Browsing by Subject "Genetic Testing"
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Item The challenge of precision medicine: ethical, legal & clinical issues in genomic medicine (The Daniel W. Foster, M.D., Visiting Lectureship in Medical Ethics)(2015-11-03) Wolf, Susan M.Genomics is advancing at a tremendous rate, bringing powerful new capabilities but also big challenges to clinical practice and research. With the federal government launching the Precision Medicine Initiative, the time to face those challenges is now. Genomic medicine raises fundamental issues including the role of patient choice, the development of quality standards, the privacy of sequence data, return of results and incidental findings, protection of patient privacy, and responsibilities to share information with the family. This lecture will analyze those challenges and suggest a way forward in biomedical research as well as clinical care.Item Evaluating the Clinical and Financial Impact of Multi-Gene Panel Testing(2021-05-01T05:00:00.000Z) Haque, Waqas Zia; Hsiehchen, David; Syed, Samira K.; Kazmi, SyedBACKGROUND: Medical management of advanced cancers is increasingly guided by predictive biomarkers. Tumor mutation testing using commercial assays examining select gene panels is now incorporated in the standard work-up of advanced cancers. With some exceptions, existing and emerging biomarkers remain inadequate clinical tools for many patients, and anecdotal evidence and small phase trials have driven much of the enthusiasm for biomarker-driven treatments. The purpose of this study is to assess predictive clinical factors of successful gene mutation testing and to determine whether tumor mutation testing directly impacts clinical practice. METHODS: All submitted test requests from UT Southwestern faculty to Foundation One were abstracted for test success and mutation results. Patients were cross-referenced in the EPIC electronic health record information. To evaluate practice changes and patient outcomes after one-year of follow-up, we collected data from the first 100 patients that underwent next generation sequencing testing (excluding PD-L1 testing) in 2020. RESULTS: Among the 100 patients studied, the typical patient was close to older age (mean age 58.7 years), female (56%), Caucasian (52%), insured (71%), and with stage 3 or 4 cancer (79%). The most common tumor types were breast (20%), colorectal (18%), and myelodysplastic syndrome (9%). 20% of patients (20/100) were found to have an actionable mutation and 2 patients were enrolled in clinical trials due to Foundation Medicine testing. Among the 20 patients with an actionable mutation, 5 of them (25%) had a change in therapy. All of these patients responded to the change in therapy with stable disease, and while three of them started the therapy within a month of the Foundation testing resulting, the other two waited 5 and 11 months. The fifth patient was actually found to not have disease but was placed on a maintenance therapy as a result of the testing. CONCLUSIONS: While precision medicine offers the promise of better understanding genomic drivers of disease, it is unclear if the benefits of such an approach outweigh the risk on a population level and if resulting changes in patient care are superior as compared investigator-chosen therapies. Medical oncologists should continue to apply intelligent and judicious use of Foundation Medicine testing.Item Familial hypercholesterolemia: improving detection and management(2017-11-03) Khera, AmitItem Genetic Analysis of Grinder Formation in Caenorhabditis Elegans: Regulation by RAB-6.2 and Its GTPase Activating Protein EAT-17(2004-12-15) Anselmo, Sarah Straud; Avery, LeonThe C. elegans grinder is an intricately designed, macromolecular structure located in the terminal bulb of the pharynx. It acts as the teeth of C. elegans, crushing bacteria before they are passed to the intestine. The grinder is a specialized cuticular structure and is shed and rebuilt at each larval molt. While we have a fairly decent view regarding the mechanics of the grinder, we know surprisingly little about its composition or how it is formed. The nematode grinder has been studied for over 100 years, but no one has yet described the molecular events controlling grinder formation and/or grinder function. To understand how the grinder is formed, I have focused on cloning and characterizing eat-17. eat-17 mutants have rudimentary, malformed grinders: the grinder plates are smaller than normal, disorganized in structure, and often improperly arranged. I found that eat-17 encodes an ~825 amino acid Rab GTPase activating protein with a series of C-terminal coiled-coil domains. Its closest human homolog is Evi5, a putative oncogene whose function is not currently understood. Rabs are key regulators of vesicle transport, and cycle between active, GTP bound and inactive, GDP bound states. GTPase activating proteins (GAPs) catalyze the hydrolysis of GTP, allowing Rabs to be extracted from membranes and recycled for additional rounds of signaling. I found that the GAP activity of EAT-17 is important for its function: 21% (16/76) of mutants expressing a wild-type version of eat-17 are rescued for defects in grinder formation, while only 2.9% (3/113) of worms expressing catalytically inactive versions of EAT-17 are rescued. I performed RNAi against the 27 putative Rabs in the C. elegans genome and found that rab-6.2 RNAi causes grinder defects similar to those seen in eat-17 mutants. GFP reporters show that both EAT-17 and RAB-6.2 are expressed in terminal bulb muscle, the site of grinder secretion. By yeast two-hybrid, I have demonstrated a direct interaction between RAB-6.2 and EAT-17. These data suggest that EAT-17 and RAB-6.2 work together in regulating grinder formation. Genetic interaction studies suggest that RAB-6.1 may play a role in a similar cellular process.Item Genetic Dissection of Heart Development in the Fruit Fly Drosophila Melanogaster(2007-12-18) Yi, Peng; Olson, Eric N.The early morphogenetic mechanisms involved in heart formation are evolutionarily conserved. The Drosophila heart, known as the dorsal vessel, functions as a pulsatile tube-like organ containing an inner layer of contractile cardial cells that adhere tightly to an adjacent layer of pericardial cells. A genetic screen for genes that control Drosophila heart development revealed a cardiac defect in which pericardial and cardial cells dissociate causing loss of cardiac function and embryonic lethality. This phenotype resulted from mutations in the genes encoding HMG-CoA Reductase, downstream enzymes in the mevalonate pathway, and G-protein Ggamma 1, which is geranylgeranylated, thus representing an endpoint of isoprenoid biosynthesis. These findings reveal a cardial cell-autonomous requirement of Ggamma 1 geranylgeranylation for heart formation and suggest the involvement of the mevalonate pathway in congenital heart disease. In addition, we found that the heterotrimeric G proteins Gbeta 13F and G-oalpha 47A together with the RGS (regulator of G protein signaling) protein Loco function in the same pathway as Ggamma 1 to regulate septate junction formation in cardial cells of the Drosophila heart. We also present evidence that the septate junction protein Sinuous interacts with Pericardin, a matrix protein secreted by pericardial cells, providing the molecular basis for cardial-pericardial cell adhesion and serving as a mediator of the actions of the mevalonate pathway and heterotrimeric G protein signaling in Drosophila heart development.Item [News](1978-10-23) Williams, AnnItem [News](1988-08-30) De La Garza, DottieItem [Southwestern News](2002-06-05) Carter, WayneItem [Southwestern News](1995-11-16) Martinez, EmilyItem Universal genomic testing of newborns: bowl of cherries or can of worms?(2019-01-08) Scheuerle, Angela E.The first gene was sequenced by "reverse genetics" in 1989, launching the Human Genome Project. Genetic technologies have advanced and found usefulness in many areas of science and medicine. Concurrently, the general public has become more comfortable with the idea of genetic testing. Testing asymptomatic minors for genetic carrier status and later-onset conditions is against the policy of the American College of Medical Genetics and Genomics. There is one exception to this policy: public health programs screen newborns for genetic conditions. These programs demonstrate the success of early screening and treatments. But they are purposefully limited in scope. Risks of early genetic diagnosis, particularly for later-onset conditions, includes both psychosocial and legal concerns. Protections are currently in place to prevent employment and health insurance discrimination, but there is no guarantee that these will continue. There are no protections with regard to education, military service, or disability or life insurance.Item [UT News](1986-09-22) Harrell, AnnItem [UT Southwestern Medical Center News](2010-05-11) Piloto, ConnieItem [UT Southwestern Medical Center News](2011-09-01) Bolles, Debbie