Dissertation (Ph.D.)--University of South Florida, 2008. / Title from PDF of title page. Document formatted into pages; contains 111 pages. Includes vita. Includes bibliographical references.

Base Teórica: O câncer de mama é provavelmente o mais temido pelas mulheres devido a sua alta freqüência e, sobretudo, pelos seus efeitos psicológicos que afetam a percepção da sexualidade e a própria imagem pessoal. Ele é relativamente raro antes dos 35 anos de idade, mas acima desta faixa etária sua incidência cresce rápida e progressivamente. Estudos indicam que fatores genéticos e ambientais são responsáveis pela incidência do câncer de mama, sendo que a hereditariedade provavelmente tenha participação restrita no desenvolvimento deste tipo de tumor. Os principais genes associados ao desenvolvimento do câncer de mama, BRCA1 e BRCA2, são responsáveis por cerca de 80% desses casos, conferindo um risco de 71 a 85% de chance de desenvolver a neoplasia em alguma fase da vida. Mutações nesses genes, classificados como supressores tumorais, demonstram que a perda de suas funções não pára o ciclo celular, não permite a ação do sistema de reparo, e não estimula a apoptose (morte celular programada), culminando em replicação anormal e câncer. A observação epidemiológica de que mulheres judias de origem Ashkenazi parecem ser mais vulneráveis ao câncer de mama está sendo explicada através de estudos moleculares dos genes BRCA1 e BRCA2, onde encontramos a prevalência de três mutações específicas: 185delAG e 5382insC, no gene BRCA1 e 6174delT, no gene BRCA2. Métodos: Utilizou-se um banco de DNA pré-existente, extraído de 209 mulheres da comunidade judaica Ashkenazi da cidade de Porto Alegre. A amplificação do DNA foi realizada por PCR, através da técnica PSM (PCR Mediated site-direct) seguida de digestão dos produtos de PCR com enzimas de restrição. Os objetivos foram verificar se as freqüências das mutações 185delAG e 5382insC, no gene BRCA1 são significativas nesta população e compará-las com demais freqüências encontradas. Resultados: Foram encontradas três pacientes com a mutação 185delAG e duas pacientes com a mutação 5382insC, com as freqüências de 1,435% (95% IC: 0,366; 3,856) e 0,957% (95% IC: 0,161; 3,125), respectivamente. / Introduction: Breast cancer is probably the worst diagnosed cancer for women due to its high frequency and furthermore by its psychological problems that affect the perception of sexuality and the self image. It is relatively rare before 35 years of age, but beyond this age its incidence increases rapidly and progressively. Studies show that genetic and environmental factors are responsible for breast cancer incidence, but heredity may play a restrict role in the development of this kind of tumor. The main genes associated to the development of breast cancer, BRCA1 and BRCA2, are responsible for almost 80% of these cases, reaching a chance between 71 and 85% of developing the disease at any life stage. Mutations in these genes, classified as tumor suppressors, do not allow the repair mechanisms of DNA to perform its action and do not stimulate apoptosis, culminating in abnormal replication and cancer. The epidemiological observation in which Ashkenazi Jewish women seems to be more vulnerable to breast cancer is explained through molecular studies of BRCA1 and BRCA2 genes, where three specific mutations have been found (185delAG and 5382insC, in the BRCA1 gene and 6174delT, in the BRCA2 gene). Methods: A pre-existent bank of DNA extracted from 209 women of the Ashkenazi Jewish community of Porto Alegre city has been used. The DNA amplification was performed through PCR, using the PSM (PCR Mediated Site-Direct) technique followed by the digestion of PCR products with restriction enzymes. The objectives of this study was to identify the frequencies of mutations 185delAG and 5382insC at the BRCA1 gene and verify if they are significantly different in this population when compared to frequencies found in other studies. Results: We found three patients with 185delAG mutation and two patients with 5382insC mutation, with frequencies of 1.435% (95% CI: 0,366; 3,856) and 0,957% (95% IC: 0,161; 3,125), respectively.

Base Teórica: O câncer de mama é provavelmente o mais temido pelas mulheres devido a sua alta freqüência e, sobretudo, pelos seus efeitos psicológicos que afetam a percepção da sexualidade e a própria imagem pessoal. Ele é relativamente raro antes dos 35 anos de idade, mas acima desta faixa etária sua incidência cresce rápida e progressivamente. Estudos indicam que fatores genéticos e ambientais são responsáveis pela incidência do câncer de mama, sendo que a hereditariedade provavelmente tenha participação restrita no desenvolvimento deste tipo de tumor. Os principais genes associados ao desenvolvimento do câncer de mama, BRCA1 e BRCA2, são responsáveis por cerca de 80% desses casos, conferindo um risco de 71 a 85% de chance de desenvolver a neoplasia em alguma fase da vida. Mutações nesses genes, classificados como supressores tumorais, demonstram que a perda de suas funções não pára o ciclo celular, não permite a ação do sistema de reparo, e não estimula a apoptose (morte celular programada), culminando em replicação anormal e câncer. A observação epidemiológica de que mulheres judias de origem Ashkenazi parecem ser mais vulneráveis ao câncer de mama está sendo explicada através de estudos moleculares dos genes BRCA1 e BRCA2, onde encontramos a prevalência de três mutações específicas: 185delAG e 5382insC, no gene BRCA1 e 6174delT, no gene BRCA2. Métodos: Utilizou-se um banco de DNA pré-existente, extraído de 209 mulheres da comunidade judaica Ashkenazi da cidade de Porto Alegre. A amplificação do DNA foi realizada por PCR, através da técnica PSM (PCR Mediated site-direct) seguida de digestão dos produtos de PCR com enzimas de restrição. Os objetivos foram verificar se as freqüências das mutações 185delAG e 5382insC, no gene BRCA1 são significativas nesta população e compará-las com demais freqüências encontradas. Resultados: Foram encontradas três pacientes com a mutação 185delAG e duas pacientes com a mutação 5382insC, com as freqüências de 1,435% (95% IC: 0,366; 3,856) e 0,957% (95% IC: 0,161; 3,125), respectivamente. / Introduction: Breast cancer is probably the worst diagnosed cancer for women due to its high frequency and furthermore by its psychological problems that affect the perception of sexuality and the self image. It is relatively rare before 35 years of age, but beyond this age its incidence increases rapidly and progressively. Studies show that genetic and environmental factors are responsible for breast cancer incidence, but heredity may play a restrict role in the development of this kind of tumor. The main genes associated to the development of breast cancer, BRCA1 and BRCA2, are responsible for almost 80% of these cases, reaching a chance between 71 and 85% of developing the disease at any life stage. Mutations in these genes, classified as tumor suppressors, do not allow the repair mechanisms of DNA to perform its action and do not stimulate apoptosis, culminating in abnormal replication and cancer. The epidemiological observation in which Ashkenazi Jewish women seems to be more vulnerable to breast cancer is explained through molecular studies of BRCA1 and BRCA2 genes, where three specific mutations have been found (185delAG and 5382insC, in the BRCA1 gene and 6174delT, in the BRCA2 gene). Methods: A pre-existent bank of DNA extracted from 209 women of the Ashkenazi Jewish community of Porto Alegre city has been used. The DNA amplification was performed through PCR, using the PSM (PCR Mediated Site-Direct) technique followed by the digestion of PCR products with restriction enzymes. The objectives of this study was to identify the frequencies of mutations 185delAG and 5382insC at the BRCA1 gene and verify if they are significantly different in this population when compared to frequencies found in other studies. Results: We found three patients with 185delAG mutation and two patients with 5382insC mutation, with frequencies of 1.435% (95% CI: 0,366; 3,856) and 0,957% (95% IC: 0,161; 3,125), respectively.

Base Teórica: O câncer de mama é provavelmente o mais temido pelas mulheres devido a sua alta freqüência e, sobretudo, pelos seus efeitos psicológicos que afetam a percepção da sexualidade e a própria imagem pessoal. Ele é relativamente raro antes dos 35 anos de idade, mas acima desta faixa etária sua incidência cresce rápida e progressivamente. Estudos indicam que fatores genéticos e ambientais são responsáveis pela incidência do câncer de mama, sendo que a hereditariedade provavelmente tenha participação restrita no desenvolvimento deste tipo de tumor. Os principais genes associados ao desenvolvimento do câncer de mama, BRCA1 e BRCA2, são responsáveis por cerca de 80% desses casos, conferindo um risco de 71 a 85% de chance de desenvolver a neoplasia em alguma fase da vida. Mutações nesses genes, classificados como supressores tumorais, demonstram que a perda de suas funções não pára o ciclo celular, não permite a ação do sistema de reparo, e não estimula a apoptose (morte celular programada), culminando em replicação anormal e câncer. A observação epidemiológica de que mulheres judias de origem Ashkenazi parecem ser mais vulneráveis ao câncer de mama está sendo explicada através de estudos moleculares dos genes BRCA1 e BRCA2, onde encontramos a prevalência de três mutações específicas: 185delAG e 5382insC, no gene BRCA1 e 6174delT, no gene BRCA2. Métodos: Utilizou-se um banco de DNA pré-existente, extraído de 209 mulheres da comunidade judaica Ashkenazi da cidade de Porto Alegre. A amplificação do DNA foi realizada por PCR, através da técnica PSM (PCR Mediated site-direct) seguida de digestão dos produtos de PCR com enzimas de restrição. Os objetivos foram verificar se as freqüências das mutações 185delAG e 5382insC, no gene BRCA1 são significativas nesta população e compará-las com demais freqüências encontradas. Resultados: Foram encontradas três pacientes com a mutação 185delAG e duas pacientes com a mutação 5382insC, com as freqüências de 1,435% (95% IC: 0,366; 3,856) e 0,957% (95% IC: 0,161; 3,125), respectivamente. / Introduction: Breast cancer is probably the worst diagnosed cancer for women due to its high frequency and furthermore by its psychological problems that affect the perception of sexuality and the self image. It is relatively rare before 35 years of age, but beyond this age its incidence increases rapidly and progressively. Studies show that genetic and environmental factors are responsible for breast cancer incidence, but heredity may play a restrict role in the development of this kind of tumor. The main genes associated to the development of breast cancer, BRCA1 and BRCA2, are responsible for almost 80% of these cases, reaching a chance between 71 and 85% of developing the disease at any life stage. Mutations in these genes, classified as tumor suppressors, do not allow the repair mechanisms of DNA to perform its action and do not stimulate apoptosis, culminating in abnormal replication and cancer. The epidemiological observation in which Ashkenazi Jewish women seems to be more vulnerable to breast cancer is explained through molecular studies of BRCA1 and BRCA2 genes, where three specific mutations have been found (185delAG and 5382insC, in the BRCA1 gene and 6174delT, in the BRCA2 gene). Methods: A pre-existent bank of DNA extracted from 209 women of the Ashkenazi Jewish community of Porto Alegre city has been used. The DNA amplification was performed through PCR, using the PSM (PCR Mediated Site-Direct) technique followed by the digestion of PCR products with restriction enzymes. The objectives of this study was to identify the frequencies of mutations 185delAG and 5382insC at the BRCA1 gene and verify if they are significantly different in this population when compared to frequencies found in other studies. Results: We found three patients with 185delAG mutation and two patients with 5382insC mutation, with frequencies of 1.435% (95% CI: 0,366; 3,856) and 0,957% (95% IC: 0,161; 3,125), respectively.

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Ongoing research in the fields of genetics and biotechnology hold the promise of improved diagnosis and treatment of genetic diseases, and potentially the development of individually tailored pharmaceuticals and gene therapies. Difficulty, however, arises in determining how these services are to be evaluated and integrated equitably into public health care systems such as Canada's. The current context is one of increasing fiscal restraint on the part of governments, limited financial resources being dedicated to health care, and rising costs for new health care services and technologies. This has led to increasing public debate in the last few years about how to reform public health care, and whether we should prohibit, permit or perhaps even encourage private purchase of health care services. In Canada, some of these concerns have crystallized around the issue of gene patents and commercial genetic testing, in particular as illustrated by the case of Myriad Genetics' patented BRACAnalysis test for hereditary breast and ovarian cancer. While most Canadians who currently access genetic services do so through the public health care system, for those with the means, private purchase is becoming an option. This situation raises serious concerns - about justice in access to health care; about continued access to safe and reliable genetic testing supported by unbiased patient information; and about the broader effects of commercialization for ongoing research and the Canadian public health care system. Commercial genetic testing presents a challenge to health care professionals, policy analysts, and academics concerned with the social, ethical and policy implications of new genetic technologies. Using the Myriad case as an exemplar, tools from moral philosophy, the social sciences, and health policy and law will be brought to bear on the larger issues of how as a society we should regulate commercial research and product development, and more coherently decide which services to cover under public health insurance and which to leave to private purchase. Generally, the thesis is concerned with the question of "how best to bring capital, morality, and knowledge into a productive and ethical relationship" (Rabinow 1999, 20).

Ongoing research in the fields of genetics and biotechnology hold the promise of improved diagnosis and treatment of genetic diseases, and potentially the development of individually tailored pharmaceuticals and gene therapies. Difficulty, however, arises in determining how these services are to be evaluated and integrated equitably into public health care systems such as Canada's. The current context is one of increasing fiscal restraint on the part of governments, limited financial resources being dedicated to health care, and rising costs for new health care services and technologies. This has led to increasing public debate in the last few years about how to reform public health care, and whether we should prohibit, permit or perhaps even encourage private purchase of health care services. In Canada, some of these concerns have crystallized around the issue of gene patents and commercial genetic testing, in particular as illustrated by the case of Myriad Genetics' patented BRACAnalysis test for hereditary breast and ovarian cancer. While most Canadians who currently access genetic services do so through the public health care system, for those with the means, private purchase is becoming an option. This situation raises serious concerns - about justice in access to health care; about continued access to safe and reliable genetic testing supported by unbiased patient information; and about the broader effects of commercialization for ongoing research and the Canadian public health care system. Commercial genetic testing presents a challenge to health care professionals, policy analysts, and academics concerned with the social, ethical and policy implications of new genetic technologies. Using the Myriad case as an exemplar, tools from moral philosophy, the social sciences, and health policy and law will be brought to bear on the larger issues of how as a society we should regulate commercial research and product development, and more coherently decide which services to cover under public health insurance and which to leave to private purchase. Generally, the thesis is concerned with the question of "how best to bring capital, morality, and knowledge into a productive and ethical relationship" (Rabinow 1999, 20). / Graduate and Postdoctoral Studies / Graduate