Tesi: "Brca1 gene mutations"

1

Oh, Yeum Mok, e Yeum Mok Oh. "BRCA1 and BRCA2 Gene Mutations in Colorectal Cancer: A Systematic Review and Meta-Analysis". Thesis, The University of Arizona, 2017. http://hdl.handle.net/10150/625685.

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Background: The relevant risks associated with BRCA1 and BRCA2 mutation in breast and ovarian cancer have been well studied. BRCA mutations have also been found to be associated with other cancers, including colorectal cancer, but with conflicting results. Aims: We performed a systematic review and meta-analysis to identify, characterize, and review published studies evaluating BRCA mutation carriers with colorectal cancer, and to quantify the risk of colorectal cancer overall and in subgroups of BRCA mutation carriers. Methods: Eligible studies were retrieved through systematic review using multiple databases. Unadjusted odds ratios were used to derive pooled estimates of colorectal cancer risk overall and in subgroups defined by mutation type, comparison group, and study design. Results: A total of 18 studies were included in the systematic review, of which 14 were also used in the meta-analysis: seven cohort studies comparing to the general population, five case-control studies, four cohort studies involving pedigree analysis, and two kin-cohort studies. Meta-analysis not differentiating between BRCA1 and BRCA2, revealed a statistically significant increased risk of colorectal cancer in BRCA mutation carriers in a fixed-effects model (OR=1.22, 95%CI=1.01-1.48, p=0.041), but not in a random-effects model (OR=1.20, 95%CI=0.96-1.50, p=0.111). Analyses stratified by study design and comparator found no association between BRCA mutation and colorectal cancer risk. In subgroup meta-analyses by BRCA type, BRCA1 mutation was associated with increased risk of colorectal cancer (OR=1.48, 95%CI=1.13-1.94, p=0.005), but not in BRCA2 mutation. Conclusion: Systematic review and meta-analysis point at potential 1.22-fold greater risk of colorectal cancer in BRCA mutation carriers, attributable largely to a 1.48-fold greater risk of colorectal cancer in BRCA1 mutation carriers, regardless of age.

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King, Heidi M. "Risk reduction decision making in women with BRCA1/2 gene mutations". [Tampa, Fla] : University of South Florida, 2008. http://purl.fcla.edu/usf/dc/et/SFE0002506.

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3

King, Heidi M. "Risk Reduction Decision Making in Women with BRCA1/2 Gene Mutations". Scholar Commons, 2007. https://scholarcommons.usf.edu/etd/334.

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With technological advances in testing for gene mutations, a new population of BRCA1/2 women is becoming aware of their increased risk for developing breast and/or ovarian cancer. A salient issue these women face is which risk-reducing option to choose. Little is known about the decision making factors underlying the choice of prophylactic mastectomy for women with a BRCA1/2 mutation. To address this issue, 137 unaffected, positive BRCA1/2 gene mutation carriers (42 who opted for prophylactic mastectomy, 95 who did not) served as participants. All women completed an on-line battery that assessed the following theory-based decision making variables: advantages and disadvantages of prophylactic mastectomy (normative decision theory), physician recommendation (shared decision making theory), cancer worry (affect theory), and information-seeking coping style. With the exception of information-seeking style (p = .8715), the decision making variables of advantages and disadvantages of prophylactic mastectomy, physician input, and cancer worry did have a significant relationship with risk-reduction option chosen. Women who rated the advantages higher than the disadvantages of prophylactic mastectomy (r = .31, p ≤ .001), whose physician had recommended prophylactic mastectomy exclusively (X² = 11.85; p < .001), and who reported higher cancer worry scores a month after receiving BRCA1/2 positive results (r = .28, p ≤ .001) were more likely to have chosen prophylactic mastectomy. The perceived impact (conflict, regret, cancer worry, and general well-being) of risk-reducing option selected was also explored. The direction of these relationships indicates that having chosen prophylactic mastectomy was associated with less decisional conflict (r = -.38, p ≤ .0001), decisional regret (r = -.58, p ≤ .0001), depressive symptomatology (r = -.19, p ≤ .05), and cancer worry (r = -.39, p ≤ .0001). The results suggest higher assessments of advantages over disadvantages of prophylactic mastectomy, doctor recommendation for prophylactic mastectomy exclusively, and higher cancer worry at time of testing is associated with choosing the risk-reducing option of prophylactic mastectomy. In addition, women who chose prophylactic mastectomy fared better psychologically than those who did not. Continued research addressing decision making variables and the impact of risk-reducing decisions may lead to improved understanding on how best to approach these difficult decisions.

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Puget, Nadine. "Prédisposition génétique au cancer du sein : recherche de mutations dans les régions régulatrices et de réarrangements structuraux du gène BRCA1". Lyon 1, 1999. http://www.theses.fr/1999LYO1T093.

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Heinlen, Christopher Charles. "Provider Perceived Clinical Utility of Enhanced Risk Assessments for Carriers of Pathogenic BRCA1/2 gene mutations". The Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1491994043693414.

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6

Cury, Nathália Moreno. "Investigação de Mutações no Gene BRCA1 em Famílias Brasileiras com Suspeita da Síndrome Hereditária do Câncer de Mama e/ou Ovário". Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/17/17135/tde-14062012-134410/.

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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, a fim de proporcionar-lhes um aconselhamento genético apropriado para a detecção precoce do câncer. No presente estudo, foram investigados 41 pacientes que preencheram os critérios para o teste genético de acordo com NCCN Clinical Practice Guidelines in Oncology v.1.2010. Um total de 21 mutações foram identificadas, duas das quais são patogênicas: a deleção dos éxons 17-18 e a deleção dos éxon 19. Ambas estão localizadas no domínio BRCT do gene BRCA1, essencial para a ligação de fosfoproteínas críticas para a ativação do complexo de reparo do DNA. Outra mutação, a S616del, foi tratada como patogênica, mas apresenta informações controversas em diferentes estudos. O trabalho também identificou uma nova mutação, Val1117Ile. Um estudo de haplótipos das mutações identificadas nos pacientes foi realizado e revelou que um dos haplótipos, denominado de 6, contendo quatro resíduos mutados (871Leu, 1038Gly, 1183Arg e 1613Gly) estava presente em 50% das pacientes. O estudo de associação com 82 indivíduos saudáveis, mostrou diferença significativa (p=0,026) nos pacientes, sugerindo assim um risco aumentado de HBOC. Adicionalmente, foi analisada a mutação germinativa R337H no gene p53 para os casos suspeitos de Síndrome de Li-Fraumeni. Em síntese, o presente estudo contribui com a identificação de uma nova mutação não-sinônina no gene BRCA1 e sugere que o haplótipo 871Leu-1038Gly-1183Arg-1613Gly possa conferir risco aumentado do câncer de mama e/ou ovário em pacientes diagnosticados com HBOC.
About 10% of cases of breast and/or ovary cancer are characterized as hereditary, where the presence of germline mutations in susceptibility BRCA1 gene increases the risk of developing these cancers during womans lifetime. BRCA1 is a tumor suppressor gene involved in DNA damage response, cell cycle control, chromatin remodeling, ubiquitination and transcriptional regulation. The present study aims to characterize BRCA1 gene mutations associated with Hereditary Breast/Ovary Cancer Syndrome (HBOC) in patients from the Cancer Genetic Counseling Service of the General Hospital of the Medical School of Ribeirão Preto, University of São Paulo (HCFMRP-USP). The twenty two coding exons of BRCA1 were analyzed using High Resolution Melting (HRM) method for the screening of point mutations, followed by DNA sequencing of the cases selected to validation. MLPA (Multiplex Ligation-dependent Probe Amplification) technique was also used to detect gross deletions and duplications. Once confirmed the mutation, family members most at risk will be analyzed for the specific mutation in order to provide them with an appropriate genetic counseling for early detection of cancer. In the present study, we investigated 41 patients that fulfilled the criteria for genetic testing according to NCCN Clinical Practice Guidelines in Oncology v.1.2010. A total of 21 mutations were identified, two of them are pathogenic: a deletion of exons 17-18 and a deletion of exon 19. Both of them are located in the BRCT domain of BRCA1 gene, impairing the binding of essential phosphoproteins critical to the activation of DNA repair complex. Another mutation, S616del, shows controversial information about its pathogenesis in different studies.The present study also describes a new mutation, Val1117Ile. A study of haplotypes of the mutations identified in patients was performed and revealed that one of the haplotypes, called 6, containing four mutated residues (871Leu, 1038Gly, and 1183Arg 1613Gly) was present in 50% of patients. The association study with 82 healthy subjects showed a significant difference (p = 0.026) in patients, thus suggesting an increased risk for HBOC. Additionally, the germline mutation R337H on p53 gene was also analyzed in the present study for suspected cases of Li-Fraumeni Syndrome. In summary, this study contributes to the identification of a new missense mutation in the BRCA1 gene and suggests that the haplotype-871Leu-1038Gly 1183Arg-1613Gly may confer increased risk of breast cancer and / or ovarian cancer in patients diagnosed with HBOC.

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Bachelier, Richard. "Expression et localisation subcellulaire des protéines murines BRCA1 et BRCA1-Δ11 : étude du rôle du gène BRCA1 et des effets de ses mutations sur la morphogénèse et la cancérogénèse de la glande mammaire et de la prostate chez la souris". Lyon 1, 2000. http://www.theses.fr/2000LYO1T014.

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8

Dillenburg, Crisle Vignol. "Incidência das mutações 185delAG e 5382insC no gene BRCA1 em mulheres judias Ashkenazi de Porto Alegre". reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2008. http://hdl.handle.net/10183/13534.

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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, onde encontramos a prevalência de três mutações específicas: 185delAG e 5382insC, no gene BRCA1 e 6174delT, no gene BRCA2. Métodos: Utilizou-se um banco de DNA pré-existente, extraído de 209 mulheres da comunidade judaica Ashkenazi da cidade de Porto Alegre. A amplificação do DNA foi realizada por PCR, através da técnica PSM (PCR Mediated site-direct) seguida de digestão dos produtos de PCR com enzimas de restrição. Os objetivos foram verificar se as freqüências das mutações 185delAG e 5382insC, no gene BRCA1 são significativas nesta população e compará-las com demais freqüências encontradas. Resultados: Foram encontradas três pacientes com a mutação 185delAG e duas pacientes com a mutação 5382insC, com as freqüências de 1,435% (95% IC: 0,366; 3,856) e 0,957% (95% IC: 0,161; 3,125), respectivamente.
Introduction: Breast cancer is probably the worst diagnosed cancer for women due to its high frequency and furthermore by its psychological problems that affect the perception of sexuality and the self image. It is relatively rare before 35 years of age, but beyond this age its incidence increases rapidly and progressively. Studies show that genetic and environmental factors are responsible for breast cancer incidence, but heredity may play a restrict role in the development of this kind of tumor. The main genes associated to the development of breast cancer, BRCA1 and BRCA2, are responsible for almost 80% of these cases, reaching a chance between 71 and 85% of developing the disease at any life stage. Mutations in these genes, classified as tumor suppressors, do not allow the repair mechanisms of DNA to perform its action and do not stimulate apoptosis, culminating in abnormal replication and cancer. The epidemiological observation in which Ashkenazi Jewish women seems to be more vulnerable to breast cancer is explained through molecular studies of BRCA1 and BRCA2 genes, where three specific mutations have been found (185delAG and 5382insC, in the BRCA1 gene and 6174delT, in the BRCA2 gene). Methods: A pre-existent bank of DNA extracted from 209 women of the Ashkenazi Jewish community of Porto Alegre city has been used. The DNA amplification was performed through PCR, using the PSM (PCR Mediated Site-Direct) technique followed by the digestion of PCR products with restriction enzymes. The objectives of this study was to identify the frequencies of mutations 185delAG and 5382insC at the BRCA1 gene and verify if they are significantly different in this population when compared to frequencies found in other studies. Results: We found three patients with 185delAG mutation and two patients with 5382insC mutation, with frequencies of 1.435% (95% CI: 0,366; 3,856) and 0,957% (95% IC: 0,161; 3,125), respectively.

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Mavaddat, Nasim. "Risk modelling in BRCA1 and BRCA2 mutation carriers". Thesis, University of Cambridge, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.610839.

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Gedminaitė, Jurgita. "Krūties vėžiu sergančių moterų BRCA1, BRCA2, CHEK2 ir NBS1 genų mutacijų tyrimas ir jų ryšio su kitais prognoziniais veiksniais paieška". Doctoral thesis, Lithuanian Academic Libraries Network (LABT), 2013. http://vddb.laba.lt/obj/LT-eLABa-0001:E.02~2013~D_20130919_143947-94587.

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Apie 5–10 proc. visų krūties navikų atvejų sudaro paveldimas vėžys. BRCA1 ir BRCA2 genai yra patys svarbiausi polinkį susirgti krūties vėžiu sąlygojantys genai. Kiti reikšmingai su padidėjusia krūties navikų išsivystymo rizika susiję – CHEK2 ir NBS1 genai. Šiame darbe ištirtos paveldimos dažniausiai Europos regione nustatomos šių genų mutacijos. Nustatytas BRCA1 ir CHEK2 genų mutacijų dažnis tarp jaunų krūties vėžiu susirgusių moterų, ištyrinėtos jų sąsajos su pacientės amžiumi, naviko klinikinėmis ir morfologinėmis savybėmis. Išanalizuota šeiminės anamnezės prognozinė vertė nustatant paveldimus BRCA1 ir CHEK2 genų pokyčius. Pirmą kartą Lietuvoje įsisavintas CHEK2 bei NBS1 genų tyrimas, nustatyta, kokios CHEK2 geno mutacijos dažniausios. Nors NBS1 geno mutacijų nerasta, bet įsisavinta metodika, kuri bus panaudota ateities tyrimams. Sukurtas kompleksinis BRCA1 bei CHEK2 genų mutacijų radimo prognozavimo modelis. Šiandien klinikinėje praktikoje panašūs modeliai naudojami įvertinti BRCA1/2 genų mutacijų tikimybę. Jų pritaikomumas ir specifiškumas skirtingose etninėse grupėse gali skirtis. Naudojant tirtų pacienčių charakteristikas, įtraukiant ne tik šeiminę anamnezę, pacientės ypatybes, bet ir klinikinius bei molekulinius navikų požymius, sukurti mūsų regionui pritaikyti modeliai bei nustatyti kriterijai, kurie padės atrinkti pacientes genetiniam konsultavimui dėl BRCA1 bei CHEK2 genų mutacijų. Šis naujas požiūris turi didžiulę praktinę naudą.
Approximately 5–10% of all breast cancer cases are considered to be hereditary. BRCA1 and BRCA2 genes are the most important breast cancer predisposing genes. Other genes significantly linked with an increased risk of breast tumors are CHEK2 and NBS1 gene. In this scientific work were studied the most prevalent in European region mutations of these genes. The rate of BRCA1 and CHEK2 gene mutations in young women with breast cancer was evaluated and the relationships between these mutations and patient's age, clinical and morphological tumor features are examined. The prognostic value of family history was analyzed when forecasting hereditary BRCA1 and CHEK2 gene mutations. For the first time in Lithuania the CHEK2, NBS1 genes tests were applied and the evaluation of which CHEK2 gene mutations are most prevalent was obtained. Although NBS1 gene mutations were not found, but applied test technique will be used in future research. There was created a prognostic model for determination of BRCA1 and CHEK2 gene mutations. In today's clinical practice similar models are used to assess the likelihood of the BRCA1/2 mutation. Their applicability and specificity in different ethnic groups may vary. Applying the studied data there was created a model adapted to our region. Testing patients, there were considered not only family medical history and personal characteristics, but also the clinical and molecular features of tumors. The criteria have been found which will help in selecting... [to full text]

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Huusko, P. (Pia). "Predisposing genes in hereditary breast and ovarian cancer". Doctoral thesis, University of Oulu, 1999. http://urn.fi/urn:isbn:9514254422.

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Abstract In the present study, mutations in BRCA1 and BRCA2, the two major genes predisposing individuals to hereditary breast and ovarian cancer, were screened in Finnish and Turkish cancer families. Germline BRCA1 mutations were found in 7% (6/88) and BRCA2 mutations in 6% (5/88) of the Finnish families studied in Oulu. Two distinct BRCA1 (3745delT, 4216nt-2A→G) and three BRCA2 (999delTCAAA, 6503delTT, 9346nt-2A→G) mutations were identified, all of which are recurrently found in Finland. In the 15 Turkish cancer families studied, 5382insC and 5622C→T were detected in BRCA1, and 3414delTCAG in BRCA2. The novel 3414del4 mutation was found in a family with a case of male breast cancer. In order to determine their ages and origin, 9 recurrent Finnish BRCA1 and BRCA2 mutations were studied further as regards haplotype conservation. Common origins approximately 18–80 generations (400–1600 years) ago were demonstrated for all studied mutations by partial haplotype sharing. The majority of the mutations showed geographical clustering, supporting the theory of regional founder effects. Four of the nine mutations are unique for Finland, whereas five have also been seen elsewhere. Mutations in the 5' end of BRCA1 tend to predispose individuals to ovarian cancer and those found in the 3' end to breast cancer. The age of ovarian cancer onset was significantly lower for BRCA1 (51 years) than for BRCA2 mutation carriers (61 years). Germline TP53 mutations were sought in the Finnish breast cancer families found to be negative after BRCA1 and BRCA2 screening but who exhibited some phenotypic features of the Li-Fraumeni syndrome. The Asn235Ser was found in a family displaying Li-Fraumeni syndrome phenotype and the Tyr220Cys in a family with a milder Li-Fraumeni-like phenotype. The nature of both mutations as cancer-predisposing alterations was supported by means of loss of heterozygosity (LOH) and p53 immunohistochemistry studies. Regional clustering of BRCA1 and BRCA2 founder mutations enables targeted genetic tests including especially those mutations characteristic of the birthplace of each patient. Additional genes are likely to explain a large proportion of the inherited susceptibility to breast cancer in particular. Germline TP53 mutations are expected to be found in the breast cancer families with other clinical features seen in the Li-Fraumeni syndrome.

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Escobar, Karina Augusto. "Determinação de mutações e polimorfismo nos genes BRCA1 e BRCA2 em pacientes com câncer de mama com indicação para teste genético". Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/5/5155/tde-05092011-152557/.

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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, 11 mutações sinônimas, 14 variantes intrônicas, duas mutações nonsense (as deletérias R2318X e R3128X) e três mutações frameshift deletérias (5844del5, 6633del5 e 6610insTT). Nenhuma mutação foi detectada pelo teste de MLPA. Discussão e considerações finais: Nove de 73 indivíduos estudados são portadores de mutações deletérias, sendo que a mutação fundadora Ashkenazi 5382insC foi encontrada em duas pacientes não aparentadas e que outro grupo de pesquisa já reportou sua alta frequência numa população paulistana. As alterações de significado clínico desconhecido foram encontradas em toda a extensão dos genes BRCA1 e BRCA2 e são inúmeras. Algumas apareceram em somente uma paciente, o que nos leva a pensar que talvez uma ou algumas destas mutações tenham algum efeito patogênico, como a mutação 6610insTT, que gera uma proteína incompleta e foi encontrada em três gerações de uma família. A técnica de MLPA não detectou grandes rearranjos em ambos os genes, mostrando que este tipo de alteração genética não é freqüente em nossa coorte e que talvez esta seja uma característica mais prevalente em populações menos miscigenadas. Salientamos, portanto, a importância de ampliar este estudo e de estimular pesquisas futuras, visando um aconselhamento genético eficiente, com a diminuição do número de casos inconclusivos gerados pelas variantes de significado indeterminado e o acompanhamento clínico das famílias
Introduction: Mutation in BRCA1 and BRCA2 genes are responsible for more than 50% of hereditarian breast and ovarian cancer cases. Nowadays, we still dont know the Brazilian mutation profile for these genes, except when founder mutations occur in specific ethnic groups. Objetives: Detection of mutation and polymorphisms in BRCA1 and BRCA2 genes in 73 breast cancer patients selected for genetic testing. Casuistic and methods: we have realized direct sequencing of BRCA1 and BRCA2 in 73 patients, whose 63 have had breast cancer and showed at least 10% of risk according to Frank, Evans and BRCAPRO, two patients with ovarian cancer and eight healthy individuals of strong family history of cancer linked to mutations in BRCA1 and BRCA2. Results: We have found 60 mutations in BRCA1: 13 missense mutations (including the deleterious R71G), seven synonymous mutations, one frameshift mutation (the deleterious 5382insC), one nonsense mutation (the deleterious R1751X), one in-frame deletion, one 3UTR mutation and 36 intronic variants. In BRCA2 we have found 57 mutations: 26 missense mutations, one 5UTR mutation, 11 synonymous mutations, 14 intronic variants, two nonsense mutations (the deleterious R2318X and R3128X) and three frameshift mutations (5844del5, 6610insTT and 6633del5). No mutation was detected by MLPA technique. Discussion and final considerations: Nine of 73 studied individuals carry deleterious mutations. Among them, the Ashkenazi founder mutation 5382insC has been found in two unrelated patients and it was previously reported by another research group for its high prevalence on a population from São Paulo. Alterations of unknown clinical significance have been found all over BRCA1 and BRCA2 gene extension and are countless. Some of them are shown only in one patient, leading us to think that maybe one or a few might have a pathogenic effect, like 6610insTT, which leads to a BRCA2 incomplete protein and was shown in 3 generations of a family. MLPA technique have not detected large genomic rearrangements in both genes, showing that this kind of mutation is not frequent on our cohort and maybe this genetic alteration characterizes less miscigenated populations. So, we emphasize the importance of enlarge this study and stimulate future researches, aiming an efficient genetic counseling, decreasing inconclusive cases generated by unknown clinical significance variants, and follow up of affected families

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Ewald, Ingrid Petroni. "Caracterização de um grupo de pacientes em risco para câncer de mama e ovário hereditários quanto a presença e frequência de rearranjos gênicos em BRCA". reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2012. http://hdl.handle.net/10183/53154.

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O câncer de mama é uma das neoplasias malignas mais comuns que afetam mulheres de todo o mundo. No Brasil, o Estado do Rio Grande do Sul tem índices de incidência e mortalidade por câncer de mama que situam-se entre os maiores do país. Aproximadamente 5-10% dos diagnósticos são causados por mutações germinativas em genes de predisposição entre os quais estão BRCA1 e BRCA2, associados à Síndrome de Câncer de mama e Ovário Hereditários (Hereditary Breast and Ovarian Cancer Syndrome ou HBOC, OMIM #114480).A identificação dos casos hereditários de câncer de mama é importante porque indivíduos afetados apresentam risco cumulativo vital muito superior ao da população para o desenvolvimento de câncer, porque familiares de um afetado podem estar igualmente em risco porque há medidas de rastreamento intensivo e intervenções preventivas que podem diminuir significativamente o risco de câncer em portadores de mutação. O diagnóstico molecular da síndrome HBOC é laborioso e caro devido à heterogeneidade molecular da doença. Famílias que apresentam características indicativas de uma síndrome de predisposição ao câncer de mama e ovário hereditários, mas que são negativas para mutações pontuais em BRCA1/2 vêm sendo testadas para grandes rearranjos visto que essas anormalidades têm sido consideradas como respondendo por, no mínimo, 10% do todos os casos HBOC com mutação identificável, incluindo grandes deleções ou duplicações. Um estudo recente de Portugal, demonstrou que um rearranjo fundador no exon 3 de BRCA2 ocorre em por 8% das famílias HBOC do Norte do país. Os objetivos deste trabalho incluíram a verificação da freqüência e caracterização de rearranjos gênicos nos genes BRCA1 e BRCA2, incluindo a mutação fundadora c.156_157insAlu no exon 3 de BRCA2 em famílias brasileiras dealto risco para a síndrome HBOC. Em um grupo de 145 indivíduos em risco nãorelacionados rastreados para a mutação fundadorac.156_157insAlu no exon 3 de BRCA2 foram encontrados 3 portadores da mutação (prevalência de 2%). Em um grupo de 145 indivíduos de risco não-relacionados rastreados para rearranjos gênicos em BRCA1 e BRCA2 pela técnica de MLPA (multiplex ligation-dependent probe amplification) foram identificados 4 portadores de mutação germinativa, sendo a mutação em dois deles um rearranjo gênico no gene BRCA1 (1,4%) envolvendo sequencias Alu. Rearranjos gênicos em BRCA1 e BRCA2 são responsáveis por uma parcela das mutações em famílias HBOC Brasileiras. O presente estudo, envolvendo uma série grande de famílias com o fenótipo da síndrome HBOC, não identificou novos rearranjos fundadores, no entanto, demonstrou a presença de rearranjos tanto em BRCA1 quanto em BRCA2, reiterando a importância da busca ativa por estas alterações, que dificilmente são identificadas por técnicas convencionais de sequenciamento gênico. A técnica de MLPA associada a um protocolo específico para detecção da mutação fundadora Portuguesa c.156_157insAlu podem ser utilizadas como estratégia inicial de rastreamento de mutações em famílias Brasileiras com a síndrome. Os resultados apresentados aqui, no entanto, indicam que mutações serão identificadas em menos de 10% dos casos utilizando esta estratégia.
Breast cancer is one of the most common malignancies affecting women worldwide. In Brazil, the State of Rio Grande do Sul has incidence rates and mortality from breast cancer are among the largest in the country. Approximately 5-10% of the cases are caused by germline mutations in predisposing genes including BRCA1 and BRCA2 are associated with the syndrome of breast and ovarian cancer Hereditary (Hereditary Breast and Ovarian Cancer Syndrome or HBOC, OMIM # 114480). The identification of inherited cases of breast cancer is important because affected individuals have cumulative risk life much higher than the population for developing cancer because of an affected family may also be at risk because there are measures of intensive screening and preventive interventions that can significantly decrease the risk of cancer in mutation carriers. The molecular diagnosis of HBOC syndrome is laborious and expensive due to the molecular heterogeneity of the disease. Families that have characteristics indicative of a cancer predisposition syndrome of hereditary breast and ovarian cancers, but are negative for mutations in BRCA1/2 have been tested for large rearrangements because these abnormalities have been identified as accounting for at least 10 % of all cases HBOC identifiable mutation, including large deletions or duplications. A recent study from Portugal, the founder showed that a rearrangement in exon 3 of BRCA2 occurs in 8% of HBOC families of the north. The objectives of this work included the verification of the frequency and characterization of gene rearrangements in BRCA1 and BRCA2 genes, including c.156_157insAlu founder mutation in exon 3 of BRCA2 mutations in Brazilian families at high risk for HBOC syndrome. In a group of 145 individuals at risk unrelated traced to c.156_157insAlu founder mutation in exon 3 of 3 found BRCA2 mutation carriers (prevalence 2%). In a group of 145 individuals at risk unrelated screened for gene rearrangements in BRCA1 and BRCA2 by the technique of MLPA (multiplex ligationdependent probe amplification) identified four carriers of germline mutation, and two of the mutation in a gene rearrangement in the gene BRCA1 (1.4%) involving Alu sequences. Gene rearrangements in BRCA1 and BRCA2 account for a portion of HBOC mutations in Brazilian families. This study, involving a large series of families with HBOC syndrome phenotype, no new rearrangements identified founders, however, showed the presence of rearrangements in both BRCA1 and BRCA2, reiterating the importance of active search for these changes, which hardly are identified by conventional techniques of gene sequencing. The technique of MLPA protocol associated with a specific mutation detection founder Portuguese c.156_157insAlu strategy can be used as initial screening for mutations in families with Brazilian syndrome. The results presented here, however, indicate mutations that will be identified in less than 10% of the cases using this strategy.

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14

Irobi, Edward Okezie. "Time to Diagnosis of Second Primary Cancers among Patients with Breast Cancer". ScholarWorks, 2016. https://scholarworks.waldenu.edu/dissertations/2661.

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Many breast cancer diagnoses and second cancers are associated with BRCA gene mutations. Early detection of cancer is necessary to improve health outcomes, particularly with second cancers. Little is known about the influence of risk factors on time to diagnosis of second primary cancers after diagnosis with BRCA-related breast cancer. The purpose of this cohort study was to examine the risk of diagnosis of second primary cancers among women diagnosed with breast cancer after adjusting for BRCA status, age, and ethnicity. The study was guided by the empirical evidence supporting the mechanism of action in the mutation of BRCA leading to the development of cancer. Composite endpoint was used to define second primary cancer occurrences, and Kaplan-Meier survival curves were used to compare the median time-to-event among comparison groups and BRCA gene mutation status. Cox proportional hazards was used to examine the relationships between age at diagnosis, ethnicity, BRCA gene mutation status, and diagnosis of a second primary cancer. The overall median time to event for diagnosis of second primary cancers was 14 years. The hazard ratios for BRCA2 = 1.47, 95% CI [1.03 - 2.11], White = 1.511, 95% CI [1.18 - 1.94], and American Indian/Hawaiian = 1.424, 95% CI [1.12 -1.81] showing positive significant associations between BRCA2 mutation status and risk of diagnosis of second primary colorectal, endometrial, cervical, kidney, thyroid, and bladder cancers. Data on risk factors for development of second cancers would allow for identification of appropriate and timely screening procedures, determining the best course of action for prevention and treatment, and improving quality of life among breast cancer survivors.

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15

Ramirez, Christina J. "BRCA genes : conserved regions and the potential effect of missense changes /". Thesis, Connect to this title online; UW restricted, 2005. http://hdl.handle.net/1773/5052.

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16

Rapakko, K. (Katrin). "Hereditary predisposition to breast cancer—evaluation of candidate genes". Doctoral thesis, University of Oulu, 2007. http://urn.fi/urn:isbn:9789514284502.

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Abstract In Western countries, breast and ovarian cancer are among the most frequent malignancies affecting women. Approximately 5–10% of the cases in the general population have been suggested to be attributed to inherited disease susceptibility. BRCA1 and BRCA2 are the main genes associated with predisposition to breast and ovarian cancer. Mutations in these two genes explain a major part of the families displaying a large number of early-onset breast and/or ovarian cancers, but at least one third of the cases appear to be influenced by other, as yet unidentified genes. Therefore, it is likely that defects in other cancer predisposing genes, perhaps associated with lower disease penetrance and action in a polygenic context, will also be discovered. In the present study, the contribution of germline mutations in putative breast and/or ovarian cancer susceptibility genes, based on their biological function, has been investigated in Finnish breast cancer families. The role of large genomic deletions or other rearrangements in the BRCA1 and BRCA2 genes was evaluated by Southern blot analysis, and mutation analysis of TP53, RAD51, the BRC repeats of BRCA2, and 53BP1 was performed by conformation sensitive gel electrophoresis and DNA sequencing. Germline TP53 mutations were searched for in 108 Finnish breast cancer families without BRCA1 or BRCA2 alterations. In this study, the pathogenic TP53 germline mutation, Arg248Gln, was identified in only one family. This family showed a strong family history of breast cancer and other cancers also fulfilling the criteria for Li-Fraumeni-like syndrome. Germline TP53 mutations are expected to be found in cancer families with clinical features seen in Li-Fraumeni or Li-Fraumeni-like syndromes. In this study, large deletions in BRCA1 and BRCA2 were not observed in 82 breast and/or ovarian cancer families. Likewise, no disease-related aberrations were detected in RAD51, the BRC repeats of BRCA2 or 53BP1 in the 126 breast and/or ovarian cancer families studied. The obtained results were validated by comparing to the occurrence in 288–300 female cancer-free control individuals. These results do not support the hypothesis that alterations in these particular genomic regions play a significant role in breast cancer predisposition in Finland. Thus, there are still genes to be discovered to explain the molecular background of breast cancer.

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17

Maguire, Paula. "Investigation of the genetic basis of familial non-BRCA1/2 breast cancer /". Stockholm, 2005. http://diss.kib.ki.se/2006/91-7140-602-6/.

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18

Reilly, Drew D. "The Narratives of Young Women with BRCA 1/2 Gene Mutation: A Qualitative Analysis". ScholarWorks@UNO, 2014. http://scholarworks.uno.edu/td/1910.

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A narrative qualitative research design was used to understand the stories of young women diagnosed with BRCA1 and BRCA 2 genetic mutation. Four participants were selected who met the following criteria: (a) the participant is diagnosed with BRCA1 or BRCA2 genetic mutation, b) is within the age range of 18 to 35, (c) is without a cancer diagnosis, and is (d) not currently pregnant and does not have children. The four participants were interviewed through open-ended inquiry. The participants’ narratives proved both similar and dissimilar. The themes were organized into within-case narratives and across-case narratives. The narratives revealed that young BRCA previvors face unique challenges and experiences, and many can be viewed from an underlying feminist lens. In response to the research questions, BRCA previvors revealed detailed narratives, explored issues of family planning, and explained the ways in which BRCA has changed their worldviews.

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19

Sarantaus, Laura. "Germline mutations of BRCA1 and BRCA1 genes : founder effects and contribution to ovarian carcinoma in Finland". Helsinki : University of Helsinki, 2002. http://ethesis.helsinki.fi/julkaisut/laa/kliin/vk/sarantaus/.

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20

Payne, Shannon Renée. "Analysis of BRCA1 genomic structure : novel germline mutations and somatic alterations in breast cancer /". Thesis, Connect to this title online; UW restricted, 2000. http://hdl.handle.net/1773/10295.

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21

Yassaee, Vahid Reza. "Towards a general strategy for breast cancer : investigation of germline mutations of BRCA1 and BRCA2 genes in Iranian women with early-onset breast cancer". Thesis, University of Sheffield, 2002. http://etheses.whiterose.ac.uk/5987/.

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Breast cancer is the most common female malignancy and a major cause of death in middle-aged women. It results from genetic and environmental factors leading to the accumulation of mutations in essential genes, BRCA 1and BRCA2. To date, germline mutations in the BRCAI and BRCA2 genes in patients with early-onset breast and/or ovarian cancer have not been identified within the Iranian population. This study was set for two main purposes, in first for a cohort study of selected population (Iranian women) with early-onset breast cancer and secondly to evaluate and improve upon existing mutation detection techniques with respect to the BRCA genes. With the collaboration of two main centres for cancer research and treatment in Tehran-Iran, clinical information, family history and peripheral blood were obtained from 96 unrelated families for scanning of germline mutations in the BRCA 1 and BRCA2 genes. These sets of samples consists of 104 women under the age of forty-five, 88 patients affected with early-onset breast cancer or ovarian cancer and 16 unaffected individuals with strong family history of breast and/or ovary cancer. BRCA1 exons 11 and BRCA2 exons 10 and 11 by the Protein Truncation Test (PTT) and BRCAI exons 2, 3, 5, 13 and 20 and BRCA2 exons 9, 17,18 and 23 with the Single Strand Conformation Polymorphism (SSCP)assay were analysed on genomic DNA amplified by polymerase chain reaction. Ten sequence variants were identified: five are frame shift (putative mutations-four novel); three missense changes of unknown significant and two polymorphisms, one seen [BRCA2 (IVSI6-14T>C)] commonly in both Iranian and British population. Identification of these novel mutations suggests that any given population should develop a mutation database for its breast cancer screening. The pattern of mutations seen in the BRCA genes does not appear to differ from other populations studied. Early-onset breast cancer (less than 45 years) and a limited family history is sufficient to justify mutation screening with a detection rate of over 250/0 in this group, whereas sporadic early-onset breast cancer (detection rate less than 5%) is unlikely to be cost-effective. To address the penetrance and mutation spectrum of germline mutation of the contributed genes within Iranian population further studies should be performed. Meta-PCR technique was evaluated for its implication of BRCA genes scanning. Three distinct sets of BRCA gene fragments were selected to assemble with different approach for downstream analysis: the first set consisted ofBReA1 exons 2, 20 and BRCA2 exon 18 and their subsequent analysis by Protein Truncation Test; the second set comprised BRCAI exons 2, 20, 23 and 24 and their subsequent analysis by direct sequencing; and the last one contained six key coding regions from the BRCA genes, the 5' and 3'termini of exon 11 from both BRCAI and BRCA2 genes and exons 2 and 20 from BRCAI. Downstream analysis of Meta-PCR products by Protein Truncation Test was used rather than direct nucleotide sequencing because the total assembled above fragments size (~2.8kb) is sufficiently big to ignore analysing by the latter approach. PTT and direct sequencing were chosen because of their high sensitivity and specificity. These three trials were performed successfully suggesting that it may be possible to assemble the entire of coding regions of BRCAI and BRCA2 genes in a multi-step procedure.

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22

Lamont, Jayne Margaret. "Radiation induced DNA damage response in carriers of the breast cancer gene mutation BRCA1". Thesis, Lancaster University, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.289050.

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23

馮敬業 e King-yip Fung. "Screening of recurrent BRCA gene mutations in Chinese breast and ovarian cancer". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2000. http://hub.hku.hk/bib/B31969720.

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24

Fung, King-yip. "Screening of recurrent BRCA gene mutations in Chinese breast and ovarian cancer". Hong Kong : University of Hong Kong, 2000. http://sunzi.lib.hku.hk/hkuto/record.jsp?B23829837.

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25

Mozersky, J. "'Ashkenazi mutations' and the BRCA genes : genetics, disease and Jewish identity". Thesis, University College London (University of London), 2009. http://discovery.ucl.ac.uk/19035/.

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This thesis explores the increased risk of genetic breast cancer for Ashkenazi Jews who are at significantly increased risk of carrying three specific mutations in the high risk breast cancer genes, BRCA1 and BRCA2. The Ashkenazi Jewish population has the highest known risk of genetic breast cancer and are the most well researched in relation to genetic disease. They are believed to have a particularly supportive and unique relationship with genetics, despite also having a history of discrimination that includes claims of biological inferiority. The use of racial or ethnic groups in genetic research is highly contentious and the implications for those populations being studied are usually assumed to be negative. There is also significant discussion about the potential of new genetic knowledge to transform individual and collective identity and alter how individuals conceive of themselves and the groups to which they belong. This thesis contributes to both of these areas of debate by exploring the implications for individuals of knowing that they are at increased risk of genetic breast cancer because they are of Ashkenazi Jewish origin. It specifically addresses whether being at increased risk has an impact on how Ashkenazi Jewish women feel about their own Jewish identity, whether they have concerns about current genetic research related to them, and if they are particularly supportive as if often claimed. Evidence is provided principally from qualitative interview material with Ashkenazi women at increased risk of genetic breast cancer as well as non high risk individuals. The qualitative data is supplemented by a quantitative survey. Ethnic identity can be an important mediating factor for the ways in which genetic knowledge is interpreted and genetic medicine can become intertwined with culturally specific issues. Ashkenazi Jews conceive of themselves, their history and their future in ways that are compatible with new genetic knowledge. While it is important not to assume there are necessarily damaging or transformative consequences for those populations that are the subjects of genetic research, there were implications for Ashkenazi women and their disease was interwoven with their identity in complex ways.

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26

Schneegans, Sarah Maj [Verfasser], Wolfgang [Akademischer Betreuer] Engel e Heike [Akademischer Betreuer] Bickeböller. "Zur Risikokalkulation für Mutationen in den Genen BRCA1 und BRCA2 in Familien mit Brustkrebs / Sarah Maj Schneegans. Gutachter: Wolfgang Engel ; Heike Bickeböller. Betreuer: Wolfgang Engel". Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2011. http://d-nb.info/1042723540/34.

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27

Lawrence, Kirsty Josephine. "Breast cancer predisposition gene BRCA1, pathogenic C61G mutation in mice : synthetic viability in DNA repair and tumour development". Thesis, University of Birmingham, 2016. http://etheses.bham.ac.uk//id/eprint/7000/.

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The N-terminus of BRCA1 is clinically important as inheritance of a mutation in this region correlates to an increased risk is breast and ovarian cancer. Whilst this is fairly clear, what specific mutations do and the aetiology of the disease is not clear. This thesis investigates N-terminal BRCA1 mutations using both in vitro and cell-based methods with a focus on DNA repair, mainly double-strand break and DNA crosslink repair. The use of chemotherapy agents is used with specific mutations to look at the individual phenotypes these create to each drug or radiation. This thesis also provides evidence on haploinsufficient or dominant negative effects of N-terminal mutations. Overall, the N-terminus of BRCA1 can affect DNA repair and increase genome instability that may lead to tumour development.

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28

Jansson, Sandra, e Lisa Candell. "Ett liv i förändring - att bära på mutation i BRCA 1- eller BRCA 2-genen: en skildring av kvinnors upplevelser : En litteraturöversikt". Thesis, Uppsala universitet, Institutionen för folkhälso- och vårdvetenskap, 2019. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-396781.

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Bakgrund: Mutation i BRCA-generna innebär kraftigt ökad risk att utveckla bröst- och ovarialcancer. Vetskap om att bära på denna genmutation innebär påfrestningar och psykosociala förändringar hos individen. Sjuksköterskor behöver insikt i hur detta tillstånd påverkar individen för att kunna tillfredsställa vårdbehovet på ett personcentrerat sätt. Syfte: Skildra kvinnors upplevelse av att bära på mutation i gen BRCA 1 eller BRCA 2. Metod: Allmän litteraturstudie med deskriptiv design. Resultatet baserades på tio originalartiklar med kvalitativ ansats från databaserna PubMed och Cinahl. Resultat: Upplevelsen varierade mellan kvinnor, och känslomönster identifierades mellan individer i liknande livssituationer. Många uppgav en initial känsla av chock, samt känslor av osäkerhet kring den upplevda hälsan. De beskrev ett informationsbehov och en upplevd brist på kunskap hos vårdgivaren. Detta resulterade i rädsla att bli vilseledd samt känslor av ensamhet, tomhet och isolering. Undersökningsgruppen beskrev en oro och rädsla inför en eventuell framtida cancerdiagnos och hur detta skulle komma att påverka dem och deras familj. De beskrev även att denna vetskap tvingade dem in i en beslutsprocess gällande framtida livshändelser, såsom profylaktisk kirurgi och familjeplanering. Slutsats: Kvinnorna upplevde mycket oro, ångest, rädsla och osäkerhet inför framtiden. De upplevde ett informationsbehov som inte tillfredsställdes samt ett stort behov av stöd. Vårdpersonalen behöver mer kunskap om hur vetskapen om genmutation i BRCA 1 eller BRCA 2 kan påverka patienten. Strategier behöver utformas för att tillfredsställa kvinnornas behov av stöd och information. Detta i syfte att främja hälsa lindra lidande.
Background: Mutation in the BRCA genes involves a significantly increased risk of developing breast- and ovarian cancer. Knowledge about carrying this gene mutation lead to stress and resulted in psychosocial changes. Nurses needs insight into how this situation affects the individual in order to satisfy the care needs with a person-centered approach. Purpose: The aim of the study was to investigate and depict women’s experience of carrying a mutation in the BRCA 1 or BRCA 2 gene. Method: General literature review with descriptive design. Results was based on ten qualitative original research articles from the databases PubMed and Cinahl. Results: The experience varied woman to women, and emotional patterns were identified between individuals in similar life situations. Many expressed an initial feeling of shock, and uncertainty about the perceived health. They described a need for information, and experienced a lack of knowledge among the caregivers, which resulted in fear of being misled. The study group described feelings of fear and worry for a future cancer diagnosis and how that would affect their families and themselves. They also described that it forced them into a decision making process regarding risk reducing surgery and family planning. Conclusion: These women experienced great levels of worry, anxiety, fear and uncertainty regarding the future. They experienced a need for information that was not satisfied, and also a great need for support. Caregivers need more knowledge about how awareness of gene mutation in BRCA 1 or BRCA 2 can affect the patient. Strategies need to be designed to meet women´s need of information and support. This in order to promote health and ease suffering.

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29

Weber, Jérémie. "Nouvelle méthode de détection de mutations inconnues : applications au diagnostic génétique". Paris 6, 2005. http://www.theses.fr/2005PA066560.

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30

Karppinen, S. M. (Sanna-Maria). "The role of BACH1, BARD1 and TOPBP1 genes in familial breast cancer". Doctoral thesis, University of Oulu, 2009. http://urn.fi/urn:isbn:9789514291593.

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Abstract Approximately 5–10% of all breast cancer cases are estimated to result from a hereditary predisposition to the disease. Currently no more than 25–30% of these familial cases can be explained by mutations in the known susceptibility genes, BRCA1 and BRCA2 being the major ones. Additional predisposing genes are therefore likely to be discovered. This study evaluates whether germline alterations in three BRCA1-associated genes, BACH1 (i.e. BRIP1/FANCJ), BARD1 and TOPBP1, contribute to familial breast cancer. Altogether 214 Finnish patients having breast and/or ovarian cancer were analysed for germline mutations in the BACH1 gene. Nine alterations were observed, four of which located in the protein-encoding region. The previously unidentified Pro1034Leu was considered a possible cancer-associated alteration as it appeared with two-fold higher frequency among cancer cases compared to controls. All the other observed alterations were classified as harmless polymorphisms. Mutation analysis of the BARD1 gene among 126 Finnish patients having family history of breast and/or ovarian cancer revealed seven alterations in the protein-encoding region. The Cys557Ser alteration was seen at an elevated frequency among familial cancer cases compared to controls (p = 0.005, odds ratio [OR] 4.2, 95% confidence interval [CI] 1.7–10.7). The other alterations appeared to be harmless polymorphisms. To evaluate further the possible effect of Cys557Ser on cancer risk, a large case-control study was performed, consisting of 3,956 cancer patients from the Nordic countries. The highest prevalence of Cys557Ser was found among breast and ovarian cancer patients from BRCA1/BRCA2 mutation-negative families (p < 0.001, OR 2.6, 95% CI 1.7–4.0). In contrast, no significant association with male breast cancer, ovarian, colorectal or prostate cancer was observed. The current study is the first evaluating the role of TOPBP1 mutations in familial cancer predisposition. The analysis of 125 Finnish patients having breast and/or ovarian cancer revealed one putative pathogenic alteration. The commonly occurring Arg309Cys allele was observed at a significantly higher frequency among familial cancer cases compared to controls (p = 0.002, OR 2.4, 95% CI 1.3–4.2). The other 18 alterations observed were classified as harmless polymorphisms.

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31

Rouault, Audrey. "Etude génomique des cancers du sein familiaux liés à une mutation constitutionnelle du gène BRCA2". Thesis, Bordeaux 2, 2013. http://www.theses.fr/2013BOR22122/document.

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L’altération constitutionnelle des gènes BRCA1 et BRCA2 est détectée dans 20 à 30% des formes familiales de cancer du sein. La fréquence de mise en évidence d’une mutation BRCA2 selon des critères généalogiques reste modeste. La définition de caractéristiques tumorales communes aux tumeurs du sein survenant dans un contexte de prédisposition lié à BRCA2 a pour objectif l’identification de caractéristiques propres aux tumeurs BRCA2 permettant de mieux définir les indications de recherche de mutation de ce gène, et l’identification de facteurs impliqués dans la tumorigénèse des cancers du sein liés à BRCA2. L’étude des profils génomiques des tumeurs BRCA2 a caractérisé la délétion récurrente des bras longs des chromosomes 13 et 14. L’analyse supervisée des données d’expression entre les tumeurs BRCA2 et les tumeurs familiales BRCAX a identifié une signature spécifique des tumeurs BRCA2. Les exomes des chromosomes 13 & 14 pour 5 tumeurs informatives et leur ADN constitutionnel ont été séquencés afin d’identifier la ou les cibles des régions délétées. Cette analyse a permis la caractérisation de variants somatiques qui seront à étudier dans une large série de cas BRCA2 et contrôles pour conclure sur leur rôle dans la tumorigénèse liée à BRCA2.La caractérisation de pertes de matériel chromosomique spécifiques aux tumeurs BRCA2, rapportée dans plusieurs études, offre une perspective diagnostique avec le développement d’un test FISH utilisable en pratique clinique pour préciser les indications d’une recherche de mutation du gène BRCA2, mais suggère également la présence de gènes cibles candidats dont l’inactivation est requise lors de la cancérisation mammaire liée à BRCA2
Germline BRCA1 and BRCA2 mutations account for 20-30% of familial breast cancer. The main indication for BRCA2 screening is a family history, but the mutation detection rate in patients selected this way is low. The identification of characteristics common to BRCA2-associated tumors would improve the criteria used to select patients for BRCA2 screening and could identify factors implicated in BRCA2-mutant breast cancer tumorigenesis. The analysis of BRCA2-mutant breast tumor genomic profiles identified deletions of chromosomes 13q and 14q as a common feature of BRCA2-tumors. Supervised gene expression analysis of BRCA2-mutant breast tumors and familial breast tumors without germline BRCA1 or BRCA2 mutations identified a specific BRCA2 gene signature. Exome sequencing of chromosomes 13q and 14q for 5 BRCA2-mutant tumors, and their associated germline DNA was performed in order to identify the target(s) of the specific genomic deletions in the BRCA2 tumors. This analysis characterized somatic variants that will be screened for in a larger cohort of BRCA2 and control tumors cases to explore their role in BRCA2-mutant breast cancer. Our study identified deletions of chromosomes 13q and 14q as a common feature of tumors with germline BRCA2 mutations, as has been observed in several previous studies. We suggest that FISH analysis for the deletion of these chromosomes would be a rapid and technically feasible first step to select tumors worth screening for germline BRCA2 mutations and we hypothesize that the inactivation of candidate genes located in these deleted regions allows the cell to resume division and progress thus contributing to tumorigenesis in BRCA2-mutant tumors

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32

Quiles, Vidal Francisco de Asís. "Síndrome de cáncer de mama y ovario hereditario: Estudio in vitro de variantes BRCA1 y BRCA2 de significado biológico desconocido y búsqueda de nuevos genes responsables de este síndrome". Doctoral thesis, Universitat de Barcelona, 2016. http://hdl.handle.net/10803/385989.

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ANTECEDENTES: Entre un 20-25% de pacientes con cáncer de mama y ovario muestran historia familiar de dicha enfermedad. Una porción de estos casos son debidos a mutaciones germinales en genes de predisposición conocidos y se engloban dentro del síndrome de cáncer de mama y ovario hereditario (SCMOH). Mutaciones en los genes BRCA1/2, genes de alta penetrancia para este síndrome, explican alrededor de un 20% de los casos familiares. El estudio mutacional de estos genes identifica entre un 2-15 de variantes cuyo significado biológico es desconocido (VSD), dependiendo de la población analizada y la casuística del laboratorio que las reporta. Debido a la imposibilidad de determinar el riesgo asociado a una VSD, éstas no pueden ser utilizadas como valor predictivo en el diagnóstico genético y dificultan el seguimiento clínico del portador. Por ello, la clasificación de estas variantes en patogénicas o neutras es de gran importancia desde del punto de vista del consejo genético. Además de lo mutaciones en los genes BRCA1/2, otras mutaciones de alta, moderada o baja penetrancia se han identificado en otros genes y con ellas se ha podido explicar una pequeña porción de los casos restantes del SCMOH. Muchos de estos genes han están involucrados en la vía de reparación de DNA de Anemia de Fanconi (FA)/BRCA, o son interactores de BRCA1/2. Si bien, más de un 50% de los casos familiares permanecen sin causa genética conocida. Estos casos son comúnmente conocidos como casos BRCAX. En este contexto, el uso de las nuevas técnicas de secuenciación de exomas ha demostrado ser una buena estrategia para la identificación de nuevos genes de predisposición al SCMOH. OBJETIVO: El objetivo global de esta tesis doctoral es mejorar el diagnóstico y el consejo genético de los pacientes con SCMOH mediante la clasificación de VSD en los genes BRCA1/2 y la búsqueda de nuevos genes de predisposición a este síndrome. RESULTADOS: Cuarenta VSD en BRCA1/2 fueron analizadas siguiendo diferentes aproximaciones experimentales. Veintiocho de ellas fueran analizadas a nivel transcripcional y 6 (4 en BRCA1 y 2 en BRCA2) fueron clasificadas como probablemente patogénicas en base a su efecto en el correcto splicing de estos genes. Otras 7 variantes, localizadas en la región C-terminal de BRCA1, fueron analizadas mediante el ensayo de actividad transcripcional. Tres de estas variantes pudieron ser clasificadas como probablemente patogénicas. Posteriormente, una de estas variantes, G1770V fué identificada por nuestro grupo como la primera mutación fundadora de origen Marroquí. Las cinco restante, situadas en BRCA2, fueron analizadas mediante el ensayo funcional basado en células embrionarias de ratón. Todas ellas mostraron un efecto hipomórfico y fueron asociadas a un riesgo bajo/moderado a sufrir cáncer d mama y/o ovario. En cuanto a la búsqueda de nuevos genes de predisposición al SCMOH se utilizaron dos aproximaciones para su identificación. Por un lado, se secuenciaron dos genes nuevos genes de la vía de FA/BRCA, los genes ERCC4 y SLX4, en un set de pacientes BRCAX. Este estudio identificó varias variantes missense nuevas en cada gen. Varias de ellas fueron clasificadas como potencialmente deletéreas por varios programas de predicción in silico. No obstante, la validación funcional de estas variantes es necesaria para elucidar su asociación con el SCMOH. Como segunda aproximación, se secuenció el exoma de varios pacientes pertenecientes a familias BRCAX con un aparente patrón de herencia autosómico dominante. Como resultado, se identificaron 20 genes potencialmente candidatos para ser genes de predisposición al SCMOH. Entre ellos, POLE destaca como firme candidato. CONCLUSIÓN: Este trabajo, en su conjunto, contribuye a la mejora del diagnóstico y consejo genético mediantes la identificación de nuevas variantes de predisposición en al SMCOH en los genes BRCA1/2 y la identificación de nuevos genes candidatos al SCMOH.
BACKGROUND: Breast cancer is the most common cáncer diagnosed among women. Between 20-25% of breast cancer cases present familial history of the disease. Around 50% of familial breast cancer is due to germline mutations in predisposing genes and are included in the Hereditary Breast and Ovarian Cancer Syndrome (HBOCS) cases. The other 50% of familial cases remains genetically unsolved which indicates the need of identifing new predisposing genes for this syndrome. The most prevalent predisposing genes for this syndrome, BRCA1/2, account for least than the 20% of the familias cases. Genetic testing of this genes identifies between 2-15% of variants of unknown significance (VUS). This variants difficult the clinical monitoring of carriers, thus the need of classyfy them as pathogenic or neutral variant is paramount from the genetic counseling point of view. OBJECTIVE: The objective of this thesis is to improve the genetic diagnosis and gentic counseling os HBOCS patients by the classification of VUS in BRCA1/2 and the identification of new predisposing genes of this syndrome. RESULTADOS: Forty VUS in BRCA1/2 were analyzed using different experimental approaches (RNA analysis or funtional assays). Fourteen of them could be associated with the HBOCS. One of this variants, G1770V was later identified as the first founder mutation of Moroccan population. In the searching of new predisposing genes of the HBOCS we used two approaches. On one hand, we sequenced two new fanconi anemia genes, ERCC4 y SLX4, in 94 BRCAX families. This study didn’t find any clear loss of function variant in these genes, so their contribution to the HBOCS couldn’t be determined. On the other hand, we sequenced the whole exome of several patients from 12 independet BRCAX i families with an apparent autosomial dominant pattern of inheritance. AS a result of this study we identified 20 potential candidate HBOCS predisposing genes. Between them, POLE highlights as strong candidate. CONCLUSION: Overall, this work, by the identification of new predisposing variants in BRCA1/2 and the identification of new susceptybility candidates genes of the HBOCS, contributes to the improvement of the genetic diagnostic and counseling of HBOCS patients

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Solyom, S. (Szilvia). "BRCA/Fanconi anemia pathway genes in hereditary predisposition to breast cancer". Doctoral thesis, Oulun yliopisto, 2011. http://urn.fi/urn:isbn:9789514294099.

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Abstract Two major genes are involved in hereditary predisposition to breast and ovarian cancer – BRCA1 and BRCA2. However, germline mutations in these tumor suppressors account for a maximum 20% of the familial breast cancer cases. A significant portion of the genes predisposing to this disease is unknown and therefore needs to be discovered. The aim of this study was to identify novel breast cancer susceptibility genes from the interweaving BRCA/Fanconi anemia (FA) pathway. Five candidate genes – MERIT40, ABRAXAS, BRIP1, CHK1, and FANCA – were screened for mutations by utilizing conformation-sensitive gel electrophoresis and sequencing, or with multiplex ligation-dependent probe amplification in blood DNA samples of Finnish familial breast cancer patients. Investigation of the MERIT40 gene revealed novel nucleotide changes, being the first report on mutation screening of this gene. None of the observed alterations, however, appeared to be disease related, suggesting that germline mutations in MERIT40 are rare or absent in breast cancer patients. A missense alteration (c.1082G>A, leading to Arg361Gln) was identified in ABRAXAS in 3 out of 125 Northern Finnish breast cancer families (2.4%), but not in any of the 867 healthy controls. The prevalence of the mutation between familial and control cases was statistically significantly different (p=0.002). ABRAXAS c.1082G>A appears to have pathological significance based on its exclusive occurrence in cancer cases, evolutionary conservation, disruption of a putative nuclear localization signal, reduced nuclear localization of the protein, and defective accumulation at DNA damage sites. The BRIP1 (FANCJ) and CHK1 genes were screened for large genomic rearrangements, but no abnormalities were detected, ruling out a significant contribution to breast cancer susceptibility in the Northern Finnish population. A novel large heterozygous deletion was identified in the FANCA gene in one out of 100 breast cancer families, removing the promoter and the first 12 exons. The deletion allele was not present in the tested controls, suggesting that it might contribute to breast cancer susceptibility. This is the first report on the association of a large-size germline deletion in a gene acting in the upstream part of the FA signaling pathway with familial breast cancer
Tiivistelmä BRCA1 ja BRCA2 ovat kaksi tärkeintä perinnöllisen rinta- ja munasarjasyövän alttiusgeeniä. Niissä esiintyvät ituradan muutokset selittävät kuitenkin vain noin 20 % familiaalisista rintasyöpätapauksista. Suurin osa alttiusgeeneistä on edelleen tunnistamatta ja näitä tekijöitä etsitään aktiivisesti. Tämän tutkimuksen tarkoituksena on ollut tunnistaa uusia alttiustekijöitä toisiinsa läheisesti liittyviltä BRCA/Fanconin anemia (FA) signaalinsiirtoreiteiltä. Viisi kandidaattigeeniä - MERIT40, ABRAXAS, BRIP1, CHK1 ja FANCA – kartoitettiin mutaatioiden suhteen suomalaisissa rintasyöpäperheissä käyttämällä konformaatiosensitiivistä geelielektroforeesia ja sekvensointia, tai multiplex ligation-dependent probe amplification- menetelmää. MERIT40-geenissä havaittiin useita aikaisemmin raportoimattomia nukleotidimuutoksia, mutta yhdenkään niistä ei havaittu liittyvän rintasyöpäalttiuteen. MERIT40-geenimuutosten mahdollista yhteyttä rintasyöpäalttiuteen ei ole tutkittu aikaisemmin. ABRAXAS-geenissä havaittiin missense-mutaatio (c.1082G>A, joka johtaa Arg361Gln aminohappokorvautumiseen) kolmessa pohjoissuomalaisessa rintasyöpäperheessä (3/125, 2.4 %). Muutosta ei havaittu terveissä kontrolleissa (N=867), ja ero mutaation esiintyvyydessä familiaalisten rintasyöpätapausten ja terveiden kontrollien välillä oli tilastollisesti merkitsevä (p=0.002). ABRAXAS c.1082G>A-muutos on todennäköisesti patogeeninen, sillä kyseinen aminohappopaikka on evolutiivisesti konservoitunut ja sijaitsee todennäköisellä tumaanohjaussignaalialueella. Funktionaaliset kokeet osoittivat, että mutatoitunut proteiinituote lokalisoitui villityypin proteiinia heikommin tumaan ja sen ohjautuminen DNA-vaurioalueille oli puutteellista. BRIP1- (FANCJ) ja CHK1-geeneistä etsittiin laajoja genomisia uudelleenjärjestelyjä, mutta niitä ei havaittu. Näin ollen kyseisillä muutoksilla ei ole merkittävää roolia perinnöllisessä rintasyöpäalttiudessa suomalaisessa väestössä. FANCA-geenissä havaittiin laaja heterotsygoottinen deleetio yhdessä tutkitusta 100 rintasyöpäperheestä. Deleetio poistaa geenin promoottorialueen lisäksi sen 12 ensimmäistä eksonia. Deleetioalleelia ei havaittu terveissä kontrolleissa, joten se mahdollisesti liittyy perinnölliseen rintasyöpäalttiuteen. Tutkimus on ensimmäinen, jossa raportoidaan laaja genominen deleetio FA-signaalinsiirtoreitin ylävirran geenissä familiaalisessa rintasyövässä

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Locke, Imogen. "The evaluation of ductal lavage for risk assessment and early breast cancer detection in BRCA 1/2 gene mutation carriers". Thesis, Institute of Cancer Research (University Of London), 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.510360.

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Abdollahian, Mehrnaz. "Estimating Likelihood of Having a BRCA Gene Mutation Based on Family History of Cancers and Recommending Optimized Cancer Preventive Actions". Scholar Commons, 2015. http://scholarcommons.usf.edu/etd/5893.

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BRCA1 and BRCA2 are gene mutations that drastically increase chances of developing breast and ovarian cancers, up to 20-fold, for women. A genetic blood test is used to detect BRCA mutations. Though these mutations occur in one of every 400 in the general population (excluding Ashkenazi Jewish ethnicity), they are present in most cases of hereditary breast and ovarian cancer patients. Hence, it is common practice for the physicians to require genetic testing for those that fit the rules as recommended by the National Cancer Comprehensive Network. However, data from the Myriad Laboratory, the only provider of the test until 2013, show that over 70 percent of those tested are negative for BRCA mutations [1]. As there are significant costs and psychological trauma associated with having to go through the test, there is a need for more comprehensive rules for determining who should be tested. Once the presence of BRCA is identified via testing, the next challenge for both mutation carriers and their physicians is to select the most appropriate types and timing of intervention actions. Organizations such as the American Cancer Society suggest drastic intervention actions such as prophylactic surgeries and intense breast screenings. These actions vary significantly in their cost, cancer incidence prevention ability, and can have major side effects potentially resulting in reproduction inability or death. Effectiveness of these intervention actions is also age dependent. In this dissertation, both an analytical and an optimization framework are presented. The analytical framework uses supervised machine learning models on extended family history of cancers, and personal and medical information from a recent nationwide survey study of women who have been referred for genetic testing for the presence of a BRCA mutation. This framework provides the potential mutation carriers as well as their physician with an estimate of the likelihood of having the mutations. The optimization framework uses a Markov decision process (MDP) model to find cost-optimal and/or quality-adjusted life years (QALYs) optimal intervention strategies for those tested positive for a BRCA mutation. This framework uses a dynamic approach to address this problem. The decisions are made more robust by considering the variation in estimates of the transition probabilities by using a robust version of the MDP model. This research study delivers an innovative decision support tool that enables physicians and genetic consultants predict the population at high risk of breast and ovarian cancers more accurately. For those identified with presence of the BRCA mutation, the decision support tool offers effective intervention strategies considering either minimizing cost or maximizing QALYs to prevent incidence of cancers.

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Tannouri, Rachelle El. "Établissement d’une cohorte de patientes ayant consulté à l’Institut de Cancérologie de Lorraine et porteuses de la mutation BRCA1-3600del11 : étude descriptive des caractéristiques cliniques et anatomo-pathologiques des cancers du sein et de l’ovaire dans cette cohorte : mise en évidence d’un phénomène d’anticipation génétique dans 38 paires mères-filles atteintes de cancer du sein ou de l’ovaire". Thesis, Université de Lorraine, 2017. http://www.theses.fr/2017LORR0072/document.

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Contexte: La grande majorité des mutations délétères identifiées sur le gène BRCA1 sont des mutations « privées ». Cependant, certaines d’entre elles proviennent d’un ancêtre commun, à l’origine d’un effet fondateur. Ainsi, la mutation BRCA1-3600del11 (c.3481_3491del11, p.Glu1161Phefs*3) est localisée en France pour 82% des familles porteuses et 85% d’entre elles sont originaires du quart Nord-Est. En 2006, cette mutation représentait respectivement 51,5% et 42,0% de toutes les mutations du gène BRCA1 identifiées dans les familles lorraines et alsaciennes atteintes d’un cancer du sein et/ou de l’ovaire. En 2004, parmi les 27 cas-index ayant consulté en Alsace et présentant une mutation de BRCA1, 37% sont porteurs de cette mutation, tous issus de familles originaires des Vosges, suggérant l’existence d’un effet fondateur. L’identification d’un haplotype commun est venue confirmer l’existence de cette hypothèse. Une équipe alsacienne a mentionné dans deux publications en 2000 et 2004 sur la mise en évidence de la mutation 3600del11 que les caractéristiques des cancers associés à cette mutation, ne plaidaient pas en faveur d’une relation génotype-phénotype. Or, les caractéristiques anatomo-pathologiques des cancers associés à cette mutation n’ont pas été abordées par ces deux publications. Nous nous sommes alors posés la question de caractéristiques anatomo-pathologiques particulières des cancers du sein et des cancers de l’ovaire diagnostiqués chez les femmes porteuses de cette mutation dans notre région. Nous nous sommes également posés la question de l’existence d’un phénomène d’anticipation génétique dans ces familles. L’anticipation génétique est la survenue plus précoce d’une pathologie et/ou l’aggravation de ses signes cliniques lors de la transmission d’une mutation d’une génération à la suivante au sein d’une même famille. Très peu d’études ont cherché à mettre en évidence ce phénomène d’anticipation dans des cohortes issues de familles de syndrome sein-ovaire associées à une mutation de BRCA1 ou BRCA2. Les études publiées présentaient des biais de sélection du fait de l’inclusion de patients non testés dans leur analyse. Les études publiées sur des cohortes issues de familles présentant une mutation sur le gène BRCA1/2 suggéraient que le dépistage ciblé et l’excès de surveillance pourraient avoir une influence sur l’âge au diagnostic d’un cancer du sein chez les jeunes femmes incluses.Les améliorations majeures au niveau de la mammographie et du traitement du cancer du sein, de même que le programme de dépistage organisé pour les femmes de 50 ans et plus sont apparues en France, après 1980. A notre connaissance, à ce jour, aucune étude n’a été réalisée en France visant à identifier un phénomène d’anticipation génétique dans les familles associées à une mutation sur BRCA1ou BRCA2 et à analyser ce phénomène.Objectif: Notre premier objectif est de constituer une première cohorte lorraine de patientes porteuses de la mutation 3600del11 et d’analyser les caractéristiques anatomo-pathologiques des cancers du sein et de l’ovaire liés à cette mutation. Notre deuxième objectif rechercher l’existence d’une anticipation génétique dans des familles présentant la mutation fondatrice BRCA1-3600del11.Patientes: Quatre cent quatre patientes sont porteuses d’une mutation BRCA1 à l’Institut de Cancérologie de Lorraine (ICL) sur la période s’étendant de 1994 à 2012, parmi elles, nous avons identifié les patientes porteuses de la mutation BRCA1-3600del11. Nous avons identifié à l’Institut de Cancérologie de Lorraine, 38 paires mères-filles atteintes d’un cancer du sein ou de l’ovaire issues de 37 familles présentant le syndrome sein-ovaire associé à cette mutation dont 25 paires mères-filles atteintes d’un cancer du sein et 13 paires mères-filles atteintes d’un cancer de l’ovaire [...]
Introduction: Over 1000 alterations in the BRCA1 gene have been documented. Most of these are frameshifts and ~10% are missense mutations that generate stop codons leading to a truncated and therefore inactive BRCA1 protein. In the French population, prevalence of BRCA1 mutations has been reported in few studies; In a preliminary study of 14 breast and/or ovarian cancer families, a frequent BRCA1 mutation was detected in five unrelated families; the c.3481_3491del11 mutation (BIC: 3600del11), an 11 base-pair deletion in exon 11 leading to a premature stop codon at 1165. In a second study carried out in 2004 involving 27 index cases, the c.3481_3491del11 mutation accounted for 37%. The haplotype analysis of the families carrying the mutation c.3481_3491del11, all originating from Alsace-Lorraine (North-East of France), revealed the presence of a common allele, indicating a founder effect. Purpose: To an attempt to better define the clinical and pathologic characteristics of breast and ovarian cancer related with the 3600del11 BRCA1 mutation, we report our experience with breast and ovarian cancer patients carrying the 3600del11 mutation at the Lorraine Oncology Institute in France. The aim of the current analysis is also to evaluate any differences of breast or ovarian cancer age at diagnosis between mothers and daughters carrying the c.3481_3491del11 mutation in the BRCA1 gene.Patients: Within the population who were referred between 1994 and 2012 to our oncogenetic clinic at the Lorraine oncology institute and who underwent genetic testing for BRCA1 and BRCA2, we identified 404 women carrying a BRCA1 mutation. Interestingly, 45% (180 of 404) of women with detected BRCA1 mutation had the germline 3600del11 mutation. These women were members of 89 different families with breast and or ovarian cancer cases. A study cohort of 38 women carrying the c.3481_3491del11 mutation and affected by first breast or ovarian cancer who reported a first breast or ovarian cancer in their mother carrying the c.3481_3491del11 mutation, was identified in 37 different families including members with breast and/or ovarian cancer at the Oncology Institute of Lorraine. Twelve mothers underwent genetic testing. Twenty five pairs of the 38 mothers-daughters pairs with c.3481_3491del11 mutation were affected by breast cancer and 13 pairs by ovarian cancer.Methods: Clinical and genetic data were collected from medical files and family pedigrees. Analyses were conducted for each cancer type. We investigated an early breast cancer detection effect due to early screening programs and also an increased breast tumor aggression. Since major improvements in breast cancer clinical management and imaging techniques appeared after 1980, we compared the age at breast cancer diagnosis and the age at death in mothers and daughters before and after 1980, first, in the group of women including mothers and daughters taken together and then in mothers and daughters separately. Genetic data were retrieved from familial files and clinical and pathological data from medical files. Descriptive statistics for the study population were calculated using the SPSS software (version 20.0). Results: Ninety one patients (71, 7%) were affected by first breast cancer and 31 (24,4%) by ovarian cancer. Breast tumors were identified in 37.4% of cases aged <40 years. Estrogen receptor status and progesterone receptor status were reported to 67 patients. Hormonal receptors status was positive in 31.4% of breast tumors. A triple-negative subtype was found in 21 cases, which accounts for 65.6% of the 32 patients with 3600del11 mutation for whom HER2 status was available. Ovarian tumors of the serous type, which constitute about 71 percent of all epithelial ovarian carcinomas, predominate among patients with 3600del11 mutation. Eighty six per cent of carriers were diagnosed at advanced stages III/IV [...]

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PRESNEAU, NADEGE. "Recherche de mutations constitutionnelles dans les genes de predispositions hereditaires aux cancers du sein et/ou de l'ovaire : brca-1, brca-2. recherche de nouveaux genes suppresseurs de tumeur impliques dans l'oncogenese mammaire". Clermont-Ferrand 2, 1999. http://www.theses.fr/1999CLF21122.

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Le gene brca-1 (breast cancer n 1), implique principalement dans une predisposition hereditaire au cancer du sein pre menopausique, localise sur le chromosome 17 en 17q12-21, a ete clone en 1994 par l'equipe de mark skolnik. Un deuxieme gene de predisposition hereditaire au cancer du sein, brca-2, a ete localise en 13q12-13 et clone en 1995. Au total, 52% des familles seraient porteuses d'une mutation brca-1, 35% porteuses d'une mutation brca-2 et 13% des familles liees a d'autres genes. Notre travail de these s'est ainsi inscrit dans un contexte general d'etude des predispositions hereditaires aux cancers du sein et/ou de l'ovaire. Cette etude a comporte deux objectifs majeurs. Notre etude a permis d'evaluer la reelle proportion de familles francaises a haut risque de cancers du sein et/ou de l'ovaire porteuse d'une mutation constitutionnelle du gene brca-1. En effet, des mutations germinales dans le gene brca-1 ont ete detectees dans 24% des familles francaises a haut risque de cancers du sein et/ou de l'ovaire, confirmant les resultats deja publies par d'autres equipes francaises. Puisque seulement 17 de nos familles sur les 70 etaient porteuses d'une mutation germinale de brca-1, nous avons recherche pour, ces meme 70 familles, l'eventuelle presence de mutations constitutionnelles dans le gene brca-2. Les premiers resultats de ce travail ont montre que 3 familles etaient porteuses d'une mutation du gene brca-2. Ainsi il apparait maintenant evident qu'il existe plusieurs genes de predispositions hereditaires aux cancers du sein et/ou des ovaires en plus de brca-1 et brca-2. Ainsi, la deuxieme partie de notre travail a consiste a rechercher des nouveaux genes de type oncosuppresseurs pouvant etre implique dans la tumorogenese mammaire. Ces genes peuvent etre impliques de facon indirecte par une eventuelle interaction avec les genes brca mais peuvent etre egalement impliques plus directement en etant eux-memes des genes candidats pour les genes brca-x. Par la technique de ddrt-pcr, nous avons ainsi recherche l'expression differentielle entre le tissu normal mammaire et le tissu tumoral mammaire d'une patiente (mme lp) dont la predisposition hereditaire semblait etre liee ni a brca-1 ni a brca-2. Ainsi, nous avons pu identifier plusieurs sequences differentielles dont une seule pourrait etre interessante a exploiter en clonant son adnc complet via une sequence genomique clone dans un vecteur de type pac (z84477 ncbi) avec la quelle notre sequence presente 100% d'homologie sur la totalite de sa sequence (82 pb).

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Cunha, Danielle Renzoni da. "Estudo de mutações no gene BRCA na população Ashkenazi e não Ashkenazi com histórico para câncer de mama e/ou ovário". Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/87/87131/tde-21032013-170410/.

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O câncer de mama é um dos mais incidentes no mundo e mais comum na população feminina. Algumas populações possuem maior risco para o câncer de mama e ovário devido a presença de mutações fundadoras nos genes BRCA1 e BRCA2 como ocorre nos Judeus Ashkenazi (JA). Os testes genéticos para detecção de mutações de ponto nos genes BRCA1 e BRCA2 foram realizados em 106 indivíduos com e sem origem judaica (IOA) através do rastreamento por dHPLC e sequenciamento. A distribuição das mutações fundadoras no gene BRCA1 foi de cerca de 55 % para 185delAG e 5382isnC no gene BRCA1 e 12 % para 6174delT, no gene BRCA2. Estas mutações também foram detectadas em 7,4 % dos casos no grupo IOA e 84,2% no grupo JA (p< 0,001). Mutações fundadoras espanholas e portuguesas, 330 A>G (11,11 %) e 7966C>T (7,4 %), foram detectadas no IOA. Os carcinomas de mama e ovário foram mais frequentes nos dois grupos, cerca de 70 % e 20 %, respectivamente. No grupo IOA foram diagnosticados carcinomas de mama masculino (9,5 %) e trompa uterina (2,9 %), e carcinoma endometrióide em 11,8 % no grupo JA.
Breast cancer is one of the most commun tumors in women. Some populations shows higher risks for breast and ovarian cancers due to founder mutations in the BRCA1 and BRCA2 genes, as well as Ashkenazi Jewish (AJ) population. Genetic tests to detect point mutations in the BRCA1 and BRCA2 genes were made in 106 individuals: Ashkenazi Jewish and non-Ashkenazi Jews (NAJ) using dHPLC screening and sequencing. The distribution of founder mutations in the BRCA1 and BRCA2. genes was about 55 % for 185delAG and 5382isnC in BRCA1 gene and 12 % for 6174delT in BRCA2 gene. Those mutations were also detected in 7,4 % of NAJ group and 84,2 % in AJ group (p<0,001). Spanish and portuguese founder mutations 330 A>G (11,11 %) and 7966C>T (7,4 %) were also detected in NAJ group. Breast and ovarian carcinomas were detected in higher frequencies in both groups, about 70 % and 20 %, respectively. Male breast carcinomas (9,5 %) and uterine tube carcinomas ( 2,9 %) were diagnosed in NAJ group, and endometrioid carcinoma in AJ group (11, 8 %).

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West, Nicola. "Being a carrier and living with the BRCA gene mutation : an interpretive phenomenological study of the experiences of women who elect risk-reducing bilateral mastectomy, their husband's and family". Thesis, Cardiff University, 2016. http://orca.cf.ac.uk/103512/.

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Women who inherit the BRCA1/2 gene have up to an 85% lifetime chance of developing breast cancer and a 63% chance of developing ovarian Cancer. Since the publication and update of the UK Nice National Guidelines (2015) for women with a strong family history and Angelina Jolie, the famous American actress declared her status and her surgery, many more women are seeking testing in order to undergo bilateral risk-reducing mastectomy and oophorectomy. Very little is known about the longer-term effect on the woman her partner and her relatives following diagnosis and bilateral mastectomy from a qualitative research perspective. Aim - The aim of this study, therefore, was to explore, interpret and develop an understanding of the experiences of women and their relatives living with the BRCA gene who elect to have bilateral risk-reducing mastectomy in an attempt to improve clinical practice by providing a new horizon of understanding. Methods - An interpretive hermeneutic phenomenological study was conducted guided by the philosophy of Gadamer (2004) with its emphasis on a fused horizon of understanding with eight BRCA positive women, five of their husbands and five of their relatives. This study is a prospective study that took place in a large teaching hospital in Wales. Findings - This study provides a new fused horizon of understanding of what it means to be a BRCA Positive woman and a relative living with the BRCA gene who elect to undergo bilateral mastectomy as a risk-reducing modality. A hermeneutic text of interpretation exposed three main horizons (Gadamer, 2004). ‘The price of survival’, which includes the journey of the overall desire to survive, not just prevent cancer. ‘The altered child’s trajectory’ which involves the transference of the fear of cancer onto (for) children and future generations and ‘disembodied, a separation from self’ which includes the effects of surgery on sexuality, femininity and identity. These horizons unite the experiences of the women and her relatives resulting in a new fused horizon of understanding, ‘being disembodied’. These findings add knowledge and understanding for clinicians, researchers and policy makers working in the field of breast care with many implications for practice.

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40

Bose, M. (Muthiah). "Molecular and functional characterization of ABRAXAS and PALB2 genes in hereditary breast cancer predisposition". Doctoral thesis, Oulun yliopisto, 2019. http://urn.fi/urn:isbn:9789526218656.

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Abstract Hereditary mutations in DNA damage response (DDR) genes often lead to genomic instability and ultimately tumor development. However, the molecular mechanism of how these DDR deficiencies promote genomic instability and malignancy is not well understood. Thus, the specific aim of this thesis is to identify the functional and molecular framework behind the elevated breast cancer risk observed in heterozygous PALB2 and ABRAXAS mutation carriers. The heterozygous germline alteration in PALB2 (c.1592delT) causes a haploinsufficiency phenotype in the mutation carrier cells. Due to PALB2 haploinsufficiency, elevated Cdk activity and consequently aberrant DNA replication/damage response was observed in the PALB2 mutation carrier cells. Excessive origin firing that is indicative of replication stress was also seen in the PALB2 mutation carrier cells. In addition to replication stress, PALB2 mutation carrier cells also experience G2/M checkpoint maintenance defects. The increased malignancy risk in females associated with heterozygosity for the Finnish PALB2 founder mutation is likely to be due to aberrant DNA replication, elevated genomic instability and multiple different cell cycle checkpoint defects. The heterozygous germline alteration in ABRAXAS (c.1082G>A) causes a dominant-negative phenotype in the mutation carrier cells. Decreased BRCA1 protein levels as well as reduced nuclear localization and foci formation of BRCA1 and CtIP was observed in the ABRAXAS mutation carrier cells. This causes disturbances in basal BRCA1-A complex localization, which is reflected by a restraint in error-prone DNA double-strand break (DSB) repair pathway usage, attenuated DNA damage response, deregulated G2/M checkpoint control and apoptosis. Most importantly, mutation carrier cells display a change in their transcriptional profile, which we attribute to the reduced nuclear levels of BRCA1. Thus, the Finnish ABRAXAS founder mutation acts in a dominant-negative manner on BRCA1 to promote genome destabilization in the heterozygous carrier cells
Tiivistelmä Perinnölliset muutokset DNA-vauriovasteen geeneissä johtavat usein genomin epävakauteen ja lopulta syövän kehittymiseen. Molekyylitason mekanismeja, joilla vauriovasteen vajaatoiminta ajaa genomin epävakautta ja syöpää, ei kuitenkaan ymmärretä kunnolla. Tämän väitöskirjan tavoitteena on tunnistaa solutoiminnan ja molekyylitason vaikuttajat heterotsygoottisten PALB2- ja ABRAXAS-geenimuutosten kantajien kohonneen rintasyöpäriskin taustalla. Heterotsygoottinen ituradan suomalainen perustajamuutos PALB2-geenissä (c.1592delT) aiheuttaa haploinsuffisienssin kantajahenkilöiden soluissa. PALB2:n haploinsuffisienssin seurauksena kantajasoluissa havaittiin kohonnutta Cdk-proteiinin aktiivisuutta ja siitä johtuvaa kiihtynyttä DNA:n kahdentumista. PALB2-mutaatiota kantavissa soluissa nähtiin myös liiallista replikaation aloituskohtien käyttöä, mikä viittaa replikaatiostressiin. Replikaatiostressin lisäksi PALB2-mutaation kantajasoluilla havaittiin vaikeuksia ylläpitää solusyklin G2/M-tarkastuspisteen toimintaa. Näiden solutoiminnan poikkeavuuksien takia heterotsygoottisen PALB2 c.1592delT -mutaation kantajilla todettiin genomin epävakautta ja kohonnut syöpäriski. Heterotsygoottinen ituradan mutaatio ABRAXAS-geenissä (c.1082G>A) aiheuttaa dominantti-negatiivisen fenotyypin mutaation kantajasoluissa. ABRAXAS-mutaatiota kantavissa soluissa havaittiin BRCA1-proteiinitasojen laskua sekä BRCA1- ja CtIP-proteiinien vähentynyttä lokalisaatiota tumaan ja DNA-vauriopaikoille. Tämä aiheuttaa häiriöitä BRCA1-A-kompleksin paikallistumisessa, mikä johtaa häiriöihin virhealttiiden DNA-kaksoisjuoste¬katkoksien korjausmekanismien käytössä, DNA-vauriovasteessa, G2/M-tarkastus-pisteen säätelyssä ja ohjelmoidussa solukuolemassa. Tärkeimpänä löydöksenä havaittiin mutaation kantajasoluissa muuttunut transkriptioprofiili, joka johtunee BRCA1-proteiinitasojen laskusta tumassa. Näin ollen suomalainen ABRAXAS-perustajamutaatio toimii dominantti-negatiivisena BRCA1:n suhteen, aiheuttaen genomin epävakautta heterotsygoottisissa kantajasoluissa

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41

"Breast cancer susceptibility gene (BRCA1) mutations in Hong Kong Chinese women with breast cancer". 1998. http://library.cuhk.edu.hk/record=b6073102.

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Wang Ya-Ping.
Thesis (Ph.D.)--Chinese University of Hong Kong, 1998.
Includes bibliographical references (p. 152-161).
Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Mode of access: World Wide Web.
Abstracts in English and Chinese.

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42

Yawitch, Tali Michelle. "Inherited predisposition to breast/ovarian cancer : the frequency and nature of BRCA1 gene mutations in South African families". Diss., 2002. http://hdl.handle.net/2263/30470.

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Breast cancer is the most common cancer in South African women. Approximately 5¬10% of all breast cancer cases are due to an inherited predisposition, resulting from mutations in tumour suppressor genes. The BRCA1 gene on chromosome 17q is one such tumour suppressor gene, that when mutated confers an increased risk of breast/ovarian cancer in carriers. To date, more than 500 different BRCA 1 mutations have been reported worldwide. Some of these mutations are frequently reported and others occur commonly in certain population groups. These population-specific differences in mutations represent founder effects, whereby a single ancestral mutation accounts for the majority of breast cancer cases. This study was undertaken as the nature and frequency of BRCA1 mutations in South African breast/ovarian cancer families is unknown. Fifty-one breast/ovarian cancer families were screened for three commonly occurring mutations (185deIAG, 4184del4 and 5382insC) using polymerase chain reaction (PCR) and allele-specific oligonucleotide (ASO) hybridisation. The protein truncation test (PTT) was utilised to detect truncating mutations in the large exon 11, and the remaining coding exons were screened for mutations using exon-by-exon PCR single strand conformation polymorphism/heteroduplex analysis (SSCP/HA). Seven disease-causing mutations were identified in 15 families, consisting of five different frameshift mutations and two different nonsense mutations. Four Ashkenazi Jewish families were found to harbour the 185delAG mutation; the 5382insC mutation was identified in two Afrikaner families and one Ashkenazi Jewish family. Haplotype analysis revealed that the four Ashkenazi families share the common Ashkenazi Jewish haplotype, suggesting a common ancestor for these families. Similarly, the two Afrikaner families share the same haplotype as families of north and east European ancestry with the 5382insC mutation. The haplotype of the Ashkenazi Jewish family with this mutation was however different to the linked haplotype, indicating a recombination event or an independent mutation. Both these mutations are thought to have occurred in or before the medieval period. Furthermore, four Afrikaner families were found to carry the novel E881X nonsense mutation, which has not been previously described. Haplotype analysis of these families suggested that these patients share a common ancestor, and genealogic studies have identified the founding couple for this mutation, who both arrived in the Cape from France in the late 1600s. Four additional families were found to harbour BRCA1 mutations by SSCP/HA. Three of these mutations have not been previously reported - the S451X nonsense mutation (identified in a family of Scottish origin), the 1493delC mutation identified in an Afrikaner family, and the 4957insC mutation identified in an Indian family. The 448insA mutation was identified in a family of German origin, where the patient had cancer of the fallopian tubes. A number of different described polymorphisms and variants of unknown functional significance were also identified. This is the first study to show that BRCA1 is involved in South African breast/ovarian cancer families, to the extent that 29.4% (15/51) of families have BRCA1 mutations. Furthermore, minor founder effects in the Afrikaner population have been demonstrated. These results enable improved genetic counselling and clinical management of mutation positive families as well as subsequent testing of family members.
Dissertation (MSc (Human Genetics))--University of Pretoria, 2005.
Genetics
unrestricted

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43

Moisan, Anne-Marie. "Contribution des mutations dans les gènes BRCA1 et BRCA2 chez les canadiennes-françaises à risque élevé de développer un cancer du sein et/ou de l'ovaire /". 2007. http://www.theses.ulaval.ca/2007/24412/24412.pdf.

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44

Lacour, Robin Ann Du Xianglin L. Lu Karen H. Krueger Philip Michael. "Response to chemotherapy, recurrence and survival in advanced-stage ovarian, fallopian tube and primary peritoneal cancer patients with non-Ashkenazi Jewish BRCA mutations, compared to those without". 2008. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:1450278.

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45

Lin, Yuan-Ping, e 林元平. "Molecular characterization of mutations in BRCA1 and BRCA2 genes from breast cancer families in Taiwan". Thesis, 2003. http://ndltd.ncl.edu.tw/handle/26440156373893755541.

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碩士
國立中山大學
生物醫學科學研究所
91
Abstract Breast cancer is a common malignancy affecting women around the world. Approximately 10 percent of breast cancer patients have a hereditary form of the disease. Women with an inherited alteration in one of the BRCA1 and BRCA2 genes have an increased risk of developing these cancers at a young age (before menopause), and often have multiple family members with the disease. A total of 6 families with multiple cases of breast cancer were identified from southern Taiwan, and five of these families were found to have missense mutations in the BRCA1 or BRCA2 genes. One novel missense mutation of A5885C (Gln1886Pro), as well as new silent mutation of A4806G (Thr1526), in the exon 11 of the BRCA2 gene was found in one(A) family. The second(F) family was found to have three missense mutations of C2731T (Pro871Leu), A3232G (Glu1038Gly) and A3667G (Lys1183Arg) in the exon 11 of the BRCA1 gene. It is very unusual to have three previously reported BRCA1 mutations in the same family and these three mutations are located on the same chromosome. Two missense mutations of A3232G (Glu1038Gly) in exon 11 and A4956G (Ser1613Gly) in exon 16, as well as silent mutations of T2430C (Leu771) and T4427C (Ser1436), of the BRCA1 gene were found in the third(E) family. The missense mutation of A4956G (Ser1613Gly) in exon 16, as well as silent mutation of T4427C (Ser1436), of the BRCA1 are found in the fourth(C) and fifth(D) family. The sixth(B) families were found to possess only one silent mutation of T4035C (Val1269) in the BRCA2 gene. The amino acid changes might cause the protein structure unstable and these could explain the moderate role of BRCA mutations in the pathogenesis of breast cancer.

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46

Schneegans, Sarah Maj. "Zur Risikokalkulation für Mutationen in den Genen BRCA1 und BRCA2 in Familien mit Brustkrebs". Doctoral thesis, 2011. http://hdl.handle.net/11858/00-1735-0000-0006-B201-5.

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47

Lakhotia, Smita. "Breast Cancer Susceptibility Gene 1 (BRCA1) And Breast Cancer". Thesis, 2006. http://hdl.handle.net/2005/456.

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Breast Cancer susceptibility gene 1 (BRCA1) & Breast Cancer Breast cancer is one of the most common malignancies affecting women worldwide. About 5-10% of all cases are estimated to be familial. Mutations in the BRCA1 (Breast Cancer susceptibility gene 1) gene account for about 15-20% of inherited breast cancer cases and 60-80% of families predisposed to both breast and ovarian cancer. BRCA1 mutations also result in susceptibility to early-onset breast and ovarian cancer. The human BRCA1 gene encodes a multi-domain 1,863 amino acid nuclear protein that is expressed in a wide variety of adult human tissues. The N-terminal end of BRCA1 contains a RING-finger domain. Exon 11 of BRCA1 contains two nuclear localization signals towards its N-terminal for targeting BRCA1 to the nucleus. The carboxyl terminus contains two BRCT (BRCA1 C-terminal) domains and a transcriptional activation domain. This study was carried out to functionally characterize BRCA1 and to find out the percentage in which BRCA1 gene is mutated in Indian familial breast and/or ovarian cancer families. The work has been divided into three sections: 1. Identification & characterization of a BRCA1 Associated Protein 2 (BAP2). 2. Germ-line BRCA1 mutation Analysis in Indian Breast and/or Ovarian Cancer Families. 3. Characterization of a novel missense mutation (E116K) in BRCA1. BRCA1 is known to interact with large number of proteins and is involved in various cellular functions like tumorigenesis, transcription, DNA damage repair, cell-cycle control, ubiquitinylation, genetic stability, cell growth and apoptosis. The interacting partners of BRCA1 have given a lot of clue about the functions of this complex protein. In the first project, we used the yeast two-hybrid system to identify novel interacting proteins of BRCA1. We used the 1-500 amino acid region of BRCA1 as bait in library screen and picked up a novel clone (clone 89) showing interaction with BRCA1. Clone 89 contains approximately 2.3 Kb long cDNA sequence. Using the nucleotide blast search, we obtained a full-length cDNA of approximately 5.4 Kb (KIAA0657) that is located on chromosome 2, 2q36.1 region. We have named this new protein BRCA1 Associated Protein 2 (BAP2). Translation of this coding sequence gave a protein that has homology to Titin protein. This protein, which has 1,236 amino acids, contains 9 Immunoglobulin like domains. The homologues of this protein exists in many other organisms but the function is not known. We have confirmed the interaction between BRCA1 and c89 using in vitro GST pull-down assay. We have studied the influence of BAP2 on various functions of BRCA1 like transcription, colony suppression and cell cycle. In the transcription assays, BAP2 activated p21 promoter activity perhaps by using endogenous BRCA1 as simultaneous ectopic expression of truncated BRCA1 (containing aa 1-500) abolished this activity. Further, BAP2 also increased the ability of BRCA1 to activate p21 promoter suggesting that BAP2 may act as a co-activator of BRCA1 functions. Surprisingly, we observed that BAP2 inhibited p53-mediated transcription both in the absence and presence of BRCA1. BAP2 failed to inhibit colony growth by itself as well as in combination with BRCA1. In the cell-cycle study, we found that BAP2 did not have any significant effect on cell cycle profile by itself. However, it drastically augmented the G2/M arrest mediated by BRCA1. Thus we conclude that we have identified a novel interacting protein of BRCA1 that regulates certain functions of BRCA1. Detection of mutations is of central importance in the study of genetic and malignant diseases. Mutation detection helps us in understanding the protein structure, function and expression. More than that, it is also important for pre-symptomatic/antenatal diagnosis, confirmation of the genetic cause of the disease and the mode of inheritance of a disease in a particular family, the prediction of clinical phenotype and the potentiation of diagnostic analysis in the case of families with incomplete pedigrees or with new mutations. Therefore, the importance of direct mutation analysis cannot be understated. The second project deals with screening of mutations in BRCA1 gene in 50 familial breast and/or ovarian cancer families using the technique of Conformation Sensitive Gel Electrophoresis (CSGE). CSGE can be used to detect mismatches in DNA heteroduplexes that contain one strand of wild type and one strand of mutated DNA. In a collaborative study with Kidwai Memorial Hospital for Oncology, Bangalore, we screened 50 families suffering from breast and/or ovarian cancer. We detected 13 mutations in this study out of which 3 are novel and 10 have already been reported earlier (Breast Information Core). All the mutations obtained in our study result in truncation of the BRCA1 protein either because of non-sense mutation or frame-shift mutation. Interestingly, 8 of the mutations detected are 185delAG mutations – the most commonly occurring mutation in Ashkenazi Jewish population. From this study, we conclude that BRCA1 is mutated in 26% of familial breast and/or ovarian cancer cases in India. Genetic testing in individuals with family history of breast, ovarian or both has become very common. It is difficult to interpret the result of genetic screen if a DNA change in the gene does not result in truncation of the protein. Rare missense changes of unknown functional and pathogenic significance are called unclassified variants. It is important to study the functional implications of these unclassified variants in order to determine the risk associated with the presence of such variations. The third project deals with characterization of one such missense variation. In an earlier mutation analysis study for BRCA1 gene in breast cancer samples, we found a novel missense variation resulting in Glu116Lys (E116K) change. In order to determine if this variant is a disease associated missense mutation or a benign sequence alteration; we introduced this variation into full length BRCA1 cDNA and studied its effect on the known functions of BRCA1, namely, transcription, colony suppression and cell cycle. We found that E116K is defective for activating transcription. However, it continued to inhibit growth in colony formation assay and arrest cells in G2/M phase of cell cycle. We conclude that E116K mutation results in loss of transactivation function of BRCA1 but has no effect on colony formation and cell cycle regulation; thus it can be categorized as a novel missense mutation.

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48

Ozakinci, Gozde. "Psychological and behavioral outcomes of genetic testing for BRCA1/2 mutations among Ashkenazi Jewish Women /". 2004. http://wwwlib.umi.com/dissertations/fullcit/3153612.

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49

鄧旭真. "Molecular Characterization of Germline Mutations in Brain Tumor NF2 Gene and Breast Cancer BRCA2 Gene from Taiwan". Thesis, 1997. http://ndltd.ncl.edu.tw/handle/31752464570994698246.

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碩士
國立中山大學
生命科學研究所
85
Neurofibromatosis type 2 (NF2) is an autosomal dominantly inherited disease by bilateral vestibular schwannomas and other tumor of the brain, spinal cord, and central nervous system. NF2 disease is caused by germline mutations in the NF2 tumor suppressor gene on chromosome 22q12. Although the tumors of NF2 are histologically benign, their anatomical location and multiplicity lead to great morbidity and early mortality. Breast cancer is the most common malignancy among women in developed countries. Recently, the incidence of breast cancer increases n Taiwan and the occurrence of breast cancer tends to be early onset. Familial breast cancer is characterized by early onset, an increased risk of bilateral breast cancer, an increasing risk and numbers of affected family members. The second breast cancer susceptibility gene, BRCA2 on chromosome 13q12-13, has recently been cloned. Germline mutations of BRCA2 are predicted to account for approximately 35% of families with early onset female breast cancer, and they are also associated with an increased risk of male breast cancer. To identify the nature of genetic mutations in familial brain tumor and breast cancer in Taiwan and develop simple diagnosis procedures for detecting these genetic mutations, we have analyzed germline mutations in the NF2 gene and BRCA2 gene by PCR (polymerase chain reaction) -based SSCP (single strand conformation polymorphism) analysis followed by cloning and sequencing of related PCR products. In this study, nonsense mutations or frameshift deletions in NF2 and BRCA2 genes had been found, and these mutations are all predicted to lead to the truncated proteins which are usually associated with severe phenotypes. Moreover, polymorphic changes of several missense and silent mutations were also observed among breast cancer patients and normal individuals. The search for genotype-phenotype correlation in NF2 and BRCA2 mutations is important not only to increase understanding of how mutated genes function, but also to improve presymptomatic detection of patients. DNA diagnosis of NF2 gene and BRCA2 gene can improve quality of genetic counseling and clinical management, and possibly reduce psychosocial difficulties in at-risk individuals.

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Maheu, Christine. "Interpreting and making sense of uninformative results of testing for BRCA 1 and BRCA 2 cancer gene mutations". Thesis, 2005. http://hdl.handle.net/2429/17030.

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Research suggests that a significant proportion of individuals from families at risk of hereditary breast and ovarian cancer will be found not to have a detectable mutation in their BRCA1 or BRCA2 cancer genes. Although the interpretation of genetic test results is relatively straightforward in families where a mutation has already been identified, little is known about how people who have had breast and/or ovarian cancer in the past as well as a family history of cancer considered at risk for HBOC interpret and make sense of test results concluding that no detectable mutation has been found. This problem is further compounded when they are told that such genetic test results do not completely rule out an inherited mutation because of their strong family history of the disease. While the clinical and research literature refers to these results as uninformative or inconclusive, this study shows that clients' interpretations are much more complex. To date, few studies have focused on affected individuals from families at risk of HBOC who receive uninformative genetic test results. We therefore have little knowledge of how these individuals interpret and make sense of such results and how these results affect their everyday lives, health and illness experiences. This dissertation addresses these lacunae by using an interpretive description approach to examine clients' experiences of genetic testing. Qualitative, in-depth interviews were conducted with 21 affected individuals with a family history of cancer considered at risk for HBOC who received genetic testing and 15 family members. The interview data show that living with a personal and family history of breast and/or ovarian cancer plays an important role in interpreting and then making sense of their genetic test results and in one's perception of probably having an inherited mutation for HBOC. Thirteen generic structures were found to organise beliefs towards the making sense process of interpreting their genetic test results while three types of interpretation of the test results were derived from the participants' accounts. The categories of interpretation are seeing results as: a confirmation of their mutation status, ambiguity regarding their mutation status, and refutation of being a mutation carrier. On the basis of these generic structures and the three types of interpretation, it is possible to see a retrospective narrative of causal reasoning of having a probable inherited mutation that builds upon recognition of a strong family history with breast and/or ovarian cancer. This 7-stage process evolves with changes in people's everyday lives, health and illness experiences. The impact of receiving uninformative test results for BRCA1 and BRCA2 mutations on the lives of affected individuals and their family members requires further examination. We need to understand how such results affect cancer and genetic risk perception and potentially contribute to clients' viewing themselves at chronic risk of cancer and of an inherited mutation. Further investigation is also needed to determine how uncertain genetic risk information is shared among and used by family members. This dissertation offers recommendations to ameliorate the experience of individuals who receive uninformative genetic test results, to improve genetic testing services, and to enhance the genetic knowledge of nurses and their clients.
Applied Science, Faculty of
Nursing, School of
Graduate

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