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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
51

BRCA genes : conserved regions and the potential effect of missense changes /

Ramirez, Christina J. January 2005 (has links)
Thesis (Ph. D.)--University of Washington, 2005. / Vita. Includes bibliographical references (leaves 76-87).
52

Inherited predisposition to breast/ovarian cancer : the frequency and nature of BRCA1 gene mutations in South African families

Yawitch, Tali Michelle 21 December 2005 (has links)
Breast cancer is the most common cancer in South African women. Approximately 5¬10% of all breast cancer cases are due to an inherited predisposition, resulting from mutations in tumour suppressor genes. The BRCA1 gene on chromosome 17q is one such tumour suppressor gene, that when mutated confers an increased risk of breast/ovarian cancer in carriers. To date, more than 500 different BRCA 1 mutations have been reported worldwide. Some of these mutations are frequently reported and others occur commonly in certain population groups. These population-specific differences in mutations represent founder effects, whereby a single ancestral mutation accounts for the majority of breast cancer cases. This study was undertaken as the nature and frequency of BRCA1 mutations in South African breast/ovarian cancer families is unknown. Fifty-one breast/ovarian cancer families were screened for three commonly occurring mutations (185deIAG, 4184del4 and 5382insC) using polymerase chain reaction (PCR) and allele-specific oligonucleotide (ASO) hybridisation. The protein truncation test (PTT) was utilised to detect truncating mutations in the large exon 11, and the remaining coding exons were screened for mutations using exon-by-exon PCR single strand conformation polymorphism/heteroduplex analysis (SSCP/HA). Seven disease-causing mutations were identified in 15 families, consisting of five different frameshift mutations and two different nonsense mutations. Four Ashkenazi Jewish families were found to harbour the 185delAG mutation; the 5382insC mutation was identified in two Afrikaner families and one Ashkenazi Jewish family. Haplotype analysis revealed that the four Ashkenazi families share the common Ashkenazi Jewish haplotype, suggesting a common ancestor for these families. Similarly, the two Afrikaner families share the same haplotype as families of north and east European ancestry with the 5382insC mutation. The haplotype of the Ashkenazi Jewish family with this mutation was however different to the linked haplotype, indicating a recombination event or an independent mutation. Both these mutations are thought to have occurred in or before the medieval period. Furthermore, four Afrikaner families were found to carry the novel E881X nonsense mutation, which has not been previously described. Haplotype analysis of these families suggested that these patients share a common ancestor, and genealogic studies have identified the founding couple for this mutation, who both arrived in the Cape from France in the late 1600s. Four additional families were found to harbour BRCA1 mutations by SSCP/HA. Three of these mutations have not been previously reported - the S451X nonsense mutation (identified in a family of Scottish origin), the 1493delC mutation identified in an Afrikaner family, and the 4957insC mutation identified in an Indian family. The 448insA mutation was identified in a family of German origin, where the patient had cancer of the fallopian tubes. A number of different described polymorphisms and variants of unknown functional significance were also identified. This is the first study to show that BRCA1 is involved in South African breast/ovarian cancer families, to the extent that 29.4% (15/51) of families have BRCA1 mutations. Furthermore, minor founder effects in the Afrikaner population have been demonstrated. These results enable improved genetic counselling and clinical management of mutation positive families as well as subsequent testing of family members. / Dissertation (MSc (Human Genetics))--University of Pretoria, 2005. / Genetics / unrestricted
53

Integrative Analysis to Evaluate Similarity Between BRCAness Tumors and BRCA Tumors

Bodily, Weston Reed 01 June 2017 (has links)
The term "BRCAness" is used to describe breast-cancer patients who lack a germline mutation in BRCA1 or BRCA2, yet who are believed to express characteristics similar to patients who do have a germline mutation in BRCA1 or BRCA2. Although it is hypothesized that BRCAness is related to deficiency in the homologous recombination repair (HRR) pathways, relatively little is understood about what drives BRCAness or what criteria should be used to assign patients to this category. We hypothesized that patients whose tumor carries a genomic or epigenomic aberration in BRCA1 or BRCA2 should be classified under the BRCAness category and that these tumors would exhibit downstream effects (additional mutations or gene-expression changes) similar to patients with germline BRCA1/2 mutations. To better understand BRCAness, we examined similarities and differences in gene-expression profiles and somatic-mutation "signatures" among 1054 breast-cancer patients from The Cancer Genome Atlas. First, we categorized patients into three categories: those who carried a germline BRCA1/2 mutation, those whose tumor carried a genomic aberration or DNA hypermethylation in BRCA1/2 (the BRCAness group), and those who fell into neither of the first two groups. Upon evaluating the gene-expression data in context of the PAM50 subtypes, we did not observe significant similarity between the germline BRCA1/2 and BRCAness groups, but we did observe enrichment within the basal subtype, especially for BRCAness tumors with hypermethylation of BRCA1/2. However, the gene-expression profiles were fairly heterogeneous; for example, BRCA1 patients differed significantly from BRCA2 patients. In agreement with prior findings, certain mutational signatures—especially "Signature 3"—were enriched for patients with germline BRCA1/2 mutations as well as for BRCAness patients. Furthermore, we observed significant similarity between germline BRCA1/2 patients and patients with germline mutations in PALB2, RAD51B, and RAD51C, genes that are key parts of the HRR pathway and that interact with BRCA1/2. Our findings suggest that the BRCAness category does have biological and clinical relevance but that the criteria for including patients in this category should be carefully defined, potentially including BRCA1/2 hypermethylation and homozygous deletions as well as germline mutations in PALB2, RAD51B, and RAD51C.
54

Oxidative stress induces DNA strand breaks may lead to genomic instability in ovarian tumorigenesis

Moreno-Ortiz, Harold-Humberto 30 April 2011 (has links)
Oxidative stress (OS) occurs when DNA repair mechanisms are overcome by the amount of single and double strand DNA breaks caused by an accumulation of reactive oxygen species (ROS). Genomic instability (GI) by microsatellite instability (MSI) accumulation is characterized by changes in DNA single tandem repeats (STR) as a direct result of ROS. Deregulation of DNA repair and tumor suppressor pathways have been described as causes of tumor progression and metastasis. Studies in mammals have focused on GI and the implications of increased mutation frequency due to accumulation of MSI leading to development of diseases, including infertility and cancer. Ovarian cancer is a deadly disease displaying the highest mortality rate among gynecological cancers. Hereditary ovarian cancer displays GI that can be established early in primordial germinal cells (PCGs) development and migration across the genital ridge, where PGCs are exposed to ROS damage. The hypothesis of this study was ROS-induced GI is marked by the accumulation of MSI on repetitive sequences of DNA that override DNA repair, tumor suppressor and redox homeostasis pathways. In this study, we induced ROS in human ovarian cell lines by hydrogen peroxide (H2O2) exposure, as well as evaluated mouse PGCs to determine whether MSI occurs in specific regions of human and mouse genomes. Our results show that MSI was present in specific markers after ROS-induced damage in human ovarian cells and in mouse Sod1 knockout PGCs during cell migration, both of which accumulate specific mutations caused by free radical damage. Ovarian tumor cells and mouse PGCs showed an increase of MSI in 12 human and 5 mouse repetitive markers that are located near important genes related to DNA repair, tumor suppression, cell proliferation, apoptosis and differentiation. This could be a signal that leads to tumor initiation, formation and progression in adult ovarian cells due to improper DNA repair and tumor suppression mechanisms or in disruption of PGC migration that determines germinal cell pool selection during early embryonic development due to absence of cell antioxidant mechanisms. Therefore, these specific unstable STRs are novel biomarkers that could be useful in early diagnostics, prognosis, and successful therapy of ovarian tumorigenesis.
55

La peur de récidive du cancer chez les femmes ayant été traitées pour un cancer et étant porteuses d'une mutation génétique BRCA1/2

Michel, Alexandra 09 November 2022 (has links)
Contexte théorique. La peur de la récidive du cancer (PRC) est la crainte que le cancer revienne dans le même organe ou dans une autre partie du corps. Elle touche pratiquement tous les patients qui ont été traités pour un cancer, à des degrés divers. Les femmes traitées pour un cancer du sein et qui sont porteuses d'une mutation des gènes BRCA1 ou BRCA2 ont un risque élevé d'avoir un nouveau cancer. Aucune étude n'a encore évalué la PRC spécifiquement dans cette population. Objectif. Cette étude, menée chez des femmes traitées pour un cancer du sein et porteuses d'une mutation des gènes BRCA1/2, vise à : (1) évaluer le niveau moyen de PRC et estimer la proportion de patientes présentant un niveau clinique de PRC globalement et dans différents sous-groupes (p. ex., BRCA1 vs BRCA2 ; groupes d'âge) ; (2) examiner la relation entre la PRC et certaines variables psychologiques (p. ex., évitement, intolérance à l'incertitude) et la qualité de vie ; (3) investiguer si le niveau de PRC varie selon le traitement curatif et préventif reçu; et (4) évaluer la relation entre la PRC et la présence de conflits décisionnels ou de regrets face aux différentes options préventives. Méthode. Les participantes ont été recrutées par le biais d'un courriel envoyé à une liste de diffusion d'un réseau en oncogénétique (Réseau ROSE). Elles ont été invitées à remplir en ligne une batterie de questionnaires autorapportés afin d'évaluer leur niveau de PRC et d'autres variables psychologiques et de qualité de vie, notamment en utilisant l'Inventaire de la peur de récidive du cancer. Résultats. Un total de 89 femmes a complété l'étude. La majorité des participantes avaient subi une mastectomie préventive (62,9%) et une salpingo-ovariectomie préventive (75,3%) au moment de l'étude. Le score moyen à la sous-échelle de sévérité de l'Inventaire de la peur de la récidive du cancer (IPRC-S) était de 16,8, ce qui dépasse le seuil clinique de 13, et 70,8% des participantes présentaient un niveau clinique de PRC. Les résultats ont également montré qu'un niveau plus élevé de PRC était significativement associé à des scores plus élevés d'anxiété et de dépression, à des scores supérieurs à l'échelle Impact de l'événement puis à de l'évitement et une intolérance à l'incertitude plus élevés, mais pas à la qualité de vie. Aucune différence significative n'a été observée au score global de PRC entre les femmes ayant subi une chirurgie préventive (mastectomie et/ou salpingo-ovariectomie) et celles qui l'envisageaient mais ne l'avaient pas reçue et celles qui ne l'envisageaient pas. Un score de PRC plus élevé était également significativement associé à des niveaux de conflits décisionnels et des regrets plus importants face au choix de recevoir ou non une chirurgie préventive. Conclusion. Ces données suggèrent que la PRC est un problème important pour les femmes traitées pour un cancer du sein et porteuses d'une mutation des gènes BRCA1/2, même après avoir subi une chirurgie prophylactique, une procédure efficace pour réduire le risque de récidive. Cela souligne l'importance de fournir à ces femmes une intervention psychologique qui cible spécifiquement la PRC.
56

Honors Thesis: BRCA1 Interactions with BACH1, BARD1, and CHK2: Recent Evidence and Potential Developments in the Diagnosis, Treatment, and Prevention of Human Breast Cancer

Rice, Ian S. 25 April 2005 (has links)
No description available.
57

THE IMPACT OF GENETIC COUNSELING ON CLINICAL DECISION MAKING AMONG WOMEN EVALUATED FOR HEREDITARY BREAST AND OVARIAN CANCER RISK

PRITZLAFF, MARY ELIZABETH 11 October 2001 (has links)
No description available.
58

Développement d'un outil d'aide à la communication : parler aux enfants mineurs du résultat d'un test BRCA1/2

Santerre-Theil, Ariane 24 April 2018 (has links)
Les individus porteurs d'une mutation des gènes BRCA1/2 s'inquiètent généralement du risque de leurs enfants d'avoir hérité de la mutation génétique familiale. Malgré l'absence d'avantages médicaux pour les enfants mineurs et l'impossibilité pour eux d'être testés avant d'être adultes, une majorité des parents leur communiquent néanmoins le résultat du test génétique BRCA1/2. Les parents confrontés à cette situation disent avoir besoin d'être accompagnés dans cette décision. L'objectif de ce projet, à devis qualitatif, était de développer un outil d'aide à la décision à l'intention des individus porteurs quant à la communication du résultat de test BRCA1/2 à leurs enfants mineurs. Développé conformément aux critères de l'International Patient Decision Aids Standards, le prototype a été évalué lors de groupes de discussion et d'entrevues individuelles menés auprès de mères porteuses d'une mutation des gènes BRCA1/2 (n=9). Des professionnels de la santé l'ont également commenté (n=3). Une analyse thématique a été effectuée à partir des transcriptions des entrevues. Globalement, les résultats de cette étude suggèrent que les mères ne présentent pas de besoin quant à la décision de communiquer ou non le résultat BRCA1/2 à leurs enfants mineurs, puisqu'elles semblent déjà avoir choisi d'en parler. Elles désirent un outil pour les préparer et les aider à communiquer l'information à leurs enfants. La visée de l'outil a donc été modifiée afin de répondre aux besoins des mères. L'outil d'aide à la communication est présenté sous la forme d'un livret. Il comprend les avantages et les inconvénients de communiquer, des étapes afin de s'y préparer, des conseils et des témoignages de parents. D'autres études seront nécessaires afin d'évaluer l'effet de cet outil pour les parents porteurs dans leur processus de communication.
59

La peur de récidive du cancer chez les femmes ayant été traitées pour un cancer et étant porteuses d'une mutation génétique BRCA1/2

Michel, Alexandra 09 November 2022 (has links)
Contexte théorique. La peur de la récidive du cancer (PRC) est la crainte que le cancer revienne dans le même organe ou dans une autre partie du corps. Elle touche pratiquement tous les patients qui ont été traités pour un cancer, à des degrés divers. Les femmes traitées pour un cancer du sein et qui sont porteuses d'une mutation des gènes BRCA1 ou BRCA2 ont un risque élevé d'avoir un nouveau cancer. Aucune étude n'a encore évalué la PRC spécifiquement dans cette population. Objectif. Cette étude, menée chez des femmes traitées pour un cancer du sein et porteuses d'une mutation des gènes BRCA1/2, vise à : (1) évaluer le niveau moyen de PRC et estimer la proportion de patientes présentant un niveau clinique de PRC globalement et dans différents sous-groupes (p. ex., BRCA1 vs BRCA2 ; groupes d'âge) ; (2) examiner la relation entre la PRC et certaines variables psychologiques (p. ex., évitement, intolérance à l'incertitude) et la qualité de vie ; (3) investiguer si le niveau de PRC varie selon le traitement curatif et préventif reçu; et (4) évaluer la relation entre la PRC et la présence de conflits décisionnels ou de regrets face aux différentes options préventives. Méthode. Les participantes ont été recrutées par le biais d'un courriel envoyé à une liste de diffusion d'un réseau en oncogénétique (Réseau ROSE). Elles ont été invitées à remplir en ligne une batterie de questionnaires autorapportés afin d'évaluer leur niveau de PRC et d'autres variables psychologiques et de qualité de vie, notamment en utilisant l'Inventaire de la peur de récidive du cancer. Résultats. Un total de 89 femmes a complété l'étude. La majorité des participantes avaient subi une mastectomie préventive (62,9%) et une salpingo-ovariectomie préventive (75,3%) au moment de l'étude. Le score moyen à la sous-échelle de sévérité de l'Inventaire de la peur de la récidive du cancer (IPRC-S) était de 16,8, ce qui dépasse le seuil clinique de 13, et 70,8% des participantes présentaient un niveau clinique de PRC. Les résultats ont également montré qu'un niveau plus élevé de PRC était significativement associé à des scores plus élevés d'anxiété et de dépression, à des scores supérieurs à l'échelle Impact de l'événement puis à de l'évitement et une intolérance à l'incertitude plus élevés, mais pas à la qualité de vie. Aucune différence significative n'a été observée au score global de PRC entre les femmes ayant subi une chirurgie préventive (mastectomie et/ou salpingo-ovariectomie) et celles qui l'envisageaient mais ne l'avaient pas reçue et celles qui ne l'envisageaient pas. Un score de PRC plus élevé était également significativement associé à des niveaux de conflits décisionnels et des regrets plus importants face au choix de recevoir ou non une chirurgie préventive. Conclusion. Ces données suggèrent que la PRC est un problème important pour les femmes traitées pour un cancer du sein et porteuses d'une mutation des gènes BRCA1/2, même après avoir subi une chirurgie prophylactique, une procédure efficace pour réduire le risque de récidive. Cela souligne l'importance de fournir à ces femmes une intervention psychologique qui cible spécifiquement la PRC.
60

Revealing Molecular Adversaries of Human Health Using Advanced Imaging Technology

Varano, Ann Cameron 07 December 2018 (has links)
Single particle electron microscopy (EM) allows us to examine the molecular world and gain insights into protein structures implicated in human disease. Visualizing the 3D architecture of the macromolecules can inform drug design and preventative care. While X-ray crystallography and NMR are able to resolve atomic structures, the methodology is better suited for smaller structures with limited flexibility. Single particle EM allows us analyze larger structures that have inherent flexibility. Protein structures can broadly be categorized as symmetry or asymmetric. There are computational advantages when analyzing symmetrical structures. Specifically, structural information can be extrapolated from fewer vantage points. Thus, symmetrical macromolecules are an advantageous for pioneering new methodologies in single particle EM. Rotavirus double layered particles (DLPs) are large macromolecular complexes that display icosahedral symmetry. Previous studies have led to a high resolution structure of transcriptionally inactive rotavirus frozen in time. However, to more fully understand rotavirus we need to examine the structure under transcriptionally active conditions. To expand our understanding, we first evaluated these viral assemblies using cryo-EM under active and inactive conditions. We found both internal and external structural differences. Based on these findings we sought to further our understanding of these nano-machines by developing a liquid cell environment to evaluate their dynamics over time. Our research not only developed a new methodology to evaluate active particles over time, we also found that the mobility of the DLPs were directly correlated to the level of transcriptional activity. When analyzing asymmetrical and flexible protein complexes previous studies have utilized methodologies to limit the proteins' conformational variability. While this does allow for a higher resolution structure, it limits our understanding to a specific orientation and compromises the biological insights. BRCA1 is an asymmetric protein containing a large flexible region and is important in the prevention of breast cancer. We utilize silicon nitride microchips with integrated wells and decorated with a lipid monolayer to capture and image BRCA1 complexes. This imaging platform minimizes heterogeneity and ensures the sample quality while not biasing confirmation. Thus, allowing for high resolution cryo-EM imaging of flexible native proteins. We were able to examine BRCA1 complexes from cells at both the primary and metastatic sites. Our ability to visualize these proteins in their native form provide insights into the variability of BRCA1 in disease progression. We found that BRCA1 complexes isolated from metastatic cells have additional density in the C-terminal domain. Our data suggests this density it due an interaction with p53. Overall, our methodologies highlight the power of single particle EM for studying protein complexes. Furthermore, our findings emphasize the importance of examining protein complexes in their native state. / PHD / Single particle electron microscopy (EM) allows us to examine the molecular world and gain insights into protein structures implicated in human disease. Visualizing the 3D architecture of macromolecules can inform drug design and preventative care. While X-ray crystallography and NMR are able to resolve atomic structures, the methodology is better suited for smaller structures with limited flexibility. Single particle EM allow us analyze larger structures that have inherent flexibility. Protein structures can broadly be categorized as symmetry or asymmetric. There are computational advantages when analyzing symmetrical structures. Specifically, structural information can be extrapolated from fewer vantage points. Thus, symmetrical macromolecules are an advantageous for pioneering new methodologies in single particle EM. Rotavirus double layered particles (DLPs) are large, highly symmetrical macromolecular complexes that represent an ideal model system for developing technology. Previous studies have led to a high resolution structure of inactive rotavirus DLP frozen in time. However, to more fully understand rotavirus we need to examine the structure under active conditions. To expand our understanding, we first evaluated these viral assemblies using cryo-EM under active and inactive conditions. We found structural differences. Based on these findings we sought to further our understanding of these nano-machines by developing a liquid cell environment to evaluate their dynamics over time. Our new methodology revealed new insights into the mobility of the DLPs. When analyzing asymmetrical and flexible protein complexes previous studies have utilized methodologies to limit the proteins’ movement. While this does allow for a higher resolution structure, it limits our understanding to a specific orientation and compromises the biological insights. BRCA1 is a highly flexible asymmetric protein implicated in the development of breast cancer. We utilize specialized microchips to capture and image BRCA1 complexes. This imaging platform ensures sample quality and allows for high resolution cryoEM imaging of flexible native proteins. We were able to examine BRCA1 complexes from cells at both the primary and metastatic sites. Our ability to visualize these proteins in their native form provide insights into the variability of BRCA1 in disease progression. Our data found that BRCA1 complexes isolated from metastatic cells are structurally different than those at the primary site. Overall, our methodologies highlight the power of single particle EM for studying protein complexes. Furthermore, our findings emphasize the importance of examining protein complexes in their native state.

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