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1
Collins, N. "BRCA2 in familial and sporadic breast cancer". Thesis, Institute of Cancer Research (University Of London), 2000. http://publications.icr.ac.uk/10070/.
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The breast cancer susceptibility gene BRCA2 is located on chromosome 13q 12-13. Using breast and ovarian cancers from a BRCA2-linked family, loss of the wild type BRCA2 allele was demonstrated in seven out of eight informative cases (87.5%) indicating that BRCA2 was a recessive oncogene. Analysis of 73 sporadic breast tumours and 12 breast cancer cell lines revealed loss of heterozygosity (LOH) in 22 (30%) of the primary tumours and seven (58%) of the breast cancer cell lines. However, it was not clear from these studies that the target for the observed LOH was the gene BRCA2 or RBl at chromosome 13q14 as the region ofLOH included both genes in all but a single case. Despite the presence of elevated levels of LOH, several separate mutation screening studies of sporadic breast and ovarian tumours have shown that somatic mutations of BRCA2 in sporadic breast and ovarian cancer are very rare. To investigate the possibility that other mechanisms of BRCA2 allelic inactivation might be operative, the methylation status of a CpG island within the promoter region of BRCA2 was examined in 64 sporadic breast tumours and 18 breast and ovarian cancer cell lines. Three CpG dinucleotides within this island were unmethylated in all the normal tissue samples (lymphocytes) examined. These three CpG dinucleotides remained unmethylated in all the breast tumours examined. Moreover, expression of BRCA2 in breast and ovarian cancer cell lines was not obviously correlated with evidence of loss of heterozygosity. These analyses indicate that methylation of the promoter region of BRCA2 and possibly other mechanisms of transcriptional silencing are unlikely to be a common mechanism of gene inactivation in these tumours. To investigate the prevalence of BRCA2 mutations, lymphocyte DNAs from a British, population-based series of 617 breast cancers diagnosed before age 45 were screened for mutations. Mutations were detected in 14 women ( 2.3%, 6/14 43% under age 35 and 8/14 57% age 36-45). This study and a parallel study of BRCA1 demonstrate that BRCA2 and BRCA1 make approximately equal contributions to early onset breast cancer in the UK. Moreover, although BRCA1 and BRCA2 account for breast cancer susceptibility in a substantial proportion of multiple case families, they only account for a small proportion of the overall familial risk conferred by an early onset case. This indicates the existence of other susceptibility genes that are more common but confer lower risks than BRCA1 and BRCA2.
2
Mohammed, Shehla Nilofer. "Familial breast cancer : a clinicopathological and genetic study". Thesis, King's College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299826.
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Luo, Liping. "A genetic study on familial breast cancer predisposing genes /". Stockholm, 2002. http://diss.kib.ki.se/2002/91-628-5184-5.
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Agenbag, Gloudi. "Molecular genetic analysis of familial breast cancer in South Africa". Thesis, Link to the online version, 2005. http://hdl.handle.net/10019/953.
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MacInnes, Emma G. E. "Psychosocial outcomes in women at increased familial breast cancer risk". Thesis, University of Sheffield, 2017. http://etheses.whiterose.ac.uk/20859/.
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Introduction There are a number of strategies that women with a vastly increased risk of familial breast cancer, particularly those with BRCA 1 and 2 gene mutations, may choose to protect themselves. The main risk management strategies have very different risk and benefit profiles and include enhanced imaging surveillance, use of chemoprevention (SERMs or AIs) and risk reducing surgery. Knowledge of hereditary breast cancer risk and cancer anxiety can impact on quality of life. Options for managing this elevated risk, whilst effective, may have long-term psychosocial consequences. This study aimed to explore the impact of living at risk, to identify the psychosocial outcomes for this group of women and for their partners and to assess factors that impact on risk management decisions and their ultimate decision satisfaction. Methodology A sequential exploratory mixed methods study was used, including a systematic review, a qualitative phase of study, using in-depth, semi-structured interviews with women and partners of women at high risk who had faced these choices, questionnaire development including focus group review and finally a quantitative phase of study using the questionnaire to explore associations and to assess the generalisability of the strength of these findings. (See figure 0.1). Results Generally psychosocial outcomes are acceptable to women with high levels of decision satisfaction, but for a minority, risk reducing measures result in long-term psychosocial morbidity. The more common causes of distress include adverse body image changes, generalised and cancer-specific anxiety and distress. Good support, particularly that of a partner, can reduce this negative impact. Partners struggle to balance existing commitments with the time demands of providing this support. Conclusion Recognising women at increased risk of adverse effects related to their choice of risk management strategy may allow targeted support to enable women to better understand and manage their risk with a reduction in associated psychosocial distress.
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Pharoah, Paul David Peter. "Familial and inherited breast cancer in the East Anglian population". Thesis, University of Cambridge, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.621725.
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Kast, Karin, i Kerstin Rhiem. "Familial Breast Cancer: Targeted Therapy in Secondary and Tertiary Prevention". Karger, 2015. https://tud.qucosa.de/id/qucosa%3A71423.
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The introduction of an increasing number of individualized molecular targeted therapies into clinical routine mirrors their importance in modern cancer prevention and treatment. Well-known examples for targeted agents are the monoclonal antibody trastuzumab and the selective estrogen receptor modulator tamoxifen. The identification of an unaltered gene in tumor tissue in colon cancer (KRAS) is a predictor for the patient’s response to targeted therapy with a monoclonal antibody (cetuximab). Targeted therapy for hereditary breast and ovarian cancer has become a reality with the approval of olaparib for platin-sensitive late relapsed BRCA-associated ovarian cancer in December 2014. This manuscript reviews the status quo of poly-ADP-ribose polymerase inhibitors (PARPi) in the therapy of breast and ovarian cancer as well as the struggle for carboplatin as a potential standard of care for triple-negative and, in particular, BRCA-associated breast cancer. Details of the mechanism of action with information on tumor development are provided, and an outlook for further relevant research is given. The efficacy of agents against molecular targets together with the identification of an increasing number of cancer-associated genes will open the floodgates to a new era of treatment decision-making based on molecular tumor profiles. Current clinical trials involving patients with BRCA-associated cancer explore the efficacy of the molecular targeted therapeutics platinum and PARPi.
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Vaittinen, Pauli. "Risk characterization of familial cancer using the Swedish Family-Cancer database with a special reference to breast cancer /". Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-723-1/.
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Renwick, A. A. "Familial breast cancer : are BRCA1 and BRCA2 mutations present in Scotland?" Thesis, University of Aberdeen, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.593342.
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Antoniou, A. C. "Developing a comprehensive risk model for familial breast and ovarian cancer". Thesis, University of Cambridge, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.596129.
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The specific aim of this thesis was to combine data on mutation prevalence and risk from both high risk families and population based series, in order to develop a model for familial breast and ovarian cancer which incorporates both the effects of BRCA1, BRCA2 and other genes. The principal methodology used was segregation analysis and the genetic models were constructed using the computer program MENDEL. The first dataset consisted of 112 families containing two or more relatives with epithelial ovarian cancer. BRCA1 and BRCA2 germline mutations were detected in 50% of these families. When the effects of BRCA1, BRCA2 and a third ovarian cancer susceptibility gene were modelled simultaneously none of the models fitted gave significant evidence for a third gene. BRCA1 and BRCA2 were estimated to account for at least 38 % of the excess familial risk of ovarian cancer. Using data on the families of twelve BRCA1 mutation carriers in a study of 374 ovarian cancer cases unselected for family history, the estimated ovarian cancer risk by age 70 was 66% and the corresponding breast cancer risk was 45%. The breast cancer dataset consisted of 1484 women diagnosed with breast cancer under the age 55 from whom blood samples were analysed for mutations in BRCA1 and BRCA2. Using information on breast and ovarian cancer history in first degree relatives, and on the mutation status of the index cases we estimated the effects of BRCA1, BRCA2, a third gene BRCA3 and a polygenic effect. For this purpose the Hypergeometric Polygenic model was implemented in MENDEL.
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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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De, Azevedo Moreira Reis Marta. "Evaluation of healthcare management issues in the provision of clinincal services for familial breast/ovarian cancer /". St Andrews, 2009. http://hdl.handle.net/10023/728.
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Giongo, Cíntia de Oliveira. "Caracterização imunogenética de variantes dos genes CCR2, CCR5 e HLA-G como potenciais alvos para diagnóstico, prognóstico e tratamento do câncer de mama feminino esporádico e familial". reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2012. http://hdl.handle.net/10183/78137.
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O câncer de mama é a neoplasia mais comum entre as mulheres. Sua etiologia é complexa, onde tanto fatores ambientais como genéticos podem contribuir para o desenvolvimento tumoral. Estima-se que 5 a 10% dos casos de carcinomas de mama sejam representados pelos carcinomas de mama familial e 90 a 95% sejam representados pelos carcinomas de mama esporádicos. Independente da etiologia, um dos principais agravantes é consequência da habilidade das células tumorais metastizar. Mutações podem levar a mudança ou perda de expressão de diferentes genes e isto possibilita que as células adquiram particularidades genéticas e fenotípicas que contribuem para a progressão do tumor através da aquisição de vantagens que medeiam a sua sobrevivência. Dentre estas vantagens adquiridas está a capacidade das células tumorais de escaparem da destruição pelas células imunológicas ou, até mesmo, utilizarem estas células a seu favor, na promoção de um microambiente tumoral inflamatório que pode auxiliar o desenvolvimento da angiogênese que posteriormente facilitará a metástase. As características dos carcinomas de mama são as principais ferramentas para avaliação do diagnóstico e prognóstico da doença. Portanto, o objetivo de nosso trabalho foi a análise de quatro variantes polimórficas de genes que codificam importantes moléculas do sistema imunológico, duas relacionadas aos genes que codificam os receptores de quimiocinas, CCR2 e CCR5, e duas relacionadas ao gene HLA-G em 188 mulheres com carcinoma de mama (105 com câncer de mama familial e 83 com câncer de mama esporádico) e em 151 mulheres sem carcinoma e sem história familiar de câncer (grupo controle), como possíveis marcadores de diagnóstico e prognóstico do carcinoma de mama. Para a análise da variante do CCR2, denominada CCR264I, e para a análise de uma das variantes que codifica a molécula de HLA-G, denominada +3142, utilizou-se a técnica PCR-RFLP. Para a análise da variante do gene CCR5, denominada CCR5delta32 e para a análise da outra variante do HLA-G, caracterizada pela inserção de 14pb na região 3’UTR do gene, utilizou-se a técnica PCR. As frequências alélicas, genotípicas e haplotípicas foram estimadas e comparadas entre os grupos de mulheres, usando o Teste Qui-Quadrado ou o Teste Exato de Fisher e, posteriormente, foram relacionadas a fatores de diagnóstico e prognóstico. Observou-se maiores frequências dos alelos selvagens do CCR2, Val (p=0,040, OR 0,61, IC 95% = 0,38 – 0,98) e do CCR5, Wt (p=0,032, OR 0,46, IC 95% = 0,23 – 0,94) e maior frequência do haplótipo duplo selvagem Wt/Val destas mesmas variantes gênicas dos genes CCR2 e CCR5, nas mulheres do grupo controle (p=0,030) em relação às mulheres com câncer de mama familial. Quando as variantes foram avaliadas em conjunto com os parâmetros clínicos, observou-se que as mulheres com carcinoma de mama esporádico apresentavam a doença em idade mais elevada (57,29 ± 8,457 anos e 44,23 ± 12,092 anos para mulheres com câncer de mama esporádico e familial, respectivamente, p < 0.001) e de forma mais agressiva, com maior frequência dos carcinomas invasores (p = 0,001) que as mulheres com carcinoma de mama familial. Além disso, as variantes de inserção/deleção de 14 pb do HLA-G e CCR264I, mostraram relação positiva com a agressividade tumoral nestas mulheres (p = 0,039 e p = 0,005). Nossos dados sugerem que os carcinomas invasores possam estar relacionados a uma maior infiltração de células imunológicas e com o aumento da inflamação no microambiente tumoral, mediados pelo receptor CCR2 e pela molécula HLA-G, respectivamente.Breast cancer is the most common cancer among women. Its etiology is complex, where genetic, environmental and endocrine factors contribute to tumor development. It is estimated that 5 to 10% of the breast cancers are represented by familial breast cancers and 90 to 95% are represented by sporadic breast cancers. Independent of the etiology, the major aggravating consequence is the ability of tumor cells to metastasize. Mutations can lead to a change or loss of expression a different genes and this allows the appearance of genetic and phenotypic features which contribute to tumor progression. Among these features is the ability of tumor cells to evade from the immune cells or even use immune cells in the promotion of a inflammatory microenvironment promotion which may help angiogenesis and, later, metastasis. The aim of our study was to evaluate four important polymorphic variants of genes which encode important immune system molecules, two related genes encoding chemokine receptors, CCR2 and CCR5, and two related to HLA-G gene in 188 women with breast cancer (105 women with familial breast cancer and 83 with sporadic breast cancer) and 151 women without cancer and family history of cancer (control group), such as potential markers for diagnosis and prognosis of breast cancer. CCR2 polymorphism, CCR264I, and one HLA-G polymorphism, +3142, were genotyped by PCR-RFLP. CCR5delta32 and 14pb HLA-G polymorphism were genotyped by PCR. Allelic, genotypic and haplotypic frequencies were estimated and compared between the groups using the Chi-square test or Fisher's exact test and subsequently were associated to diagnostic and prognostic factors. We observed a higher allelic frequency of the CCR2 wild type allele, Val (p = 0.040, OR 0.61, 95% CI = 0.38 - 0.98) e CCR5 wild type allele, Wt (p = 0.032, OR 0.46, CI 95% = 0.23 - 0.94) and higher haplotype frequency of the double wild type variants (Wt/Val) of these same genes (CCR2 and CCR5) in women in the control group (p = 0.030) compared to women with familial breast cancer. All polymorphisms were evaluated together with the clinical parameters and it was observed that women with breast cancer showed sporadic cancer latter (57.29 ± 8.457 years and 44.23 ± 12.092 years for women with sporadic breast cancer and familial breast cancer, respectively, p < 0.001) and more invasiveness (p = 0.001) as compared to women with familial breast cancer. Moreover, the HLA-G 14pb and CCR264I polymorphism, showed a positive association with tumor aggressiveness in women with sporadic breast cancer (p = 0.039 and p = 0.005, respectively). Our data suggest that invasive cancers may be associated with increased immune cells infiltration and inflammation in the tumor microenvironment mediated by both CCR2 receptor and HLA-G molecule.
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Lloyd, Susannah. "Understanding the experience of prophylactic bilateral mastectomy : a grounded theory study". Thesis, University of East Anglia, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.302194.
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Catucci, Irene. "Identification of low-penetrance alleles, genetic modifiers and mutation analysis in familial breast cancer cases". Thesis, Open University, 2013. http://oro.open.ac.uk/54681/.
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To date, germline mutations in known high-penetrance genes, mainly BRCAI and BRCA2, and in moderate- and low-penetrance genes are responsible for approximately 30- 35% of breast cancer familial clustering, leaving the majority of them unexplained. In addition, the variability of the risk conferred by BRCAI and BRCA2 mutations suggests the presence of genetic modifiers of this risk. Therefore, the identification and characterization of as many as possible of genetic factors is crucial for risk prediction in members of breast cancer families. In this context, the aim of this thesis was firstly to investigate the role of the two Fanconi Anemia (FA) genes PALB2 and SLX4 as breast cancer predisposing loci. In the PALB2 screening, I observed a frequency of deleterious mutation of 2.1 % in familial cases recruited in cancer centers in Milan. Interestingly, I also identified the recurrent mutation c. l 027C > T, detected with 10-fold increased frequency in cases from Bergamo with respect to those ascertained in Milan, suggesting a founder effect. On the contrary. the SLX 4 analysis failed to identify any clearly deleterious mutation, excluding a major role of this gene in breast cancer susceptibility in the Italian population. In addition, I genotyped the candidate low-risk rs895819 polymorphism, located in the gene coding for miR-27a, to evaluate its role in reducing breast cancer risk, previously reported in the German population. No such an association was observed in our sample set. Finally, I investigated the role of the CASPS rs3834129 ins/del polymorphism as a genetic modifier in Italian BRCA1 and BRCA2 mutation carries and I observed an association of this SNP with increased breast cancer risk only in individuals carrying BRC1 mutations. In conclusion, our investigation contributed to assess the role of candidate predisposing loci and genetic modifiers of breast cancer risk, providing further knowledge on the susceptibility to this disease.
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Bubien, Virginie. "Identification de nouveaux gènes de prédisposition héréditaire au cancer du sein par génotypage tumoral et séquençage de nouvelle génération". Thesis, Bordeaux, 2016. http://www.theses.fr/2016BORD0393/document.
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5 à 10% des cancers du sein sont héréditaires mais parmi ceux-ci seulement la moitié est expliquée par une altération constitutionnelle d’un gène de prédisposition connu tels que les gènes BRCA1 et BRCA2. L’importante hétérogénéité génétique qui caractérise les famillesBRCAx rend difficile la réalisation d’études familiales groupées et ne permet pas l’identification de nouveaux gènes de prédisposition au cancer du sein selon les méthodes classiques de liaison génétique ou d’association. Les techniques de séquençage de nouvelle génération (NGS) à l’échelle de l’exome ou du génome entier, autorisent en revanche l’étude de familles individuelles à la recherche de mutations constitutionnelles privées mais le nombre considérable de variants génétiques identifiés impose leur tri sur des critères de pathogénicité ou de récurrence. Un autre critère de tri peut être représenté par l’identification de régions candidates définies en fonction de réarrangements génomiques tumoraux communs à plusieurs tumeurs au sein d’une même famille. Le génotypage tumoral par puces SNP (pour single nucleotide polymorphism) permet en effet la détection d’haplotypes conservés dans des régions récurrentes de LOH (pour loss of heterozygosity) communes à plusieurs tumeurs familiales et donc l’identification de régions candidates suspectes d’abriter des mutations germinales dans des gènes de prédisposition au cancer. La combinaison de ces deux approches, génotypage tumoral puis NGS, a été appliquée à une série de 17 familles avec agrégation de cancers du sein pour lesquelles au moins deux échantillons tumoraux étaient disponibles. Aucun nouveau gène de prédisposition au cancer du sein n’a été identifié mais une mutation délétère constitutionnelle du gène ATM a ainsi été retrouvée, associée à une perte de l’allèle sauvage dans les 2 tumeurs d’une famille BRCAx. L’analyse de 17 tumeurs du sein supplémentaires provenant de 10 familles avec agrégation de cancers du sein et mutation constitutionnelle du gène ATM identifiée chez le cas index, a révélé que l’allèle sauvage d’ATM était fréquemment perdu dans ces tumeurs (>80% contre 20% attendu en situation sporadique ; p<0.001). Ce résultat plaide fortement en faveur de l’implication d’ATM dans la carcinogénèse de ces cancers du sein tel un gène suppresseur de tumeur et suggère que les mutations constitutionnelles d’ATM sont impliquées dans des formes familiales de cancer du seinHereditary breast cancers (BCs) account for 5-10% of all diagnosed BCs, yet only 50% of such tumors arise in the context of a germline mutation in known tumor suppressor genes such as BRCA1 or BRCA2. The vast genetic heterogeneity which characterizes BRCAx families makes grouped studies impossible to perform. Next generation sequencing (NGS) techniques, however, allow individual families to be studied in order to identify private mutations. Single nucleotide polymorphism (SNP) arrays allow the detection of conserved haplotypes within recurrent regions of loss of heterozygosity, common to several familial tumors, therefore identifying genomic loci likely to harbor a germline mutation in cancer predisposition genes. The combination of both exome sequencing and SNP arrays for a series of 17 familial BC did not allow the identification of a novel BC predisposition gene, but revealed a germline ATM mutation associated with a loss of the wild-type allele in a BRCAx family. The analysis of 17 additional breast tumors from ten BC families in which a germline ATM mutation had been identified revealed a high frequency of wild-type allele loss in these tumors (>80% compared to the 20% expected in sporadic BC; p <0.001). This result argues strongly in favor of the involvement of ATM in the carcinogenesis of these tumors as a tumor suppressor gene and suggests that germline ATM mutations are involved in a subset of familial BC
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Elliott, Diana. "The impact of genetic counselling for familial breast cancer on women's psychological distress, risk perception and understanding of BRCA testing". University of Western Australia. School of Population Health, 2008. http://theses.library.uwa.edu.au/adt-WU2008.0190.
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[Truncated abstract] Background: A review of the literature indicated there was a need for more long-term randomised controlled studies on the effects of BRCA counselling/testing on high risk women, including improved strategies for risk communication. Reviews have also shown women are confused about the significance of inconclusive or non informative results with a need for more research in this area. Aims: The general aim of this study was to evaluate the impact of breast cancer genetic counselling on psychological distress levels, perception of risk, genetic knowledge and understanding of BRCA testing/test results in a cohort of 207 women from high risk breast cancer families who were referred for genetic counselling in Perth during the period 1997 to 2001. Short- and long-term impact of BRCA genetic counselling/testing was determined in women with and without cancer in a randomised controlled trial as part of which women were randomised to either receive immediate versus delayed genetic counselling. This included family communication patterns before BRCA testing, anticipated outcomes of testing on oneself and family including intentions for result disclosure. Comprehension of index and predictive BRCA testing with possible results was assessed both in the short- and the long-term and understanding of individual or family BRCA test results was evaluated at long-term. The effect of genetic counselling on breast cancer risk perception in unaffected women was evaluated. This study considered a theoretical framework of educational learning theories to provide a basis for risk communication with possible relevance for future research. ... Only 25% of the original study population (52/207) reported BRCA results and women's understanding of results is concerning. Key findings were: 1. The majority of affected women received an inconclusive result. 2. Out of twelve unaffected women who reported results, seven were inconclusive which are not congruent with predictive testing. This implies that these women did not understand their test result. 3. A minority of untested relatives did not know whether a family mutation had or had not been found in their tested family member or what their actual test result was. This implies either a lack of disclosure or that woman did not understand the rationale for and significance of testing for a family mutation. 4. Three relatives did not understand a positive result was a mutation. Conclusion: The implication of this research for breast cancer counselling and testing services is that women who wait for counselling are no worse off in terms of short- or long-term general psychological distress than women who receive the intervention early. There is a suggestion that unaffected women without the disease found counselling more advantageous than affected women. The meaning of BRCA results as reported by women is concerning particularly women's understanding of negative and inconclusive results and further research is needed in this area. Too much information presented at counselling may affect women's comprehension of risk, BRCA testing and future test results and further research is required to evaluate the effects of information overload.
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de, Azevedo Moreira Reis Marta. "Evaluation of healthcare management issues in the provision of clinical services for familial breast/ovarian cancer". Thesis, University of St Andrews, 2009. http://hdl.handle.net/10023/728.
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Despite there being pragmatic national guidelines for assigning risk to women with a family history of breast cancer, the evidence base is still sparse. There are three major questions: First, how can an assignment of "low" risk be made most efficiently? Second, what are the actual outcomes for higher-risk women enrolled in special surveillance programmes? Third, what are the costs and benefits of current management of members of breast cancer families? My thesis reviews the evolution of clinical services for familial breast cancer and the existing literature in the field. I describe the gathering of information from the service records of the Tayside Breast Cancer Family History Clinic and from specific research exercises that involved collaboration with other centres in the UK and abroad. My findings are as follows: 1. Histories provided by the families are not sufficient to assign risk accurately. They must be extended and verified from other records by clinical geneticists. Women assigned a low risk can be informed by post, but some may require further support. The 2004 NICE guidelines for assigning risk are fairly accurate, but may under-estimate it for some women aged 45--55 years. 2. Annual screening of young women at increased risk results in detection of most cancers at a curable stage. Women who carry BRCA1 mutations fare less well, even when tumours are detected at an apparently early stage. 3. Costs of accurate risk assessment are outweighed by savings from the better targeting of surveillance programmes. Early cancer detection in young women enrolled in these programmes achieves a substantial gain in life expectancy at a cost of £3,700 per quality adjusted life year (QALY). Prophylactic surgery for carriers of BRCA1 mutations is highly cost-effective. The thesis concludes with a discussion as to how these findings might be extended and clinical practice improved in the future.
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Erkko, H. (Hannele). "TOPBP1, CLSPN and PALB2 genes in familial breast cancer susceptibility". Doctoral thesis, University of Oulu, 2008. http://urn.fi/urn:isbn:9789514289682.
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Abstract
The currently known susceptibility genes account for approximately 25% of familial breast cancer predisposition. Additional factors contributing to the pathogenesis of breast cancer are, therefore, likely to be discovered. Most of the known genes affecting breast cancer predisposition function in the DNA damage response pathway. In this study three genes, TOPBP1, CLSPN and PALB2, involved in this complex process were investigated to reveal potentially pathogenic mutations associated with breast cancer susceptibility.
In the analysis of the TOPBP1 gene, one novel putative pathogenic alteration was observed. The Arg309Cys variant was found at an elevated frequency among familial cases (19/125) vs. controls (49/697) (p = 0.002; OR 2.4; 95% CI 1.3–4.2). In addition, altogether 18 other germline alterations were observed in this gene, but they all appeared to be harmless polymorphisms.
Investigation of CLSPN alterations among familial breast cancer families revealed altogether seven different changes. No clearly pathogenic alterations were observed. However, a potential modifier effect was discovered for the 1195delGlu change. The obtained results suggest that CLSPN alterations are unlikely to be significant breast cancer susceptibility alleles.
In the PALB2 gene, a pathogenic mutation c.1592delT was identified at an elevated frequency among breast cancer patients (0.9%) compared to controls (0.2%) (p = 0.003, OR 3.94, 95% CI 1.5–12.1). Among familial cases the frequency of c.1592delT was even higher (2.7%). This mutation was also functionally deficient. It had a markedly decreased BRCA2-binding affinity and was unable to support homologous recombination or to restore cross link repair in PALB2 knock-down cells. Additionally, this mutation was discovered in a familial prostate cancer family and was found to segregate with the disease, suggesting some association also with prostate cancer.
The penetrance and hazard ratio associated with PALB2 c.1592delT were determined in unselected breast cancer families. A substantially increased risk of breast cancer (HR 6.1; 95% CI 2.2–17.2; p = 0.01) was discovered resulting in an estimated 40% (95% CI 17–77) breast cancer risk by age 70 years, comparable to that for carriers of BRCA2 mutations. This markedly increased cancer risk suggests that genetic counselling for carriers is needed and screening for this mutation should be considered.
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Zheng, Guoqiao [Verfasser], i Kari [Akademischer Betreuer] Hemminki. "Breast and ovarian cancers in women: familial clustering, second primary cancer and cause of death / Guoqiao Zheng ; Betreuer: Kari Hemminki". Heidelberg : Universitätsbibliothek Heidelberg, 2019. http://d-nb.info/1195710216/34.
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Kamon, Phochana Pimpicha Patmasiriwat. "Variant analysis at 5' and 3' untranslated regions of BRCA2 in thai familial breast and ovarian cancer /". Abstract, 2004. http://mulinet3.li.mahidol.ac.th/thesis/2547/cd364/4436684.pdf.
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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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Coignard, Juliette. "Nouvelles stratégies pour l’étude des facteurs génétiques impliqués dans le cancer du sein familial". Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS426.
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Avoir une apparentée atteinte d’un cancer du sein (CS) multiplie par 2 le risque de développer un CS. Environ 20 % du risque familial de CS est attribué à une mutation fortement pénétrante dans les gènes BRCA1 ou BRCA2. D’autres gènes connus, comme ATM ou TP53, ainsi que des variants génétiques fréquents (SNP) identifiés dans des études pangénomiques (GWAS) réalisées en population générale, expliqueraient 30 % supplémentaires des cas familiaux. La majorité des formes familiales de CS restent donc inexpliquées. Par ailleurs, il existe de fortes variations du risque parmi les porteurs d’une mutation BRCA1/2. Il a été montré que certains SNP identifiés dans les GWAS modifient leur risque. Cependant, l'effet propre de ces SNP n'a pu être estimé puisque ces études ont été réalisées chez les porteurs de mutation BRCA1/2. Dans une première partie de ma thèse, j’ai développé une stratégie intégrant aux analyses sur les facteurs génétiques des facteurs « environnementaux ». Cette stratégie a été utilisées pour analyser les données de l'étude GENESIS qui inclut des paires de sœurs atteintes de CS et sans mutation BRCA1/2 et des témoins de population générale. Elle regroupe 5 000 cas de CS et témoins génotypés pour les 200 000 SNP de la puce iCOGS. Les femmes de GENESIS ont été réparties dans des groupes selon leur profil d’expositions aux radiations ou aux facteurs gynéco-obstétriques. Alors que l’analyse stratifiée sur les groupes construits à partir des expositions aux facteurs gynéco-obstétriques ne nous permet pas de mettre en évidence de potentiels SNPs spécifiques, l’analyse stratifiée sur les groupes construits à partir des expositions aux radiations a permis de mettre en évidence des SNPs spécifiques potentiels aux femmes non exposées, dans les gènes XRCC4 et MAGI1, et à celle fortement exposées aux radiations, dans le gène FGFR2, déjà trouvés en population générale.Le deuxième objectif de ma thèse visait à optimiser la caractérisation des gènes BRCA1/2 en étudiant leurs interactions avec des SNPs modificateurs à partir des données des consortia internationaux CIMBA (Consortium of Investigators of Modifiers of BRCA1/2) et BCAC (Breast Cancer Association Consortium). J’ai développé une stratégie d’analyse GWAS case-only, comparant la fréquence de 60 212 cas de cancer du sein de la population générale (BCAC) et 13,007 cas porteurs d’une mutation BRCA1/2 (CIMBA). J’ai identifié 4 nouvelles régions associés au CS chez les femmes porteuses d’une mutation BRCA1 et 4 autres chez les femmes porteuses d’une mutation BRCA2. Les gènes MADD, SPI1 et EIF1, déjà associées à la biologie du cancer du sein dans d’autres études, ont été prédits par l’outil INQUISIT comme étant des gènes cibles des potentiels variants causaux se trouvant dans la région 11p11.2 associée au statut BRCA1.Ces nouveaux SNPs mis en évidence pourraient être utilisés pour améliorer les prédictions de risque des PRS (Polygénic Risk Score). Les analyses prenant en compte des profils d’exposition devraient être poursuivies sur des études de grande dimension. Les modèles pourraient alors évoluer vers une adaptation des PRS en fonction des profils d’expositions des femmes et cela tout au long de leur vieOne of the most important risk factors for breast cancer (BC) is having a family history of BC. Around 20% of the familial BC risk is explained by rare mutations in the genes BRCA1 and BRCA2 (BRCA1/2). An additional 30% of the risk is accounted for mutations in other known genes, like ATM or TP53, and by common genetic variants, called single nucleotide polymorphism (SNPs), identified in population-based GWAS. Therefore, the majority of the familial forms of BC remains unexplained. Furthermore, there are large variations in the estimation of the BC lifetime risk for BRCA1/2 mutation carriers. It has been shown that some SNPs identified in the general population by GWAS (Genome Wide Association Studies) modified BC risk for BRCA1/2 mutation carriers. Therefore, little is known on how these SNPs interact with BRCA1/2 mutations since association studies have been performed within the population of BRCA1/2 mutation carriers so far.In the first part of this PhD project, I developed a novel strategy to analyze genetic factors by integrating simultaneously environmental and lifestyle factors. This strategy was used to analyze the data of GENESIS study composed of pairs of sisters affected by BC without BRCA1/2 mutation and controls from the general population. 5,000 BC cases and controls were genotyped for the 200,000 SNPs targeted by the iCOGS array. Groups of subjects was created according to their exposition profile reflecting expositions to radiation or reproductive factors. Analyses stratified on groups built according to their reproduction factors exposures did not highlighted specific variants. However, analyses stratified on groups reflecting the chest X—ray exposures showed potential specific SNPs for women who had never been exposed to chest X—ray, in genes XRCC4 and MAGI1, and for women highly exposed to X-ray exposures, in gene FGFR2, already known in the general population.The second aim was to identify and characterize genetic modifiers of BC risk for BRCA1/2 mutation carriers using data from the international consortia CIMBA (Consortium of Investigators of Modifiers of BRCA1/2) and BCAC (Breast Cancer Association Consortium). I developed a case-only GWAS analysis where we compare genotype frequencies between 60,212 unselected BC cases from the BCAC and 13,007 BC cases from CIMBA. We identified 4 novel variants associated with BC for BRCA1 mutation carriers and 4 for BRCA2 mutation carriers at P<10-8. MADD, SPI1 and EIF1 genes, already associated with BC biology, was predicted by the tool INQUISIT, to be target genes of the potential causal variants located in the locus 11p11.2 associated with BRCA1 status.These new SNPs could be used to improve polygenic risk scores (PRS). Studies considering the exposure profile should be implemented in larger population. The models could then evolve towards an adaptation of the PRS according to women’s exposure profiles and that throughout their life
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Gold, Stefan M. "Acute endocrine stress reactivity and recovery in women at familial risk of breast cancer association with perceived stress and depressive symptoms /". [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=968355358.
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Kechik, Joy E. "Comparing Family Sharing Behaviors in BRCA Carriers with PALB2 Carriers". Scholar Commons, 2019. https://scholarcommons.usf.edu/etd/7825.
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Identifying individuals with hereditary cancer predisposition can improve health outcomes for patients and their family members through early cancer detection and prevention strategies. Prior research about family sharing of genetic test results among those with hereditary breast cancer has overwhelmingly been limited to the BRCA1 and BRCA2 genes. The present study sought to compare family sharing behaviors in women with pathogenic BRCA variants to women with pathogenic variants in the more recently identified and characterized PALB2 gene. A total of 18 BRCA carriers and 13 PALB2 carriers were interviewed about family sharing practices using a semi-structured guide based on the Integrated Behavioral Model. Barriers and facilitators to family sharing were similar for both BRCA and PALB2 carriers, with logistical difficulties and emotional struggles related to anticipated negative reactions from relatives being the most salient barriers. The most important facilitators were: attitude that sharing enables health protection, provider recommendation, strong family relationships, confidence in sharing basic information, knowledge of what to share and how to share, and belief that sharing is highly important. Given similar attitudes, norms, and control beliefs related to family sharing, similar, but tailored interventions may be effective at increasing family disclosures among both groups. Such interventions should involve a discussion of patients’ attitudes towards sharing with healthcare providers to strengthen motivations and address barriers and provision of informational resources to increase confidence and knowledge. Family sharing resources should clearly specify which relatives need to be informed, why sharing is important, and how at-risk relatives may benefit.
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Domaison, Sophie. "Étude longitudinale du fonctionnement des familles confrontées au cancer de la mère". Thesis, Toulouse 2, 2012. http://www.theses.fr/2012TOU20135.
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Toute pathologie grave, survenant chez un patient, menace et modifie l’équilibre de son groupe familial. L’objectif de cette étude est d’identifier l’impact du cancer du sein de la mère sur sa famille nucléaire, lorsque des enfants jeunes sont présents, grâce à l’évaluation longitudinale du fonctionnement familial, de la détresse psychologique et des stratégies d’adaptation, au travers du point de vue des différents membres du groupe : la mère malade, le père et l(es)’enfant(s). Méthode : 39 parents (23 mères et 16 pères), ont complété des auto-questionnaires et 22 enfants âgés de 6 à 12 ans, ont participé à des entretiens de recherche à quatre temps d’évaluation : lors de la 1ère (T1), de la 3ème (T2) et de la 5ème (T3) cure de chimiothérapie de la mère, ainsi que deux mois après la fin du traitement par chimiothérapie (T4).Résultats : Le fonctionnement familial perçu par les membres de la famille est typique et stable au cours du temps. Les conjoints perçoivent plus de difficultés au sein de la famille que les patientes et les enfants. L’évolution temporelle des variables met en évidence le T3 comme un moment de répit pour la famille nucléaire. Les niveaux de détresse psychologique exprimés sont non pathologiques, mais évoluent différemment selon la place du sujet dans la famille. Les femmes sont plus en détresse que leurs conjoints et leurs enfants et ont plus recours aux stratégies de coping centrées sur le problème et à la recherche de soutien social. Le niveau de dépression, d’hostilité et le recours aux stratégies de coping centrées sur l’émotion chez les mères expliquent leur perception du fonctionnement familial. A l’inverse, l’état psychologique et le mode d’adaptation des conjoints et des enfants n’influent pas sur leur perception du fonctionnement familial.Conclusion : Ces résultats montrent l’importance de combiner une méthodologie longitudinale qualitative et quantitative, afin de recueillir le point de vue de tous les membres de la famille et ainsi améliorer la compréhension de leur vécu face à la maladie de la mèreAny serious illness occurring in a patient threatens and alters the balance of their family group. The objective of this study is to identify the impact of breast cancer on a mother's nuclear family, when young children are present, with the longitudinal assessment of family functioning, psychological distress and adaptation strategies, through the perspective of different members of the group: the sick mother, the father and child(ren).Method: 39 parents (23 mothers and 16 fathers) of children aged between 6 and 12 completed self-assessment questionnaires as well as 22 children participated in research interviews at four evaluation times: the first (T1), the third (T2) and fifth (T3) of the mother’s chemotherapy, and two months after the end of chemotherapy (T4).Results: Family functioning as perceived by the family’s members is typical and stable over time. Spouses perceive more difficulties within the family than the patients and the children. The temporal evolution of variables highlights the T3 as a respite for the nuclear family. Levels of psychological distress are not pathological, but are different depending on the member’s place in the family. Women are more distressed than their spouses and children, and have more use of coping strategies focused on problem solving and seeking social support. The level of depression, hostility and the use of coping strategies focused on emotion in mothers explain their perception of family functioning. By contrast, the psychological state and the mode of adaptation of spouses and children do not affect their perception of family functioning.Conclusion: These results show the importance of combining qualitative and quantitative longitudinal methodology to analyse the views of all members of the family and improve the understanding of their experiences with the disease of the mother
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Vehmanen, Paula. "Breast cancer-predisposing genes in Finnish breast and ovarian cancer families". Helsinki : University of Helsinki, 2001. http://ethesis.helsinki.fi/julkaisut/mat/bioti/vk/vehmanen/.
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Bailey, A. Kathleen (Ann Kathleen). "Interactional Patterns in Families of Patients with Breast Cancer". Thesis, North Texas State University, 1985. https://digital.library.unt.edu/ark:/67531/metadc330997/.
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This study utilized ethnographic methodology to describe the communicative interactional patterns in families with a member who has breast cancer. Three breast cancer patients whose families were between the adolescent and launching of children developmental lifestage (McGoldrick & Carter, 1982) were chosen for the study. Data were collected from a series of three interview sessions over a period of four weeks with a two week time lapse between each of the interview sessions. Interview sessions were conducted in the families' homes by the researcher. All interviews were video and audio tape recorded for the purpose of preserving data for transcribing and coding. Research questions examined individual perception of meaning in regard to the disease, the structure and organization of the family in relation to the illness, and the effects of family communicative interaction on the course and management of the disease. Findings indicated that family members' responses to the diagnosis of "breast cancer were influenced by multi-generational "beliefs. All three families formulated a collective belief which supported the mother's belief about the disease. Each of the three families were mother-centered, and each mother seemed to use a metacommunicative approach to mediating family transactions. Each of the three fathers were reported as having been isolated and withdrawn within the family at various times. However, each father appeared to play a protective role in deflecting tension and stress away from the mother. All three couples appeared to have constructed an egalitarian relationship with an implicit agreement as to who was more skilled to hold the power within a particular context. In all three families, the generational boundaries were clearly defined. Conflict and affect were most generally expressed in an indirect manner through wit and sarcasm. However, because each of these three families were structured to allow for personal autonomous functioning of each individual member, patients were supported in seeking a modality outside of the family system to express more ambivalent feelings.
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Ford, Deborah. "Genetic epidemiology of breast and ovarian cancer". Thesis, Institute of Cancer Research (University Of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.367527.
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Davis, Sarah Harmon. "Does Family Communication Matter? Exploring Knowledge of Breast Cancer Genetics in Cancer Families". BYU ScholarsArchive, 2018. https://scholarsarchive.byu.edu/etd/7246.
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Purpose: Knowledge of breast cancer genetics is critical for those at increased risk whomust make decisions about breast cancer screening options. The purpose of this study was toexplore cognitive and emotional variables that might influence knowledge of breast cancergenetics.Methods: This descriptive, exploratory study analyzed theory-based relationships amongvariables related to knowledge of breast cancer genetics in cancer families. Participants includedfirst-degree relatives of women with breast cancer who had received genetic counseling andtesting; participants themselves did not have breast cancer and had not received geneticcounseling or testing. Data were collected by telephone interview and survey. Variables analyzedinclude numeracy, health literacy, cancer-related distress, age, education, and the reportedamount of information shared by the participants<'> family members about genetic counseling.Results: The multiple regression model explained 13.9% of variance in knowledge of breastcancer genetics (p = 0.03). Best fit of the multiple regression model included all variables excepteducation. Reported amount of information shared was the only independently significantpredictor variable (p = 0.01).Conclusion: Participants who reported higher levels of information shared by a familymember about genetic counseling also demonstrated increased knowledge about breast cancergenetics.
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Toviessi, Paula. "The family health decision-making model family influence on breast cancer screening adherence /". Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1180551704.
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Yong, JinSun. "Factors influencing family functioning in families with breast cancer in the mother /". Thesis, Connect to this title online; UW restricted, 1997. http://hdl.handle.net/1773/7367.
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Simpson, Margaret Anne. "Family beliefs of women with breast cancer in Hong Kong". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2003. http://hub.hku.hk/bib/B31245900.
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Izatt, Louise Patricia. "Ataxia telangiectasia : mutation detection in ataxia telangiectasia families and early-onset breast cancer cases". Thesis, King's College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.343596.
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Mentoor, J. L. D. (Juliet Lewie Dionee). "Identification of rare gene variants in South African breast cancer families through next generation sequencing". Thesis, University of Pretoria, 2017. http://hdl.handle.net/2263/63043.
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Breast cancer (BC) has become the leading cancer amongst women in South Africa. The
overall life time risk for developing this disease is one in 12 (National Cancer registry, 2000-
2011). A strong family history (≥3 affected) is an important factor for inherited predisposition to
BC that accounts for approximately 10% of cases worldwide. Mutations in several high- and
moderate risk breast cancer genes have been associated with familial BC and includes
BRCA1, BRCA2, TP53, PALB2, and CHEK2. Individuals that carry germline mutations in
BRCA1 and BRCA2 possess an 80% lifetime risk for BC. Mutations in BRCA1 and BRCA2 are
responsible for 29% and 25% of familial BC worldwide. In South Africa BRCA1 mutations
account for 19% and BRCA2 for 47% of familial breast cancer. Mutations associated with a
moderate risk for BC account for ~1% of cases. This data suggests that ~30% of South African
BC families are not characterised by pathogenic mutations in known breast/ovarian (BC/OVC)
genes. The purpose of the present study was to identify gene variants that may predispose to breast
cancer. Next generation sequencing was performed to investigate the germline DNA of highrisk
BC/OVC families that have previously tested negative for premature truncating mutations
in BRCA1/2, PALB2 and RAD51C. Paired-end whole exome sequencing was performed with
nine index cases, selected from six families with a strong background for BC/OVC. This
resulted in the discovery of an average of 26 000 coding variants in index cases. Gene
prioritisation strategies were incorporated to filter all exome variants and identify high-priority
genes for further analysis. After sequence verification, three high-priority genes were selected
for further analysis. The three genes coded for; a novel putative tumour suppressor (TCHP) that is pro-apoptotic;
the XPF-endonuclease homolog, EME2; and a POLQ like helicase enzyme (HELQ). Prioritised
genes were screened in a total of 61 high-risk families and cohorts of patients with BC or OVC
without a family history for their disease. Two potentially damaging variants (stop-gain & inframe
amino acid deletion) were identified in TCHP, four (frameshift, nonsense & two in-frame
deletions) in EME2 and one frameshift mutation in HELQ in high-risk families and cases that
were without a family history for BC/OVC.
The analyses performed in the last section of this project was aimed at identifying other
potential genes of interest by making use of a list of 516 well recognised and putative DNA repair genes. Through this approach, one additional truncating mutation in POLN
(p.Q837SfsX7) was highlighted as a potential gene of interest for future investigation.
Despite the key roles that the high-priority genes play in their respective processes, the
present study could not verify that the potential loss of function variants discovered make an
appreciable contribution towards BC/OVC susceptibility in our setting. Further investigation is
necessary to validate their involvement in breast/ovarian cancer predisposition.Thesis (PhD)--University of Pretoria, 2017.
Genetics
PhD
Unrestricted
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Biffi, Raquel Gabrielli. ""A dinâmica familiar de um grupo de mulheres com câncer de mama"". Universidade de São Paulo, 2003. http://www.teses.usp.br/teses/disponiveis/22/22133/tde-11042005-152406/.
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O diagnóstico do câncer de uma maneira geral, em particular do câncer de mama, tem o potencial de provocar desequilíbrio psicosocial não somente nas pessoas acometidas pela doença, mas também no contexto familiar. Assim, objetivou-se neste estudo identificar as percepções de familiares sobre a dinâmica familiar após o câncer de mama, bem como as diferenças quanto: composição familiar, gênero, idade, nível educacional e ocupação. O estudo seguiu as premissas da pesquisa tipo exploratória-descritiva. Participaram do estudo 23 familiares constituintes de 10 famílias de mulheres com câncer de mama. Utilizou-se como procedimento metodológico para coleta de dados, entrevistas individuais gravadas e transcritas na íntegra. Analisaram-se os dados por meio de análise de conteúdo, buscando identificar unidades temáticas relacionadas às dimensões da dinâmica familiar, conforme descrito por Barnhill. Os resultados revelaram que os familiares independente da idade, nível educacional e ocupação, mostraram aspectos positivos da dinâmica familiar. Quanto ao gênero feminino, este na visão dos maridos e filhos coloca-se em posição de destaque na reorganização da unidade familiar. Os achados mostraram que o câncer de mama em um membro familiar tem a capacidade de provocar alterações na dinâmica familiar; por outro lado, as famílias utilizaram potenciais de cada membro, em particular, na busca da estabilidade familiar.The diagnosis of cancer, in general, and of breast cancer in particular has the potential to cause a psychosocial instability not only in the person with the disease, but also in the family context. Therefore, the author aimed at identifying the perceptions of family members about the family dynamics after breast cancer, as well as the differences regarding: family composition, gender, age, literacy level and occupation. This was an exploratory and descriptive research with 23 family members of 10 families of women with breast cancer. In order to collect data, the author used individual interviews that were recorded and transcribed. Data were analyzed through content analysis, aiming at identifying the thematic units related to the family dynamics as described by Barnhill. The results revealed that the family members, independently of their age, literacy level and occupation, showed positive aspects of the family dynamics. Regarding the feminine gender, this in the view of husband and children was placed in an important position in the reorganization of the family unit. The findings showed that the breast cancer in a family member causes alterations in the family dynamics and, on the other hand, the families use the potentials of each member, in particular, in the search for family stability.
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Schuler, Tammy A. "Marital Quality Affects Biobehavioral Outcomes in Advanced and Recurrent Breast Cancer Patients". The Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1306854906.
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Ginter, Amanda Christine. "The Consequences of Mothers' Breast Cancer Experiences for Their Adult Daughters' Intimate Relationship Decisions: A Phenomenological Approach". Oxford, Ohio : Miami University, 2010. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=miami1271940770.
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Santana, dos santos Elizabeth. "Contribution of the Missense and Non-Coding BRCA1/2 Variants for the Hereditary Predisposition and Response to Treatment of Breast and Ovarian Cancers Assessment of the Functional Impact of Germline BRCA1/2 Variants Located in Non- Coding Regions in Families with Breast and/or Ovarian Cancer Predisposition Non-Coding Variants in BRCA1 and BRCA2 Genes: Potential Impact on Breast and Ovarian Cancer Predisposition". Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASS027.
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Les cancers de l'ovaire et du sein sont définis par les principales voies impliquées dans la tumorigénèse. Dans les cancers héréditaires du sein/ovaire (HBOC), les tumeurs présentant des variants pathogènes (PV) de BRCA1/2 présentent une altération de la réparation de l'ADN par recombinaison homologue (RH). Des années après la découverte des gènes BRCA1/2, les PV ont été uniquement recherchés sur l'ADN constitutionnel. Aujourd’hui, cette information est également recherchée au niveau tumoral car en plus de leur utilité pour améliorer le conseil génétique, elle est aussi impliquée dans le choix thérapeutique. Cependant, les données recueillies indiquent que les PV inactivant la protéine ne seraient pas l’unique mécanisme d’inactivation de la voie de réparation de l’ADN par RH. Dans ce contexte, l'objectif principal de cette thèse est d'identifier des mécanismes alternatifs d'inactivation de la voie HR pour améliorer à la fois: le conseil génétique et la prise en charge thérapeutique. À cette fin, nous avons tenté de contribuer à la classification de variants non-codants et faux-sens (autre que provoquant un stop prématuré) de BRCA1/2 et également recherché de nouveaux biomarqueurs de réponse thérapeutique dans d’autres gènes de la voie de HR.Nous avons décrit des variants constitutionnels dans des régions potentiellement importantes de régulation des gènes BRCA1 et BRCA2, et démontré qu'une partie d'entre eux étaient fonctionnellement actifs à mettre en lien avec la pathogénicité. Nous avons également exploré les caractéristiques moléculaires des tumeurs du sein et de l'ovaire des porteurs des variants BRCA1 et observé une prédominance de la perte de l'allèle sauvage pour les tumeurs des porteurs de variants pathogènes. Etant donné ces résultats, nous proposons d’intégrer les informations de LOH dans le modèle multifactoriel de classification des variants BRCA1. Enfin, nous avons mis en évidence des mécanismes alternatifs d'inactivation de la voie RH, dans une cohorte de patientes avec un cancer de l'ovaire présentant une excellente réponse aux platines, y compris des mutations constitutionnelles et somatiques des gènes BRCA1/2, l'hyperméthylation du promoteur BRCA1 ainsi que des mutations dans d'autres gènes de la voie RHOvarian and breast cancers are currently defined by the main pathways involved in the tumorigenesis. In hereditary breast/ovarian cancers (HBOC), tumors with BRCA1/2 pathogenic variants (PV) present an impairment of DNA repair by homologous recombination (HR). For many years, BRCA1/2 PV were only searched on germline DNA. Currently, this information is also searched at tumor level to personalize treatment. Even so, the reason of the inactivation of this pathway remains uncertain for most cases, even in the presence of HR deficient signature.Gathered evidence indicates that protein inactivating PV may not be the only mechanism of HR dysfunction. In this context, the main objective of this thesis is to identify alternative mechanisms of HR inactivation to improve both: genetic counseling and therapeutic response. For this purpose, we have attempted to contribute to non-coding and missense (other than premature stop codon) BRCA1/2 variant classification and searched for new biomarkers of therapeutic response to DNA damage agents in other HR genes.We identified germline variants in key transcriptional regulatory elements of BRCA1 and BRCA2, and demonstrated that part of them were functionally active and had additional arguments suggesting pathogenicity. We also explored molecular features of breast and ovarian tumors from BRCA1 variant carriers and observed a predominance of loss of the wild-type allele. Conforming to this evidence, we propose to incorporate LOH information, into the multifactorial model for BRCA1 variant classification. Finally, besides the enrichment of BRCA1/2 germline and somatic PV, we described alternative mechanisms of HR inactivation in a OC population presenting optimal response to platinum-based chemotherapy, including BRCA1 promoter hypermethylation and also mutations in other genes of HR pathway
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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 BRCA2Germline 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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Imada, Teresa Cristina Martins Leite. "Adaptação transcultural e validação da Family Dynamics Measure II (FDM II) para familiares de mulheres portadoras de câncer de mama no Brasil". Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/22/22133/tde-03092008-115235/.
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O câncer de mama é uma doença que mobiliza o sistema familiar da mulher que o apresenta, e a forma como os familiares ajustam-se à doença tem efeito sobre o processo de enfrentamento da mulher. Conhecer a dinâmica familiar e identificar aspectos da interação entre os membros da família que ficam comprometidos com o surgimento da doença e que prejudicam o ajustamento e a qualidade de vida das mulheres e seus familiares é uma das etapas iniciais para se desenvolver serviços adequados à população em foco. A utilização de instrumentos de avaliação do funcionamento familiar, adequadamente construídos e validados, é uma estratégia que tem se mostrado como de grande relevância. No Brasil, não foram encontrados instrumentos que atendessem a esse fim. Portanto, optou-se pela adaptação transcultural e validação de um instrumento norte-americano de avaliação familiar, o que consistiu no objetivo desse estudo. O instrumento escolhido foi a Family Dynamics Measure II (FDM II), uma escala composta por 66 itens construída por um grupo de enfermeiras com base na teoria do sistema familiar saudável de Barnhill. O processo de adaptação do instrumento envolveu a tradução, a retro-tradução, a verificação da equivalência da versão retro-traduzida pela autora principal da escala, a análise semântica e duas análises da validade de face e de conteúdo por juízes. Para o teste das propriedades psicométricas do instrumento, foram realizadas análises de construto por meio da análise fatorial e por meio da validade convergente com a Escala de Ansiedade e Depressão Hospitalar (HADS), e a análise da fidedignidade por meio do cálculo da consistência interna dos itens (alfa de Cronbach). A versão adaptada da FDM II, a HADS e uma ficha de identificação sócio-demográfica foram aplicadas a uma amostra de 251 familiares de mulheres portadoras de câncer de mama, atendidas em dois serviços de saúde do interior do estado de São Paulo. O produto da análise semântica e da validade de face e de conteúdo por juízes resultou em uma versão da FDM II em português adaptada para uso no Brasil. A análise fatorial mostrou que a versão adaptada não confirmou a dimensionalidade teórica do instrumento. Porém, foi semelhante à obtida pelas autoras na análise fatorial do instrumento original. Na análise da validade convergente da FDM II com a HADS, as correlações entre as medidas de ansiedade e depressão e as medidas das dimensões da FDM II foram inversas de moderada a baixa intensidade. E na análise da fidedignidade, a consistência interna dos itens foi muito boa (α = 0,90), apesar dos coeficientes por dimensão serem mais baixos. Concluindo, a versão adaptada da FDM II foi considerada válida, e sugerem-se novos estudos para fortalecer essa evidência.Breast cancer is a disease that affects the woman\'s family and, the way the family faces the disease affects the woman coping process. Knowing the family dynamics and identifying interaction aspects among the relatives affected by the disease, and that may damage the coping process and life quality of the woman and her family, is an initial stage to develop adequate services for the focused population. The use of well constructed and reliable tools to assess the family dynamics is a relevant strategy. Tools of that kind, to achieve such results, were not available in Brazil. Therefore, the cross-cultural adaptation and validation of a north-American instrument for family assessment was chosen to supply this need and became the purpose of this study. The chosen scale was the Family Dynamics Measure II (FDM II), a 66 items questionnaire, built by a group of nurses and based on Barnhill\'s healthy family system. The adaptation process involved the translation, back-translation, assessment of the equivalence between the original and the back-translated version by the main scale\'s author, a semantic analysis and two face and content validity assessments by judges. For the psychometric properties tests of the instrument, analysis of the construct were carried out by means of factor analysis and convergent validity towards Hospital Anxiety and Depression Scale (HADS); and reliability analysis, through items internal consistency calculation (Cronbach\'s alpha). The FDM II adapted version, HADS, and a socio-demographic identification form were submitted to a sample with 251 breast cancer women\'s relatives, in treatment at two health services facilities in Sao Paulo state. The product of the semantic and the face and content validity analysis resulted in a version of the FDM II in Portuguese adapted for use in Brazil. Factor analysis showed that the adapted version did not confirm the theoretical dimensionality. However, it was like to those obtained by the authors at the factor analysis on the original instrument. At the convergent validity analysis on FDM II and HADS, the correlation between anxiety and depression measurements and the FDM II dimensions measurements were inverted, from moderate to low intensity. At the reliability analysis, the items internal consistency were very good (α = 0,90), despite the low coefficients by dimension. The conclusion is that the FDM II adapted version was considered valid and new studies to strengthen this evidence are suggested.
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Sánchez-Cid, Pérez Lourdes. "Análisis de los perfiles de expresión de microRNAs en cáncer de mama y de la implicación de la familia miR-200 en metástasis". Doctoral thesis, Universitat de Barcelona, 2017. http://hdl.handle.net/10803/402827.
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Esta tesis consiste en el estudio de la regulación por microRNAs del proceso de metástasis de carcinomas ductales invasivos de mama. Hemos encontrado una expresión alterada de varios microRNAs en muestras tumorales, incluyendo las familia miR-200 y miR-181, miR-210, miR-101 y miR-10b, a lo largo de la progresión desde tumores primarios a metástasis regionales y a distancia. miR-7, miR-30, miR-148 y miembros de la familia let-7 se encontraron diferencialmente expresados entre tumores primarios no metastáticos vs primarios metastáticos a ganglios linfáticos. Además, los miembros del cluster 1 de la familia miR-200 se econtraban sobreexpresados en las metástasis ganglionares, las cuales mantenían o tenían una expresión más elevada de E-cadherina respecto de sus correspondientes tumores primarios. Adicionalmente y de acuerdo con la tendencia observada en los tejidos tumorales, observamos niveles elevados de miR-200b y miR-7 en la sangre de pacientes con metástasis regional o a distancia en comparación con pacientes con tumores primarios no metastáticos en el momento del diagnóstico.
Centrándonos en la significación biológica de la mayor expresión de los miembros de la familia miR-200 en asociación con la progresión metastática, utilizamos el modelo celular MCF10CA1h para inducir la expresión de miR-200. Observamos que miR-200 promovía una transición mesénquima-epitelio que conllevaba la inducción de un marcado programa epitelial. Éste era acompañado de un fuerte incremento de la actividad aldehido deshidrogenasa (ALDH), mayor capacidad de crecimiento en mamoesferas y la transición de un immunofenotipo CD44+ CD24- a CD44+ CD24+, lo cual era indicativo de la adquisición de características de progenitor luminal por parte de células que expresaban miR-200. Además, las células MCF10CA1h que expresaban miR-200 desarrollaron la capacidad de diferenciarse y organizarse en estructuras tubuloalveolares ramificadas similares a las de la mama normal. Se observó además una mayor capacidad de crecimiento tumoral y de colonización metastática in vivo. Además de la expresión de marcadores epiteliales, la expresión de miR-200 resultó en la inducción de la expresión de marcadores basales y de diferenciación luminal in vitro y de forma más prominente in vivo. Todo ello refueza la idea de que miR-200 induce características de progenitor luminal así como de agresividad en células tumorales mamarias. A nivel mecanístico encontramos que la mayor capacidad de autorrenovación promovida por miR-200 era debida en parte a la inhibición de su ya conocidad diana ZEB2 así como de una activación de la ruta de señalización PI3K-AKT.
Finalmente, la morfología de los tumores formados in vivo por células que expresaban miR-200 recordaba a la de los carcinomas metaplásicos mamarios, por lo que decidimos estudiarlos. De hecho, observamos que el componente epitelial de tumores metaplásicos expresaban niveles significativamente superiores de miR-200 que el componente mesenquimal y además, mostraban un perfil de marcadores compatible con el de células luminales progenitoras.
En vista de los resultados, proponemos que los microRNAs de la familia miR-200 inducen características de células progenitoras luminales, las cuales asociadas a un fenotipo epitelial, promueven la capacidad metastática de las células tumorales.The maintenance of an epithelial gene program is essential for the metastatic growth of epithelial cancers, including breast cancer. However, little is known of the molecular and cellular mechanisms leading to the enhanced proliferative and survival properties of metastatic epithelial cells. We report here that forced expression of miR-200s in MCF10CA1h mammary cells induced not only a strong epithelial program but also aldehyde dehydrogenase (ALDH) activity, mammosphere growth and ability to form branched tubuloalveolar structures while promoting orthotopic tumor growth and lung colonization in vivo. This was accompanied with the expression of luminal differentiation markers in vitro and in vivo, the overall phenotype being compatible with a promotion of luminal progenitor traits. Interestingly, the morphology of tumors formed in vivo by MCF10CA1h cells expressing miR-200s was reminiscent of metaplastic breast cancer (MBC) and the epithelial components of MBC samples expressed significantly higher levels of miR-200s than their mesenchymal components and displayed a marker profile compatible with luminal progenitor cells. Additionally, the miR-200 family showed enhanced expression along progression of invasive ductal breast cancer (IDC) from primary tumors to distant metastases, further reflected in higher blood levels of miR-200b in patients with regional or distant metastases relative to patients with primary node-negative tumors. We propose that the expression of epithelial gene programs through miR-200 family microRNAs promote traits of highly proliferative mammary luminal progenitor cells, thereby exacerbating the growth and metastatic properties of transformed mammary epithelial cells.
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López, Nicolás Rubén. "Estudio de la función de la familia de Proteínas Quinasas C en el cáncer de mama". Doctoral thesis, Universidad de Murcia, 2011. http://hdl.handle.net/10803/28234.
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En esta Tesis Doctoral se ha estudiado el efecto de una serie de ácidos grasos como el araquidónico, docosahexaenoico, eicosapentaenoico y oleico, así como un conjunto de derivados de DAG-lactonas en la activación de diferentes isoenzimas de PKC. El sistema modelo de estudio utilizado han sido diferentes líneas celulares de cáncer de mama (BT-474, MCF-7 y MDA-MB-231). Mediante técnicas de biología molecular y celular, microscopía confocal, ARN de interferencia y microarrays de expresión diferencial de genes se ha estudiado la función de la PKCalpha en la capacidad proliferativa, invasiva y de migración de las células modelo de cáncer de mama, revelando nuevos mecanismos moleculares por los que la PKCalpha se localiza en la membrana plasmática y se activa en dichas células. También se pone de manifiesto el efecto antiproliferativo e inductor de apoptosis de los diversos ácidos grasos estudiados, así como la implicación directa de la PKCalpha en la capacidad proliferativa, migr
atoria e invasiva de dichas célulasIn this Doctoral Thesis, the role of several fatty acids like arachidonic, docosahexaenoic, eicosapentaenoic and oleic, as well as some DAG-lactones derivatives, on the activation of different PKC isoforms has been studied. Some breast cancer cell lines, specifically BT-474, MCF-7 and MDA-MB-231, have been used as a model. The role of PKC in proliferation, invasion and migration has been studied by means of cellular and molecular techniques, confocal microscopy, siRNA and gene expression microarrays. The results obtained reveal new molecular mechanisms of PKCalpha; localization and activation in breast cancer cell lines. It is also interesting the anti-proliferative and pro-apoptosis role of several fatty acids tested, as well as the direct involvement of PKCalpha; in proliferation, migration and invasion of breast cancer cells
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Clark, Cammi. "When Bad Genes Ruin a Perfectly Good Outlook: Psychological Implications of Hereditary Breast and Ovarian Cancer via Narrative Inquiry Methodology". Antioch University / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=antioch1565254126257837.
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Crafford, Johannes Daniel. "Die groei van hoop na mastektomie 'n narratiewe, pastoraal-gesinsterapeutiese studie /". Thesis, Pretoria : [s.n.], 2003. http://upetd.up.ac.za/thesis/available/etd-06242004-110440/.
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Fernandes, Simone Batista de Abreu. "Diagnóstico de um grupo de familiares em risco para o câncer de mama: contribuição para a assistência de enfermagem". Universidade do Estado do Rio de Janeiro, 2012. http://www.bdtd.uerj.br/tde_busca/arquivo.php?codArquivo=3733.
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Devido a sua alta incidência, mortalidade e custos elevados, o câncer de mama feminino é considerado um problema de saúde pública no Brasil. Sua etiologia envolve uma interação de diversos fatores denominados de risco os quais podem ser ambientais e genéticos. A história familiar positiva para câncer de mama é um importante fator de risco para o desenvolvimento dessa patologia. Conhecer esses fatores e as medidas de proteção permite que mulheres com risco elevado possam criar estratégias pessoais que venham minimizar os danos causados pela doença. Diante do exposto, o presente estudo tem como objetivos avaliar o nível de conhecimento de mulheres acerca do risco de desenvolverem câncer de mama em decorrência do vínculo familiar com a população portadora desta neoplasia matriculada no Hospital do Câncer III, unidade do Instituto Nacional de Câncer (INCA) especializada no tratamento e controle do câncer de mama, localizada no município do Rio de Janeiro, Brasil; descrever as características sociodemográficas das mulheres familiares de pacientes portadoras de câncer de mama e descrever a história reprodutiva e hormonal, bem como seus hábitos de cuidado com a saúde. Metodologia: trata-se de um estudo exploratório sob a perspectiva quantitativa, transversal e descritiva com 52 mulheres que acompanhavam suas familiares internadas em unidade clínica e cirúrgica do Hospital do Câncer III. A coleta de dados ocorreu no período entre julho e agosto de 2011. A técnica de amostragem adotada foi a não probabilística, intencional Para o cálculo amostral aplicou-se a fórmula de população infinita. Foram selecionadas as seguintes variáveis para compor o estudo: aspectos sociodemográficos, aspectos da vida reprodutiva e hormonal, aspectos de cuidados com a saúde e aspectos de esclarecimento relacionados à patologia/doença. Realizou-se entrevista estruturada com utilização de um formulário composto por 63 questões. A descrição das variáveis foi feita através de frequência simples e porcentagem. Resultados: 61,5% eram filhas, 34,6% eram irmãs e 3,8% eram mães, 40,4% moram no município do Rio de Janeiro, 86,4% encontram-se na faixa etária entre 29 e acima de 51 anos de idade, 32% são pardas, 46,1% apresentavam 2 grau completo, 46,2% são do lar, 15,4% tiveram menarca precoce, 7,7 % tiveram na menopausa tardia, 7,7% fizeram Terapia de Reposição Hormonal, 38,5% nunca engravidaram, 3,8% engravidaram após 30 anos, 3,8% não amamentaram, 42,4% usam anticoncepcional hormonal por mais de 5 anos e 40,4% nunca fizeram descanso ou faz por tempo inferior a 6 meses, 7,7% e 7,6% nunca fizeram e apresenta mais de 24 meses que fizeram exame ginecológico. Quanto ao grau de esclarecimento 34% concordaram com as afirmativas sobre fatores de risco, 65% concordaram com medidas preventivas e os profissionais de saúde foram os que mais transmitiram informação sobre o câncer de mama. Conclusão: ser familiar de primeiro grau associado à falta de esclarecimento sobre a doença torna essas mulheres mais vulneráveis em relação à população geral feminina. Torna-se oportuno para a enfermagem estratégias educativas que visem à promoção da saúde e que contribuam para a modificação do panorama da doença, em razão da detecção mais precoce.Due to the incidence, mortality and high costs, female breast cancer is considered a Health Care issue in Brazil. Its etiology binds an interaction of various risk factors which can be environmental and genetic ones. A positive family history for breast cancer is an important risk factor for the development of this pathology. Knowing the factors and protection measures allow the women with high risk create personal strategies that minimize the damage caused by the disease. Objectives: evaluate the level of knowledge of the women regarding the risk of breast cancer development related to family history with population which carries this neoplasia assisted by the Hospital do Câncer III, Cancer National Institute (INCA) branch specialized on breast cancer treatment and control, located at the city of Rio de Janeiro, Brazil; describe the social demographical characters of the women whose relatives are breast cancer patients and report their hormonal and reproductive history as well as their health care habits. Methodology: It consists of an exploratory study under a quantitative perspective in a descriptive and transversal way with 52 women that accompanied their hospitalized relatives in a clinic and surgery unity of Hospital do Câncer III. The data collection was performed between July and August 2011. The sampling technique adopted was intentionally the non-probabilistic. The applied sample size calculation was infinite population. The selected variables to compose the study were the following: social demographical aspects, reproductive and hormonal life aspects, health care aspects and awareness concerning the pathology/disease. The structured interview counted with a form of 63 questions. Results: 61,5% were daughters 34,6% were sisters and 3,8% were mothers, 40,4% lived in the city of Rio de Janeiro, 86,4% were between 29 and 51 years old, 32% were yellow, 46,1% finished high school, 46,2% were housewives, 15,4% had premature menarche, 7,7 % had late menopause, 7,7% adopted Hormone Replacement Therapy (HRT), 38,5% never got pregnant 3,8% got pregnant after 30 years old, 3,8% did not breastfeed, 42,4% took hormonal contraceptive for more than 5 years and 40,4% never stopped taking hormone contraceptive or stopped for period under 6 months, 7,7% and 7,6% never stopped taking hormone contraceptive and had more than 24 months from their last gynecological exam. Regarding the degree of awareness 34% agreed with the risk factor affirmatives, 65% agreed with preventive measures and the health professionals were the main source of information about breast cancer. Conclusion: first-degree relative associated with lack of knowledge put the women more vulnerable in relation to general feminine population. Here resides the chance for nursery assistance educational strategies which achieve health promotion and contribute for a disease changing panorama caused by early detection.
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Rieger, Michael A. "CYP4Z1 und CYP4Z2P: Identifizierung neuer Mitglieder der humanen Cytochrom P450 Familie mit präferentieller Expression in Brustdrüsengewebe und Mammakarzinom". Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2004. http://nbn-resolving.de/urn:nbn:de:swb:14-1093525824984-91466.
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Bei der adjuvanten Immuntherapie soll das Immunsystem von Tumorpatienten gezielt gegen Mikrometastasen aktiviert werden, die nach der operativen Entfernung des Primärtumors im Körper verbleiben. Tumor-assoziierte Antigene (TAA) spielen dabei die zentrale Rolle. Um der Heterogenität eines Tumors in der Expression einzelner TAAs Rechnung zu tragen, werden in modernen Vakzinierungsstrategien Pools von verschiedenen TAAs eingesetzt. Für das Mammakarzinom sind aber bislang nur wenige TAAs bekannt. Auf der Suche nach unbekannten Genen mit Mamma- bzw. Mammakarzinom-restringierter Expression in der Transkriptomdatenbank GeneExpress® wurde ein EST gefunden, das nur in 2 % der getesteten weibl. Normalgewebe ohne Mamma mit einer marginalen mittleren Expression von 16 FE (Fluoreszenzeinheit) detektiert wurde, aber in 63 % der Mammanormalgewebe (159 FE) und in 61 % der Mammakarzinome (339 FE) exprimiert wurde. Das korrespondierende UniGene-Cluster gab erste Hinweise auf die Zugehörigkeit dieses neuen Gens zu der Cytochrom P450 (CYP) Familie. Durch computergestützte Homologievergleiche mit verwandten Mitgliedern dieser Familie in Kombination mit RT-PCR konnte die cDNA-Sequenz dieses neuen CYP ermittelt werden: Durch Amplifikation der Gesamtlängen-cDNA wurden drei Transkripte in der Mammakarzinomzelllinie SK-BR-3 gefunden, die von zwei neuen CYP Genen stammen, CYP4Z1 und dem Pseudogen CYP4Z2P. Die cDNA von CYP4Z1 kodiert für ein 505 As großes Protein, das aufgrund von Homologien einer neuen Subfamilie innerhalb der CYP4 Familie zugeordnet werden kann. Sowohl die Sequenz als auch die vorhergesagte Sekundärstruktur zeigen alle charakteristischen Merkmale eines funktionellen Mitglieds dieser Familie. Aufgrund einer Nonsensemutation in Exon 8 kodiert die cDNA von CYP4Z2P (1436 bp) für ein verkürztes, nichtfunktionelles P450 von 340 As, das zu 96% identisch mit P450 4Z1 ist. Außerdem wurde in SK-BR-3 eine Spleißvariante von CYP4Z1 identifiziert. CYP4Z1 (50,8 kb) und CYP4Z2P (57,3 kb) liegen auf Chromosom 1p33-p34.1 und bestehen aus 12 Exons mit konservierten Exon-Intron-Grenzen. CYP4Z2P ist aus einer inversen Duplikation von CYP4Z1 hervorgegangen. Mittels Realtime RT-PCR mit cDNA von 17 Normalgeweben von gepoolten Spendern und von Mammakarzinomen konnte die auf Brustdrüsengewebe restringierte Expression beider Gene demonstriert werden: Die Expression von CYP4Z1 war in Mammakarzinomgewebe 3,6-mal höher als in Mammanormalgewebe, 60-mal höher als in Lunge und 84-mal höher als in Leber. Alle anderen getesteten weibl. Normalgewebe zeigten eine noch geringere Expression. Ein ähnlich stringentes Expressionsprofil ergab die Analyse von CYP4Z2P, allerdings mit einer deutlich niedrigeren Expressionsstärke. Das Mamma-restringierte Expressionsverhalten von CYP4Z1 wurde durch einen ?Cancer-Profiling-Array? (241 Tumor-/Normalgewebepaare von 13 Gewebetypen) bestätigt. Damit konnte gezeigt werden, dass CYP4Z1 bei 52 % der getesteten 50 Brustkrebspatientinnen im Tumor versus peritumoralem Normalgewebe überexprimiert war. Mit einem spezifischen Kaninchen-Antiserum konnte die Expression von P450 4Z1 Protein sowohl in CYP4Z1-transduzierten Zelllinien als auch in Mammagewebeproben mittels Western-Blot nachgewiesen werden. Konfokale Laser-Scanning Mikroskopie von MCF-7 Zellen, die das Fusionsprotein CYP4Z1-EGFP exprimierten, und die subzelluläre Fraktionierung der CYP4Z1-Transduktanten zeigten P450 4Z1 als integrales Membranprotein des endoplasmatischen Retikulums (ER). Für die Lokalisation und die Zurückhaltung im ER ohne Recycling aus dem Prä-Golgiapparat sind die ersten 32 As erforderlich, was Studien mit unterschiedlichen Deletionsmutanten aus der N-terminalen Sequenz von 4Z1 zeigten. Die Entdeckung eines neuen Mamma-spezifisch exprimierten P450 Enzyms eröffnet neue Möglichkeiten sowohl in Hinsicht auf eine Immuntherapie von Brustkrebs als auch für die Entwicklung neuer Chemotherapeutika, die spezifisch durch P450 4Z1 am Tumorort umgesetzt werden können.
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Viale-Garrone, Audrey. "Période de la ménopause, état de santé orale et facteurs systémiques". Thesis, Aix-Marseille, 2014. http://www.theses.fr/2014AIXM5028/document.
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Dans le cadre d'une étude transversale menée sur 202 patientes ménopausées et non ménopausées,les objectifs sont de démontrer l'existence d'un lien entre ménopause et altération de l'état de santé buccodentaire. D'évaluer l'action du THM sur la morbidité dentaire et «in fine» sur la mortalité dentaire.De préciser les liens entre santé bucco-dentaire et diverses pathologies générales et d'apprécier les liens entre psychisme et soma chez les femmes ménopausées. D'apprécier l'influence des biphosphonates sur l'état de santé parodontal.De placer l'étude des liens état bucco-dentaire- ménopause dans une optique sociétale et anthropologique.La ménopause a pour conséquence une altération du parodonte (p=0,003).Le THM a une action bénéfique sur le parodonte.L'effet biologique du diabète est drastique quant à la perte des organes dentaires (p=0,050).L'étude souligne l'influence «per se» d'un mauvais état bucco-dentaire pour la pathologie coronarienne (OR=1,214). De plus,évènements stressants,sècheresse buccale,pathologies ostéo articulaires,carence hormonale sont des facteurs diversement liés de la mortalité dentaire durant cette période. Par ailleurs, il est apparu que les femmes ayant été récemment traitées pour un cancer du sein développaient plus de caries dentaires (p=0,031 OR=2,161). L'étude met en évidence les effets des biphosphonates sur l'altération du parodonte (p=0,011) malgré la prise d'un THM (p=0,020).Un milieu socioculturel aisé contribueraient à la médicalisation du phénomène physiologique.Le fait de vivre seule influerait sur la perte des organes dentaires (p=0,035). Enfin,la pratique régulière d'un sport améliorerait l'état de santé orale (p=0,036)In a cross-sectional study of 202 postmenopausal and premenopausal women,the objectives of this study are to demonstrate a link between menopause and altered state of oral health.To evaluate the action of HRT on dental disease and finally on the tooth mortality. To assess and clarify the relationship between oral health and various general diseases and links between psyche and soma in postmenopausal women.Also discussed was the influence of bisphosphonates on the state of periodontal health.Finally,it was decided to place the study links oral menopausal status in a social and anthropological perspective.It appears then that menopause results in an altered state of oral health,(p = 0.003).HRT has a beneficial effect on the periodontal disease.The biological effects of diabetes are related to dental mortality (p = 0.050). This study emphasize the influence "per se" a bad oral health status for coronary artery disease (OR = 1.214).In postmenopausal women, stressful events, dry mouth, joint and bone diseases, hormonal deficiency are factors variously related dental mortality during this period. Moreover, it was found that women who have recently been treated for breast cancer developed more dental caries (p = 0.031 OR = 2.161).The study related the effects of bisphosphonates on the alteration of periodontal (p = 0.011), despite taking HRT (p = 0.020).In addition,background socio-economic favored contribute to the medicalization of physiological phenomenon. The fact of living alone would affect the loss of dental organs (p = 0.035). Finally, the regular practice of a sport improve the state of oral health (p = 0.036)
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Bosch, Gutiérrez Almudena. "Role of Ring1B in ephitelial to mesenchimal transition, invasion and migration of mammary epithelial cells". Doctoral thesis, Universitat Pompeu Fabra, 2009. http://hdl.handle.net/10803/7230.
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The Polycomb group (PcG) family of proteins form chromatin-modifying complexes essential for embryonic development, and stem cell renewal and are commonly deregulated in cancer. There are several reports that address the possible implication of PcG proteins in tumor progression and metastasis, but very little is known about the specific role of these proteins in tumor progression and invasion. On the other hand, the molecular processes of the worst cancer prognosis, metastasis, which leads to an incurable disease, are yet incompletely elucidated. Here we show a role for Ring1B, a PcG protein, in three processes related to metastasis: in the Epithelial-mesenchymal transition (EMT), a critical morphogenic event that occurs during embryonic development and during the progression of various epithelial tumors, an in the migration and the invasion of mammary epithelial cells.Las proteínas del grupo Polycomb (PcG) forman complejos modificadores de la cromatina esenciales en el desarrollo embrionario y en la renovación de las células madre, y su desregulación ha sido asociada al cáncer. Varios estudios muestran la posible implicación de las proteínas de PcG en la progresión tumoral y en la metástasis, pero a pesar de ello se sabe muy poco de los procesos moleculares en los que estas proteínas están participando. Por otro lado, los procesos moleculares responsables del peor pronóstico en cáncer, la metástasis, que continua siendo una enfermedad incurable, siguen sin estar completamente elucidados. En esta disertación mostramos el papel de Ring1B, una proteína del PcG, en tres procesos implicados en la metástasis: en la transición epitelio-mesénquima (EMT), un proceso morfogénico crítico en el desarrollo embrionario y durante la progresión de varios cánceres epiteliales, y en la migración y la invasión de las células epiteliales mamarias.
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Lourenço, Rita Adubeiro. "Functional Characterization of Variants of Unknown Significance in Familial Breast Cancer". Master's thesis, 2018. http://hdl.handle.net/10362/56683.
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Familial breast cancer (BC) cases account for 5-10 % of all BC cases and are mainly associated with inherited mutations in BRCA1 and BRCA2 genes. Many other genes related with BC development have already been identified and are mostly related with Homologous Recombination (HR) repair system, one of the main pathways that repair DNA double-strand breaks (DSBs). Genetic testing for BC has become standard and with more widespread genetic testing, an increased detection of variants of unknown significance (VUS) as either benign or pathogenic will occur. Functional analyses on VUS may identify pathogenicity, and clearly categorize their mutational status. We carried-out a proof-of concept in vitro functional analysis in peripheral blood lymphocytes of VUS-harboring individuals and controls assessing the cellular response to -radiation. Six samples were collected, two BC patient with a pathogenic ATM mutation, two BRCA1 VUS carriers, and two controls. Several methodologies were selected to evaluate the cellular response to genetic lesions induced by -radiation (2Gy): chromosomal aberrations (CA), micronuclei (MN) and comet assay. The CA assay results present no statistical difference between samples. In the MN assay the carriers show lower amount of binucleated cells with MN when compared to control samples, which is possibly due to cellular death events. The comet assay results show a clear increase in sensitivity to ionizing radiation, possibly associated with deficiency in repair, of samples from carrying a pathogenic mutation in the ATM gene and those with the BRCA1 VUS. Overall, except for the CA assay, the results show an increased susceptibility to ionizing radiation in pathogenic ATM mutation carriers and BRCA1 VUS carriers. However, some additional studies should be performed to completely understand the results obtained, and the impact of alterations in cancer risk.