Thesis (M.S.)--University of Delaware, 2009. / Principal faculty advisor: . Includes bibliographical references.

No description available.

Zugl.: Berlin, Freie Univ., Diss., 2008

Für die hier beschriebene Studie wurde ein Fragebogen erstellt, welcher von 80 Trägerinnen und Trägern einer pathogenen Mutation in den Genen BRCA1 oder BRCA2 ausgefüllt wurde. Die Befragung sollte untersuchen, ob den Befragten das Risiko ihrer Verwandten, ebenso Mutationsträger zu sein, bewusst war. Weiterhin sollte ermittelt werden, ob sie die jeweiligen Risikopersonen darüber informierten. Es zeigte sich, dass den meisten Befragten dieses Risiko bekannt war. Einigen Personen schienen jedoch nicht genau zu wissen, welche Verwandten als „Risikopersonen“ zählen. Insbesondere war nicht allen Befragten die Möglichkeit bewusst, dass auch Männer die Mutation tragen und an ihre Kinder weitergeben sowie selbst an Brustkrebs erkranken können. Weiterhin gaben mehr als ein Viertel der Befragten an, dass sie mindestens ein Familienmitglied, obwohl es ihnen als Risikoperson bekannt war, nicht informierten. Als häufigste Grund hierfür wurde mangelnder Kontakt genannt. Vor dem Hintergrund der Angaben der Befragten sowie der aktuellen Forschungslage werden in der vorliegenden Arbeit Möglichkeiten diskutiert, wie die Anzahl der informierten Angehörigen verbessert werden könnte. / A questionnaire was sent to carriers of BRCA1/2 mutations to survey whether they knew about the risk of their relatives to be carriers as well and whether they informed those relatives about that risk. Among the 80 participants, most were aware of the risk of their relatives. However, the risk of male relatives to be mutation carriers seemed to have been undererstimated and more than one in four participants stated they did not inform every relative they knew to be at risk. The most frequently stated reason for not informing at-risk relatives was lack of contact.

A bilateral salpingo oophorectomy (BSO), removal of the ovaries, is recommended for carriers of BRCA1/2 mutations to reduce cancer risks. However, BSO induces surgical menopause, and is associated with an increased risk of dementia (Rocca et al., 2007a) and Parkinsonism (Rocca et al, 2007b). This study investigated the cognitive outcomes of BSO one to ten years post-surgically. The present dataset (n=37) revealed there was a significant difference between the BSO group and their age matched cohort on the Logical Memory task assessing verbal, episodic memory. Levels of E1G (estrogen metabolite) was a significant predictor of the RAVLT primacy subscale indicating higher levels were associated with better recall at the beginning of a list of words. Controlling for age, performance on the RAVLT A1 measuring short-term memory degraded further out from BSO. While limited by the sample size, results are consistent with reports of post-BSO cognitive changes (Vearncomb & Panchana, 2009).

A bilateral salpingo oophorectomy (BSO), removal of the ovaries, is recommended for carriers of BRCA1/2 mutations to reduce cancer risks. However, BSO induces surgical menopause, and is associated with an increased risk of dementia (Rocca et al., 2007a) and Parkinsonism (Rocca et al, 2007b). This study investigated the cognitive outcomes of BSO one to ten years post-surgically. The present dataset (n=37) revealed there was a significant difference between the BSO group and their age matched cohort on the Logical Memory task assessing verbal, episodic memory. Levels of E1G (estrogen metabolite) was a significant predictor of the RAVLT primacy subscale indicating higher levels were associated with better recall at the beginning of a list of words. Controlling for age, performance on the RAVLT A1 measuring short-term memory degraded further out from BSO. While limited by the sample size, results are consistent with reports of post-BSO cognitive changes (Vearncomb & Panchana, 2009).

This thesis assesses the main risk factors contributing to contralateral breast cancer(CBC) amongst high-risk breast cancer patients with a view to formulating clinicallyuseful guidelines. The work has focused on several keys areas; a literature review ofthe various factors contributing to CBC, changing trends towards increasingnumbers of contralateral risk-reducing mastectomies (CRRMs), internationalvariations amongst breast surgeons’ attitudes towards risk-reducing mastectomy(RRM), attitudes towards CRRM amongst UK breast and plastic surgeons,assessment of CBC risk amongst BRCA1/2 mutation carriers and finally theformation of the ‘Manchester Guidelines for CRRM’.Breast cancer patients harbouring mutations in high penetrance genes (i.e. BRCA1/2,TP53, CHEK2, PALB) have the highest risk of developing breast cancer. A positivefamily history also increases the risk of subsequent breast cancer, with not muchevidence to support variation in risk with histological type. Risk reducing strategiesinclude anti-endocrine treatment, risk-reducing bilateral salpingo-oophorectomy(RRBSO) and CRRM with the former likely to account for the global trend ofdecreasing rates of CBC.Over the last decade, rates of CRRM have trebled in the USA – such a clear trendhas not yet been confirmed in Europe. Factors driving this trend include young ageat diagnosis, histological type (lobular carcinoma, lobular carcinoma in situ [LCIS]and ductal carcinoma in situ [DCIS]) and female surgeons. A direct comparison(USA v 4 European countries) found that American surgeons overall had a greaterknowledge of cancer genetics and nearly all (including Dutch and British surgeons)had positive attitudes towards RRM.A proportion of British surgeons were quoting inaccurate levels of CBC risk to theirpatients. Practices in the UK varied regarding CRRM – only 58% of surgeons alwaysdiscussed these cases in the MDT, with less than a third ever seeking apsychological or formal genetic assessment. Surgeons primarily offered thisprocedure to high-risk patients (gene mutation carriers or positive family history)but felt that the main reason patients requested CRRM was to alleviate anxiety. Studying over 1000 breast cancer patients who also had a mutation in either BRCA1or BRCA2 gene revealed that the risk of CBC was approximately 2-3% per year, forat least 2 decades. Young age at first breast cancer development (<40 years) affectedthis risk most. The effect bilateral risk-reducing salpingo-oophorectomy (BRRSO)was initially significant in an unadjusted analysis, but when accounting for delayedentry BRRSO did not appear to affect CBC risk. The use of SNPs was not able tostratify risk of CBC further. By considering the above, the Manchester Guidelines for CRRM have beenformulated. This 5-step protocol allows clinicians to objectively assess the risk ofCBC based on the evidence base and makes suggestions of a multi-disciplinaryapproach to managing requests for CRRM. Several breast units in the UK havealready adopted these guidelines and future studies hope to validate them so thatthey can be used more widely.

BRCA1 is a caretaker of genome integrity with various molecular functions, which are required for development and tumor suppression. These include the homology-directed repair (HDR) of DNA double strand breaks, stalled replication fork protection (SFP), transcription, chromatin remodeling and cell cycle checkpoint control. Recent studies reported that BRCA1 is required for reprogramming to pluripotency, but its specific role remains unknown. In this work, we use separation of function mutants for the roles of BRCA1 in HDR and SFP to show that BRCA1 is required to repair replication-associated DNA double strand breaks by homologous recombination during reprogramming. Deficiency in SFP proved inconsequential to induced pluripotent stem (iPS) cell generation and cells with this phenotype did not experience reduced reprogramming. Thus, the primary limiting factor for the transition to pluripotency is a specific class of DNA damage: double strand breaks, likely occurring in late replicating regions which require repair by homologous recombination. These findings identify an important role of DNA damage, linked to the progression of DNA replication, in limiting cell type transitions during reprogramming. Most studies on iPS cell generation have focused on gene expression as a limiting step, in part due to the wide availability of tools to analyze transcription. Since the progression of DNA replication and DNA damage during S-phase are cell type specific, we have started the development of a sequencing platform to map various aspects of replication progression, such as origin usage, polymerase direction,pausing and stalling. In this work, we demonstrate that nucleotide analogs, incorporated during DNA synthesis in mammalian cells, can be detected by Nanopore sequencing.

Thesis (Ph. D.)--Rutgers University, 2004. / Includes bibliographical references. Also available on the Internet.

No description available.