Search Results - EGA European Genome-Phenome Archive

Clinical and genetic factors associated with tumor response to neoadjuvant (chemo)radiotherapy, survival and recurrence risk in rectal cancer

Rectal cancer poses challenges in preoperative treatment response, with up to 30% achieving a complete response (CR). Personalized treatment relies on accurate identification of responders at diagnosis. This study aimed to unravel CR determinants, overall survival (OS), and time to recurrence (TTR) using clinical and targeted sequencing data. Analyzing 402 patients undergoing preoperative treatment, tumor stage, size, and treatment emerged as robust response predictors. CR rates were higher in smaller, early-stage, and intensively treated tumors. Targeted sequencing analyzed 216 cases, while 120 patients provided hotspot mutation data. KRAS mutation dramatically reduced CR odds by over 50% (odds ratio [OR]=0.3 in the targeted sequencing and OR=0.4 hotspot cohorts, respectively). In contrast, SMAD4 and SYNE1 mutations were associated with higher CR rates (OR=6.0 and 6.8, respectively). Favorable OS was linked to younger age, CR, and low baseline carcinoembryonic antigen levels. Notably, CR and an APC mutation increased TTR, while a BRAF mutation negatively affected TTR. Beyond tumor burden, SMAD4 and SYNE1 mutations significantly influenced CR. KRAS mutations independently correlated with radiotherapy resistance, and BRAF mutations heightened recurrence risk. Intriguingly, nonresponding tumors with initially small sizes carried a higher risk of recurrence. These findings offer insights into rectal cancer treatment response, guiding personalized therapeutic strategies. By uncovering factors impacting CR, OS, and TTR, this study underscores the importance of tailored approaches for rectal cancer patients. These findings, based on extensive analysis and mutation data, pave the way for personalized interventions, optimizing outcomes in the challenges of rectal cancer preoperative treatment.

Study EGAS00001007501

The University of Hong Kong Intestinal Metaplasia Organoids Study

Background: Gastric intestinal metaplasia (IM) is a pre-cancerous stage spanning a morphological spectrum that is poorly represented by human cell line models. Objective: We aim to establish and characterize human IM cell models to better understand IM progression along the cancer spectrum. Design: A large human gastric IM organoid (IMO) cohort (n=28), their clonal derivatives and normal gastric organoids (n=42) for comparison were established. Comprehensive multi-omics profiling and functional characterization were performed. Results: Single-cell transcriptomes revealed IMO cells spanning a spectrum from hybrid gastric/intestinal to advanced intestinal differentiation. Their lineage trajectories connected different cycling and quiescent stem and progenitors, highlighting differences in gastric to IM transition and the potential origin of IM from STMN1 cycling isthmus stem cells. Hybrid IMOs showed impaired differentiation potential, high lineage plasticity beyond gastric or intestinal fates, and reactivation of a fetal gene program. Cell populations in gastric IM and cancer tissues were highly similar to those derived from IMOs and exhibited a fetal signature. Genomically, IMOs showed elevated mutation burden, frequent chromosome 20 gain, and epigenetic de-regulation of many intestinal and gastric genes. Functionally, IMOs were FGF10 independent and showed downregulated FGFR2. Several IMOs exhibited a cell-matrix adhesion independent (CMi) subpopulation that displayed chromosome 20 gain but lacked key cancer driver mutations, potentially representing the earliest neoplastic precursor of IM-induced gastric cancer. Conclusions: Overall, our IM organoid biobank captured the heterogeneous nature of IM, revealing mechanistic insights on IM pathogenesis and progression, offering an ideal platform for studying early gastric neoplastic transformation and chemoprevention.

Study EGAS00001007899

NHLBI GO-ESP: Family Studies (Mendelian Lipid Disorders)

The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied. These data may help researchers understand the causes of disease, contributing to better ways to prevent, diagnose, and treat diseases, as well as determine whether to tailor prevention and treatments to specific populations. This could lead to more effective treatments and reduce the likelihood of side effects. GO-ESP is comprised of five collaborative components: 3 cohort consortia - HeartGO, LungGO, and WHISP - and 2 sequencing centers - BroadGO and SeattleGO. In this study, we seek to identify the genetic cause of two monogenic lipid disorders-severe hypercholesterolemia and familial hypoalphalipoproteinemia. Monogenic severe hypercholesterolemia is clinically characterized by elevated total and low-density lipoprotein (LDL) cholesterol levels in plasma. Elevated LDL-cholesterol levels lead to excessive deposition of cholesterol in arterial walls, which eventually results in accelerated atherosclerosis and premature cardiovascular disease (CVD). Monogenic hypercholesterolemia has a prevalence of approximately one in 500 individuals, making it one of the most common inherited disorders. To date, mutations in the LDL receptor (LDLR) ligand-binding domains of APOB and PCSK9 have been shown to cause hypercholesterolemia. While mutations in these genes can explain a large percentage of clinically diagnosed patients, the underlying molecular determinant in a substantial fraction of patients remains unknown. Familial hypoalphalipoproteinemia (low HDL-C) is defined by an HDL-C below the age- and sex- specific 10th percentile. ABCA1, LCAT, and APOA1 are known to cause familial hypoalphalipoproteinemia. We hypothesize that: (1) additional novel genes responsible for Mendelian forms of low HDL-C exist; and (2) the causal gene and mutation(s) in each family may be discovered with exome analysis of just a few affected individuals in each pedigree.

Study phs000587

Atherosclerosis Risk in Communities (ARIC) Cohort

The Atherosclerosis Risk in Communities (ARIC) Study, sponsored by the National Heart, Lung and Blood Institute (NHLBI), is a prospective epidemiologic study conducted in four U.S. communities. The four communities are Forsyth County, NC; Jackson, MS; the northwest suburbs of Minneapolis, MN; and Washington County, MD. ARIC is designed to investigate the etiology and natural history of atherosclerosis, the etiology of clinical atherosclerotic diseases, and variation in cardiovascular risk factors, medical care and disease by race, gender, location, and date. ARIC includes two parts: the Cohort Component and the Community Surveillance Component. The Cohort Component began in 1987, and each ARIC field center randomly selected and recruited a cohort sample of approximately 4,000 individuals aged 45-64 from a defined population in their community. A total of 15,792 participants received an extensive examination, including medical, social, and demographic data. These participants were examined with the baseline visit occurring in 1987-89, the second visit in 1990-92, the third visit in 1993-95, the fourth visit in 1996-98, the fifth visit in 2011-13, the sixth visit 2016-17 and the seventh visit 2018-19. Follow-up occurs yearly by telephone to maintain contact with participants and to assess health status of the cohort. In the Community Surveillance Component, these four communities were investigated to determine the community-wide occurrence of hospitalized myocardial infarction and coronary heart disease deaths in men and women aged 35-84 years. Hospitalized stroke is investigated in cohort participants only. Starting in 2006, the study conducted community surveillance of inpatient (ages 55 years and older) and outpatient heart failure (ages 65 years and older) for heart failure events beginning in 2005. Community Surveillance for non-cohorts ended in event year 2014. ARIC is currently funded through 2028. The ARIC Cohort is utilized in the following dbGaP sub-studies. To view genotypes, other molecular data, and derived variables collected in these sub-studies, please click on the following sub-studies below or in the "Sub-studies" section of this top-level study page phs000280 ARIC Cohort. phs000557 ARIC_CARe phs000090 GENEVA_ARIC phs000223 PAGE_CALiCo_ARIC phs000398 GO-ESP: HeartGo_ARIC phs000668 CHARGE_ARIC phs000860 MICORTEX phs001536 CCDG_ARIC

Study phs000280

NHLBI GO-ESP: Lung Cohorts Exome Sequencing Project (Pulmonary Arterial Hypertension)

The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied. These data may help researchers understand the causes of disease, contributing to better ways to prevent, diagnose, and treat diseases, as well as determine whether to tailor prevention and treatments to specific populations. This could lead to more effective treatments and reduce the likelihood of side effects. GO-ESP is comprised of five collaborative components: 3 cohort consortia - HeartGO, LungGO, and WHISP - and 2 sequencing centers - BroadGO and SeattleGO. The syndrome of pulmonary hypertension (PH) is a pulmonary disease that carries very high morbidity and mortality. Pulmonary arterial hypertension (PAH) is a category of PH (WHO Group 1) that includes several entities (idiopathic or heritable PAH, and PAH associated with other diseases such as connective tissue diseases including scleroderma-associated PAH) and carries a dismal prognosis, in particular when it relates to scleroderma-associated PAH (median survival of about 4 years). It is believed that the severity of structural changes involving the pulmonary vasculature and right ventricular failure are genetically determined. The 'Genomics and Genetics of Pulmonary Arterial Hypertension' study at Johns Hopkins University aims to identify genetic determinants associated with risk of PAH in a cohort of European American and African American participants with and without PAH. The study also focuses on patients with scleroderma, who are further stratified according to those who have or do not have PAH. The broad goals of the Lung GO/ESP-GO falls into two general categories: (i) discovery of all variants (i.e., common and rare) in all protein-coding regions of the human genome (i.e., the exome) conferring risk to complex pulmonary diseases including PAH. The Johns Hopkins University PAH cohort offers a unique opportunity to elucidate genetic variants that cause PAH.

Study phs000290

Multi-omic and functional analysis for classification and treatment of sarcomas with FUS-TFCP2 or EWSR1-TFCP2 fusions(H021/INF)

Many rare cancers are not well understood, and pathogenesis-directed therapies are often lacking, resulting in poor patient outcomes. Leveraging two (inter)national precision oncology trials that enroll large numbers of rare cancers, we investigated the clinical, histopathologic, molecular, and functional characteristics of rhabdomyosarcoma (RMS) with fusions of FUS or EWSR1 to the TFCP2 transcription factor, a recently discovered ultra-rare entity whose classification, pathogenesis, and optimal treatment are unclear. Unusually for fusion-driven sarcomas, most cases had highly rearranged genomes, including chromothripsis, and signs of defective homologous recombination DNA repair. All tumors showed extreme expression of a truncated TERT variant and the ALK receptor tyrosine kinase, which was additionally affected by intragenic deletions and aberrant splicing, resulting in the expression of shortened variants in 58% of cases. Three ALK variants were oncogenic in immortalized cells, and patient-derived tumor cells expressing two variants responded to certain ALK inhibitors. Other recurrent alterations included CDKN2A/MTAP co-deletions and mutations in PAPPA2, encoding an IGFBP5-specific proteinase, in 67% and 25% of cases, respectively. DNA methylation analysis, along with 19 other soft-tissue sarcoma classes, revealed a close relationship with undifferentiated sarcoma but not other RMS subtypes, suggesting that TFCP2-rearranged RMS is a separate entity, possibly arising from a distinct cell of origin. Expression of TFCP2 fusions in immortalized human cells blocked late myogenic differentiation and significantly induced genes that were also highly expressed in patient tumors, including ALK, TERT, and two known regulators of skeletal muscle cells, IGFBP5 and PTH1R. Genome-wide chromatin profiling demonstrated direct binding of FUS-TFCP2 to the ALK and TERT loci outside their regular promoters, which correlated with the expression of alternative transcript variants. Finally, FUS-TFCP2 inhibited the repair of DNA double-strand breaks in immortalized cells, rendering them sensitive to treatment with cisplatin. This study provides insight into the pathogenesis and therapeutic vulnerabilities of a new RMS subtype and illustrates the value of linking comprehensive molecular diagnostics and functional annotation within multicenter consortia to improve the understanding and clinical management of rare cancers.

Study EGAS00001006939

National Cancer Institute Cancer Genome Characterization Initiative (CGCI)

The Office of Cancer Genomics at the National Cancer Institute sponsored a series of studies as part of the Cancer Genome Characterization Initiative (CGCI) to assess novel emerging sequencing technologies in cancer. The CGCI program included comprehensive characterization of the genetic aberrations found in different pediatric and/or adult tumors. CGCI characterized a number of B-cell non-Hodgkin lymphomas (including diffuse large B-cell lymphoma (DLBCL) from patients with and without HIV+ infection, follicular lymphoma (FL), as well as adult and pediatric Burkitt lymphomas), and additional HIV-associated tumors (including DLBCL, lung, and cervical cancers). All data from these projects is available at the NCI Genomic Data Commons. Individual project descriptions are available by disease on the substudy pages (links are included at the top of this page). Brief summaries are as follows: Non-Hodgkin Lymphoma (NHL) - CGCI investigators probed genomic alterations more deeply than had previously been possible by using state-of-the-art RNA sequencing (mRNA-seq) and whole genome shotgun sequencing (WGS) coupled with leading edge bioinformatics, data management and analysis approaches. The project sequenced tumor DNA and/or RNA from 117 NHL tumor samples and 10 cell lines. This included the genomes or exomes of 1 Follicular Lymphoma (FL) and 13 diffuse large B-cell lymphoma (DLBCL) cases, all with matched constitutional DNA sequenced to comparable depths, RNA-sequencing (mRNA-seq) of 92 DLBCL, 12 FL and 8 B-cell NHL cases with other histologies and 10 DLBCL-derived cell lines. The DLBCL cases and cell-lines are from the two major subtypes of DLBCL: germinal center B-cell (GCB) and activated B-cell (ABC). HIV+ Tumor Molecular Characterization Project (HTMCP) - This project was a joint effort of the Office of Cancer Genomics (OCG) and the Office of HIV and AIDS Malignancy (OHAM). Its goals were to characterize HIV-associated cancers (obtained from HIV-infected patients) and compare them to the same types of cancers from patients without HIV infection. Investigators performed 30X genome sequencing of 100 cases of paired tumor and germline DNA, along with transcriptome sequencing in each of 3 types of HIV+ tumors (DLBCL, lung and cervical cancers). These platforms allow discovery of mutations both in coding and non-coding genomic regions, gene expression and genomic alterations (including translocations, insertions and deletions). Comparing tumors of cancer patients both with and without HIV-infection provides insight into the potential function of this virus in certain cancers. Burkitt Lymphoma Genome Sequencing Project (BLGSP) - This project was a collaborative effort between the National Cancer Institute and the Foundation for Burkitt Lymphoma Research to develop a databank of the many alterations found in Burkitt lymphoma (BL), an uncommon type of Non-Hodgkin lymphoma that occurs most often in children and young adults. The goal of the BLGSP was to explore potential genetic changes in patients with BL that could lead to better prevention, detection and treatment of the cancer. The project characterized the alterations of the tumors' genomes (with matched normal as control) and transcriptomes by sequencing the DNA and RNA of each case. Using the data generated, the ultimate goals of the project was to discover the molecular changes that are present in BL patients and then determine how those changes correlate with treatment regimen and outcome. CGCI data is accessible at the NCI's Genomic Data Commons (GDC) via the GDC's Data Portal and from each of the CGCI Publication Pages at the GDC (Please see the "Supplemental Links" section of any CGCI publication's "Publication Information and Associated Data Files page" at the GDC.). Available datasets include raw sequencing data, datasets generated by the original CGCI research teams (fully annotated clinical information and higher-level/analyzed molecular characterization data), as well as higher level data generated by the GDC. Please see the CGCI Use and Publication Guidelines for updated details on the sharing of any CGCI substudy data, including how to cite CGCI.To learn more about the CGCI studies, please visit the CGCI Program website.

Study phs000235

International Consortium to Identify Genes and Interactions Controlling Oral Clefts

Oral clefts represent the most common group of craniofacial birth defects in humans, and include cleft lip with or without cleft palate (CL/P) and cleft palate (CP). Oral clefts have a complex and heterogeneous etiology, with strong evidence for both genetic and environmental causal factors. Candidate gene studies and genome wide linkage studies have yielded compelling but inconsistent evidence that multiple genes control risk, and several studies have shown evidence for interaction between genes and environmental exposures, especially maternal smoking and nutrient intake. This consortium pulls together a very large collection of cases and their parents from multiple populations, and offers a unique opportunity to expand the search for genes controlling risk to the genome wide level. The specific aims are: To conduct a genome wide analysis on 2000+ case-parent trios ascertained through a case with isolated, non-syndromic CL/P or CP to test for linkage and disequilibrium. Initial analysis will consist of individual tests for gene effects while simultaneously testing for GxE interaction with common maternal exposures including vitamin supplementation, cigarette smoking and alcohol consumption (which have all been implicated as environmental risk factors for oral clefts). To use haplotypes in tests for GxE interaction incorporating population specific estimates. Since haplotype frequencies vary among populations, trios will be assigned haplotypes in a stratified estimation and then a pooled test statistic will be constructed. To test for interaction between SNPs in different genes showing evidence of influencing risk in a test for GxG interaction. To test for interaction between genes and maternal biomarkers using trios from Utah where measures of plasma folate, vitamin B-6, homocysteine and zinc in mothers are available. This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org), which was developed through the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to oral clefts through large-scale genome-wide association studies of well-characterized cases and their parents from multiple populations. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). The study was supported by the National Institute of Dental and Craniofacial Research (NIDCR). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington.

Study phs000094

Whole-exome and targeted sequencing of pediatric hyperdiploid B-cell precursor acute lymphoblastic leukemia

High hyperdiploidy defines the largest genetic entity of childhood acute lymphoblastic leukemia (ALL). Despite its relatively low recurrence risk, this subgroup generates a high proportion of relapses. The cause and origin of these relapses remains obscure. We therefore explored the mutational landscape in high hyperdiploid (HD) ALL with whole-exome (n=19) and subsequent targeted deep sequencing of 60 genes in 100 relapsing and 51 non-relapsing cases. We identified multiple clones at diagnosis that were primarily defined by a variety of mutations in receptor tyrosine kinase (RTK)/Ras pathway and chromatin-modifying genes. The relapse clones consisted of reappearing as well as new mutations, and overall contained more mutations. Although RTK/Ras pathway mutations were similarly frequent between diagnosis and relapse, both intergenic and intragenic heterogeneity was essentially lost at relapse. CREBBP mutations, however, increased from initially 18-30% at relapse, then commonly co-occurred with KRAS mutations (P<0.001) and these relapses appeared primarily early (P=0.012). Our results confirm the exceptional susceptibility of HD ALL to RTK/Ras pathway and CREBBP mutations, but, more importantly, suggest that mutant KRAS and CREBBP might cooperate and equip cells with the necessary capacity to evolve into a relapse-generating clone.

Study EGAS00001001113

Characterizing microbiome-directed fibre snacks in gnotobiotic mice and humans

Knowledge of the interrelationships between what we eat and the configurations of our gut microbial communities is providing important insights into how food components that are not directly metabolized by human enzymes are linked to our physiology and health status. Changing food preferences brought about by Westernization that have deleterious health effects1,2, plus rapid population expansion, ongoing challenges to sustainable agriculture, and other forces contributing to increased food insecurity, are catalyzing efforts to identify more nutritious and affordable foods3. The gut microbial community is complex, dynamic, and exhibits considerable intra- and interpersonal variation in its composition and functions. The massive number of potential interactions between its components makes it challenging to define the mechanisms by which food ingredients affect community properties. There is also a paucity of information about the ‘bioactive’ ingredients of foods that influence the fitness and expressed functions of community members. Here, plant fibres, from different sustainable sources and targeting distinct features of obese human gut microbiomes in gnotobiotic mice, were formulated into snack prototypes and used to supplement controlled diets consumed by overweight and obese adults; the results revealed fibre-specific changes in their microbiomes that were linked to changes in their plasma proteomes indicative of altered physiologic state.

Study EGAS00001005268

Comprehensive Genomic Characterization of Refractory Multiple Myeloma Reveals a Complex Mutational and Structural Landscape Associated with Drug Resistance (H067)

Outcome of patients with multiple myeloma (MM) refractory to immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs) is still very poor. To elucidate the genetic landscape of relapsed/refractory MM (RRMM) we performed whole genome and transcriptome sequencing of 39 heavily pretreated RRMM patients with at least double refractoriness revealing complex structural changes and a high mutational load (H067/K08K). We found a median of 67 structural variants and 116 nonsynonymous exonic mutations per patient. Assessment of oncogenic drivers showed NRAS, BRAF, TP53, KRAS, SLC4A7, FAM46C, DIS3, RB1, KMT2C, MLLT4, EWSR1, HCFC2, and COPS3 as significantly mutated. We found multiple genomic regions with bi-allelic events affecting known tumor suppressor genes, most frequently TP53, RB1, and TRAF3. Supervised analysis of mutational signatures showed a major contribution of Cosmic signature 6 associated with deficiency in DNA mismatch repair and the ‘BRCAness’ signature which coincided with mutations in genes known to confer PARP inhibitor sensitivity. Recurrently mutated gene networks included genes with relevance for PI and IMiD activity, the latter including in particular members of the Cereblon and the COP9 signalosome complex. In conclusion, this comprehensive genomic characterization revealed a complex mutational and structural landscape in RRMM and highlights potential implications for therapeutic strategies.

Study EGAS00001004363

Predicting Chemotherapy-Induced Mucositis with Genetic and Clinical Factors

We hypothesized that genetic variability in the enzymes/proteins involved in drug metabolism, inflammation, and immune function is a major underlying contributor to mucositis incidence and progression and that, based on this variability we can identify variants that influence risk, and develop a mucositis progression prediction model that improves on existing models by incorporating genetic variability along with clinical factors. Using genome wide association study (GWAS) combined with a pathway candidate gene approach and a modified case-control study method, we investigated the hypothesis in a sample of 1092 patients who received a myeloablative dose of melphalan (MEL) followed by autologous hematopoietic stem cell (ASCT) transplantation as treatment for multiple myeloma and for whom banked blood stem cell samples and clinical data were available.

Study phs000545

Exome Sequencing of a family with thrombocytopenia, red cell macrocytosis, and lymphoblastic leukemia predisposition

A family with a history of bleeding, variable thrombocytopenia, red cell macrocytosis and two cases of pre B-cell acute lymphoblastic leukemia was studied in a single visit. The family was assessed for bleeding history using a bleeding questionnaire. Additionally, complete blood counts were measured and whole blood was collected from five affected individuals and three unaffected individuals for DNA extraction and whole exome sequencing. The goal of this study is to determine the genetic cause of thrombocytopenia, red cell macrocytosis, and predisposition to leukemia in a family. It is hoped that the information obtained from this study will help researchers understand the genetic and molecular basis of platelet and red cell production, as well as leukemia predisposition.

Study phs000873

CIDR Estrogen Receptor Negative Breast Cancer in African American Women: DNA Methylation, Reproductive Events, and Mammary Epithelial Cell Populations

We conducted methylation profiling of breast tumor DNA from Formalin-Fixed Paraffin-Embedded (FFPE) samples for 1,550 cases from a cohort of Black women from the Black Women’s Health Study (BWHS), the Women’s Circle of Health Study (WCHS), and from the Pathways Study using the Illumina MethylationEPIC array. We will examine differentially methylated loci (DML) between ER+ and ER- tumors, and by age at onset of breast cancer. Combining these data with previously analyzed samples (n=385), we will consider associations between reproductive risk factors and top DML by age at diagnosis and ER status, examining the complex relationships between methylation, tumor and patient characteristics, and reproductive risk factors using structural equation modeling.

Study phs002688

DNA Methylation Characterization of Fusion-Positive and Fusion-Negative Rhabdomyosarcoma

Rhabdomyosacoma (RMS) is a common pediatric soft tissue tumor that is associated with the skeletal muscle lineage. RMS comprises two major subtypes: fusion-positive (FP, most commonly PAX3- FOXO1 or PAX7-FOXO1) and fusion-negative (FN, frequently associated with mutations in RAS pathway). Our previous study demonstrated that FP and FN tumors exhibit distinct DNA methylation profiles. In this study, further investigation of genome-wide DNA methylation profiles in RMS tumors revealed DNA methylation differences between AX3-FOXO1 and PAX7-FOXO1 subsets in FP RMS, and between RAS mutation and RAS wild-type subsets in FN RMS. These data provide new insight into the relationship of DNA methylation with mutational changes and transcriptional organization in FP and FN RMS.

Study phs001970

Germline variants in UHRF1 are associated with multi-locus imprinting disturbance in humans and mice

Genomic imprinting provides is an epigenetic process crucial for normal development and is disrupted in congenital imprinting disorders(CIDs). There is great interest in the clinical consequences and aetiology of multilocus imprinting disturbance(MLID) which occurs in some individuals with CID, though the cause of MLID is unknown in most cases. We investigated a kindred with a CID and MLID and identified a rare genetic variant in the UHRF1 gene which has a critical role in the establishment and maintenance of DNA methylation. We generated a mouse model and found that the equivalent Uhrf1 variant was associated with prenatal lethality and disruption of normal imprinting mechanisms. These findings support UHRF1 as a novel candidate gene for CIDs with MLID.

Study EGAS50000001179

Combined – whole blood and skin fibroblasts - transcriptomic analysis in Psoriatic arthritis.

Whole blood RNA sequencing was performed longitudinally in 27 subjects with PsA at the beginning, one month and six months after treatment and response to therapy was defined at 6 months. As control groups 7 healthy individuals and 9 subjects with rheumatoid arthritis were recruited combined with public RNA-sequencing datasets from patients with psoriasis and systemic lupus erythematous. Differential expression analysis and weighted gene co-expression network analysis were performed to identify gene expression signatures, while deconvolution and flow cytometry to characterize the peripheral blood immune cell profile. RNA sequencing of skin fibroblasts was performed in a subset of affected (n=3) and healthy individuals (n=3) combined with CellChat to identify the blood-skin fibroblasts interaction network.

Study EGAS00001006288

Genomic and immune profiling of pre-invasive lung adenocarcinoma

Adenocarcinoma in situ and minimally invasive adenocarcinoma are the pre-invasive forms of lung adenocarcinoma. The genomic and immune profiles of these lesions are poorly understood. Here we report exome and transcriptome sequencing of 98 lung adenocarcinoma precursor lesions and 99 invasive adenocarcinomas. We have identified EGFR, RBM10, BRAF, ERBB2, TP53, KRAS, MAP2K1 and MET as significantly mutated genes in the pre/minimally invasive group. Classes of genome alterations that increase in frequency during the progression to malignancy are revealed. These include mutations in TP53, arm-level copy number alterations, and HLA loss of heterozygosity. Immune infiltration is correlated with copy number alterations of chromosome arm 6p, suggesting a link between arm-level events and the tumor immune environment.

Study EGAS00001004006

NHLBI TOPMed: The Genetic Epidemiology of Asthma in Costa Rica

This administrative supplement to the project, "The Genetic Epidemiology of Asthma in Costa Rica" (R37 HL066289) is in response to NOT-HL-14-029 to perform whole genome sequencing (WGS) on existing NHLBI populations. We focus on asthma because of its public health significance. Asthma affects 26 million U.S. children and adults, remains a major cause of morbidity (one-half million hospitalizations a year) and is the most common cause of school and work days lost. Asthma-related costs are estimated to be over $12.7 billion annually. The Asthma Probands for both the extended pedigrees and the trios utilized in this study were selected on the basis of a physician diagnosis of asthma; a history of recurrent asthma attacks or at least 2 respiratory symptoms; and either airway hyperresponsiveness to methacholine or significant response to bronchodilator (Albuterol) administration. These criteria are identical to the criteria used in the Childhood Asthma Management Program (CAMP). The three primary goals of this project are to: (1) identify common and rare genetic variants that determine asthma and its associated phenotypes (height, weight, IgE level, lung function, bronchodilator response, steroid treatment response) through whole genome sequencing (WGS); (2) perform novel family based association analysis of our WGS data to identify novel genes for asthma; and (3) integrate epigenomic and transcriptomic data with our WGS data and determine the epistatic interactions present using systems genomics approaches. Identification of the molecular determinants of asthma remains an important priority in translational science. Genome-wide association studies (GWAS) have been successful in this regard, identifying at least 10 novel susceptibility genes for asthma. However, as with most complex traits, the variants identified by GWAS explain only a fraction of the estimated heritability of this disorder. Herein, we propose a novel family-based study design and state-of-the-art genome sequencing techniques to map a set of sequence variants for asthma and its associated phenotypes and assess the interrelationships of the identified genes and variants using systems genomics methods. We have assembled a team of investigators highly-skilled and expert in whole genome sequencing (Drs. Michael Cho and Benjamin Raby), genetic association analysis (Drs. Scott T. Weiss, Jessica Lasky-Su and Christoph Lange), integrative genomics (Drs. Raby, Kelan Tantisira, Augusto Litonjua and Dawn DeMeo), and systems genomics (Drs. Weiss, Amitabh Sharma, Lange and Raby) to address this important problem with both a novel study design and data set.

Study phs000988

A genotype-phenotype study of tumors from patients with inherited mutations in DNA repair genes

This study investigated the genomic landscape of tumors from patients with inherited mutations in DNA repair genes. The aim of this study was to determine the relationship between locus-specific loss of heterozygosity (LOH) and genomic signatures of homologous recombination-based DNA repair (HR) deficiency in tumors associated with pathogenic germline variants in DNA repair genes. Cohorts of pathogenic germline variant (PGV) carriers with different cancer types were identified via a cancer genetics registry and clinical practice at Penn Medicine and through our collaborator network. Tumors were analyzed with next generation sequencing (whole exome and/or targeted panel sequencing) with or without transcriptomic analyses. Sub-study #1 "Non-breast/ovarian tumors in germline BRCA1/2 carriers". This study investigated primary non-breast/ovarian tumors that arise in individuals with BRCA1/BRCA2 pathogenic germline variants (PGVs). Whole exome sequencing (WES) using Agilent All-Exon Kit v7 hybrid capture probes was performed on matched tumor and blood germline normal DNA on an Illumina HiSeq. Individual WES data from DNA samples from tumor and normal are available. Sub-study #2: "Breast tumors in germline CHEK2 carriers". This study investigated primary breast tumors that arise in individuals with CHEK2 pathogenic germline variants (PGVs). Whole exome sequencing (WES) using Agilent All-Exon Kit v7 hybrid capture probes was performed on matched tumor and blood germline normal DNA on an Illumina HiSeq. Whole transcriptome RNAseq was performed on tumors. Individual WES data from DNA samples from tumor and normal and RNAseq data from tumor are available. Sub-study #3: "Breast tumors in germline TP53 carriers". This study investigated primary breast tumors that arise in individuals with TP53 pathogenic germline variants (PGVs). Whole genome sequencing (WGS) and/or custom panel targeted sequencing was performed on matched tumor and blood germline normal DNA on an Illumina HiSeq. Whole transcriptome RNAseq was performed on tumors and normal breast tissue. Individual WGS or targeted data from DNA samples from tumor and normal and RNASeq data from tumor and normal are available. Sub-study #4: "Prostate tumors in germline DNA repair carriers". This study investigated prostate tumors that arise in individuals with a variety of pathogenic germline variants (PGVs). Whole genome sequencing (WGS) and/or custom panel targeted sequencing was performed on matched tumor and blood germline normal DNA on an Illumina HiSeq. Whole transcriptome RNAseq was performed on tumors and normal prostate tissue. Individual WGS or targeted data from DNA samples from tumor and normal and RNASeq data from tumor and normal are available.

Study phs003348

Enrichment of PTPRT and JAK2 mutations in lung cancer from African Americans and evidence for increased GI and HRD in LUSC

The goal of this study is to compare the somatic mutation landscape between European Americans and African Americans. It includes various histological forms of lung cancer. In LUAD, we find increased prevalence of PTPRT and JAK2 mutations among African Americans. These proteins function in the same pathway and as such, this may be a new actionable target for lung cancer. We have also examined the landscape of copy number profiles in African Americans and European Americans.

Study phs001895

NHLBI TOPMed: Children's Health Study (CHS) Integrative Genomics and Environmental Research of Asthma (IGERA)

The Integrative Genomics and Environmental Research of Asthma (IGERA) Study was proposed to collect immortalized cell lines, RNA, cDNA and DNA from 400 well-characterized subjects who participated in the southern California Children's Health Study (CHS) and to develop an accompanying database for these samples consisting of extensive phenotype, exposure, genome-wide genotype, gene expression, and methylation data. A subset of Hispanic-White participants (n=160) were included in the TOPMed project, including 77 asthma cases and 83 controls.

Study phs001603

Genome-Wide Analysis of Aberrant Position and Sequence of Plasma DNA Fragment Ends in Patients With Cancer

This study investigated fragmentation characteristics in plasma cell-free DNA and evaluated the relevance of such analysis for cancer diagnostics. Specifically, we performed whole genome sequencing (WGS) of healthy individuals and cancer patients, and evaluated genome-wide coverage and sequences surrounding fragment ends. This was a retrospective study of archived plasma samples. The WGS data are available through this submission. Detailed study design and findings were published in Budhraja et al. Science Translational Medicine 2023.

Study phs003170

Longitudinal Assessment of Methylmercury and Gut Microbes During Pregnancy

Methylmercury is a potent neurotoxin, and the fetal period is the most vulnerable exposure period. There is significant variability in methylmercury metabolism, which has been attributed to differences in the structure and function of the gut microbiome. Our main objective was to better understand the interplay between gut microorganisms and methylmercury metabolism during pregnancy. To address this aim, associations were investigated between maternal biomarkers (blood, hair, stool) for prenatal methylmercury exposure and maternal gut microbiota during early and late gestation.

Study phs001768

Single cell targeted DNA-sequencing (and antibody sequencing) of high hyperdiploid B-ALL

This dataset contains all sequencing data of the publication "Single-cell DNA and Surface Protein Characterization of High Hyperdiploid Acute Lymphoblastic Leukemia at Diagnosis and During Treatment". We provide both the raw fastq-files as well as the processed data in the form of .h5 files. There are 13 patients: XJ176, XH135, XJ180, XI145, XI148, XI167, XI150, XJ175, XJ178, XI162, XF98, XG111 and XG115. Of 9 patients, also follow-up samples during/after treatment were sequenced: XJ180, XI145, XI148, XI167, XI150, XJ175, XJ178, XI162 and XG111. To identify the cell types and distinguish between normal and leukemic cells, cell surface proteins were also captured for 6 samples: XF98, XG111 (at diagnosis and during treatment), XG115, XI162 (after treatment) and XJ175 (after treatment). All samples were processed on the MissionBio platform with a custom amplicon panel, and DaB-seq for the combined targeted DNA and protein sequencing.

Dataset EGAD50000000829

Sequencing of serial plasma and multiregional tumor samples in a patient with metastatic breast cancer

Circulating tumor DNA analysis can be used to track tumor burden and analyze cancer genomes non-invasively but the extent to which it represents metastatic heterogeneity is unknown. Here, we follow a patient with metastatic ER and HER2 positive breast cancer receiving two lines of targeted therapy over 3 years. We characterize genomic architecture and infer clonal evolution in 8 tumor biopsies and 9 plasma samples collected over 1,193 days of clinical follow-up using exome and targeted amplicon sequencing.

Study EGAS00001001466

WGS of breast cancer diagnosed during pregnancy and matched control

The aim of this study was to compare the mutational landscape of breast cancer diagnosed during pregnancy (BCP) and breast cancer from age/stage non-pregnant patients (controls). We present whole genome sequencing data (Illumina HiSeq X ten platform) of tumor and matched normal tissues from 35 BCP patients and 20 controls. This work provides important novel biological insights and a unique resource to study the biology of breast cancer in young women and how pregnancy could modulate tumor biology.

Study EGAS00001002685

Mutagenic impact of radiotherapy in B-cell lymphoma and multiple myeloma

For refinement of the single base substitution and indel profiles induced by genotoxic platinum and ionizing radiation, DHL4 cells were treated with cisplatin or radiotherapy. Single cells from doses corresponding to lethal and half-lethal (medium), were expanded into single-cell derived colonies and then subjected to 60x whole genome sequencing. 16 bam files were generated.

Study EGAS50000000997

Transcriptomic changes in placenta associated with anesthesia, delivery mode and maternal diabetes

The goal of this study was to analyse the impact of maternal diabetes and other maternal factors such as birth mode and anaesthesia on placental transcriptomics. Placental tissue samples from both, the villous and the decidua were prepared and RNAseq was conducted; samples were from mothers with Type1 Diabetes or gestational diabetes or from control mothers.

Study EGAS50000000489

InterPregGen-GWAS-KAZ-3

Preeclampsia (PE) is a syndrome affecting pregnant mothers and fetus/babies characterised by hypertension and proteinuria, and is a leading cause of maternal and fetal death and of premature births worldwide. The InterPregGen Consortium was funded by a European Framework 7 (FP7) grant and grew out of the WTCCC3 GWAS comparing ~2000 UK PE mothers with ~6000 common UK controls. This dataset includes Infinium GSA genotyping of maternal, paternal and fetal PE cases and controls from Kazakhstan. This study is one component of the InterPregGen FP7 project. DNA samples for this component were collected by InterPregGen Consortium collaborators at the Scientific Center of Obstetrics, Gynecology and Perinatology, Almaty, Kazakhstan (Gulnara Svyatova, Principal Investigator).

Dataset EGAD00010001949

InterPregGen-GWAS-KAZ-2

Preeclampsia (PE) is a syndrome affecting pregnant mothers and fetus/babies characterised by hypertension and proteinuria, and is a leading cause of maternal and fetal death and of premature births worldwide. The InterPregGen Consortium was funded by a European Framework 7 (FP7) grant and grew out of the WTCCC3 GWAS comparing ~2000 UK PE mothers with ~6000 common UK controls. This dataset includes OmniExpress genotyping of maternal and fetal PE cases and controls from Kazakhstan. This study is one component of the InterPregGen FP7 project. DNA samples for this component were collected by InterPregGen Consortium collaborators at the Scientific Center of Obstetrics, Gynecology and Perinatology, Almaty, Kazakhstan (Gulnara Svyatova, Principal Investigator).

Dataset EGAD00010001947

InterPregGen-GWAS-KAZ-1

Preeclampsia (PE) is a syndrome affecting pregnant mothers and fetus/babies characterised by hypertension and proteinuria, and is a leading cause of maternal and fetal death and of premature births worldwide. The InterPregGen Consortium was funded by a European Framework 7 (FP7) grant and grew out of the WTCCC3 GWAS comparing ~2000 UK PE mothers with ~6000 common UK controls. This dataset includes lllumina 2.5-8 genotyping of maternal and fetal PE cases and controls from Kazakhstan. This study is one component of the InterPregGen FP7 project. DNA samples for this component were collected by InterPregGen Consortium collaborators at the Scientific Center of Obstetrics, Gynecology and Perinatology, Almaty, Kazakhstan (Gulnara Svyatova, Principal Investigator).

Dataset EGAD00010001945

Analysis of exonic somatic variants in light-chain amyloidosis (ALA) and ALA concomitant with multiple myeloma

We aim to provide the very first insight into ALA+MM molecular profiles and compare the results with ALA and with MM. Our detailed study of ALA and ALA+MM represents an important step towards improved understanding of their genetic and transcriptomic background, which is a prerequisite for development of optimal treatment strategies in the future.

Study EGAS00001004214

Characterizing the immune and genome landscapes for osteosarcoma

Osteosarcoma have heavily rearranged genomes and moderate tumor mutation burden, which suggests that the patients may express neoantigens that could be targeted by immune cells. To characterize the immunogenomic landscape of this disease, we performed genome, transcriptome, immune and proteomic profiling of 48 patients comprised largely of relapsed and metastatic cases from both pediatric and adult patients.

Study EGAS00001003247

Whole genome sequencing, DNA methylation, and gene expression data from gastrointestinal stromal tumor 30 patients

We performed WGS along with genome-wide DNA methylation and gene expression analyses in 30 GIST cases to determine the genomic and epigenomic differences between KIT exon 11 557��558 deletions and other KIT exon 11 mutations.

Study JGAS000604

Prospective cohort patients with Multiple sclerosis and controls

The sys4MS cohort comprises 350 patients with Multiple Sclerosis (MS) and 9 controls, with 2 years of follow-up. Baseline data includes demographics, clinical scales, disease duration and subtype and use of disease-modifying drugs, brain MRI (volumetry and lesion load), retinal thickness by OCT, genomics (GWAS), cytomics, and phosphoproteomics. Data at the end of follow-up includes clinical scales, brain MRI and OCT.

Dataset EGAD00010002505

Whole genome amplification and whole genome sequencing of human single cells

Human single fibroblasts and T-lymphocytes were amplified using multiple annealing and looping-based amplification and multiple displacement amplification. Amplified products were next subjected to whole genome sequencing with the goal of performing a genetic variant analysis.

Study EGAS00001003108

Molecular and clinical effects of selective TYK2 inhibition with deucravacitinib in psoriasis

Investigate changes in IL-23/Th17- and type I interferon-pathway biomarkers and gene responses, and measures of selectivity for TYK2 over Janus kinases (JAKs) 1–3, in patients with moderate to severe psoriasis receiving deucravacitinib.

Study EGAS00001005875

RNA seq before and after cold pressor test

The cold pressor test (CPT) is a widely used pain provocation test to investigate both pain tolerance and cardiovascular responses. Twenty-two females were phenotypically assessed before and after a CPT, and blood samples were taken for RNA-sequencing.

Study EGAS00001006690

VESPA: Vanderbilt Electronic Systems for Pharmacogenomic Assessment

The Vanderbilt Electronic Systems for Pharmacogenomic Assessment (VESPA) Project is a large electronic medical record (EMR)- and biobank-based initiative for translational pharmacogenomics discoveries. Key research resources utilized in this effort include the BioVU DNA databank and associated Synthetic Derivative database of clinical information, and software tools developed to identify drugs and clinical events using EHR-derived structured and unstructured ("free text") data. Cohorts include subjects with primarily drug-response phenotypes, and most cases and controls identified include three data types: ICD-9 codes, medication regimens, and medical test results. Advanced informatics methods, such as natural language processing, were also used for some phenotypes. Algorithms used event-sequence analyses to establish temporal relationships between drugs and phenotypes. Both cases and control algorithms excluded records that contained specific comorbidities and were refined to achieve positive predictive value (PPV) > 90%. For automated algorithms failing to meet this threshold, manual review was coupled with algorithms to validate that the included cases were true positives. A total of 11,639 subjects met phenotyping criteria for a least one of the 28 phenotypes investigated. Across all phenotypes cases and controls, 90% were reused as either a case or control for a least one other phenotype. Data are deposited for individual phenotypes in the VESPA substudies. Substudies: VESPA: Genome Wide Association Study of Serum Creatinine during Vancomycin Therapy and Vancomycin Pharmacokinetics - phs000894 VESPA: Genome Wide Study of Clinically Diagnosed Ace Inhibitor Cough - phs000992

Study phs000991

Risk Factors for Asymptomatic Diverticulosis

Data for this analysis came from a prospective study of colonic diverticulosis at the University of North Carolina Hospital in Chapel Hill, North Carolina (NIH R01DK094738). This is a case-control genetic and transcriptomic study to identify the genetic and cellular determinants underlying colonic diverticulosis and the relationship with other gastrointestinal disorders. The study inclusion and exclusion are described below. DNA and RNA sequencing were performed on colonic tissue from 404 patients with (N=172) and without (N=232) diverticulosis. We assessed variation in the transcriptome associated with diverticulosis and integrated this variation with human intestine single-cell RNA-seq data. We integrated our expression quantitative trait loci with GWAS using Mendelian Randomization. A polygenic risk score analysis examined associations between severity of diverticulosis and other gastrointestinal disorders. We identified 38 genes with differential expression and 17 genes with varied transcript usage linked to diverticulosis. Our results suggest tissue remodeling as a primary mechanism for diverticula formation. The presence of diverticulosis was linked to stromal and epithelial cells in the colon including endothelial cells, myofibroblasts, fibroblasts, goblet, tuft, enterocytes, neurons, and glia. MR highlighted five genes including CCN3, CRISPLD2, ENTPD7, PHGR1, and TNFSF13. In diverticulosis cases, ENTPD7 upregulation was confirmed. A greater burden of diverticula was positively correlated with genetic predisposition to diverticulitis. The data related to the study including total RNA-Seq, SNP array and imputed genotypes will be available through dbGaP.

Study phs003556

Open_Targets_020_Epigenomes_of_Cell_Lines

There is currently a drive to establish cell based assay systems of greater human biological and disease relevance through the use of well characterised transformed cell lines, primary cells and complex cellular models (e.g. co-culture, 3D models). However, although the field is gaining valuable experience in running more non-standard & complex cell assays for target validation and compound pharmacology studies, there is the lack of a systematic approach to determine if this expansion in cell assay models is reflected in increased human biological and disease relevance. The increasing wealth of publically available transcriptomic, and epigenome (ENCODE and Epigenome Roadmap) data represents an ideal reference mechanism for determining the relationship between cell types used for target & compound studies to primary human cells and tissues from both healthy volunteers & patients. The CTTV020 epigenomes of cell line project aims to generate epigenetic and transcriptomic profiles of cell lines and compare these with existing and newly generated reference data sets from human tissue and cell types. The aim is to identify assay systems which will provide greater confidence in translating target biology and compound pharmacology to patients. Multiple cell types commonly used within research have been grouped according to biology. Examples include erythroid, lung epithelial, hepatocyte cell types and immortalised models of monocyte / macrophage biology. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute please see http://www.sanger.ac.uk/datasharing/

Study EGAS00001003138

Integration of genomics and histology reveals diagnosis and effective therapy of refractory cancer of unknown primary with PDL1 amplification (H021)

Identification of the tissue of origin in cancer of unknown primary (CUP) poses a diagnostic challenge and is critical for directing site-specific therapy. Currently, clinical decision making in patients with CUP primarily relies on histopathology and clinical features. Comprehensive molecular profiling has the potential to contribute to diagnostic categorization and, most importantly, guide CUP therapy through identification of actionable lesions. We here report the case of an advanced-stage malignancy initially mimicking poorly differentiated soft-tissue sarcoma that did not respond to multi-agent chemotherapy. Molecular profiling within a clinical whole-exome and transcriptome sequencing program revealed a heterozygous, highly amplified KRAS G12S mutation, compound-heterozygous TP53 mutation/deletion, high mutational load, and focal amplification of chromosomes 9p (including PDL1 [CD274] and JAK2) and 10p (including GATA3). Integrated analysis of molecular data and conventional histopathology suggested a diagnosis of triple-negative breast cancer (TNBC) and provided a rationale for immune checkpoint inhibitor therapy with pembrolizumab, which resulted in rapid clinical improvement and a lasting partial remission. Analysis of 157 TNBC samples from The Cancer Genome Atlas revealed focal, high-level PDL1 amplification coinciding with excessive PDL1 mRNA expression in 24% of cases. Collectively, these results illustrate the diagnostic utility of multidimensional tumor profiling in cases with non-descript histology and immune phenotype, demonstrate the predictive power of genomic PDL1 amplification for immune checkpoint inhibition, and suggest a targeted therapeutic strategy in chromosome 9p24.1/PDL1-amplified cancers.H021

Study EGAS00001001846

Altered Blood and Keratinocyte microRNA/transfer RNA Fragment Profiles Related to Fibromyalgia Syndrome and its Severity

We show dysregulated microRNA and tRNA fragment profiles related to FMS pathopyhsiology and opening new perspectives for FMS diagnostics and symptom monitoring. This dataset includes all sequencing raw files from whole blood (tempus tube) and keratinocyte sequencing.

Dataset EGAD50000000900

Colon adenomas and adenocarcinomas and matched mucosae

Whole exome sequencing in sporadic colorectal cancers (CRC) and advanced adenomas (Ad-As), and their paired healthy mucosa, for a deeper understanding of the biology of this cancer.

Study EGAS00001007255

Myeloma_Targeted_Follow_up_Study

390 samples, perform WGA, and send the WGA’d DNA to core for pre-capture library and tagging, pulldown with ELID 631172 (16 samples per reaction tube), and sequencing (24 samples per lane)

Study EGAS00001000880

Patient-derived conditionally reprogrammed cells (CRCs) were established and characterized to assess their biological properties and to apply these to test the efficacies of drugs.

RNA seq data was used for the characterization and profiling of the created patient-derived cells and in vivo tissue.

Study EGAS00001001702

HumanMethylation450K data from Purified Plasma Cells of Monoclonal gammopathy of unknown significance and Multiple myeloma patients and Healthy donors

Study EGAS00001000841

Understanding the genetic risk underlying racial disparities in uterine fibroids

Fibroids affect 77% of women by onset of menopause in the U.S. and account for $2.1 billion in healthcare costs each year. Fibroids negatively impact reproductive health causing heavy and painful menses, pelvic pain and pressure, pregnancy complications, and interventions including myomectomy and hysterectomy. Until recently, tumor tissue and cell culture studies investigating fibroid growth have been the primary sources for understanding fibroid pathophysiology. Genetic analysis can provide a powerful and cost effective tool to identify etiological and causal factors, especially since a genetic predisposition to fibroids has already been documented from twin studies. As much as 69% of risk is explained by genetic factors. Racial disparities also support a role for genetics with fibroid risk. African American women have earlier age of onset, more numerous and larger fibroids with a greater lifetime incidence compared to Caucasians. We propose to identify genetic markers for risk of fibroids through a genome-wide association study (GWAS) of African American and Caucasian participants, leveraging ancestral differences to narrow down genomic regions for targeted follow- up analyses. To accomplish this we will take advantage of a unique Vanderbilt resource, the BioVU DNA databank. BioVU currently has over 122,470 adults linked to electronic medical records. From BioVU we have already identified 2,902 African American and Caucasian subjects who meet our stringent inclusion criteria to conduct a GWAS of fibroids, including pelvic imaging. Available imaging is critical, because many women with fibroids are asymptomatic and without imaging, studies may misclassify as many as 51% of women. We have also defined definitive controls who reached menopause without fibroids. We have a strong group of nationally known fibroid researchers who will provide over 10,000 samples for replication. Our first Specific Aim is to conduct a GWAS for association between common single nucleotide polymorphisms (SNPs) and fibroid risk. Using a case-control design we will perform a GWAS in 2,902 (1,451 fibroid cases and 1,451 controls) women from BioVU stratified by African American and Caucasian race. Secondary admixture mapping (AM) analyses will also be performed to identify chromosomal regions of interest to prioritize for replication. Our second Aim is to resequence chromosome regions identified from GWAS and AM to discover rare variants. Finally, in Aim 3 we will replicate SNPs selected from Aim 1 and 2 in independent samples of at least 3,230 fibroid cases and 7,097 controls. We propose an efficient and cost-effective approach to identify genetic risk factors for fibroids, by taking advantage of imaging information and DNA available through BioVU. This study represents the largest GWAS of uterine fibroids and the first among African Americans leveraging emerging technologies and new statistical approaches to conduct this study. Our proposed study will fundamentally change knowledge about fibroids and lay the ground work for breakthroughs in understanding mechanisms of fibroid formation and in identifying novel therapeutic approaches.

Study phs001409

ONT and PacBio data of 22q11 patient-parent duos/trios

ONT and PacBio FASTQ files generated for de novo assembly and resulting de novo assemblies

Study EGAS50000001647

16758 results for "sec+and+unspecified+malignant+neoplasm"

in 24.83 milliseconds.