Medical Genetics Commons^™

Immune Landscape Of Early Liver Metastatic Lesions In A Novel Immunocompetent Murine Colorectal Cancer Metastasis Model, Alaa Mohamed

Dissertations and Theses (Open Access)

Colorectal cancer minimal residual disease (MRD) represents a major clinical problem for colorectal cancer patients, with failure rates of surgery and adjuvant chemotherapy between 5% to 40% depending on stage of disease. In our study, we simulated MRD using genetically engineered organoids with precise somatic editing of APC and TP53, creating a murine model that mimics human liver metastatic colorectal cancer. By implementing a meticulously timed experimental metastatic model, we could detect microscopic tumor lesions. Through genomic and transcriptomic analyses, we pinpointed the importance of macrophages, particularly those expressing high levels of CSF1R, in these microscopic metastatic focal lesions. We …

Elucidating The Multi-Omics Of Early-Onset Colorectal Cancer, Jumanah Alshenaifi

Dissertations and Theses (Open Access)

The incidence and mortality rates of sporadic early-onset colorectal cancer have increased in recent decades, but there is no clear etiological basis for this trend. EOCRC is commonly defined as colon and rectal cancers diagnosed before the age of 50 years. The rising incidence of EOCRC has made it the second most common cancer and the third leading cause of cancer death in this age group. The rising incidence of EOCRC is also documented internationally in more than 20 countries across different continents. Clinically, EOCRC has a distinct, more aggressive clinical profile than LOCRC. While approximately 15% of EOCRC cases …

Denial Of Inpatient Genetic Testing: A Study On Outpatient Yield And Outcomes, Cindy Y. Canales

Dissertations and Theses (Open Access)

This study investigates the difference in diagnostic yield between patients approved for inpatient genetic testing compared to those denied inpatient testing and the effect of an earlier diagnosis on outcomes and medical/clinical care. In the literature, research has explored the impact of a diagnostic delay for patients with genetics conditions, assessed the utility of genetic testing in the inpatient setting, and described the impact to care of an earlier diagnosis. However, gaps remain on research exploring the diagnostic yields of inpatient versus outpatient settings and the potential impact to care an inpatient genetic testing request denial may pose. This is …

Sleep Disturbances In Adults With Tsc: Influences Of Treatment And Clinical Features, Kirstin Risgaard

Dissertations and Theses (Open Access)

Tuberous sclerosis complex (TSC) is a rare genetic condition caused by pathogenic variants in the TSC1 or TSC2 genes. TSC is characterized by a multisystem, neurocutaneous phenotype including skin lesions, hamartomas, and epilepsy. Additionally, TSC can present with an array of behavioral, psychiatric, academic, psychosocial, intellectual, or neuropsychological difficulties comprehensively known as TAND, or TSC-associated neuropsychiatric disorders. Sleep disorders are a common feature of TAND; however, they are not well characterized in the adult TSC population. Likewise, little is known about how clinical features of the condition and commonly prescribed medications impact sleep. Therefore, this study aimed to determine the …

Mutational Landscape Of Noncoding Ultraconserved Elements In Human Cancers: Functional Relevance And Clinical Utility, Recep Bayraktar

Dissertations and Theses (Open Access)

The mutational landscape of phylogenetically ultraconserved elements (UCEs), especially those in noncoding DNA regions (ncUCEs), and their functional and clinical relevance in cancers remain poorly characterized. In this thesis, we perform a systematic analysis of whole-genome sequencing (WGS) data from the International Cancer Genome Consortium (ICGC) and in-house targeted sequencing of 13,736 UCEs and demonstrate that ncUCE somatic alterations are pervasive. Using a genome-wide multiplexed CRISPR knockout screen in colorectal cancer (CRC) cell lines, we show that the loss of several mutated ncUCEs impacts cancer cell proliferation. In-depth functional studies in vitro and in vivo further reveal that UCE_11311 is …

Inclusion Of Adoption As A Pregnancy Management Option In Prenatal Genetic Counseling Practice, Emma Billings

Dissertations and Theses (Open Access)

Prenatal genetic counselors are essential to providing education, psychosocial support, and guidance on pregnancy options to patients who receive a fetal diagnosis of an anomaly or genetic condition. Therefore, genetic counselors should be well-educated on comprehensive pregnancy management options consisting of parenting, abortion, and adoption. The landscape of adoption education in genetic counseling practice was last characterized in 2010 by Perry and Henry, revealing substantial variability in both the inclusion of adoption-specific education in genetic counseling program (GCP) curricula and the discussion of pregnancy options with patients in prenatal practice. As a result, the authors published a call to action …

Role Of Phosphorylated Dicer1 In Tumor Progression, Raisa Reyes-Castro

Dissertations and Theses (Open Access)

DICER1 is a multidomain enzyme discovered and widely recognized for its function in small non-coding microRNA (miRNA) synthesis. In cancer development, DICER1 functions as a haploinsufficient tumor suppressor which regulates miRNAs and Epithelial-to-Mesenchymal Transition (EMT). The Arur laboratory discovered that DICER1 is phosphorylated by active ERK and that ERK-mediated phosphorylation triggers DICER1 to translocate from the cytoplasm to the nucleus of cells in worms, mice and humans. Further, a heterozygous allele of a genetically engineered mouse model of phosphomimetic Dicer1 when combined with heterozygous Kras oncogenic background contributes to lung tumor progression in vivo. Mechanisms through which phosphomimetic Dicer1 …

The Impact Of Treatment With Palynziq® On Quality Of Life For Individuals With Pku, Teresa Heller

Dissertations and Theses (Open Access)

Management for phenylketonuria (PKU) has traditionally involved adhering to a strict low-protein diet to maintain phenylalanine (Phe) levels within the recommended range (μmol/L). The time commitment and financial, emotional, and social burdens of adhering to a restrictive diet, as well as the neurocognitive symptoms associated with elevated Phe levels, make it challenging to manage PKU and lead to reductions in quality of life. Palynziq^® is an enzyme substitution therapy used to lower blood Phe levels and liberate individuals with PKU from their restrictive diets. Previous studies have demonstrated the safety and efficacy of Palynziq^®, but our study …

Vascular Disease Pathogenesis In Smooth Muscle Dysfunction Syndrome And Majewski Osteodysplastic Primordial Dwarfism Type Ii, Jamie Wright

Dissertations and Theses (Open Access)

Vascular diseases are a leading cause of morbidity and mortality world-wide. Understanding their pathogenesis is crucial to better diagnosis and management of these life-threatening conditions. Through the study of rare mutations that lead to early onset and severe vascular diseases, we can elucidate underlying mechanisms for vascular disease pathogenesis and develop better treatments to prevent and manage more common causes of vascular diseases. In this study we look at two rare diseases that lead to severe vascular phenotypes, Smooth Muscle Dysfunction Syndrome (SMDS) and Majewski Osteodysplastic Primordial Dwarfism Type II (MOPDII). SMDS is a rare condition due to pathogenic variants …

Genetics In The Nicu: Nurses’ Perceived Knowledge And Desired Education, Kathleen Shields

Dissertations and Theses (Open Access)

A large proportion of infants admitted to neonatal intensive care units (NICUs) have genetic conditions. NICU nurses play an important role in providing comprehensive care to these patients and their families. Previous research has demonstrated gaps exist in the genetics knowledge of nurses and that they lack comfort applying genetics information to clinical practice, but no research has been done assessing the knowledge of or comfort with genetics of NICU nurses specifically. NICU nurses (n=122) completed an online survey assessing their perceived knowledge of genetics, comfort with clinical scenarios involving genetics, and desired genetics education. Participants reported the highest levels …

Genetic Counselors' Approaches To Direct-To-Consumer Genetic Testing For Hereditary Breast Cancer, Sarah Burke

Dissertations and Theses (Open Access)

Given the increasing availability of health-related direct-to-consumer genetic testing (DTC-GT) and third-party interpretation (TPI) services, it is likely that genetic counselors (GCs) will continue to encounter consumers that require follow-up counseling for their results. The National Comprehensive Cancer Network recommends clinical-grade genetic testing to confirm commercial results; however, the type of testing that GCs select remains uncharacterized. Therefore, we aimed to describe the specific recommendations that cancer GCs make for confirmatory genetic testing in probands who have already obtained DTC-GT results or TPI data that reported a BRCA1/2 pathogenic variant. We recruited 80 GCs specializing in hereditary cancer and administered …

Investigating Medical Examiners' Practices: Genetic Evaluation For Fatal Acute Aortic Dissection, Bradley Power

Dissertations and Theses (Open Access)

Acute thoracic aortic dissection (TAD) is a life-threatening event with a hereditary component. Currently, pathogenic variants in 11 genes associated with aortic aneurysm and dissection predispose to a heritable form of disease thereby conferring an increased risk for TAD. Genetic testing plays a pivotal role not only in diagnosis, but also in risk stratification for relatives and medical management to prevent premature death from dissection. Due to its high fatality rate, medical examiners and coroners (ME/Cs) may be the first to identify TAD cases and initiate genetic testing for the decedent and at-risk relatives. ME/Cs were surveyed using three clinical …

Frequency Of Copy Number Variants Involving The Sex Chromosomes In A Clinical Setting, Autumn Vara

Dissertations and Theses (Open Access)

Copy number variants (CNVs) are a common finding in the clinical setting and contribute to both genetic variation as well as disease. Recently, studies have described the accumulation of multiple CNVs as a disease modifying mechanism. While it has been characterized how additional CNVs may play a role in phenotype, in which ways and to what extent sex chromosomes are involved has not been fully described. We performed a secondary data analysis using the DECIPHER database on 2,273 de-identified individuals with 2 CNVs. CNVs were designated primary and secondary based on our criteria and characteristics of both CNV groups were …

Genetic Counselors' Experiences With And Approaches To Discordant Genotypic And Phenotypic Sex Detected Via Non-Invasive Prenatal Testing, Emily Stiglich

Dissertations and Theses (Open Access)

As the use of non-invasive prenatal testing becomes more ubiquitous during pregnancy, genetic counselors (GCs) will see clients more frequently for discordant sex identification via non-invasive prenatal testing (NIPT-DSI). Thus, it is imperative to investigate what GCs consider important when counseling about NIPT-DSI and assess how GCs perceive their role in such cases. Prenatal and pediatric GCs were surveyed regarding previous experiences of NIPT-DSI, comfort levels of topics relating to NIPT-DSI, and perceived importance of potential discussion topics in a counseling session (n = 108). The survey consisted of two vignettes, presenting cases of NIPT-DSI identified prenatally in one …

Identification And Molecular Analysis Of Dna In Exosomes, Jena Tavormina

Dissertations and Theses (Open Access)

Exosomes are heterogeneous nanoparticles 50-150nm in diameter. Exosomes contain many functional cargo components, such as protein, DNA, and RNA. While protein and RNA exosome content has been extensively studied, very little work has been done to characterize exosomal DNA. Here, we demonstrate that exosomal DNA is heterogeneous and its packaging into exosomes is dependent on the cell of origin. Furthermore, through a rigorous assessment of various isolation methods, we identify Size Exclusion Chromatography (SEC) as the best method for the isolation of exosomal DNA for downstream applications. Additionally, we evaluate the methylation status of exosomal DNA and demonstrate that exosomal …

Exploring The Potential Yield Of Prenatal Testing By Evaluating A Postnatal Population With Structural Abnormalities, Peyton Busby

Dissertations and Theses (Open Access)

After identification of one or more structural abnormalities in a fetus, pregnant women are offered a host of different testing options to identify a possible genetic cause for the structural abnormality(ies). When considering what type of test to undertake, there is limited information on the diagnostic yield of the varying testing options. Some women may miss an opportunity to gain the information they are seeking or make a less informed decision when they choose a testing option after identification of a structural abnormality due to this lack of information. This study aimed to identify the potential diagnostic yield of all …

The Impacts Of Insurance And Billing Considerations On The Practice And Attitudes Of Genetic Counselors, Emily Krosschell

Dissertations and Theses (Open Access)

Genesurance counseling has been identified as an integral part of many genetic counseling sessions, but little is known about the workflow impacts and genetic counselor perceptions of genesurance-related tasks. In this study, we aimed to characterize how insurance and billing considerations for genetic testing are being incorporated into genetic counselors’ practice; as well as describe current attitudes and challenges associated with their integration. An electronic survey was sent by email to members of the National Society of Genetic Counselors (NSGC). A total of 325 genetic counselors that provided direct patient care were included in data analysis. Results showed that the …

Outcomes Of Genetic Testing In A Genitourinary Genetics Clinic, Annelise Pace

Dissertations and Theses (Open Access)

Several known hereditary cancer syndromes confer an increased risk for genitourinary (GU)related malignancies. Various guidelines indicate when to refer patients to genetic counseling for GU-related hereditary cancer syndromes but there is limited research on the clinical picture of these patients, including their cancerous and non-cancerous features, the genetic testing strategy for this population, and the probability of having a positive germline mutation if testing is performed. The purpose of this study is to determine the most common indications for ordering genetic testing in a GU Genetics Clinic and evaluate whether there is a relationship between the indication for genetic testing …

Tumor Immunotherapy: Mechanisms Of Acquired Resistance And Characterization Of Immune Related To Xicities, Ashvin Jaiswal

Dissertations and Theses (Open Access)

Tumor immunotherapy has shown very promising clinical benefit across an array of cancers; however, two major challenges remain unresolved in the field. First, many patients do not respond to therapy at all or relapse after a period of remission. Second, there are often dose-limiting immune related adverse effects associated with immunomodulation.

In order to understand the mechanisms employed by tumors to evade immunotherapeutic responses, we established a murine model of melanoma designed to elucidate the molecular mechanisms underlying immunotherapy resistance. Through multiple in vivo passages, we selected a B16 melanoma tumor line that evolved complete resistance to combination blockade of …

Managing Variant Discrepancy In Hereditary Cancer: Clinical Practice, Barriers, And Desired Resources, Ellen Zirkelbach

Dissertations and Theses (Open Access)

Variants are changes in the DNA whose phenotypic effects may or may not be definitively understood. Because variant interpretation is a complex process, sources sometimes disagree on the classification of a variant, which is called a variant discrepancy. This study aimed to determine the practice of genetic counselors regarding variant discrepancies and to identify the barriers to counseling a variant discrepancy in hereditary cancer genetic testing. This investigation was unique because it was the first to address variant discrepancies from a clinical point of view. An electronic survey was sent to genetic counselors in the NSGC Cancer Special Interest Group. …

Genesurance Counseling: Patient Perspectives, Chelsea Wagner

Dissertations and Theses (Open Access)

Genetic counselors (GCs) have recently reported an increase in the discussion of insurance-related, or “genesurance,” topics during genetic counseling sessions. Despite increasing frequency, little knowledge exists about genesurance conversations and patient expectations. This study aimed to assess patient expectations of GCs in genesurance discussions and evaluate if health insurance literacy impacted these expectations. A 38-item survey, including a validated tool to assess health insurance literacy (HIL) was administered prior to patients receiving prenatal or cancer genetic counseling at three participating institutions. A total of 360 responses were analyzed. Key variables were compared using chi-square analysis and multivariable logistic regression was …

The Utilization Of Prenatal Microarray: A Survey Of Current Genetic Counseling Practices And Barriers, Leslie N. Durham, Leslie Durham

Dissertations and Theses (Open Access)

Chromosomal microarray (CMA) assesses chromosome copy number variants (CNVs) missed by standard karyotyping. The American College of Obstetricians and Gynecologists (ACOG) recommends CMA for all patients with fetuses with an ultrasound anomaly and suggests that it be made available to all women undergoing invasive testing. In order to assess prenatal genetic counselors’ (GCs) practices regarding the utilization of CMA we conducted a survey of their current practices, attitudes, and perceived barriers. Of the 192 respondents, 183 (95%) have incorporated CMA into clinical practice with the majority (64%) believing that the benefits of CMA outweigh the harms. However, only half (52%) …

Ethnic Identity And Teratogenic Risk Perceptions, Katie M. Chan

Dissertations and Theses (Open Access)

Elevated perceptions of teratogenic risk can cause anxiety and confusion among pregnant women. To assess whether ethnic identity and demographic factors can influence teratogenic risk perceptions, 194 pregnant women in Houston were surveyed using the Multigroup Ethnic Identity Measure (MEIM) and visual analog scales to quantify perceptions of teratogenic risk for common exposures during pregnancy. Overall, participants estimated an elevated baseline risk of 25% for birth defects among the general population. In addition, participants overestimated birth defect risks for specific exposures, such as alcohol and marijuana. Based on the MEIM scores, ethnic identity was not significantly associated with teratogenic risk …

No Difference In Health Related Quality Of Life Between Therapeutic Options For Type 1 Gaucher Disease, Victoria Wagner

Dissertations and Theses (Open Access)

Type 1 Gaucher disease (GD) is the most common lysosomal storage disorder. Previously, treatment for GD was limited to intravenous enzyme replacement therapy (ERT). ERT reduces symptoms and increases health­related quality of life (HRQoL) in people with this condition. In 2014, oral substrate reduction therapy (SRT) was approved for type 1 GD treatment. Although both therapies alleviate disease symptoms, effects of SRT on HRQoL and preferences for therapy are not well established. Electronic surveys were administered to adults with type 1 GD. HRQoL was scored with the Short Form­36 Version 2 ® Health Survey and descriptive statistics were used to …

Factors Influencing Uptake Of Risk-Reducing Salpingo-Oophorectomy By Brca1 And Brca2 Mutation Carriers, Victoria E. Breen

Dissertations and Theses (Open Access)

Germline mutations in the BRCA1 and BRCA2 genes are associated with significantly increased risks for ovarian cancer. The National Comprehensive Cancer Network (NCCN) currently recommends that female BRCA mutation carriers undergo risk-reducing salpingo-oophorectomy (RRSO) after age 35; however, not all women elect this option. The purpose of this study was to prospectively survey women with BRCA mutations currently undergoing ovarian cancer screening about their intention to have an RRSO and the various factors influencing their decision. Of the 26 women who completed our survey, 26 (100%, CI: 86.8-100) plan to undergo an RRSO in their lifetime. The average woman reported …

Cancer Incidence In First And Second Degree Relatives Of Brca1 And Brca2 Mutation Carriers, Haley Streff

Dissertations and Theses (Open Access)

Mutations in the BRCA1 or BRCA2 genes are associated with increased risks for breast, ovarian, and several other cancers. The purpose of this study was to evaluate the incidence of cancers in first and second degree relatives of BRCA mutation carriers compared to the general population. A total of 1086 pedigrees of BRCA mutation carriers were obtained from a prospectively maintained, internal review board approved study of persons referred for clinical genetic counseling at The University of Texas MD Anderson Cancer Center. We identified 9032 first and second degree relatives from 784 pedigrees which demonstrated a clear indication of parental …

Obstetrician And Gynecologist Utilization Of The Nipt Expanded Testing Option, Sarah Mayes Ba

Dissertations and Theses (Open Access)

Noninvasive prenatal testing (NIPT) enables the detection of common fetal aneuploidies such as trisomy 21, trisomy 18, trisomy 13, and sex chromosome abnormalities via analysis of cell-free fetal DNA circulating in maternal serum. Although the accuracy of NIPT for fetal aneuploidy is expected to be higher than that of currently available alternative maternal serum screening options, the implications of results are not straight forward. In October 2013, the option to screen for additional trisomies and select microdeletion syndromes, such as 22q11.2 deletion syndrome and 5 p- syndrome, became clinically available. Due to this rapidly evolving prenatal screening technology, clinicians must …

Genetics Of Obesity In Starr County, Texas Mexican Americans, Heather M. Highland

Dissertations and Theses (Open Access)

Currently, over two-thirds of Americans are classified as over-weight or obese. Obesity increases risk for many other diseases including type 2 diabetes, heart disease, stroke, and cancer, making obesity the largest public health problem in America and most other Westernized nations. Hispanics have a higher rate of both obesity and type 2 diabetes, making them a particularly interesting population in which to study obesity. For the last 33 years, the Starr County Health Studies has collected an array of phenotypes and biological samples from residents of Starr County, along Texas-Mexico border. This study includes 825 subjects who were not known …

Correlation Matrix Analysis Identifies Gene Signatures Of Immune Cell Subsets And Their Interactions In Follicular Lymphoma, Jason R. Westin

Dissertations and Theses (Open Access)

There are important but ill-defined interactions between benign immune cell subsets and neoplastic B cells within follicular lymphoma (FL). Using the novel technique of correlation matrix analysis (CMA) of publicly available FL whole-tumor gene expression profiling (GEP) data, we have identified signatures of immune cell subsets. Overall survival correlated most highly with a model using signatures of macrophages, T cells, and stroma, which was able to add significantly to existing clinical prognostic tools. From our own data of a cohort of 43 FL tumors sorted into B-cell and non-B cell (NB) fractions for GEP, CMA of the tumor infiltrating NB …

Dissecting The Roles Of Trim24 In Regulation Of Hepatic Lipid Metabolism And Inflammation, Lindsey C. Minter

Dissertations and Theses (Open Access)

DISSECTING THE ROLES OF TRIM24 IN REGULATION OF HEPATIC LIPID

METABOLISM AND INFLAMMATION

Lindsey Cauthen Minter, B.S., B.A.

Advisory Professor: Michelle C. Barton, Ph.D.

In this dissertation, I report the characterization of a new mouse model that recapitulates development of hepatocellular carcinoma (HCC) following spontaneous hepatic lipid accumulation, inflammation, and damage of liver tissue, due to complete loss of Trim24 expression. In human HCC and other cancers, TRIM24 expression is aberrantly high, while deletion of TRIM24 in the mouse has been shown to act as a liver specific tumor suppressor. The hypothesis tested here was that TRIM24, the E3 ubiquitin …