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1.
J Histochem Cytochem ; 55(11): 1105-13, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17625228

RESUMO

Only 20-25% of families screened for BRCA1/2 mutations are found positive. Because only a positive result is informative, we studied the role of BRCA1/2 immunohistochemistry as an additional method for patient selection. From 53 high-risk-affected probands, 18 (34%) had available paraffin blocks of their tumors and were selected for this study. Mutation screening was done by conformation-sensitive gel electrophoresis and multiplex ligation-dependent probe amplification. For immunohistochemistry, 21 neoplastic specimens (15 breast carcinomas, 5 ovary neoplasms, and 1 rectal adenocarcinoma) were analyzed with BRCA1 (monoclonal antibody, Ab-1, oncogene) and BRCA2 (polyclonal antibody, Ab-2, oncogene) antibodies. Absence of the BRCA1 protein was confirmed in negative tumors by Western blotting. Seven patients were positive for BRCA1/2 mutations: 5 for BRCA1 and 2 for BRCA2. Four out of five positive patients had tumors negative for BRCA1 immunostaining, and the remaining 13 BRCA1-negative patients had positive BRCA1 immunostaining in all tumor samples. Sensitivity to predict for BRCA1 mutation carriers was 80%, and specificity was 100%, with a positive predictive value of 100% and a negative predictive value of 93%. This correlation was statistically significant (p=0.001). No correlation was observed for BRCA2. If larger studies confirm these results, high-risk patients with BRCA1-negative tumors should be screened first for this gene.


Assuntos
Proteína BRCA1/metabolismo , Proteína BRCA2/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Proteínas Reguladoras de Apoptose , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/complicações , Feminino , Testes Genéticos , Heterozigoto , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/complicações , Mutação , Neoplasias Ovarianas/complicações , Valor Preditivo dos Testes , Neoplasias Retais/complicações
2.
J Clin Oncol ; 25(15): 2027-34, 2007 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-17513806

RESUMO

PURPOSE: BRCA2 rearrangements are rare genetic events. A large BRCA2 genomic insertion was recurrently observed in our participants, and we sought to characterize it at the molecular and phenotypic level. PATIENTS AND METHODS: We studied 210 high-risk breast/ovarian cancer families. Fifty-three probands were fully screened for BRCA1/2 mutations, and three of 53 had a large insertion in exon 3 of BRCA2. This finding was analyzed by polymerase chain reaction (PCR), reverse transcriptase PCR (RT-PCR), and sequencing. An additional 157 consecutive families were screened for this mutation by a three-step PCR method. Phenotype and haplotype analysis was also performed. RESULTS: Sixteen BRCA mutations were observed in 19 of 53 patients (36% detection rate). A recurrent Alu motif insertion in position c.156_157 was observed after sequencing of an abnormal fragment obtained after the amplification of BRCA2 exon 3. RT-PCR revealed exon 3 skipping. Screening of this rearrangement identified 14 additional families (out of 157). In total, 17 (8%) of 210 high-risk families ascertained in our clinic were positive for this mutation. Segregation of a common haplotype (from D13S260 to D13S1695) confirmed a common origin, estimated to have occurred 2,400 to 2,600 years ago. The following four cancer phenotypes were observed in the 17 positive families: female breast (n = 9), male breast (n = 4), breast/ovarian (n = 2), and heterogeneous (n = 2). Male breast cancer was more frequently observed in c.156_157insAlu-positive families compared with negative families (23% v 12%, respectively), and 33% of all male breast cancer families with an identified BRCA mutation were c.156_157insAlu positive. CONCLUSION: c.156_157insAlu is a founder mutation of Portuguese origin and is the most frequent BRCA2 rearrangement described to date.


Assuntos
Proteína BRCA2/genética , Neoplasias da Mama/genética , Efeito Fundador , Rearranjo Gênico/genética , Predisposição Genética para Doença , Neoplasias Ovarianas/genética , Adulto , Idoso , Análise Mutacional de DNA , Feminino , Testes Genéticos , Mutação em Linhagem Germinativa , Humanos , Judeus , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Linhagem , Fenótipo
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