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‣ Determinação de mutações e polimorfismo nos genes BRCA1 e BRCA2 em pacientes com  câncer de mama com indicação para teste genético; Determinação de mutações e polimorfismos nos genes BRCA1 e BRCA2 em pacientes com câncer de mama com indicação para teste genético

Escobar, Karina Augusto
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 08/08/2011 Português
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Introdução: Mutações nos genes BRCA1 e BRCA2 são responsáveis por cerca de 50% dos casos de câncer de mama e/ou ovário hereditários. Atualmente não conhecemos o perfil de mutações destes genes na população brasileira, com exceção de mutações fundadoras que ocorrem em grupos étnicos específicos. Objetivos: Detectar mutações e polimorfismos nos genes BRCA1 e BRCA2 em 73 pacientes com câncer de mama selecionadas para o teste genético. Casuística e métodos: Realizamos o sequenciamento direto e o teste de MLPA para os genes BRCA1 e BRCA2 em 73 indivíduos, sendo 63 pacientes com câncer de mama com risco maior ou igual a 10% de acordo com os critérios de Frank, Evans e BRCAPRO, dois pacientes com câncer de ovário e oito indivíduos saudáveis com forte histórico familiar de câncer ligado a mutações em BRCA1 e/ou BRCA2. Resultados: Encontramos 60 mutações no gene BRCA1: 13 alterações missense (incluindo a deletéria R71G), sete mutações sinônimas, uma mutação frameshift (a deletéria 5382insC), uma mutação nonsense (a deletéria R1751X), uma deleção in frame, uma alteração 3UTR e 36 variantes intrônicas. Em BRCA2 encontramos 57 mutações, entre as quais 26 mutações missense, uma alteração 5UTR...

‣ Investigação de Mutações no Gene BRCA1 em Famílias Brasileiras com Suspeita da Síndrome Hereditária do Câncer de Mama e/ou Ovário.; Investigation of Mutations in the BRCA1 Gene in Brazilian Families with Suspected of Hereditary Breast and Ovarian Cancer Syndrome.

Cury, Nathália Moreno
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 27/04/2012 Português
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Cerca de 10% dos casos de câncer de mama e/ou ovário são caracterizados como hereditários, onde a presença de mutações germinativas no gene de suscetibilidade BRCA1 aumenta o risco de desenvolver esses cânceres durante a vida da mulher. O BRCA1 é um gene supressor tumoral envolvido na resposta de danos ao DNA, controle do ciclo celular, na remodelação da cromatina, ubiquitinação e regulação da transcrição. O presente estudo tem como objetivo central caracterizar as mutações do gene BRCA1 associadas a Síndrome Hereditária do Câncer de Mama e/ou Ovário (HBOC) em pacientes atendidos no Serviço de Aconselhamento Genético do Câncer do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (HCFMRP/USP). Os vinte e dois éxons codificantes do BRCA1 foram analisados utilizando o método de High Resolution Melting (HRM) para triagem de mutações pontuais, seguido pelo sequenciamento de DNA dos casos selecionados para validação. A técnica de MLPA (Multiplex Ligation-dependent Probe Amplification) também foi usada para detectar grandes deleções e duplicações. Uma vez confirmada a mutação, membros da família considerados de alto risco, serão investigados para a mutação específica...

‣ Incidência das mutações 185delAG e 5382insC no gene BRCA1 em mulheres judias Ashkenazi de Porto Alegre

Dillenburg, Crisle Vignol
Fonte: Universidade Federal do Rio Grande do Sul Publicador: Universidade Federal do Rio Grande do Sul
Tipo: Dissertação Formato: application/pdf
Português
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Base Teórica: O câncer de mama é provavelmente o mais temido pelas mulheres devido a sua alta freqüência e, sobretudo, pelos seus efeitos psicológicos que afetam a percepção da sexualidade e a própria imagem pessoal. Ele é relativamente raro antes dos 35 anos de idade, mas acima desta faixa etária sua incidência cresce rápida e progressivamente. Estudos indicam que fatores genéticos e ambientais são responsáveis pela incidência do câncer de mama, sendo que a hereditariedade provavelmente tenha participação restrita no desenvolvimento deste tipo de tumor. Os principais genes associados ao desenvolvimento do câncer de mama, BRCA1 e BRCA2, são responsáveis por cerca de 80% desses casos, conferindo um risco de 71 a 85% de chance de desenvolver a neoplasia em alguma fase da vida. Mutações nesses genes, classificados como supressores tumorais, demonstram que a perda de suas funções não pára o ciclo celular, não permite a ação do sistema de reparo, e não estimula a apoptose (morte celular programada), culminando em replicação anormal e câncer. A observação epidemiológica de que mulheres judias de origem Ashkenazi parecem ser mais vulneráveis ao câncer de mama está sendo explicada através de estudos moleculares dos genes BRCA1 e BRCA2...

‣ Prevalence of BRCA1 and BRCA2 gene mutations in families with medium and high risk of breast and ovarian cancer in Brazil

Esteves,V.F.; Thuler,L.C.S.; Amêndola,L.C.; Koifman,R.J.; Koifman,S.; Frankel,P.P.; Vieira,R.J.S.
Fonte: Associação Brasileira de Divulgação Científica Publicador: Associação Brasileira de Divulgação Científica
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/05/2009 Português
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Of all malignant neoplasias affecting women, breast cancer has the highest incidence rate in Brazil. The objective of the present study was to determine the frequency of genetic modifications in families with medium and high risk for breast and ovarian cancer from different regions of Brazil. An exploratory, descriptive study was carried out on the prevalence of the BRCA1 and BRCA2 mutations in case series of high-risk families for breast and/or ovarian cancer. After heredogram construction, a blood sample was taken and DNA extraction was performed in all index cases. The protein truncation test was used to screen for truncated mutations in exon 11 of the BRCA1 gene and in exons 10 and 11 of the BRCA2 gene. Of the 612 individuals submitted to genetic testing, 21 (3.4%), 19 women and 2 men, had mutations in the BRCA1 or BRCA2 genes. Of the 19 BRCA1 mutations found in the 18 participants, 7 consisted of ins6kb mutations, 4 were 5382insC, 3 were 2156delGinsCC, 2 were 185delAG, 1 was C1201G, 1 was C3522T, and 1 was 3450del4. With respect to the BRCA2 gene, 3 mutations were found: 5878del10, 5036delA and 4232insA (one case each). The prevalence of germline mutations in the BRCA1 and BRCA2 genes found in the present study was lower than reported by other studies on high-risk Brazilian populations. The inclusion of individuals with medium risk may have contributed to the lower prevalence observed.

‣ Analysis of BRCA1 and BRCA2 mutations in Brazilian breast cancer patients with positive family history

Dufloth,Rozany Mucha; Carvalho,Sílvia; Heinrich,Juliana Karina; Shinzato,Júlia Yoriko; Santos,César Cabello dos; Zeferino,Luiz Carlos; Schmitt,Fernando
Fonte: Associação Paulista de Medicina - APM Publicador: Associação Paulista de Medicina - APM
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/01/2005 Português
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CONTEXT AND OBJECTIVE: BRCA1 and BRCA2 are the two principal hereditary breast cancer susceptibility genes, and the prevalence of their mutations among Brazilian women is unknown. The objective was to detect BRCA1 and BRCA2 mutations in Brazilian patients with breast cancer, so as to establish genetic profiles. DESIGN AND SETTING: Cross-sectional study, in Centro de Atenção Integral à Saúde da Mulher, Universidade Estadual de Campinas, Brazil, and Institute of Pathology and Molecular Immunology, University of Porto, Portugal. METHODS: Thirty-one breast cancer patients with positive family history (criteria from the Breast Cancer Linkage Consortium) were studied, and genomic DNA was extracted from peripheral blood. Single-strand conformation polymorphism was used for the analysis of exons 2, 3, 5, and 20 of BRCA1. Cases showing PCR products with abnormal bands were sequenced. Exon 11 of BRCA1 and exons 10 and 11 of BRCA2 were directly sequenced in both directions. RESULTS: Four mutations were detected: one in BRCA1 and three in BRCA2. The BRCA1 mutation is a frameshift located at codon 1756 of exon 20: 5382 ins C. Two BRCA2 mutations were nonsense mutations located at exon 11: S2219X and the other was an unclassified variant located at exon 11: C1290Y. CONCLUSION: The BRCA1 or BRCA2 mutation prevalence found among women with breast cancer and such family history was 13% (4/31). Larger studies are needed to establish the significance of BRCA mutations among Brazilian women and the prevalence of specific mutations.

‣ Impacto prognóstico da expressão imuno-histoquímica do BRCA1 nos carcinomas mamários esporádicos

Ribeiro-Silva,Alfredo; Garcia,Sérgio Britto; Chahud,Fernando; Zucoloto,Sérgio
Fonte: Sociedade Brasileira de Patologia Clínica; Sociedade Brasileira de Patologia; Sociedade Brasileira de Citopatologia Publicador: Sociedade Brasileira de Patologia Clínica; Sociedade Brasileira de Patologia; Sociedade Brasileira de Citopatologia
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/06/2005 Português
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INTRODUÇÃO: Embora mutações no BRCA1 sejam raras nos carcinomas mamários não-familiares, é comum haver perda de expressão da proteína codificada por esse gene. A importância prognóstica desse achado não está bem estabelecida. OBJETIVOS: analisar a expressão imuno-histoquímica do BRCA1 em carcinomas mamários esporádicos e comparar os resultados obtidos com dados clínicos e histopatológicos de importância prognóstica. MATERIAL E MÉTODO: 102 carcinomas ductais sem outras especificações foram submetidos ao método imuno-histoquímico com os anticorpos BRCA1, RE, RP, p53, c-erbB-2 e Ki67. Os dados clínicos foram obtidos dos prontuários médicos. RESULTADOS: No epitélio normal, o BRCA1 apresentou apenas marcação nuclear, enquanto os carcinomas apresentaram tanto marcação nuclear quanto a citoplasmática. Os carcinomas com baixa expressão imuno-histoquímica do BRCA1 foram pouco diferenciados, com alta taxa proliferativa, negativos para receptores hormonais e positivos para c-erbB-2. Não houve correlação da expressão do BRCA1 com idade, estado menstrual, tamanho tumoral, acometimento de linfonodos, estadiamento patológico e expressão do p53. As sobrevidas média e livre de doença das pacientes cujos tumores expressaram menos e mais de 25% de marcação para o BRCA1 nas células neoplásicas foram de 4...

‣ The role of ubiquitination and deubiquitination in the regulation of BRCA1 function during genotoxic stress

Pak, Helen
Fonte: Université de Montréal Publicador: Université de Montréal
Tipo: Thèse ou Mémoire numérique / Electronic Thesis or Dissertation
Português
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BRCA1 est un suppresseur de tumeur majeur jouant un rôle dans la transcription, la réparation de l’ADN et le maintien de la stabilité génomique. En effet, des mutations dans le gène BRCA1 augmentent considerablement le risque de cancers du sein et de l’ovaire. BRCA1 a été en majorité caractérisé pour son rôle dans la réparation de l’ADN par la voie de recombinaison homologue (HR) en présence de bris double brins, par example, induits par l’irradiation gamma (IR). Cependant, la fonction de BRCA1 dans d’autres voies de réparation de l’ADN, comme la réparation par excision de nucléotides (NER) ou par excision de base (BER), demeurent toutefois obscures. Il est donc important de comprendre la régulation de BRCA1 en présence d’agents génotoxiques comme le méthyle méthanesulfonate (MMS) ou l’UV, qui promouvoient le BER et le NER respectivement. Nos observations suggèrent que BRCA1 est dégradée par le protéasome après traitement avec le MMS ou les UV, et non avec l’IR. Par ailleurs, cette dégradation semble compromettre le recrutement de Rad51, suggérant que la voie de HR est inhibée. Nos résultats suggèrent que la HR est inhibée afin d’éviter l’activation simultanée de multiples voies de réparation. Nous avons aussi observé que la dégradation BRCA1 est réversible et que la restauration des niveaux de BRCA1 coïncide avec le recrutement de Rad51 aux sites de dommages. Cela suggère que la HR est réactivée tardivement par les bris double brins générés suite à l’effondrement des fourches de réplication. Ayant observé que BRCA1 est hautement régulé par l’ubiquitination et est ciblé par le protéasome pour dégradation...

‣ Preimplantation genetic diagnosis for BRCA1 exon 13 duplication mutation using linked polymorphic markers resulting in a live birth

Jasper, M.; Liebelt, J.; Hussey, N.
Fonte: John Wiley & Sons Ltd Publicador: John Wiley & Sons Ltd
Tipo: Artigo de Revista Científica
Publicado em //2008 Português
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BACKGROUND: The risk of breast cancer associated with inheriting a BRCA1 mutation is extremely high, in addition, there is a 50% chance of transmitting this familial cancer mutation to any offspring. METHODS: A 31-year-old woman with a strong maternal family history of early onset of breast cancer had experienced 3 years of primary infertility. Presymptomatic testing confirmed the woman had inherited a 6 kb duplication of exon 13 (ins6KbEx13) in BRCA1 from her mother. Neither gamete donation or adoption were acceptable options for this infertile couple, and as termination of pregnancy after prenatal diagnosis following in vitro fertilization (IVF) was not ethically acceptable, preimplantation genetic diagnosis (PGD) was sought. A single-cell PCR protocol for PGD for the breast and ovarian cancer predisposing BRCA1 exon 13 duplication mutation was developed which involved amplification of three specific gene regions, including the BRCA1 mutation (ins6KbEx13), an intragenic marker (D17S855) and a flanking marker (D17S1185). RESULTS: In the first cycle of IVF, three embryos were analyzed and two were determined to be at low risk of having inherited the maternal BRCA1 mutation. Following the transfer of both embryos on day 5, a singleton pregnancy resulted. Declining confirmatory prenatal diagnosis...

‣ Skewed X chromosome inactivation and breast and ovarian cancer status: Evidence for X-linked modifiers of BRCA1

Lose, F.; Duffy, D.; Kay, G.; Kedda, M.A.; Spurdle, A.; Oehler, M.
Fonte: Oxford Univ Press Inc Publicador: Oxford Univ Press Inc
Tipo: Artigo de Revista Científica
Publicado em //2008 Português
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BACKGROUND: X chromosome inactivation, which silences gene expression from one of the two X chromosomes in females, is usually random. Skewed X inactivation has been implicated in both the expression and the suppression of X-linked disease phenotypes and has been reported to occur more frequently in breast and ovarian cancer patients, including BRCA1 or BRCA2 mutation carriers, than in control subjects. METHODS: We assessed the pattern of X chromosome inactivation using methylation-specific polymerase chain reaction amplification of the exon 1 microsatellite region of the X-linked androgen receptor (AR) gene in DNA from blood samples obtained from control subjects without a personal history of breast or ovarian cancer (n = 735), ovarian cancer patients (n = 313), familial breast cancer patients who did not carry mutations in BRCA1 or BRCA2 (n = 235), and affected and unaffected carriers of mutations in BRCA1 (n = 260) or BRCA2 (n = 63). We defined the pattern of X chromosome inactivation as skewed when the same X chromosome was active in at least 90% of cells. The association between skewed X inactivation and disease and/or BRCA mutation status was assessed by logistic regression analysis. The association between skewed X inactivation and age at cancer diagnosis was assessed by Cox proportional hazards regression analysis. All statistical tests were two-sided. RESULTS: The age-adjusted frequency of skewed X inactivation was not statistically significantly higher in ovarian cancer or familial breast cancer case subjects compared with control subjects. Skewed X inactivation was higher in BRCA1 mutation carriers than in control subjects (odds ratio [OR] = 2.7...

‣ Analysis of a set of missense, frameshift, and in-frame deletion variants of BRCA1

Carvalho, M.; Pino, M.; Karchin, R.; Beddor, J.; Godinho-Netto, M.; Mesquita, R.; Rodarte, R.; Vaz, D.; Monteiro, V.; Manoukian, S.; Colombo, M.; Ripamonti, C.; Rosenquist, R.; Suthers, G.; Borg, A.; Radice, P.; Grist, S.; Monteiro, A.; Billack, B.
Fonte: Elsevier Science BV Publicador: Elsevier Science BV
Tipo: Artigo de Revista Científica
Publicado em //2009 Português
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Germline mutations that inactivate BRCA1 are responsible for breast and ovarian cancer susceptibility. One possible outcome of genetic testing for BRCA1 is the finding of a genetic variant of uncertain significance for which there is no information regarding its cancer association. This outcome leads to problems in risk assessment, counseling and preventive care. The purpose of the present study was to functionally evaluate seven unclassified variants of BRCA1 including a genomic deletion that leads to the in-frame loss of exons 16/17 (Delta exons 16/17) in the mRNA, an insertion that leads to a frameshift and an extended carboxy-terminus (5673insC), and five missense variants (K1487R, S1613C, M1652I, Q1826H and V1833M). We analyzed the variants using a functional assay based on the transcription activation property of BRCA1 combined with supervised learning computational models. Functional analysis indicated that variants S1613C, Q1826H, and M1652I are likely to be neutral, whereas variants V1833M, Delta exons 16/17, and 5673insC are likely to represent deleterious variants. In agreement with the functional analysis, the results of the computational analysis also indicated that the latter three variants are likely to be deleterious. Taken together...

‣ Targeted prostate cancer screening in men with mutations in BRCA1 and BRCA2 detects aggressive prostate cancer: preliminary analysis of the results of the IMPACT study

Mitra, A.; Suthers, G.
Fonte: Blackwell Publishing Ltd Publicador: Blackwell Publishing Ltd
Tipo: Artigo de Revista Científica
Publicado em //2011 Português
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Study Type – Diagnostic (validating cohort) Level of Evidence 1b What’s known on the subject? and What does the study add? Scientists have found a number of genetic factors that increase prostate cancer risk, including heritable mutations in the genes BRCA1 and BRCA2. These mutations are not common but can have major impact, as a BRCA2 mutation increases risk by up to seven-fold while a BRCA1 mutation is thought to double risk in men under 65. The IMPACT study aims to determine whether targeted screening in men with a known BRCA1 or BRCA2 mutation would lead to earlier diagnosis of prostate cancers. This data from the IMPACT study adds to the increasing evidence that BRCA mutation carriers develop more aggressive disease. Although these are early results, it appears that PSA screening is more accurate at predicting potentially aggressive prostate cancer among men at higher risk of the disease due to a genetic predisposition than general population screening. This study provides support for continued screening in men with genetic mutations. OBJECTIVE: To evaluate the role of targeted prostate cancer screening in men with BRCA1 or BRCA2 mutations, an international study, IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls)...

‣ Report of endometrial cancer in Australian BRCA1 and BRCA2 mutation-positive families

Duffy, D.L.; Antill, Y.C.; Stewart, C.J.; Young, J.P.; Spurdle, A.B.
Fonte: Cambridge University Press (CUP) Publicador: Cambridge University Press (CUP)
Tipo: Artigo de Revista Científica
Publicado em //2011 Português
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There is evidence that tamoxifen treatment of BRCA1 and BRCA2 carriers for prior breast cancer increases risk of endometrioid subtype endometrial cancer (EC), and suggestive evidence that BRCA1 and BRCA2 mutation carriers may be predisposed to EC in the absence of tamoxifen exposure. We assessed the association of EC with BRCA1 or BRCA2 mutation status in Australasian breast-ovarian families. Report of at least one case of EC was significantly greater in BRCA1-positive families (35/218 (16%); p = .03) and non-significantly greater in BRCA2-positive families (23/189 (12%); p = .6), compared to high-risk breast cancer families without a BRCA1/2 mutation (86/796 (11%)). EC was the first/concurrent cancer for 41% of EC cases with multiple cancer diagnoses from BRCA1/2 families, and early onset for most of these diagnoses. Mutation status was imputed for ungeno-typed individuals from 57 BRCA1/2 pedigrees reporting EC using BRCAPRO. Effects of genotype on EC diagnosis age, and interaction with tamoxifen therapy, were assessed using Cox proportional hazards regression analysis. EC risk was non-significantly marginally greater for BRCA1 carriers (hazard ratio = 1.25, 95%CI = 0.65-2.41), and BRCA2 carriers (HR = 1.12, 95%CI = 0.51-2.45), compared to non-carrier family members. Tamoxifen therapy was highly significantly associated with EC (HR = 6.68...

‣ Analysis of cancer risk and BRCA1 and BRCA2 mutation prevalence in the kConFab familial breast cancer resource

Mann, G.; Thorne, H.; Balleine, R.; Butow, P.; Clarke, C.; Edkins, E.; Evans, G.; Fereday, S.; Haan, E.; Gattas, M.; Giles, G.; Goldblatt, J.; Hopper, J.; Kirk, J.; Leary, J.; Lindeman, G.; Niedermayr, E.; Phillips, K.A.; Picken, S.; Pupo, G.; et al.
Fonte: Biomed Central Ltd Publicador: Biomed Central Ltd
Tipo: Artigo de Revista Científica
Publicado em //2006 Português
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INTRODUCTION: The Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab) is a multidisciplinary, collaborative framework for the investigation of familial breast cancer. Based in Australia, the primary aim of kConFab is to facilitate high-quality research by amassing a large and comprehensive resource of epidemiological and clinical data with biospecimens from individuals at high risk of breast and/or ovarian cancer, and from their close relatives. METHODS: Epidemiological, family history and lifestyle data, as well as biospecimens, are collected from multiple-case breast cancer families ascertained through family cancer clinics in Australia and New Zealand. We used the Tyrer-Cuzick algorithms to assess the prospective risk of breast cancer in women in the kConFab cohort who were unaffected with breast cancer at the time of enrolment in the study. RESULTS: Of kConFab's first 822 families, 518 families had multiple cases of female breast cancer alone, 239 had cases of female breast and ovarian cancer, 37 had cases of female and male breast cancer, and 14 had both ovarian cancer as well as male and female breast cancer. Data are currently held for 11,422 people and germline DNAs for 7,389. Among the 812 families with at least one germline sample collected...

‣ Validation of a Gene-Expression Based Assay for BRCA1 Function

Uy, PAOLO MIGUEL
Fonte: Quens University Publicador: Quens University
Tipo: Tese de Doutorado
Português
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Breast cancer is a disease that afflicts a significant proportion of women globally. 5-10% of breast cancer cases are linked to inherited polymorphisms in critical genes such as BRCA1, a tumour suppressor essential for genomic stability. A dysfunctional BRCA1 gene can increase breast cancer risk by 60-80%. Previous microarray analysis established that differential gene expression in unperturbed Epstein-Barr virus transformed lymphocyte cell lines (EBV-LCL) was able to distinguish BRCA1 mutation carriers from controls with a high degree of accuracy. A 43-gene radiation-independent classifier for BRCA1 status was constructed. We hypothesize that this differential gene expression can be observed in a subset of these genes using quantitative PCR (qPCR) in both EBV-LCL and B-lymphocytes isolated from patients with known BRCA1 mutation carrier status. The 43-gene classifier was analyzed using gene ontology analysis and 4 target genes selected based on predictive value, expression intensity and gene ontology similarity. Genes selected were CXCR3, TBX21, MX2, and IFIT1, with GusB as an endogenous reference gene. EBV-LCL established from known BRCA1 mutation carriers and from BRCA1 wildtype individuals were obtained and RT-qPCR (reverse transcriptase qPCR) performed on isolated RNA. Our results showed significant downregulation of CXCR3 and TBX21 in BRCA1 mutation carriers (p=0.018 and p=0.003...

‣ THE NRF-1/GABP/BRCA1 TRANSCRIPTIONAL NETWORK IN MAMMARY EPITHELIAL DIFFERENTIATION

Thompson, Crista
Fonte: Quens University Publicador: Quens University
Tipo: Tese de Doutorado
Português
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Evidence indicates that the mammary epithelium is arranged in a hierarchy in which mature luminal and myoepithelial cells are derived from stem cells through a series of lineage-restricted intermediates. One of the more compelling hypotheses in breast cancer research is that transformation of a particular cell within the hierarchy will initiate a tumour with a specific molecular profile and clinical outcome. If this is true, valuable insight into tumourigenesis can be gained by investigating normal and malignant pathways of differentiation. A well-known tumour suppressor in breast cancer, BRCA1, plays a role in mammary epithelial differentiation. It has been proposed that haploinsufficiency or loss of BRCA1, either by germline mutation or sporadic downregulation, blocks differentiation producing a pool of genetically unstable mammary stem/progenitor cells that are prime targets for transformation. Thus, investigation of BRCA1 regulation and its role in differentiation are important to our understanding of breast cancer etiology. In this study, we determined that BRCA1 is at the end of a transcriptional network comprised of NRF-1 and GABP, a transcription factor comprised of two distinct subunits GABPalpha and GABPbeta. Decreased BRCA1 transcription in SK-BR-3 cells was found to be caused by aberrant activation of the GABPbeta promoter by an NRF-1 binding protein complex. We determined that the SWI/SNF family members BRG1...

‣ DEVELOPMENT OF A FUNCTIONAL ASSAY FOR DETERMINATION OF BRCA1 CARRIER STATUS

BATHURST, LAUREN
Fonte: Quens University Publicador: Quens University
Tipo: Tese de Doutorado
Português
Relevância na Pesquisa
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Given the high risk of cancer development associated with BRCA1 mutation carriers, it is important that they be identified early and accurately. Identification is impeded however, by the large number of variants of unknown significance (VUS) and the pleiotropic nature of BRCA1 function. Our lab has developed a novel functional assay that identifies BRCA1 mutation carriers based on gene signatures in Epstein-Barr virus (EBV)-transformed lymphoblastoid cells (LCLs). Given that this assay was developed using blood-derived cells, we hypothesized that the same abnormally regulated genes would be detected in fresh blood samples and that this could be used to develop a novel blood-based functional assay for the determination of BRCA1 status in a patient population. The first part of the study used selected reaction monitoring-mass spectrometry (SRM-MS) as well as flow cytometry (FC) to determine protein expression in LCLs and identify potential targets for the development of a protein-based functional assay. Interestingly, many of the strong predictors of BRCA1 carriers were proteins involved in two signalling pathways: Interferon (IFN)-regulated signalling and B cell development. If validated in fresh blood samples, these observations represent potentially novel findings and suggest yet unexplored functions for BRCA1. Next...

‣ The Identification of BRCA1 and BRCA2 Mutation Carriers Using Functional Genomic Assays

Michel, CLAIRE S.
Fonte: Quens University Publicador: Quens University
Tipo: Tese de Doutorado Formato: 4883165 bytes; application/pdf
Português
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An estimated 5-10% of breast cancers are hereditary in nature and are due to the presence of a mutation in a breast cancer predisposition gene; approximately half of these cases possess a mutation in BRCA1 or BRCA2. Many BRCA1/BRCA2 mutations result in a truncated protein and hence are unequivocally disease-causing. However another class of mutations, the Variants of Unknown Significance (VUS), are more problematic as the effect of these mutations on protein function is unclear. The inability to classify these mutations as disease causing generates significant problems in risk evaluation, counseling and preventive care. Accordingly we sought to determine whether carriers of either a BRCA1 or BRCA2 mutation could be identified from non-carriers based on the gene expression patterns of non-cancerous cells. EBV-transformed lymphoblastoid cell lines established from BRCA1/BRCA2 mutation carriers and normal individuals were obtained through the NIH Breast Cancer Family Registries. Cell lines were mock-irradiated or treated with ionizing radiation (2 Gy). Following a recovery period of 6 hours total RNA was extracted and whole genome gene expression profiling was carried out. Molecular classifiers comparing the baseline expression profiles and the radiation-dependent expression profiles of BRCA1/BRCA2 mutation carriers to control individuals were created using a Support Vector Machine (SVM) coupled with a recursive feature removal (RFR) algorithm. Our results suggest that cell populations derived from BRCA1/BRCA2 mutation carriers display unique expression phenotypes from those of control individuals in both the basal and radiation-induced cases. In the task of classification using baseline expression...

‣ Étude du transcriptome des cellules non tumorales de l’épithélium de surface de l’ovaire des femmes porteuses d’une mutation des gènes BRCA1 et BRCA2

Abd Rabbo, Diala
Fonte: Université de Montréal Publicador: Université de Montréal
Tipo: Thèse ou Mémoire numérique / Electronic Thesis or Dissertation
Português
Relevância na Pesquisa
37.277036%
Nous avons étudié le transcriptome de neuf échantillons d'ARN extraits de cultures primaires de cellules non tumorales de l’épithélium de surface de l’ovaire (NOSE) provenant de quatre donneuses non porteuses de mutation, deux mutées sur BRCA1 et trois sur BRCA2, ainsi que de quatre échantillons d’ARN extraits de cultures primaires de cellules tumorales de l’ovaire (TOV) provenant de trois donneuses porteuses de mutation sur BRCA1 et une sur BRCA2. Nous avons identifié, pour la première fois, les signatures moléculaires associées à la présence d’une mutation de BRCA1 et BRCA2 dans les cellules NOSEs ainsi que la signature associée à la transformation tumorale des cellules NOSEs en TOVs chez les porteuses de mutation de BRCA1. Nous avons également localisé les domaines chromosomiques comportant des gènes corégulés en association avec la présence d’une mutation de BRCA1 dans les cellules NOSEs. Les allèles sauvage et muté de BRCA2 étaient exprimés dans les cellules TOVs provenant des porteuses de la mutation 8765delAG sur BRCA2. Nous avons observé que le niveau d’expression des transcrits de BRCA2 était plus élevé dans les cellules provenant des tumeurs ovariennes les plus agressives chez les femmes porteuses de la mutation 8765delAG sur BRCA2...

‣ Rol de BRCA1 en la regulación de la transcripción en cáncer de próstata; BRCA1 role in transcriptional regulation in prostate cancer

De Luca, Paola
Fonte: Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires Publicador: Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires
Tipo: info:eu-repo/semantics/doctoralThesis; tesis doctoral; info:eu-repo/semantics/publishedVersion Formato: application/pdf
Publicado em //2011 Português
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El gen de susceptibilidad al cáncer de mama (BRCA1) es un supresor tumoral. Las mutaciones germinales en este gen confieren predisposición al cáncer de mama, ovario y están asociadas con una mayor agresividad del cáncer de próstata (PCa). Varias evidencias demuestran que BRCA1 tiene numerosas funciones, sin embargo, no se conoce aún cuál es el rol de este supresor tumoral en el PCa. En esta tesis determinamos por primera vez que BRCA1 regula directamente su propia transcripción y la de otros genes que intervienen en la respuesta al daño en el ADN, el ciclo celular y la apoptosis en el PCa. Establecimos un mecanismo por el cual la regulación de la transcripción de BRCA1 es una característica fundamental en la modulación de la sensibilidad a los agentes genotóxicos. Comprobamos que BRCA1 forma un complejo multriproteico integrado por E2F1 y Rb, que se asocia a su promotor autorreprimiéndolo. Luego del estrés genotóxico generado por doxorrubicina, BRCA1 se libera activando su transcripción y asociándose a los promotores de otros genes, entre ellos GADD153. Así, BRCA1 induce la transcripción de GADD153 aumentando la apoptosis y el arresto del ciclo celular. Además, generamos un modelo in vivo de xenotransplantes de PCa que poseen disminuída la expresión de BRCA1. Con este modelo demostramos que la disminución de la expresión de BRCA1 aumenta el desarrollo tumoral de próstata. Considerando que los agentes quimioterapéuticos utilizados comúnmente en el tratamiento del cáncer causan daño en el ADN...

‣ Rol de BRCA1 en la regulación de la transcripción en cáncer de próstata; BRCA1 role in transcriptional regulation in prostate cancer

De Luca, Paola
Fonte: Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires Publicador: Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires
Tipo: Tesis Doctoral Formato: text; pdf
Publicado em //2011 Português
Relevância na Pesquisa
37.306997%
El gen de susceptibilidad al cáncer de mama (BRCA1) es un supresor tumoral. Las mutaciones germinales en este gen confieren predisposición al cáncer de mama, ovario y están asociadas con una mayor agresividad del cáncer de próstata (PCa). Varias evidencias demuestran que BRCA1 tiene numerosas funciones, sin embargo, no se conoce aún cuál es el rol de este supresor tumoral en el PCa. En esta tesis determinamos por primera vez que BRCA1 regula directamente su propia transcripción y la de otros genes que intervienen en la respuesta al daño en el ADN, el ciclo celular y la apoptosis en el PCa. Establecimos un mecanismo por el cual la regulación de la transcripción de BRCA1 es una característica fundamental en la modulación de la sensibilidad a los agentes genotóxicos. Comprobamos que BRCA1 forma un complejo multriproteico integrado por E2F1 y Rb, que se asocia a su promotor autorreprimiéndolo. Luego del estrés genotóxico generado por doxorrubicina, BRCA1 se libera activando su transcripción y asociándose a los promotores de otros genes, entre ellos GADD153. Así, BRCA1 induce la transcripción de GADD153 aumentando la apoptosis y el arresto del ciclo celular. Además, generamos un modelo in vivo de xenotransplantes de PCa que poseen disminuída la expresión de BRCA1. Con este modelo demostramos que la disminución de la expresión de BRCA1 aumenta el desarrollo tumoral de próstata. Considerando que los agentes quimioterapéuticos utilizados comúnmente en el tratamiento del cáncer causan daño en el ADN...