraine with known frequencies in other countries. RESULTS: For patients with TNBC, BRCA1 mutations frequency was 11.3%, while in patients with luminal types of breast cancers, the frequency was 2.8%. Prevalence of 5382insC among TNBC patients reported in this study was not different from those in Tunisia, Poland, Russia, and Bulgaria, but was higher than in Australia and Germany. CONCLUSION: The BRCA1 c.5382 mutation rate was recorded for the first time for TNBC patients in a Ukrainian population. The results presented in this study underscore the importance of this genetic testing of mutations in patients with TNBC. Our study supports BRCA1/2 genetic testing for all women diagnosed with TNBC, regardless of the age of onset or family history of cancer and not only for women diagnosed with TNBC at <60y.o., as guidelines recommend.


Assuntos
Neoplasias da Mama , Neoplasias Ovarianas , Neoplasias de Mama Triplo Negativas , Proteína BRCA1/genética , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Feminino , Genes BRCA1 , Predisposição Genética para Doença , Testes Genéticos , Humanos , Mutação , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Neoplasias de Mama Triplo Negativas/epidemiologia , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Ucrânia/epidemiologia
5.
Medicina (Kaunas) ; 58(7)2022 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-35888662

RESUMO

Background and Objectives: BRCA 1 and 2 mutations have a cumulative risk of developing ovarian cancer at 70 years of 41% and 15%, respectively, while a cumulative risk of breast cancer by 80 years of age was 72% for BRCA1 mutation carriers and 69% for BRCA2 mutation carriers. The NCCN recommends risk-reducing salpingo-oophorectomy (RRSO), typically between 35 and 40 years, and upon completion of childbearing in BRCA1 mutation, while it is reasonable to delay RRSO for management of ovarian cancer risk until age 40-45 years in patients with BRCA2. In recent years there have been two main lines of evolution in laparoscopy. The former concerning the development of a single-site laparoscopic and the latter concerning the miniaturisation of laparoscopic instruments (mini/micro-laparoscopy). Materials and Methods: In this case report, we show our experience in prophylactic adnexectomy, on a mutated-BRCA patient, using the MiniLap® percutaneous surgical system. Results: This type of technique is safe and effective and does not require a particular learning curve compared to single-port laparoscopy. Conclusions: The considerable aesthetic advantage of the scars, we believe, albeit to a lesser extent, is useful to find in these patients burdened by an important stress load.


Assuntos
Neoplasias da Mama , Laparoscopia , Neoplasias Ovarianas , Adulto , Neoplasias da Mama/cirurgia , Cicatriz/cirurgia , Feminino , Genes BRCA1 , Genes BRCA2 , Humanos , Laparoscopia/efeitos adversos , Laparoscopia/métodos , Pessoa de Meia-Idade , Mutação , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/prevenção & controle , Neoplasias Ovarianas/cirurgia , Ovariectomia/métodos
6.
Breast Cancer Res Treat ; 195(2): 153-160, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35842521

RESUMO

PURPOSE: The United States Preventive Services Task Force recommends primary care physicians refer patients at high risk for BRCA1/2 mutations to genetic testing when appropriate. The objective of our study was to describe referrals for BRCA1/2 testing in a large integrated health system and to assess factors associated with referral. METHODS: This retrospective cohort study includes female patients between 18 and 50 years who had a primary care visit in the Cleveland Clinic Health System between 2010 and 2019. We used multivariable logistic regression to estimate differences in the odds of a woman being referred for BRCA1/2 testing by patient factors and referring physician specialty. We also assessed variation in referrals by physicians. RESULTS: Among 279,568 women, 5% were high risk. Of those, 22% were referred for testing. Black patients were significantly less likely to be referred than white patients (aOR 0.87; 95% CI 0.77, 0.98) and Jewish patients were more likely to be referred than non-Jewish patients (aOR 2.13; 95% CI 1.68, 2.70). Patients primarily managed by OB/GYN were significantly more likely to be referred than those cared for via Internal/Family Medicine (aOR 1.45; 95% CI 1.30, 1.61). Less than a quarter of primary care physicians ever referred a patient for testing. CONCLUSION: The majority of primary care patients at high risk for a BRCA1/2 mutation were not referred for testing, and over a decade, most physicians never referred a single patient. Internal/Family Medicine physicians, in particular, need support in identifying and referring women who could benefit from testing.


Assuntos
Neoplasias da Mama , Médicos de Atenção Primária , Proteína BRCA1/genética , Proteína BRCA2 , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Feminino , Genes BRCA1 , Genes BRCA2 , Aconselhamento Genético , Predisposição Genética para Doença , Testes Genéticos , Humanos , Encaminhamento e Consulta , Estudos Retrospectivos , Estados Unidos
7.
Genes (Basel) ; 13(7)2022 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-35886069

RESUMO

Germline pathogenic variants (PVs) in oncogenes and tumour suppressor genes are responsible for 5 to 10% of all diagnosed cancers, which are commonly known as hereditary cancer predisposition syndromes (HCPS). A total of 104 individuals at high risk of HCPS were selected by genetic counselling for genetic testing in the past 2 years. Most of them were subjects having a personal and family history of breast cancer (BC) selected according to current established criteria. Genes analysis involved in HCPS was assessed by next-generation sequencing (NGS) using a custom cancer panel with high- and moderate-risk susceptibility genes. Germline PVs were identified in 17 of 104 individuals (16.3%) analysed, while variants of uncertain significance (VUS) were identified in 21/104 (20.2%) cases. Concerning the germline PVs distribution among the 13 BC individuals with positive findings, 8/13 (61.5%) were in the BRCA1/2 genes, whereas 5/13 (38.4%) were in other high- or moderate-risk genes including PALB2, TP53, ATM and CHEK2. NGS genetic testing showed that 6/13 (46.1%) of the PVs observed in BC patients were detected in triple-negative BC. Interestingly, the likelihood of carrying the PVs in the moderate-to-high-risk genes calculated by the cancer risk model BOADICEA was significantly higher in pathogenic variant carriers than in negative subjects. Collectively, this study shows that multigene panel testing can offer an effective diagnostic approach for patients at high risk of hereditary cancers.


Assuntos
Síndromes Neoplásicas Hereditárias , Neoplasias de Mama Triplo Negativas , Genes BRCA1 , Predisposição Genética para Doença , Células Germinativas , Humanos , Síndromes Neoplásicas Hereditárias/genética , Neoplasias de Mama Triplo Negativas/genética
8.
Cancer Res ; 82(18): 3201-3208, 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-35834270

RESUMO

Women who have had breast cancer in the past are at increased risk of developing a second primary cancer (SPC), including second primary breast cancer (SPBC) or a second primary non-breast cancer (SPNBC). In the Multiethnic Cohort (MEC) Study, we conducted a prospective cohort analysis in 3,223 female breast cancer survivors from five racial/ethnic populations (White, African American, Japanese American, Latino, and Native Hawaiian) to assess the association of rare pathogenic variants (PV) in 37 known cancer predisposition genes with risk of SPC. A total of 719 (22.3%) women developed SPC, of which, 323 (10.0%) were SPBC. Germline PVs in BRCA1 (HR, 2.28; 95% CI, 1.11-4.65) and ERCC2 (HR, 3.51; 95% CI, 1.29-9.54) were significantly enriched in women with SPC. In the subtype analysis for SPBC, a significant association of ERCC2 PVs (HR, 5.09; 95% CI, 1.58-16.4) and a suggestive association of BRCA2 PVs (HR, 2.24; 95% CI, 0.91-5.55) were observed. There was also a higher risk of SPNBC in carriers of BRCA1 PVs (HR, 2.98; 95% CI, 1.21-7.36). These results provide evidence that germline PVs in BRCA1, BRCA2, and ERCC2 contribute to the development of SPC in breast cancer survivors. These findings also suggest that compromised DNA repair mechanisms could be a predisposition factor for SPC in patients with breast cancer, supporting the need for closer monitoring of SPC in women carrying PVs in these genes. SIGNIFICANCE: This multiethnic study links germline pathogenic variants in BRCA1, BRCA2, and ERCC2 to the development of second primary cancer in breast cancer survivors, providing biological insights and biomarkers to guide patient monitoring.


Assuntos
Neoplasias da Mama , Sobreviventes de Câncer , Segunda Neoplasia Primária , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Estudos de Coortes , Feminino , Genes BRCA1 , Predisposição Genética para Doença , Humanos , Masculino , Segunda Neoplasia Primária/genética , Estudos Prospectivos , Proteína Grupo D do Xeroderma Pigmentoso/genética
9.
Biomed Res Int ; 2022: 5886269, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35837379

RESUMO

Background: Breast cancer is one of the most common types of cancer diagnosed and the second leading cause of death among women. Breast cancer susceptibility proteins of type 1 and 2 are human tumor suppressor genes. Genetic variations/mutations in these two genes lead to overexpression of human breast tumor suppressor genes (e.g., BRCA1, BRCA2), which triggers uncontrolled duplication of cells in humans. In addition, multidrug resistance protein 1 (MDR1), an important cell membrane protein that pumps many foreign substances from cells, is also responsible for developing resistance to cancer chemotherapy. Aim of the Study. The aim of this study was to analyze some natural compounds or their derivatives as part of the development of strong inhibitors for breast cancer. Methodology. Molecular docking studies were performed using compounds known in the literature to be effective against BRCA1 and BRCA2 and MDR1, with positive control being 5-fluorouracil, an antineoplastic drug as a positive control. Results: The binding affinity of the compounds was analyzed, and it was observed that they had a better binding affinity for the target proteins than the standard drug 5-fluorouracil. Among the compounds analyzed, α-hederin, andrographolide, apigenin, asiatic acid, auricular acid, sinularin, curcumin, citrinin, hispolon, nerol, phytol, retinol palmitate, and sclareol showed the best binding affinity energy to the BRCA1, BRCA2, and MDR1 proteins, respectively. Conclusions: α-Hederin, andrographolide, apigenin, asiatic acid, auricular acid, hispolon, sclareol, curcumin, citrinin, and sinularin or their derivatives can be a good source of anticancer agents in breast cancer.


Assuntos
Neoplasias da Mama , Citrinina , Curcumina , Apigenina , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Curcumina/farmacologia , Feminino , Fluoruracila , Genes BRCA1 , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Simulação de Acoplamento Molecular
10.
Bioorg Med Chem Lett ; 72: 128859, 2022 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-35716865

RESUMO

Overexpression of RAD51 protein was found to increase drug resistance in breast cancer cells. Breast cancer susceptibility gene 1 (BRCA1) protein can specifically bind to RAD51 protein and regulate the expression level of RAD51 protein. Based on previous studies, eight modified peptides were obtained by modifying the N-terminus of the key peptide segment 856-871 of BRCA1 with nicotinic acid (NA) and its derivatives. The interaction of BRCA1856-871 and modified peptides with the RAD51158-180 target peptide was investigated by fluorescence and circular dichroism spectroscopies. The results showed that the binding ability of 2-TFM-NA-PP to RAD51158-180 was significantly enhanced. BRCA1856-871 and modified peptides were studied by in vitro cell experiments. The results showed that the antitumor activity of 5-TFM-NA-PP was significantly enhanced compared with BRCA1856-871.


Assuntos
Neoplasias da Mama , Rad51 Recombinase , Proteína BRCA1/genética , Proteína BRCA2/genética , Feminino , Genes BRCA1 , Humanos , Peptídeos/farmacologia
11.
Cancer Genet ; 266-267: 19-27, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35671604

RESUMO

A significant number of hereditary breast or ovarian cancers are caused by germline variants, mostly BRCA1/BRCA2 genes. Because genetic predispositions vary by ethnicity, several studies have reported founder variants of BRCA1/BRCA2 genes. Such founder variants were reported primarily based on their relevant population frequencies. We reviewed the variant data relating to BRCA1 and BRCA2 genes from January 2012 to March 2019 at Samsung Medical Center, Seoul, Korea. Among the cases with pathogenic variants (PVs) or likely pathogenic variants (LPVs), we defined recurrent variants as those found in more than five unrelated patients. Using single nucleotide polymorphisms, we analyzed patient haplotypes. There were 14 recurrent variants in the BRCA1 gene and seven variants in the BRCA2 gene. Of note, three variants in each gene were primarily detected in Korean populations. Among them, the c.5339T>C (p.Leu1780Pro) BRCA1 variant had a long block sized 74.5 kb. In BRCA2, the c.1399A>T (p.Lys467*) variant had a long block sized 35.5 kb. We suggest that BRCA1 c.5339T>C (p.Leu1780Pro) and BRCA2 c.1399A>T (p.Lys467*) are founder variants of the Korean population. These two recurrent variants were ethnicity-prevalent, primarily found in Korean populations, and the sizes of the linkage disequilibrium blocks are longer than others.


Assuntos
Neoplasias da Mama , Neoplasias Ovarianas , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Feminino , Frequência do Gene , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Mutação em Linhagem Germinativa/genética , Haplótipos/genética , Humanos , Neoplasias Ovarianas/genética
12.
J Fluoresc ; 32(5): 1733-1741, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35675001

RESUMO

In this research, DNA-modified carbon dots (CDs) were exploited to construct a fluorescence assay for breast cancer genes (BRCA1, a potential marker for cancer diagnosis) detection. For this purpose, water-soluble synthesized CDs were functionalized with 19 mer-modified oligonucleotides (capture probe). By adding the DNA target, the specific binding between the DNA probe and DNA target causes fluorescence quenching. The assay displayed a fine capability of sensing the BRCA1 gene with a linear range (R2 = 0.9918) of 36 attomolar (aM) to 532 femtomolar (fM) and a detection limit of 2 attomolar. This homogeneous process does not need additional separation and washing steps of un-hybridized DNA. To assess the selectivity, the prepared biosensor responses were evaluated in solutions containing single-base mismatched DNA sequences, three-base mismatched DNA sequences, or non-complementary DNA sequences, separately. To demonstrate the practical application of the designed biosensor, the extracted DNA from blood samples of breast cancer patients was utilized as real samples. When the CDs-DNA bioassay was exploited in the imaging of MCF-7 cancer cells, strong fluorescence emission was observed. After incubation times, both the cells' size and shape remained unchanged. The results validated that the CDs are an extremely great bioimaging candidate in disease diagnosis, biomedicine investigation, and managing cancer diseases.


Assuntos
Neoplasias da Mama , Pontos Quânticos , Proteína BRCA1/genética , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/genética , Carbono , DNA/genética , Feminino , Corantes Fluorescentes , Genes BRCA1 , Humanos , Espectrometria de Fluorescência/métodos
13.
Br J Cancer ; 127(5): 879-885, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35710751

RESUMO

BACKGROUND: Several clinical and tumour factors impact on ovarian cancer survival. It is important to evaluate if germline mutations impact long-term outcomes among patients with epithelial ovarian cancer. METHODS: We followed 1422 Ontario women with ovarian cancer. Clinical information was obtained from medical records and vital status was determined by registry linkage. Germline genetic testing was performed for 12 susceptibility genes. We estimated 20-year cancer-specific survival according to various factors. RESULTS: Twenty-year survival was inferior for women with serous cancers vs. other types (22.3% vs. 68.6%; P < 0.0001). Of the 1422 patients, 248 (17.4%) carried a germline mutation; 119 BRCA1; 75 BRCA2; 7 in a mismatch repair (MMR) gene and 47 in one of seven other genes. Among serous patients, 20-year survival was 28.9% for similar for women with a BRCA1 (28.9%), BRCA2 (21.2%) or no mutation (21.6%). Among endometrioid patients, 20-year survival was poor for women with a BRCA vs. no mutation (47.3% vs. 70.4%; P = 0.004). Six of the seven MMR mutation carriers are currently alive, while all three PALB2 mutation carriers died within 3 years of diagnosis. Among women with Stage III/IV serous cancers, 20-year survival was 9.4% for those with vs. 46.5% for those with no residual disease (HR = 2.91; 95% CI 2.12-4.09, P < 0.0001). CONCLUSIONS: The most important predictor of long-term survival was no residual disease post surgery. BRCA mutation status was not predictive of long-term survival while those with MMR mutations had excellent survival. Larger studies on PALB2 carriers are needed.


Assuntos
Carcinoma Epitelial do Ovário , Mutação em Linhagem Germinativa , Proteína BRCA2/genética , Carcinoma Epitelial do Ovário/genética , Feminino , Genes BRCA1 , Genes BRCA2 , Humanos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Prognóstico
14.
Breast Cancer Res Treat ; 194(1): 187-198, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35578052

RESUMO

PURPOSE: Breast cancer (BC) is the most common form of female cancer around the world. BC is mostly sporadic, and rarely hereditary. These hereditary forms are mostly BRCA1- and BRCA2-associated hereditary breast and ovarian cancer syndrome. BRCA1 and BRCA2 genes are large and had some recurrent mutations specific to some populations. Through this work we analyze the most recurrent mutations in Moroccan population and compared them to a large review of other BRCA1/2 spectrum mutations in the MENA region. METHODS: We report in this work a series of 163 unrelated patients (the largest series of Moroccan patients) with familial breast and/or ovarian cancer, selected among patients referred to our oncogenetic outpatient clinic, from 2006 to 2021. To identify genetic variants in these two genes, different genetic analysis strategies have been carried out, using Sanger Sequencing DNA or Target Panel Sequencing. RESULTS: Pathogenic variants were identified in 27.6% of patients. The most frequent mutation identified in our patients was the c.1310_1313delAAGA, BRCA2 (33%), and three other mutations seem more frequent in the Moroccan population (33%) of all reported patients: c.798_799delTT, BRCA1; and c.3279delC, BRCA1; and c.7234_7235insG in BRCA2 gene. CONCLUSION: Through this work, we emphasize the importance of screening for BRCA1 and BRCA2 recurrent mutations in Moroccan patients. Other MENA (MENA: English-language acronym referring to the Middle East and North Africa region) countries had also some recurrent BRCA mutations, which will allow a fast and unexpensive first line genetic analysis and a precise molecular diagnosis. This will allow an adapted follow-up of the patients and a pre-symptomatic diagnosis of their relatives.


Assuntos
Neoplasias da Mama , Genes BRCA1 , Genes BRCA2 , Neoplasias Ovarianas , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Mutação , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética
15.
Ann Surg Oncol ; 29(9): 5821-5825, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35604619

RESUMO

Risk-reducing mastectomy is considered a safe and effective surgical procedure in high-risk individuals with BRCA1/2 germline mutations. Multigene panels identify women with alterations in breast cancer susceptibility genes other than BRCA1/2. International guidelines classify these genes as high-, moderate-, and low-penetrance based on their associated relative risk for breast cancer. Classification of specific genes is not always concordant among guidelines, and the indications for risk-reducing mastectomy are not defined. In this opinion paper, we review some considerations to clarify these controversial points.


Assuntos
Neoplasias da Mama , Mastectomia , Neoplasias da Mama/genética , Neoplasias da Mama/cirurgia , Feminino , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Humanos , Mastectomia/métodos , Mutação , Penetrância
16.
Cancer Treat Res Commun ; 32: 100569, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35567913

RESUMO

BACKGROUND: BRAF V600E+ microsatellite stable (MSS) metastatic colorectal cancer (mCRC) patients comprise up to 10% of advanced CRC. They have a poor prognosis with a median survival typically <1 year. Despite use of multi-agent 1st line chemotherapy regimens and combination targeted therapies, outcomes are still poor. In our Institutional Molecular Tumor Board (MTB) database, we identified 3 mCRC patients with MSS/BRAF V600E who also had a BRCA1 or BRCA2 co-mutation and had relatively long overall survivals. Prior studies suggested that BRCA mutations are uncommon in CRC and we queried the Foundation Medicine (FM) genomic database to evaluate the prevalence of these cases as well as those with co-mutations in other homologous recombination genes. METHODS: 36,966 CRC pts were sequenced by FMI using hybrid capture comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GA) for pathogenic BRAF mutations and/or a mutation in BRCA1/2 or a co-mutation in other homologous recombination (HR) genes (BARD1, CDK12, FANCL, PALB2, ATM, RAD54L, CHEK2, BRAF, BRIP1, RAD51D, RAD51C, RAD51B, CHEK1). Selected cohort analysis of BRAF V600E co-mutated with BRCA1 and BRCA2 were separated into MSI-H and MSS cohorts. The clinicopathological features and genomic loss of heterozygosity (gLOH) of those with a BRAF V600E and a BRCA1/BRCA2 mutation were collected and analyzed. We also describe 3 consecutive cases of mCRC patients, identified through the Inova Schar Cancer Institute (ISCI) MTB registry, whom had prolonged OS. RESULTS: Of 36,966 colorectal cancer pts, 6.6% were BRAF V600E+ and 1.5% had any co-occurring HR gene mutation(s) with 0.6% of the total mCRC population having co-ocurring BRAF V600E and BRCA1/2 alterations. BRCA co-mutations were higher in MSI-High BRAF V600E, however 24.1% of co-occurrences were observed in MSS samples. BRCA1 co-mutation was more commonly associated with MSS BRAF V600E and was associated with a higher gLOH than MSI-H BRAF V600E (18.7% vs 2.8%; p <0.001). In our institutional MTB database, (3/241;1.2%) CRC patients were MSS, BRAF V600E+ with BRCA1 or BRCA2 co-mutations, all somatic in origin, with an average gLOH of 21.4% and overall survivals of 72+(alive), 17+(alive), and 30 months, respectively. CONCLUSION: Co-existence of BRAF V600E/BRCA1/2 may represent a unique subset of advanced MSS CRC that may have a better prognosis and represent an opportunity to test novel targeted therapies. The elevated gLOH in these cases may also be a valuable biomarker for these pts. Larger prospective clinical validation trials in this subset is warranted.


Assuntos
Neoplasias Colorretais , Proteínas Proto-Oncogênicas B-raf , Neoplasias do Colo/diagnóstico , Neoplasias do Colo/genética , Neoplasias do Colo/secundário , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Neoplasias Colorretais/secundário , Genes BRCA1 , Genes BRCA2 , Humanos , Instabilidade de Microssatélites , Mutação , Prevalência , Prognóstico , Estudos Prospectivos , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Retais/diagnóstico , Neoplasias Retais/genética , Neoplasias Retais/secundário
17.
J Gynecol Oncol ; 33(4): e51, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35557034

RESUMO

OBJECTIVE: Examine the risks of fractures and osteoporosis after risk-reducing bilateral salpingo-oophorectomy (RRBSO) among women with BRCA1/2 mutations. METHODS: In this retrospective population-based study in British Columbia, Canada, between 1996 to 2017, we compared risks of osteoporosis and fractures among women with BRCA1/2 mutations who underwent RRBSO before the age of 50 (n=329) with two age-matched groups without known mutations: 1) women who underwent bilateral oophorectomy (BO) (n=3,290); 2) women with intact ovaries who had hysterectomy or salpingectomy (n=3,290). Secondary outcomes were: having dual-energy X-ray absorptiometry (DEXA) scan, and bisphosphonates use. RESULTS: The mean age at RRBSO was 42.4 years (range, 26-49) and the median follow-up for women with BRCA1/2 mutations was 6.9 years (range, 1.1-19.9). There was no increased hazard of fractures for women with BRCA1/2 mutations (adjusted hazard ratio [aHR]=0.80; 95% confidence interval [CI]=0.56-1.14 compared to women who had BO; aHR=1.02; 95% CI=0.65-1.61 compared to women with intact ovaries). Among women who had DEXA-scan, those with BRCA1/2 mutations had higher risk of osteoporosis (aHR=1.60; 95% CI=1.00-2.54 compared to women who had BO; aHR=2.49; 95% CI=1.44-4.28 compared to women with intact ovaries). Women with BRCA1/2 mutations were more likely to get DEXA-scan than either control groups, but only 46% of them were screened. Of the women with BRCA1/2 mutations diagnosed with osteoporosis, 36% received bisphosphonates. CONCLUSION: Women with BRCA1/2 mutations had higher risk of osteoporosis after RRBSO, but were not at increased risk of fractures during our follow-up. Low rates of DEXA-scan and bisphosphonates use indicate we can improve prevention of bone loss.


Assuntos
Neoplasias da Mama , Osteoporose , Neoplasias Ovarianas , Adulto , Proteína BRCA1/genética , Densidade Óssea/genética , Neoplasias da Mama/genética , Difosfonatos , Feminino , Genes BRCA1 , Genes BRCA2 , Humanos , Pessoa de Meia-Idade , Mutação , Osteoporose/epidemiologia , Osteoporose/genética , Neoplasias Ovarianas/genética , Ovariectomia/efeitos adversos , Estudos Retrospectivos , Salpingo-Ooforectomia/efeitos adversos
18.
Sci Rep ; 12(1): 8547, 2022 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-35595798

RESUMO

Only up to 25% of the cases in which there is a familial aggregation of breast and/or ovarian cancer are explained by germline mutations in the well-known BRCA1 and BRCA2 high-risk genes. Recently, the BRCA1-associated ring domain (BARD1), that partners BRCA1 in DNA repair, has been confirmed as a moderate-risk breast cancer susceptibility gene. Taking advantage of next-generation sequencing techniques, and with the purpose of defining the whole spectrum of possible pathogenic variants (PVs) in this gene, here we have performed a comprehensive mutational analysis of BARD1 in a cohort of 1946 Spanish patients who fulfilled criteria to be tested for germline pathogenic mutations in BRCA1 and BRCA2. We identified 22 different rare germline variants, being 5 of them clearly pathogenic or likely pathogenic large deletions, which account for 0.26% of the patients tested. Our results show that the prevalence and spectrum of mutations in the BARD1 gene might vary between different regions of Spain and expose the relevance to test for copy number variations.


Assuntos
Neoplasias da Mama , Variações do Número de Cópias de DNA , Neoplasias Ovarianas , Proteínas Supressoras de Tumor , Ubiquitina-Proteína Ligases , Proteína BRCA1/genética , Neoplasias da Mama/genética , Variações do Número de Cópias de DNA/genética , Feminino , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Neoplasias Ovarianas/genética , Espanha/epidemiologia , Proteínas Supressoras de Tumor/genética , Ubiquitina-Proteína Ligases/genética
20.
Int J Mol Sci ; 23(7)2022 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-35409408

RESUMO

Germline mutations in the BRCA1 gene have been reported to increase the lifetime risk of developing breast and/or ovarian cancer (BOC). By new sequencing technologies, numerous variants of uncertain significance (VUS) are identified. It is mandatory to develop new tools to evaluate their functional impact and pathogenicity. As the expression of pathogenic BRCA1 variants in Saccharomyces cerevisiae increases the frequency of intra- and inter-chromosomal homologous recombination (HR), and gene reversion (GR), we validated the two HR and the GR assays by testing 23 benign and 23 pathogenic variants and compared the results with those that were obtained in the small colony phenotype (SCP) assay, an additional yeast-based assay, that was validated previously. We demonstrated that they scored high accuracy, sensitivity, and sensibility. By using a classifier that was based on majority of voting, we have integrated data from HR, GR, and SCP assays and developed a reliable method, named yBRCA1, with high sensitivity to obtain an accurate VUS functional classification (benign or pathogenic). The classification of BRCA1 variants, important for assessing the risk of developing BOC, is often difficult to establish with genetic methods because they occur rarely in the population. This study provides a new tool to get insights on the functional impact of the BRCA1 variants.


Assuntos
Neoplasias da Mama , Neoplasias Ovarianas , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Proteína BRCA2/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Genes BRCA1 , Predisposição Genética para Doença , Humanos , Mutação de Sentido Incorreto , Neoplasias Ovarianas/genética , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo
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