14430 results for ""Pennsylvania+German"+ACS+study+'Socius'+open+access"

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• Liverpool Preterm Birth Biomarker Study

  Preterm birth is a multifactorial condition defined as birth less than 37 weeks of gestation. This study aimed to identify early pregnancy biomarkers from maternal genome-wide and transcriptome-wide data of women experiencing two types of spontaneous PTB (sPTB): spontaneous preterm birth (SPTB) and preterm premature rupture of membranes (PPROM). Whole blood samples were obtained from women with singleton pregnancies (N=567) recruited at the Liverpool Women’s Hospital at 16 and 20 weeks of gestation. Women with a previous history of sPTB pregnancies <34 weeks were categorised on their index pregnancy outcome as spontaneous preterm birth (SPTB) and preterm premature rupture of membranes (PPROM) or high-risk term control (HTERM, ≥37 weeks). Women with no history of SPTB/PPROM and delivered at term were LTERM (≥39 weeks of gestation). DNA was genotyped on the UK Biobank Axiom™ array (Applied Biosystems™, Thermo Fisher Scientific) and RNA who processed using the Clariom™ D Human assay (Thermo Fisher Scientific). Genome-wide association analysis, differential expression analysis and expression quantitative trait loci (eQTL) were completed.

  Study EGAS00001005076

• Study of pediatric hepatocellular carcinoma caused by bile salt export pump deficiency

  Hepatocellular carcinoma (HCC) is almost invariably associated with an underlying inflammatory state, whose direct contribution to the acquisition of critical genomic changes is unclear. We mapped the acquired genomic alterations in human and mouse HCCs induced by defects in hepatocyte biliary transporters, which expose hepatocytes to bile salts and cause the onset of chronic inflammation that develops into cancer. In both human and mouse cancer genomes we found few somatic point mutations with no impairment of cancer genes, but instead massive gene amplification and rearrangements. This genomic landscape differs greatly from that of virus- and alcohol-associated liver cancer. Copy number gains preferentially occurred at late stages of cancer development and frequently targeted the MAPK signaling pathway, and in particular direct regulators of JNK. The pharmacological inhibition of JNK retarded cancer progression in the mouse. Our study demonstrates that intrahepatic cholestasis leading to hepatocyte exposure to bile acids and inflammation promotes cancer through genomic modifications that can be clearly distinguished from those determined by other etiological factors.

  Study EGAS00001000749

• early-stage ESCC sequencing study

  We performed a comprehensive multi-omics analysis of 786 trace-tumor-samples from 154 esophageal squamous cell carcinoma phase (ESCC) patients, covering 9 histopathological stages in 3 phases as nontumor phase (NT phase), intraepithelial neoplasia phase (IEN phase), and ESCC phase. Proteogenomics elucidated the stage-specific molecular characterization and defined the cancer-driving waves along with the mutation accumulation in EC progression. The integrated multi-omics uncovered the chromosome 3q gain was the key event in the transmit from the NT to IEN phase, disclosed the top mutation of TP53 enhanced cell cycle and DNA replication in the IEN phase, and revealed the ESCC phase mutations of AKAP9 and MCAF1 elevated glycolysis and Wnt signaling, respectively. Furthermore, the trajectory analysis identified 6 major tracks related to different clinical features during ESCC progression. Growingly enhanced and hyperphosphorylated phosphoglycerate kinase 1 (PGK1, S203) was detected and considered as a drug target in ESCC progression. Collectively, this study provides insight into the understanding of ESCC molecular mechanism and a valuable resource for the development of therapeutic targets.

  Study EGAS00001006126

• Randomized Phase II 2 x 2 Factorial Trial of the Addition of Carboplatin +/- Bevacizumab to Neoadjuvant Weekly Paclitaxel Followed by Dose-Dense AC in Hormone Receptor-Poor/HER2-Negative Resectable Breast Cancer

  This randomized phase II trial studies how well paclitaxel with or without carboplatin and/or bevacizumab followed by doxorubicin and cyclophosphamide works in treating patients with breast cancer that can be removed by surgery. Drugs used in chemotherapy, such as paclitaxel, carboplatin, doxorubicin, and cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Bevacizumab may stop the growth of tumor cells by blocking blood flow to the tumor. Giving chemotherapy together with bevacizumab before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. All participants in this study were female.

  Study phs001863

• NHLBI TOPMed: The Genetics and Epidemiology of Asthma in Barbados

  Asthma is a complex disease where the interplay between genetic factors and environmental exposures influences susceptibility and disease prognosis. Asthmatics of African descent tend to have more severe asthma and more severe clinical symptoms than individuals of European ancestry. The baseline prevalence of asthma in Barbados is high (~20%), and from admixture analyses, we have determined that the proportion of African ancestry among Barbadian founders is similar to U.S. African Americans, rendering this a unique population to disentangle the genetic basis for asthma disparities among African ancestry populations in general. We therefore performed whole genome sequencing on 1,100 individuals from the Barbados Genetics of Asthma Study (BAGS), in order to generate additional discovery of rare and structural variants that may control risk to asthma.

  Study phs001143

• The Intestinal Bacterial Metagenome in Pediatric Non-Alcoholic Fatty Liver Disease (NAFLD)

  Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children in the United States. NAFLD is associated with obesity and metabolic syndrome; however, there is limited understanding of the development and progression of NAFLD. There is evidence of abnormalities of bacterial colonization, and intestinal bacterial product-induced inflammation associated with NAFLD and disease progression. The goal of this study was to characterize the intestinal microbiome in pediatric participants with NAFLD and in both obese and normal weight controls to determine the relationship between alterations in the intestinal microbiome, inflammation, and the development of NAFLD. We hypothesized that alterations in the intestinal microbiome are associated with increased systemic inflammation and the development and severity of NAFLD.

  Study phs001837

• Integrated Genomic Analyses of Cutaneous T Cell Lymphomas Reveal the Molecular Bases for Disease Heterogeneity

  Cutaneous T cell lymphomas (CTCLs) are a clinically diverse collection of lymphomas of the skin-homing T cell. In the present study, we performed DNA and RNA sequencing on a cohort of CTCLs with representative samples from varying disease subtypes and stages. We characterized the landscape of putative driver genes, identified genetic relationships between CTCLs across disease stages, and inferred molecular subtypes in patients with stage-matched leukemic disease. Collectively, our findings clarify CTCL genetics and provide novel insights into pathways that drive diverse disease phenotypes. DNA and RNA sequencing was performed on 114 and 96 samples respectively. Tumor samples were obtained from University of Chicago (Chicago, IL), Northwestern University (Chicago, IL) and Yale University (New Haven, CT). 

  Study phs002456

• Inhibition of CDK4/6 Promotes CD8 T Cell Memory

  Inhibitors of Cyclin-Dependent Kinase 4 and 6 (CDK4/6) have been recently deployed for the treatment of advanced breast cancer. Despite their success, the mechanism of action of these drugs is unclear. In mice, treatment with a CDK4/6 inhibitor improve T cell memory responses and protect mice against tumor rechallenge. We aimed to identify the correlates of this finding in human subjects. In this study, blood was collected from 5 breast cancer patients before and during treatment with the CDK4/6 inhibitors abemaciclib or palbociclib. Blood was also collected from 2 breast cancer patients who did not receive a CDK4/6 inhibitor. Recently activated CD8 T cells (CD45RO+ CD45RA+) were sorted and subjected to single-cell RNA sequencing.

  Study phs002448

• Pharmacogenomics of Metformin Dose Response in T2DM Patients

  Type 2 Diabetes Mellitus (T2DM) is a chronic and sometimes debilitating disease that affects millions of adults in the USA. Metformin is commonly prescribed for T2DM; yet some T2DM patients do not tolerate it or respond well. This pharmacogenomics study will examine response, as both change in T2DM patients' weight and hemoglobin A1c (HbA1c) levels, to different doses of metformin, by extracting this data from the electronic health record (EHR), for T2DM subjects taking metformin found by prescription orders in the EHR, and identified as cases with the EHR phenotype algorithm published by Kho et. al. in 2012 (PMID: 22101970 as part of the eMERGE (electronic Medical Records and Genomics; dbGaP phs000237, phs000297, phs000360, phs000368, phs000888, and phs000948) project.

  Study phs000984

• Transcriptome and Epigenome of TIL Infusion for Cancer Immunotherapy

  Adoptive T cell therapy (ACT) using ex vivo–expanded autologous tumor-infiltrating lymphocytes (TILs) can mediate complete regression of certain human cancers. The impact of TIL phenotypes on clinical success of TIL-ACT is currently unclear. Samples were analyzed from TIL infusion products from metastatic melanoma human patients who responded to TIL-ACT (responders) and patients who did not (non-responders). Single cell transcriptome of TIL infusion products were analyzed for CD8 TIL phenotype and function. In patients with available neoantigen reactive TIL, single cell TCR clonotyping was performed to study anti-tumor TIL states between responders and non-responders. Epigenetic studies on TIL infusion products were performed using ATAC sequencing between paired CD39- C69- and CD39+ CD69+ CD8+ TILs.

  Study phs002436

• DNA Replication Timing Alterations in Genetic Diseases

  This study contains a collection of lymphoblastoid cell line (LCL) and induced pluripotent stem cell (iPSC) whole genome sequencing from individuals with an without a diagnosed genetic disease. Several types of genetic diseases are included such as translocations, repeat expansions, and heritable or spontaneous mutations of genes. We used the whole genome sequencing to generate DNA replication timing profiles for these individuals and compared the profiles of diseased individuals to presumed healthy samples. We aimed to identify replication timing alteration linked to a specific genetic disease and therefore elucidate trans-acting factors of DNA replication timing. We found that replication timing was highly consistent across almost all diseased samples. Only one genetic disease, a mutation in MCM10, demonstrated an altered profile of replication timing.

  Study phs002597

• Next Generation Mendelian Genetics: Malignant Hyperthermia

  Malignant hyperthermia (MH) is a genetic disorder that causes a profound metabolic derangement following exposure to certain anesthetics. While approximately half of all cases are associated with ryanodine receptor-1 gene (RYR1) mutations, many cases have an unknown genetic cause. We sought to identify rare variants in novel MH candidate genes by sequencing the protein-coding regions of the genomes of individuals whose disease was either ruled in or out by the gold-standard diagnostic test. We also carefully selected individuals from well-characterized families to use gene-sharing information and maximize efficiency in the study design. Exome sequencing has helped identify the causes of over a dozen Mendelian disorders, has high power at low sample sizes, and is cost-efficient compared to whole-genome sequencing.

  Study phs000405

• Genentech whole genome and transcriptome sequencing of four hepatocellular carcinoma patients

  Hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC). In this study we sequenced the whole genome (~80X) and transcriptome of tumor and non-tumor samples from four HCC patients and identified over two hundred HBV integration sites. We found significant clonal expansion of HBV-integrated hepatocytes specifically in the tumor samples. We observed a diverse collection of genomic perturbations near viral integration sites, including gene disruption, viral promoter-driven human transcription, viral-human transcript fusion and DNA copy number alteration. We also sequenced one patient at ultra-high coverage (~240X) to build the most comprehensive HBV-integration landscape yet attempted. Our data suggest that the viral integration significantly expands carcinogenic opportunities in HBV-infected individuals.

  Study phs000384

• Early Onset and Progression of Primary Ciliary Dyskinesia Lung Disease Prior to 10 Years of Age

  Primary Ciliary Dyskinesia (PCD) is a genetic defect in airway host-defense, and typically results in chronic infection of the airways. Patients with PCD have chronic lung, sinus and ear infections. This longitudinal study is designed to define the rate of progression of PCD lung function in participants prior to 10 years of age using special lung function tests, which help to track lung impairment and prognosis in other disorders of the airways such as cystic fibrosis. This longitudinal protocol will also systematically track other specific outcomes, including pathogens infecting the airways (assessed by respiratory cultures), and age at onset and progression of airway damage and bronchiectasis [assessed by high-resolution computerized tomography (HRCT) of the chest].

  Study phs001310

• Impaired HLA Class I Antigen Processing and Presentation as a Mechanism of Acquired Resistance to Immune Checkpoint Inhibitors in Lung Cancer

  Mechanisms of acquired resistance to immune checkpoint inhibitors (ICIs) are poorly understood. The purpose of this study was to investigate whether alterations in genes encoding components of the HLA Class I antigen processing and presentation machinery or interferon signaling pathways play a role in acquired resistance to PD-1 or PD-L1 antagonistic antibodies. Whole exome sequencing was performed on tumor samples collected from patients with advanced non-small cell lung cancer at the time of resistance to PD-1 axis inhibitors and on available matched pre-treatment and normal samples. Patient-derived xenografts successfully established from the ICI-resistant samples were also exome sequenced. Additionally, RNA sequencing was performed on cases with sufficient tissue.

  Study phs001464

• Identification of Recurrent NAB2-STAT6 Gene Fusions in Solitary Fibrous Tumor by Integrative Sequencing

  Transcriptome sequencing of solitary fibrous tumors / hemangiopericytomas from a variety of anatomic sites revealed recurrent gene fusions between two genes, NAB2 and STAT6. All SFTs examined exhibited an in-frame fusion transcript encoding a fusion protein containing the EGR1 interaction domain of NAB2 with the transcriptional activation domain of STAT6. Functional testing of the fusion alleles confirmed the conversion of the wt NAB2 repressor into a transcriptional activator. A range of individual fusion junctions can be detected by next-generation sequencing acro the sample set, highlighting the suitability of this method in the diagnostic characterization of SFTs. This study indentified the pathognomonic alteration in solitary fibrous tumors and illuminates a pathway towards targeted therapeutics for this cancer.

  Study phs000567

• GWAS for Membranous Nephropathy

  Primary membranous nephropathy (MN) is a rare autoimmune cause of kidney failure. This dataset is from a genome-wide association study (GWAS) designed to identify novel genetic risk loci for MN. The provided cohort (named as European-1 Cohort) is composed of 611 cases of primary MN and 1,246 healthy controls of European ancestry. This cohort was used in the GWAS meta-analysis, as described in the manuscript entitled "Genetic architecture of membranous nephropathy and its potential diagnostic implications" (Nature Communications 2020, in press).The genome-wide summary statistics, including trans-ethnic meta-analysis across 8 GWAS cohorts of European and East Asian ancestry and ethnicity specific meta-analyses, are freely available for download on the Kiryluk lab website: http://www.columbiamedicine.org/divisions/kiryluk/resources.php.

  Study phs001984

• Identification of Genomic Markers of Cervical Dystonia and Subtypes

  As the third most common movement disorder, dystonias collectively affect more than 2 million people worldwide. Despite their high prevalence, their biological roots are largely unknown. Genetic influences are suggested in familial studies, however, no specific genetic variants are responsible for a significant proportion of identified cases. Previous genome-wide association studies of the dystonias were limited by smaller sample size and lack of coverage of rare variants. In this study, we use a high-throughput genomic approach to effectively investigate relationships between over genome-wide genetic variations and dystonias. We conduct targeted analyses of candidate genes, as well as agnostic searches for any genomic with the dystonias and subtypes in a large sample of dystonia patients available.

  Study phs001803

• Drug Resistant Hypertension in African Americans' Exome

  Resistant hypertension is defined as blood pressure that remains above goal in spite of the concurrent use of 3 antihypertensive agents of different classes or the concurrent use of 4 or more antihypertensive agents regardless of control. Its diagnosis is important for the identification of patients who are at high risk of having reversible causes of hypertension and/or patients who, because of persistently high blood pressure levels, may benefit from special diagnostic and therapeutic considerations. Resistant hypertension represents an extreme phenotype, thus, it has been predicted that genetic factors could play a larger role than for the general hypertensive population. Genetic assessments of patients with resistant hypertension have been limited. The current study assayed the exome of 91 African American patients with treatment resistant hypertension.

  Study phs000442

• Cross-site Concordance Evaluation of Tumor DNA and RNA Sequencing Platforms of CIMAC-CIDC Network

  The Cancer Immune Monitoring and Analysis Centers (CIMACs) and the Cancer Immunologic Data Commons (CIDC)  has engaged in efforts to harmonize Whole-exome (WES) and RNA-sequencing (RNA-seq) data from three different experimental platforms (MD Anderson, NCI MoCha lab, and Broad Institute) and are using a series of developed pipelines to process the early trial samples. To evaluate the consistency of tumor WES and RNA-seq profiling platforms across different centers, the CIMACs-CIDC conducted a systematic harmonization study. DNA and RNA were centrally extracted from fresh frozen (FF) and formalin-fixed paraffin-embedded (FFPE) non-small cell lung carcinoma (NSCLC) tumors and distributed to three centers for WES and RNA-seq profiling

  Study phs002295

• Multicenter International Cross-Sectional Evaluation of Pulmonary Alveolar Proteinosis (MICEPAP) Trial

  The purpose of this study is to (1) compare a technically improved assay with an existing assay used to measure serum anti-GM-CSF antibodies in stored serum samples previously obtained from patients diagnosed with either primary, secondary, congenital or idiopathic pulmonary alveolar proteinosis (PAP), other chronic diseases or disease-free, healthy individuals; (2) determine the prevalence and levels of anti-GM-CSF autoantibodies and (3) define the breadth of the autoimmune antibody responses in primary PAP patients from the United States, Japan, Australia, and Europe using previously collected serum samples; and (4) using a chart review approach, compare the clinical, radiologic and laboratory features of primary PAP patients to determine if differences exist among patients in these globally geographically distributed regions.

  Study phs001309

• Analysis of Recurrently Protected Genomic Regions in Urine Cell-Free DNA

  This study investigated fragmentation patterns in urine and plasma cell-free DNA and evaluated the relevance of such analysis for cancer diagnostics using urine samples. Specifically, we performed whole-genome sequencing at variable depths and evaluated genome-wide coverage in urine and plasma samples, relative to known genome annotation features. Tumor/germline exome sequencing data included was used to identify genome-wide copy number changes and their effect on cfDNA fragmentation in corresponding genomic regions in urine samples. Data included in this submission is whole-genome sequencing of urine and/or plasma cell-free DNA from healthy volunteers and/or cancer patients, and whole-exome sequencing of tumor DNA and germline DNA (peripheral blood cells) from cancer patients. 

  Study phs002273

• Transcriptomic Analysis of Pluripotent Stem Cell-Based Model of Human Amniogenesis

  The amniotic epithelium is the innermost layer of the amniochorionic membrane that physically divides the maternal and fetal environments. Amniogenesis is initiated during implantation in humans. In implanting blastocysts, the pluripotent epiblast cells undergo apical-basal polarization to form a cyst with a central lumen, the future amniotic cavity. This event is followed by the fate transition of pluripotent epiblast cells at the uterine-proximal pole of the cyst to squamous amniotic ectoderm, forming a sharp boundary between amnion and pluripotent epiblast portions of the cyst. To enable mechanistic investigations into amnion fate progression, several in vitro models based on human pluripotent stem cells were recently developed. In this study, transcriptomic features of human pluripotent stem cell-derived amniogenesis models were examined.

  Study phs002184

• Cergentis FFPE-TLC

  In this study, formalin-fixed paraffin-embedded targeted locus capture (FFPE-TLC) sequencing is used as a novel technology for targeted detection of tumor-specific genomic structural variants (SVs) in the primary tumor of 29 colorectal cancer patients with metastatic disease. The tumor region was macrodissected and sequenced for 29 patients, and the "normal" region of the same slide was macrodissected and sequenced for 8 of these patients. SVs were found in the common fragile site (CFS)-associated genes MACROD2, PRKN, FHIT and WWOX as well as SVs caused by three LINE transposable elements. Tumor-specificity of selected SVs was independently verified by droplet digital PCR of tumor tissue DNA and their applicability as plasma circulating tumor DNA biomarkers was demonstrated.

  Study EGAS50000000427

• Combined single-cell transcriptomics and T-cell receptor sequencing reveal heterogeneity of mycosis fungoides between and within patients and identify a CD4+ cytotoxic subtype

  Comprehensive analysis of the malignant cells present in the skin lesions of Mycosis fungoides, the most common subtype of cutaneous T-cell lymphoma, is complicated by the fact that malignant from reactive T cells are challenging to distinguish with certainty. To this end, combined single-cell RNA and TCR sequencing allows unambiguous identification of MF cells, thereby revealing a marked heterogeneity between and within patients with unexpected functional phenotypes. It should be further noted, that mRNA expression of established CTCL protein markers in single-cell transcriptomics to identify MF cells should be used with caution; however, our study uncovered an exciting gene expression pattern that serves as a beacon separating malignant from reactive T cells.

  Study EGAS50000000226

• Gene-Specific RNA Sequencing in PLCG2-Associated Immune Dysregulation with Cold Urticaria

  This study utilized gene-specific RNA-sequencing of PLCG2 to screen for disease causing in-frame exon-skipping transcripts of PLCG2 in a collection of 9 subjects with cold urticaria, 2 subjects with known PLCG2-associated antibody deficiency and immune dysregulation (PLAID)-causing deletions of PLCG2 (positive controls) and 3 healthy subjects (negative controls). Full length cDNA of PLCG2 was generated using gene specific reverse transcription of peripheral blood mononuclear cell RNA. The full length PLCG2 cDNA was used as the template to create Illumina sequencing libraries. To identify the underlying genetic basis for the exon-skipping transcripts, trio-based whole genome sequencing was performed for probands in whom in-frame exon-skipping transcripts of PLCG2 were identified.

  Study phs003807

• Synchronous patterning of hiPSC-derived CNS progenitors generates comprehensive axial spinal cord organoids (CASCOs) containing diverse motor neuron population

  Advancements in human induced pluripotent stem cell (hiPSC) culture have enabled the generation of spinal cord organoids (SCOs), though achieving distinct axial identities in spinal motor neurons (spMNs) along the rostro-caudal (RC) axis remains a challenge. By optimizing the timing and sequence of patterning factors, we developed a mixed stem cell model of rostral neural stem cells (NSCs) and caudal neuromesodermal progenitors (NMPs) to generate SCOs with enhanced spMN heterogeneity, including a wide range of axial identities and benchmarked this against commonly used protocols. Our approach, termed CASO (Comprehensive Axial Spinal Organoids), also incorporates endothelial networks and skeletal muscle to improve organoid complexity and health, offering a novel method to study spMN axial specification and model neurodegenerative diseases.

  Study EGAS50000000891

• Genomic Changes in Breast Cancer Among Chinese Women in Hong Kong

  Recently, tumor sequencing and profiling analyses have improved molecular classification and refined existing breast cancer subtypes. However, epidemiologic data are absent in most somatic profiling studies even in extensively studied Western populations. The expansion of genomic studies to understudied populations with the integration of etiologic factors will allow the capture of a much wider range of genetic structure and mutagenic exposures associated with breast cancer risk. We therefore conducted a detailed molecular characterization of paired breast tumor/normal tissues using fresh frozen tissues collected from breast cancer cases in an ongoing breast cancer case-control study in Hong Kong. These analyses included whole genome (WGS)/exome sequencing (WES), targeted DNA panel sequencing, RNA sequencing (RNA-Seq), and genome-wide methylation profiling analyses.

  Study phs001870

• Ultrasensitive Detection and Monitoring of Circulating Tumor DNA using Structural Variants in Early-Stage Breast Cancer

  Circulating tumor DNA (ctDNA) detection has an emerging role in the management of breast cancer, offering a non-invasive means to monitor disease status and detect recurrence. This study demonstrates that longitudinal monitoring of tumor-specific structural variants - frequent alterations observed across many tumor types including all subtypes of breast cancer derived from Whole Genome Sequencing data - allows for ctDNA detection in nearly all participants in this cohort with untreated early breast cancer prior to starting neoadjuvant therapy. On-treatment ctDNA monitoring enabled the early identification of patients at high risk of recurrence and ctDNA was detected prior to relapse in participants across all receptor subtypes. These findings demonstrate the clinical validity of this assay approach for ultrasensitive ctDNA monitoring.

  Study EGAS50000000799

• NHLBI TOPMed: TReating Children to Prevent EXacerbations of Asthma (TREXA)

  TREXA is a 44-week randomized, double-blind, double-masked, four-treatment, parallel trial that will evaluate the weaning strategy that provides the best protection against the development of exacerbations in children whose asthma is acceptably controlled on a low dose of ICS (per NAEPP guidelines). Following the 4 weeks of the run-in period on a 1x dose of ICS (100 µg fluticasone b.i.d. or its equivalent), children who do not meet the definition of acceptable asthma control will be randomized to the parallel BADGER protocol; those who meet the definition of acceptable asthma control will be enrolled into the 44-week treatment phase of the study. The primary outcome measure will be time to first exacerbation requiring a prednisone course.

  Study phs001732

• Construction of endoscopic biopsy banking for understanding the intestinal environment in colorectal diseases and exploratory studies using these banking systems.

  Colorectal cancer is the most common type of cancer in Japan. Although some colorectal cancers have a genetic background, most colorectal cancers are sporadic. Known risk factors for colorectal cancer include smoking, obesity, lack of exercise, and red and processed meat. Furthermore, although it has been suggested that changes in the intestinal environment due to changes in diet and lifestyle may be involved in the increased incidence of colorectal cancer in Japan, the molecular mechanism has not yet been fully elucidated. The main objective of this study is to elucidate the changes in the intestinal environment that cause colorectal tumors, and also to contribute to the establishment of colorectal mucosal tissue banking in Japan.

  Study JGAS000655

• Profiling the genomic landscape and evolutionary history of polyploid giant cancer cells in undifferentiated pleomorphic sarcomas

  Polyploid giant cancer cells (PGCCs), characterised by multi-nucleation and atypical nuclear morphology, are a common feature of undifferentiated pleomorphic sarcomas. While PGCCs may be a critical substrate for cancer evolution, their formation pathways and the genomic consequences of PGCCs remain relatively under explored. In this study, we characterise PGCCs in undifferentiated pleomorphic sarcomas, as well as their histological mimics, and use topographic single-cell DNA sequencing (scDNA-seq) to investigate their genomic landscape. We selected PGCCs based on their nuclear morphology, including mono-nucleated or multi-nucleated bizarre, misshapen nuclei and analysed them at single-cell resolution. Our findings highlight PGCCs as a highly heterogeneous and evolutionarily dynamic component of undifferentiated pleomorphic sarcomas.

  Study EGAS50000001445

• Research on the identification of cancer stem cells for peidatric and adult malignancies.

  In recent years, "cancer stem cells" have been reported to exist in many cancers. Many reports have shown that they are the main cause of cancer recurrence. The aim of this study is to test whether cancer stem cells can be identified using patient samples. We will perform omics analysis of rare pediatric cancers by integrating genomics, transcriptomics, proteomics and metabolomics, including somatic and germline mutations, to deepen our understanding of the biological characteristics of the target disease. Based on the knowledge gained and clinical information from patients, we will conduct preclinical pharmacological studies using mouse models and in vitro models to investigate the therapeutic effects of novel therapeutic agents and novel therapeutic strategies such as cellular therapies.

  Study JGAS000623

• C-MACH reduced-representation bisulfite sequencing (RRBS)

  Umbilical cord blood (CB) has been commonly used as an epigenetic surrogate of fetuses. Here, we propose umbilical cord tissue (UC) as an alternative surrogate for epigenetic studies on fetuses. To explore the feasibility to examine UC epigenome by deep sequencing, we determined CpG methylation profiles of human postnatal UC by reduced representation bisulfite sequencing. We compared DNA methylomes between UC and CB. To investigate the effect of folate during pregnancy on fetal DNA methylation, we compared fetal UC DNA methylation between low and high levels of maternal plasma folate. Our study suggests that UC is useful as an alternative surrogate for studying environmental effects on DNA methylation in human fetuses, compensating CB by providing additional information about epigenetic regulation of genes.

  Study JGAS000171

• Single cell transcriptomics to characterize the tumor microenvironment of prostate cancer fusion biopsies

  The primary objective of this study was to characterize the tumor microenvironment in fusion-guided transperineal biopsy samples from patients undergoing PC diagnosis. For each patient, one biopsy was taken from a suspected tumor region and another from a non-suspicious area, which were later classified as high- or low-tumorigenicity based on anatomopathological analysis. Using scRNA-seq data, we performed cancer-oriented cell annotation, differential expression analysis, and functional pathway enrichment studies across key cellular subpopulations. Additionally, differential abundance analysis was conducted to identify cell groups representative of different tumorigenicity levels. Finally, classification models were developed using gene expression data to differentiate high- vs. low-tumorigenicity samples, with the long-term goal of establishing a diagnostic classifier for PC stratification.

  Study EGAS50000000888

• Whole-exome sequencing identifies new pathogenic germline variants in patients with colorectal polyposis

  Adenomatous polyposis confers an increased risk of colorectal cancer development. Here, we investigated probably underlying predisposition variants in patients with suspected colorectal polyposis without variants in APC and MUTYH genes by whole exome sequencing (WES). Twenty-seven patients were included and subjected to germline WES. After filtering out variants for sequencing quality, variant allele fraction frequency, and population frequency, variants were manually prioritized by the ACMG criteria. Among the variants identified, 17 were classified as pathogenic or likely pathogenic (in 12 patients). This study gives information of probably associated polyposis variants in Brazilian patients without germline pathogenic variants in APC and MUTYH genes, supporting the utilization of next-generation sequencing for screening in these patients beyond these genes.

  Study EGAS50000000591

• ICGC PanCancer Analysis of Whole Genomes

  The Pancancer Analysis of Whole Genomes (PCAWG) study is an international collaboration to identify common patterns of mutation in more than 2,800 cancer whole genomes from the International Cancer Genome Consortium. Building upon previous work which examined cancer coding regions (Cancer Genome Atlas Research Network, The Cancer Genome Atlas Pan-Cancer analysis project, Nat. Genet. 2013 45:1113), this project is exploring the nature and consequences of somatic and germline variations in both coding and non-coding regions, with specific emphasis on cis-regulatory sites, non-coding RNAs, and large-scale structural alterations.

  Study EGAS00001001692

• RNAseq data of polyA+ RNA from Leukocytes from 624 individuals of the SardiNIA cohort.

  We sequenced the polyA+ of the RNA of the leukocytes from 624 sardinian individuals with RNAseq (Illumina 2000, an average of round 60M reads per sample, 51 + 51 nt). Combining the genotype information of the same individuals (already available from the ProgeNIA project) with the transcriptome data we identified 21,183 independent expression quantitative trait loci (eQTLs) and 6,768 independent splicing quantitative trait loci (sQTLs), including 619 novel QTLs that exhibit population-specific trait associations. Using family relationships, we identified 809 segregating expression outliers and provide a new approach to study large effect regulatory variants and their relevance to traits. Our results provide insight into the effects of regulatory variants and their relationship to population history and individual genetic risk.

  Study EGAS00001002105

• Assessment of de novo copy number variations in Italian patients with schizophrenia.

  We investigated de novo CNVs in the whole genomic DNA of schizophrenia patients and their parents and, specifically, in putative enhancer motifs.Study participants were part of a wider multicenter study, involving an Italian cohort of schizophrenia patients recruited by members of INRP - Italian Network for Research on Psychoses.Whole genomic DNA obtained from 46 family trios of schizophrenia probands was analyzed using the Enhancer Chip, a customized array CGH developed using the Agilent SurePrint G3 8X60K format, which is able to investigate the whole genome with a 300Kb resolution, specific disease loci at a tenfold higher resolution, and that was highly enriched in probes in more than 1.250 enhancer elements selected from the Vista Enhancer Browser (PLoS One. 2012;7(12):e52264).

  Study EGAS00001002159

• The 3D evolution of glioma cell populations

  Study description: A detailed understanding of heterogeneity in solid tumors has been limited due to insufficient sampling and a lack of knowledge from where within the tumor the sample was taken from. We present here a novel resource - the 3D Glioma Atlas - in which we record the precise, three-dimensional (3D) coordinate for each of 8-20 spatially-distinct samples obtained from each patient tumor.By revealing how genetic alterations and tumor cell states are patterned in glioma in 3D space, our Atlas shows that genetic diversity is more regionally confined in indolent as compared to aggressive tumors, that recurrent tumors have a greater density of genetic diversity, and that more aggressive tumors have greater tumor-wide transcriptomic heterogeneity.

  Study EGAS00001003710

• Mutational_landscape_in_haemochromatosis__WGS_

  Somatic mutation has recently been shown to play a role in disease other than cancer. Driver mutations associated with lipid metabolism and insulin pathway have been identified in non-alcoholic fatty liver disease (NAFLD). It is plausible that driver mutations seen in NAFLD are a consequence of selection pressure exerted on hepatocytes in the context of excess fat accumulation. It has not been investigated whether selection pressure and driver landscape varies between chronic liver diseases of different aetiologies. This study aims to investigate mutational landscape in haemochromatosis, which is a disorder caused by a build-up of iron in the liver. We aim to use data generated by whole-genome sequencing of laser-dissected microbiopsies from diseased livers to characterize driver landscape and mutational signatures in haemochromatosis patients.

  Study EGAS00001005157

• Single-cell profiling of the leukemic and non-leukemic immune cell compartments in CD8+ T-cell Large Granular Lymphocytic Leukemia

  We performed a detailed and precise characterisation of the clonally expanded leukemic cells in CD8+ T cell Large Granular Lymphocytic Leukemia (T-LGLL). By combining scRNA+TCRαβ-seq with bulk RNA sequencing data we showed evidence of a strong antigen-driven immune response that shapes the entire immune cell repertoire in T-LGLL. Our study highlights how the whole immune cell repertoire including the hyperexpanded CD8+ T-LGLL cells, the non-leukemic CD8+ cells, CD4+ cells, and monocytes contribute to the CD8+ T-LGLL disease phenotype. Please note that this submission contains the fastq files while the processed count matrices can be found in ArrayExpress by the accession E-MTAB-11170.

  Study EGAS00001005297

• Hematopoietic differentiation at single-cell resolution in NPM1-mutated AML

  To investigate the relationship between somatic mutations and phenotypic hematologic differentiation at the single-cell level, we used a droplet-based multi-omics single-cell platform on eleven NPM1-mutated AML diagnostic samples. We developed a bioinformatics framework to perform phylogeny-driven genotype correction, that allowed us to study 52 103 single cells. Intra-leukemic genetic heterogeneity was detectable in all patients, including a branched architecture in nine of them, always owing to co-occurring signaling mutations. We identified two groups of NPM1-mutated AML, one characterized by a progenitor immunophenotype and a second one with a predominant monocytic differentiation. We also identified various degrees of intra-leukemic immunophenotype heterogeneity, sometimes associated with strong genetic/phenotype correlations.

  Study EGAS00001006565

• H3Africa - An integrated approach to the identification of genetic determinants of susceptibility to trypanosomiasis

  The over-arching aim of this network is to improve the health of people living in some of the poorest countries in the world that carry a disproportionate burden of infectious diseases. Despite their importance, the study of many tropical diseases has lagged behind that of diseases of developed countries. This network will redress the balance by performing high quality research into two neglected tropical diseases, human African Trypanosomiasis (HAT) and schistosomiasis. Our aim is to investigate the genetic determinants of the human reservoirs of HAT and schistosomiasis, filling an important knowledge gap, while extending and strengthening the underpinning infrastructure to deliver these scientific objectives in particular by developing the next generation of African geneticists.

  Study EGAS00001007173

• Identification_of_rare_variants_associated_with_cardiovascular_traits_in_Cilento_isolates

  The aim of this project is to identify rare genetic variants of large effect implicated in complex diseases by focusing on the study of cardiovascular diseases and related quantitative traits in a well characterized isolated population in Cilento area, Italy.The reference panel has been selected carefully in order to maximize the imputation coverage and quality on the all population samples. The selected individuals should meet three criteria: selected individuals should be chip-genotyped and closely related to the maximum number of chip-genotyped individuals so as to maximize imputation coverage; relatedness between selected individuals should be minimal, so as to minimize redundancy in genetic information of the reference panel.We perform exome sequencing on samples from 250 individuals from the Campora and Gioi-Cardile populations.

  Study EGAS00001000620

• Fixation effects on variant-calling in a clinical resequencing panel

  Formalin fixation is the standard method for preservation of tissue for diagnostic purposes, including pathological review and molecular assays. However, this method is known to cause artifacts that can affect the accuracy of molecular genetic tests. We assessed the applicability of alternative fixatives to determine whether these perform significantly better on next-generation sequencing assays, and whether adequate morphology is retained for primary diagnosis, in a prospective study using a clinical-grade laboratory-developed targeted resequencing assay. We examined and quantified several parameters relating to sequencing quality and variant-calling from tumor and normal colon epithelial tissues. We identify one alterative fixative, Sakura Universal Molecular Fixative that suppresses many formalin-related artifacts while retaining adequate morphology for pathological review.

  Study EGAS00001003507

• Papuan Genomes: whole genome sequencing

  The genomes of 25 individuals from Papua New Guinea was sequenced to high depth (30x) to address population genetic questions relating to the spread of humans outside of Africa and the peopling of Sahul (the continent of Greater Australia). The study design of this project was to sequence small numbers of genomes from several geographically distinct Papuan groups, focusing on the highland regions that are thought to have been more isolated, to enable comparisons between populations within Papua New Guinea and with Australian Aboriginal populations. Data from this project feed directly into on-going projects on the genetic history of Australia and also serve as a first look at the population genomics of the Papuan highlands.

  Study EGAS00001001247

• Targeted next-generation sequencing detects novel gene-phenotype associations and expands the mutational spectrum in cardiomyopathie

  Cardiomyopathies are a heterogeneous group of primary diseases of the myocardium,including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), andarrhythmogenic right ventricular cardiomyopathy (ARVC), with higher morbidity andmortality. These diseases are genetically diverse and associated with rare mutations ina large number of genes, many of which overlap among the phenotypes. To betterinvestigate the genetic overlap between these three phenotypes and to identify newgenotype-phenotype correlations, we designed a custom gene panel consisting of 115genes known to be associated with cardiomyopathic phenotypes and channelopathies.A cohort of 38 unrelated patients, 16 affected by DCM, 14 by HCM and 8 by ARVC,was recruited for the study on the basis of more severe phenotypes and family historyof cardiomyopathy and/or sudden death.

  Study EGAS00001002506

• Understanding_the_multicellular_dynamics_of_clear_cell_renal_cell_carcinoma___DNA_sequencing

  This study will reconstruct the single cellular phylogeny of tumour and immune cells in relation to both genomic, functional, and spatial location. 20 tumours in total will be studied, including non-progressing small renal masses, progressing small renal masses, relatively indolent larger tumours, and high risk tumour with metastatic sampling. We aim to: Generate a focused, comprehensive phylogenetic characterisation of tumour cells Understand the dependencies of the cancer genome, transcriptome, tissue architecture and the single cellular micro-environment Quantify the single cellular composition and functional intra- and inter- tumoural heterogeneity Determine the phylogeny of tumour associated lymphocytes and their relationship to neo-epitopes and the immune microenvironment Investigate the mechanisms by which the tumour-normal interface constrains tumoural growth

  Study EGAS00001003517

• TGS___Comprehensive_Molecular_Characterization_of_Colorectal_Cancer_Metastases__MOSAIC_

  Systematic next generation sequencing efforts are beginning to define the genomic landscape across a range of primary tumours, but we know very little of the mutational evolution that contributes to disease progression.We therefore propose to obtain a comprehensive description of genomic, transcriptomic and epigenomic changes in a cohort of matched primary and metastatic colorectal cancers, and additionally to explore the extent to which those mutations identified as recurrent in the metastatic setting are able to subvert normal biological processes using both genetically engineered mouse models and established cancer cell lines. This study will enable us to define to what extent primary tumour profiling can capture the biological processes operative in matched metastases as well as the significance of intratumoural heterogeneity.

  Study EGAS00001000958