15013 results for "cancer studies using rna-seq"

in 30.36 milliseconds.

• North American Mitochondrial Disease Consortium Patient Registry and Biorepository

  Mitochondrial diseases are caused by dysfunction of the mitochondria, which are specialized compartments that are present in every cell of the body except red blood cells. Mitochondria generate more than 90% of the energy that the body needs to sustain life and support growth. When they fail, less and less energy is generated within the cell. This injures the cell and can cause its death. If this process is repeated throughout the body, whole organ systems begin to fail, and the life of the person in whom this is happening is severely compromised. Mitochondrial diseases primarily affect children, but adult onset is becoming more and more common. Mitochondrial diseases are probably the most diverse human disorders at every level: clinical, biochemical, and genetic. Some affect only the nervous system but most affect many body systems, including the brain, heart, liver, skeletal muscles, kidney, and the endocrine and respiratory systems. Although mitochondrial disorders vary in severity, they are usually progressive, and often crippling. They can cause paralysis, seizures, mental retardation, dementia, hearing loss, blindness, weakness and premature death. Because of the range of symptoms and the frequent involvement of multiple body systems, mitochondrial diseases can be a great challenge to diagnose. Even when accurately diagnosed, they pose an even more formidable challenge to treat, as there are very few therapies and most are only partially effective. About this Study The first objective of this study is to establish a clinical registry of patients with suspected or confirmed mitochondrial diseases. We are collecting medical and family history, diagnostic test results, and prospective medical information for these patients and, using agreed procedures developed by the leading research clinicians in the field, providing, for the first time, standardized diagnoses of these complex disorders for the patients. The clinical information we collect from the participants will be used to learn about the spectrum of mitochondrial disorders and their prevalence. We will also develop studies which allow us to better understand how these diseases progress, which we do not understand well enough. When we begin clinical trials for mitochondrial diseases, patients enrolled in the registry who are identified as potentially eligible will be offered enrollment. Patients will only be included in studies if they give their consent in advance. The second objective of this study is to establish a biorepository for specimens and DNA from patients with mitochondrial diseases, in order to make materials easily available to consortium researchers.

  Study phs001538

• Heart Failure Network Oral Iron Repletion Effects on Oxygen Uptake in Heart Failure (HFN IRONOUT-BioLINCC)

  ObjectivesTo test the hypothesis that, compared to placebo, oral iron repletion in heart failure patients with iron deficiency improves exercise capacity after 16 weeks of therapy.Background Iron deficiency affects approximately one half of patients with symptomatic heart failure. The presence of iron deficiency in patients with heart failure is associated with reduced functional capacity, poorer quality of life, and increased mortality. Despite growing recognition of the significance of iron deficiency, randomized multicenter trials exploring the utility of oral iron supplementation, a therapy that is inexpensive, readily available, and safe, have not been performed in patients with heart failure. Moreover, patient characteristics and biochemical profiles that may influence responsiveness to oral iron in patients with heart failure have not been defined. Results of intravenous iron repletion trials have been favorable, but regularly treating patients with intravenous iron products is expensive and poses logistical challenges for outpatients. Therefore, the HFN-IRONOUT study was initiated to investigate the efficacy of oral iron in patients with heart failure with reduced ejection fraction (HFrEF). ParticipantsA total of 225 participants were enrolled, 111 randomized to receive oral iron and 114 randomized to receive the placebo. Design The HFN-IRONOUT study was a phase 2, double-blind, placebo-controlled randomized clinical trial that enrolled participants at 23 sites in the United States. Participants were randomly assigned, in a 1:1 ratio, to receive either oral iron polysaccharide or placebo with the use of an automated web-based system. A permuted block randomization method (with 4 participants per block) was stratified by enrolling site and anemia status (defined as hemoglobin At baseline, 8 weeks, and 16 weeks participants underwent studies including history and physical examination, cardiopulmonary exercise testing (CPET), Kansas City Cardiomyopathy Questionnaire (KCCQ), and 6-minute walk test. CPETs were performed using a 10 Watt/minute incremental ramp protocol and breath-by-breath measures of oxygen uptake were uniformly analyzed by the CPET Core Lab. Participants also underwent phlebotomy for biomarkers. Iron studies, including iron, total iron binding capacity, and ferritin, were measured at baseline and after 16 weeks to determine the extent to which oral iron led to iron repletion. The primary end point was the change in peak oxygen uptake (peak VO2) after 16 weeks of therapy. Conclusions Among participants with HFrEF with iron deficiency, high-dose oral iron did not improve exercise capacity over 16 weeks.

  Study phs003557

• EXPRESSION OF ANTIBODY-DRUG CONJUGATE TARGETS IN BREAST CANCER METASTASES AND NORMAL TISSUE

  Using bulk mRNA sequencing, we investigated the expression of 72 ADC targets, which are clinically approved or under investigation, in 909 samples (64 primary untreated, 749 metastatic, 96 normal) from 30 female patients from our post-mortem tissue donation program UPTIDER (NCT04531696). The study explores changes in target expression across multiple samples to identify novel targets of clinical interest and validation

  Study EGAS50000001334

• Amplicon_based_sequencing_of_drug_resistant_lung_cancer_cell_lines

  A EGFR mutant NSCLC cell line which is sensitive to AZD9291 inhibition was mutagenised with the chemical mutagen ENU and then drug selected using a AZD9291. Single cell derived colonies were then manually picked and expanded in drug. Resistance was confirmed in a 14 day assay and DNA was collected. These then underwent targeted amplicon-based sequencing to confirm candidate resistance effectors hypothesised from currently available literature.

  Study EGAS00001001675

• Molecular Signature of Saudi Thyroid Cancer Using whole exome sequencing

  In Saudi Arabia, thyroid cancer ranked second only to breast cancer among females, eleventh among males and this increased incidence is prevalent in other Gulf Council Countries also. Differentiated thyroid cancer, which includes papillary thyroid cancer (PTC) and follicular subtypes, accounts for 90% of all thyroid malignancies. Currently, there are no clinical or molecular diagnostic tools to predict recurrence and aggressiveness of a subset of PTC. With the goal of better understanding the pathobiology of thyroid carcinogenesis we will use Whole Exome Sequencing to decipher the molecular and genetic signature of Saudi PTC based on International Cancer Genome Consortium (ICGC) Guidelines. The study will provide a better understanding of PTC and should have important clinical implications in the development of new and better strategies for targeted therapeutic intervention for the treatment of Saudi Arabian PTC

  Study EGAS00001000680

• 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

• A super-enhancer associated with CD47 links pro-inflammatory signaling to CD47 upregulation in breast cancer

  CD47 is a cell surface molecule that inhibits phagocytosis of cells that express it by binding to its receptor, SIRPα, on macrophages and other immune cells. CD47 is expressed at different levels in normal cells, however, in cancer cells, CD47 transcript and protein expression is aberrantly increased. Here we sought to uncover the regulators of CD47 transcription, including active enhancers that increase its aberrant expression in cancer cells, in order to reveal mechanisms by which different neoplastic cells generate this dominant 'don't eat me' signal. Enhancers are genomic regions, often referred to as "switches", that can turn on or off the transcription of target genes. Recently the discovery of super-enhancers (SEs) has given more insight into the regulatory architecture of key genes that are highly expressed in a specific cell type, during a particular developmental stage or in disease. By analyzing the CD47 regulatory genomic landscape, we discovered: i) A distinct super-enhancer (SE) is associated with CD47 upregulation in breast cancer cells ii) Disruption of CD47 SEs by using the BRD4 inhibitor JQ1 robustly reduces CD47 gene expression; and iii) The TNF-NFKB1 signaling pathway is directly involved in the regulation of CD47 by interacting with a distal downstream constituent enhancer located within a CD47-associated SE specific to breast cancer. Our results describe a novel mechanism that cancer cells have evolved to drive CD47 overexpression to escape immune surveillance.

  Study phs001264

• Genome-Wide Association Study of Leprosy and Dapsone Hypersensitivity Syndrome (DHS) in Chinese population

  Leprosy GWAS (1) Leprosy is a chronic infectious disease caused by Mycobacterium leprae (M. leprae). Due to M. leprae's narrow host range and an inability to be cultured in vitro, the biological investigation of this disease has been difficult. Host genetic factors have been suggested to play an important role in disease development, but few have been identified. In this study, we attempted to identify the host genetic factors by performing a two-stage genome-wide association study (GWAS) in Chinese population. The initial genome-wide scan was done by genotyping 706 patients and 1225 controls using the Illumina HumanHap610 BeadChip, and the follow-up study was performed by genotyping 93 SNPs in three independent samples consisting of 3254 cases and 5955 controls. We identified significant association (P < 10-10) within six genes CCDC122 (13q14), C13orf31 (13q14), NOD2(16q12), TNFSF15 (9q32), HLA-DR (6p21) and RIPK2 (8q21), and suggestive association (P = 5.68x10-6) within LRRK2 (12q12). We also revealed suggestive evidence for C13orf31, LRRK2, NOD2 and RIPK2 to show stronger association in the multibacillary form than the paucibacillary form of leprosy. Our findings highlight the importance of the innate immune response, particularly NOD2-mediated signaling, in leprosy and suggests a new therapeutic target for leprosy. DHS GWAS Dapsone (DDS), as both an antibiotic and an anti-inflammatory agent, has been widely used for preventing and treating pathogen-caused infectious diseases and chronic inflammatory diseases. Currently, about 0.5-3.6% of individuals treated with DDS develop severe dapsone hypersensitivity syndrome (DHS) and the mortality rate is up to about 11-13%. However, until now, no tests are available to predict the risk of DHS. To identify the genetic risk factors of DHS, we performed a two-stage GWAS in Chinese population. In this study, the initial genome-wide scan was done by genotyping 39 DHS cases and 833 controls using Illumina Human 660W-Quad Beadchips and imputed human leukocyte antigen (HLA) molecules. Validation was performed by genotyping 24 SNPs using the Sequenom MassARRAY platform in additional 31 DHS cases and 1,089 controls through genotyping and 32 four-digit HLA-B alleles in an independent series of 37 DHS cases and 201 controls through Roche 454 sequencing. We identified significant association (OR =6.18, P = 3.84x10-13) with SNP rs2844573, which located between the HLA-B and MICA loci. HLA-B*13:01 was confirmed to be a strong risk factor for DHS (OR = 20.53, P = 6.84x10-25) and responsible for the association at rs2844573. The presence of HLA-B*13:01 had a sensitivity of 85.5% and specificity of 85.7% as a predictor for DHS, and its absence can reduce the risk by 7 fold (from 1.4% to 0.2%). HLA-B*13:01 is strongly associated with the development of DHS and can be used as a risk predictor of DHS in the individuals of Chinese and other Asian populations. Leprosy GWAS (2) This is a three-stage GWAS of leprosy in the Chinese population. The genome-wide discovery analysis involved two independent data sets: the new unpublished data set by genotyping 842 leprosy patients and 925 controls from northern and southern China using the Human660w-quad beadchips and a previously published GWAS data set of 706 leprosy cases, 1,225 healthy controls and 4,362 individuals with immune-related diseases as population controls from northern China of Chinese Han descent. Further validation studies were performed in two stages in a total of 6,765 cases and 9,505 controls from Chinese Han and minority descent in multiple areas of China, similar to the discovery stage. From this study, we discovered six new susceptibility loci with a combined P-value from discovery and validation stage surpassing genome-wide significance, including BATF3 at 1q32.3, CDH18 at 5p14.3, DEC1 at 9q32, EGR2 at 10q21.3, CCDC88B at 11q13.1 and CIITA at 16p13.13. Our current study has advanced the genetic understanding of leprosy by substantially increasing the number of confirmed genetic susceptibility loci. Leprosy GWAS (3) To discover additional leprosy susceptibility loci, we carried out a large-scale three-stage GWAS analysis of leprosy in Chinese population. The genome-wide discovery analysis (Stage 1) involved a new GWAS data set of 1,197 leprosy cases and 1,426 controls from northern and southern China conducted by using Illumina Omni Zhonghua chips with 900,015 single-nucleotide polymorphisms (SNPs), two published GWAS dataset (GWAS2 data set including 706 leprosy cases, 1,225 healthy controls genotyped by Illumina HumanHap610 beadchips, GWAS3 data set including 842 leprosy patients and 925 controls from northern and southern China genotyped by the Human660w-quad beadchips). Further validation studies were performed in two stages in a total of 5,413 cases and 9,771 controls from Chinese Han descent in multiple areas of China. In this study, we identified four novel associations at genome-wide significance (P < 5 x 10-8), all of which can indicate candidate genes within the susceptibility loci, SYN2 (3p25.2), BBS9 (7p14.3), CTSB (8p23.1) and MED30 (8q24.11), through a differential gene expression and eQTL analysis. Altogether, these findings have provided new insight and significantly expanded our understanding of the genetic basis of leprosy. Leprosy GWAS (4) In this study, we attempted to systematically investigate the contribution of protein-coding variants to leprosy susceptibility by performing a three-stage genome-wide association study (GWAS) of protein-coding variants in Chinese population. The initial genome-wide scan was done by genotyping 1,670 persons affected by leprosy and 2,321 controls using the Illumina Infinium Human Exome Beadchips (v1.0).The validation study was performed by genotyping 39 SNPs in an additional 3,169 leprosy patients and 9,814 healthy controls from the northern region of China, and the replication study was performed by genotyping eight SNPs in three independent samples from the southern regions of China consisting of 2,231 cases and 2,266 controls. We identified significant association (P < 1.23 x 10-6) within seven genes FLG (Gene ID: 2312), IL23R (Gene ID: 149233), CARD9 (Gene ID: 64170), NCKIPSD (Gene ID: 51517), TYK2 (Gene ID: 7297), SLC29A3 (Gene ID: 55315), IL27 (Gene ID: 246778). Our findings discover novel involvement of skin barrier and endocytosis/phagocytosis/autophagy, besides known innate and adaptive immunity, in the pathogenesis of leprosy, highlight the merits of protein coding variant studies for complex diseases. Here, the summary statistics from the five genome-wide association analyses were published.

  Study phs000217

• TK-EP862 - Patient-derived xenograft model of Posterior Fossa A Ependymoma - WSG data

  In Vivo Loss of Tumorigenicity in a Patient-Derived Orthotopic Xenograft Mouse Model of Ependymoma. Whitehouse et al. 2023 Frontiers in Oncology. We describe the establishment of a patient-derived orthotopic xenograft (PDOX) model of posterior fossa A (PFA) EPN, derived from a metastatic cranial lesion. Patient and PDOX tumors were analyzed using RNA sequencing. WSG data (paired end) provided here correspond to germline DNA, Surgical sample 4 (described in the above manuscript as a cranial metastasis of PFA ependymoma), and a patient-derived xenograft derived from the patient.

  Dataset EGAD00001010008

• Whole Genome-sequencing of rhabdomyosarcoma tumour tissue (2025-09-30)

  This study investigates high-risk rhabdomyosarcoma (RMS) using multiple single-cell and spatial genomic technologies. We generated and analysed single-cell and single-nucleus RNA-sequencing, chromatin accessibility, and spatial transcriptomics data from primary tumours and validation samples. These datasets characterise cellular diversity within rhabdomyosarcoma and identify cell states associated with aggressive disease. The data support research into tumour biology, risk stratification, and therapeutic target discovery. This repository houses the whole-genome sequencing of RMS tumours data. . This dataset contains all the data available for this study on 2025-09-30.

  Dataset EGAD00001015712

• Breast cancer women lack normal lifelong immune response after full-term pregnancies

  Immunological tolerance during pregnancy is necessary for women’s bodies to accept the semi-allogenic fetus. Interestingly, “immune evasion”, which consists of some similar immunological changes, was recently proposed as a hallmark of cancer. Looking at these results, it seems paradoxical that increasing number of full-term pregnancies (FTP) reduces the risk of breast cancer in women. Our aim was to use a systems epidemiology approach to investigate this paradox by modelling breast cancer incidence as a function of parity in the Norwegian Women and Cancer (NOWAC) cohort, then testing the mathematical model using gene expression from blood in a subcohort of these women: the NOWAC postgenome cohort. Lastly, we undertook a gene set enrichment analysis for immunological gene sets. A linear trend nicely fitted the dataset showing an 8% decrease in risk for each FTP, independent of stratification on other risk factors and lasting for decades after a woman’s last FTP. However, when we looked at gene expression we found that hundreds of genes showed linear trends in cancer-free controls, but this was not the case in /any/ of the samples from breast cancer cases. In the gene set enrichment analysis, samples consisted of human blood or cord blood and mouse bone marrow or spleen. We found more adaptive gene sets than expected in humans and more innate gene sets than expected in mice. None of the gene sets provided information about the long-term effects of immunological tolerance during pregnancy, but the lack of relevant reductionist experiments hampers our interpretation. We suggest that, after resolution at birth, the immunological tolerance induced by pregnancy augments immune response to cancer development.

  Study EGAS00001002616

• Accurate mutation detection in leukemia by re-sequencing a cancer gene set

  With the advent of whole-genome and whole-exome sequencing, high-quality catalogs of recurrently mutated cancer genes are becoming available for many cancer types. Increasing access to sequencing technology, including bench-top sequencers, provide the opportunity to re-sequence a limited set of cancer genes across a patient cohort with limited processing time. Here, we re-sequenced a set of cancer genes in T-cell acute lymphoblastic leukemia (T-ALL) using the Roche/454 technology coupled with Nimblegen sequence capture. First, we investigated how a maximal sensitivity and specificity of mutation detection can be achieved through a benchmark study. We tested nine combinations of different mapping and variant-calling methods, varied the variant calling parameters, and compared the predicted mutations with a large independent validation set obtained by capillary re-sequencing. We found that the combination of two mapping algorithms, namely BWA-SW and SSAHA2, coupled with the variant calling algorithm Atlas-SNP2 yields the highest sensitivity (95%) and the highest specificity (93%). Next, we applied this analysis pipeline to identify mutations in a set of 58 cancer genes, in a panel of 18 T-ALL cell lines and 15 T-ALL patient samples. We confirmed mutations in known T-ALL drivers, including PHF6, NF1, FBXW7, NOTCH1, KRAS, NRAS, PIK3CA, and PTEN. Interestingly, we also found mutations in several cancer genes that had not been linked to T-ALL before, including JAK3. Finally, we re-sequenced a small set of 39 candidate genes and identified recurrent mutations in TET1, SPRY3 and SPRY4. In conclusion, we established an optimized analysis pipeline for Roche/454 data that can be applied to accurately detect gene mutations in cancer, which led to the identification of several new candidate T-ALL driver mutations.

  Study EGAS00001000268

• Dataset for negative_WES

  WES/WGS sequencing data of 242 chromothriptic tumor and control runs, which were uploaded to umbrella studies. The sequencing was always paired

  Dataset EGAD00001009278

• Longitudinal Studies of Patients with Familial Platelet Disorder with Associated Myeloid Malignancy (FPDMM)

  FPDMM (OMIM #601399) is a rare autosomal dominant disease characterized by defective megakaryocytic development, thrombocytopenia, platelet functional defects, and a life-long risk of developing hematological malignancies. FPDMM is caused by germline mutations in the RUNX1 gene, which encodes a master regulator of hematopoiesis. The overall lifetime risk of hematological malignancies in FPDMM patients is 35 - 45%. It is hypothesized that mutations in other genes cooperate with the germline RUNX1 mutations for leukemia development. However, it is not clear which genes need to be mutated for leukemia to develop and which biomarkers or clinical tests can be used to predict which patients will progress to leukemia. Likewise, there are no treatments and/or preventative measures that can reduce or stop disease progression except for stem cell transplantation, which is not available for all patients and may be associated with significant complications. To address these questions, we launched a longitudinal natural history study of patients associated with RUNX1 germline mutations at the NIH Clinical Center in early 2019 (Trial Registration ID: NCT03854318). The goals of this study are to: (1) perform comprehensive longitudinal phenotyping of FPDMM patients to document the full spectrum of both hematopoietic and non-hematopoietic manifestations of the disease; and (2) perform extensive genomic analyses of FPDMM patient samples to identify cooperating genomic variants, which may confer growth advantage that leads to clonal expansion of affected hematopoietic cells that may serve as the precursor to malignancies. The data available through dbGaP include exome sequencing and RNA-seq data from these patients. Diverse germline mutation types were identified in the RUNX1 gene, including splice site mutations and large deletions, in addition to nucleotide substitutions and small indels. Somatic mutations, especially in genes associated with clonal hematopoiesis of indeterminate potential (CHIP), were found in a substantial proportion of FPDMM patients who were leukemia-free. The findings suggest that the genomes in these patients are prone to somatic mutations and monitoring the dynamic changes of these somatic mutations prospectively may provide a way to predict progression to malignancies.

  Study phs003075

• National Heart, Lung and Blood Institute: Regulation of Motile Cilia Assembly in Lung Disease

  This study of 59 primary ciliary dyskinesia (PCD) patients utilized whole-exome capture sequencing to help identify variants that may be causative for PCD. Our goal was to provide insights into disease pathophysiology in samples, most of which had no obvious phenotype from transmission electron microscopy. This class of patients has been understudied. The patient samples were collected through UNC or under the auspices of Genetic Disorders of Mucociliary Clearance Consortium (GDMCC), which consists of eight geographically diverse clinical research sites across North America. It collectively studies inherited respiratory diseases related to impaired mucociliary clearance and airway host defense, which result in chronic suppurative respiratory diseases. The goal is to enhance diagnostic capabilities as the Consortium has been pivotal in the identification and/or characterization of 34 primary ciliary dyskinesia-associated genes. In this phase of the work, we used immunocytochemistry in patient samples and in shRNA hTEC cultures to show the localization of the CFAP57 protein to cilia and the role of a short region in trafficking of CFAP57 into the cilia. This work was complemented by proteomic studies in the Chlamydomonas reinhardtii

  Study phs002035

• A Genome-Wide Association Study on Cataract and HDL in the Personalized Medicine Research Project Cohort

  The primary goals of this project are to develop and validate electronic phenotyping algorithms, to accurately identify cases and controls while maintaining a positive predictive value (PPV) of >95%, and to conduct a genome wide association study that advances understanding of two specific yet interrelated disease states, while simultaneously engaging the community in these research efforts. Lipid abnormalities and cataracts are both diseases of public health significance, they share common risk factors, and they are both complex diseases which likely have many genes contributing to disease development. Whole genome association studies with these two outcomes and environmental risk factors could yield novel data about the etiology of the two separate outcomes as well as their interaction. PhenX is a project designed to prioritize Phenotypes and eXposure measures for Genome-wide Association Studies (GWAS). The PhenX Toolkit is a valuable resource for researchers who are planning or expanding a study and would like to incorporate well established measures that have been recommended by experts in the field. We are currently interested in gene-environment interactions for "age related cataract".

  Study phs000170

• Pediatric Investigation of Genetic Factors Linked with Renal Progression (PediGFR): Chronic Kidney Disease in Children Cohort (CKiD)

  The Pediatric Investigation for Genetic Factors Associated with Renal Progression (PediGFR) (RO1-DK082394) is an international collaborative study among three large prospective cohort studies of children with chronic kidney disease. The participating parent cohort studies are the "Chronic Kidney Disease in Children (CKiD)", the "Effect of Strict Blood Pressure Control and ACE Inhibition on CRF Progression in Pediatric Patients (ESCAPE)", and the "Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C)" study. In these cohorts, pediatric subjects with CKD have been prospectively followed with standardized measurements for renal progression. The current version of the upload includes the genotype and baseline phenotype for the CKiD cohort. In brief the CKiD study is a prospective study of children with chronic kidney disease (CKD) between the ages of 1 year to 16 years of age and an estimated glomerular filtration rate (eGFR) by Schwartz equation between 30 and 75 ml/min per 1.73m2. Included in this upload are the phenotypic data for anemia traits utilized for the sub-study, "Role of Genetic Variation in the Anemia of Chronic Kidney Disease" (K24DK078737), with the RBC trait and anemia data pertaining to CKiD as well.

  Study phs000650

• Kids First: The Genomic Architecture of Hirschsprung Disease (HSCR)

  Hirschsprung disease (HSCR) is a male biased developmental disorder associated with a lack of innervation of the gastrointestinal tract. Genetic studies have been instrumental in understanding its multifactorial inheritance, high heritability, syndromic associations, and genetic heterogeneity with variable penetrance and expressivity. At least 24 genes and 9 loci with pathogenic alleles (PAs) are known to underlie HSCR pathogenesis and explain 62% of its population attributable risk (PAR). Despite this heterogeneity, there is functional unity in HSCR: ~53% of HSCR PAs disrupt RET and EDNRB signaling in the developing enteric nervous system (ENS) in which 11 genes comprising a gene regulatory network control RET and EDNRB gene expression. We propose to identify the remaining 30% PAR by studying 857 unrelated HSCR cases, their 125 affected and 1,446 unaffected firstdegree relatives by whole genome sequencing to increase statistical power of gene discovery through improved detection of all types of coding and regulatory PAs. HSCR arises from cell autonomous defects in enteric neural crest cell precursors (ENCCs) affecting their proliferation, differentiation and migration in the ENS, functional studies that will guide our detection of novel genes.

  Study phs003662

• An_exome_sequencing_study_of_the_HIV_elite_long_term_non_progressors_and_rapid_progressors__CASCADE_cohorts_

  Background: A rare subgroup of HIV infected individuals naturally controls infection withouttreatment. These ?elite controllers? constitute an important model for the natural control ofHIV infection. Indeed, the study of these individuals may provide insights into strategies forthe development of HIV vaccines. Although several HLA and chemokine alleles are knownto be over-represented in elite controllers, only a small portion of HIV phenotypic variation isexplained by known genetic variants. The elite controller phenotype is rare and distinct,representing the extreme of an infectious disease trait. As such, this phenotype may be partlyexplained by variation in host immune control, which may be characterized by differences inrare functional genetic variants. Genomic regions underlying elite control can be potentiallyidentified by comparing the presence or frequency of variants in this group to thatrepresenting the opposite extreme. In this context, ?rapid progressors? is a group defined byits rapid immunological and clinical disease progression.Aim: To extend an existing study, in order to identify DNA sequence variants involved in thecontrol of HIV infection with greater statistical resolution. Specifically, we aim to sequence upto 200 exomes from multiple cohort studies within the EuroCoord CASCADE collaboration (acollaboration of 25 HIV seroconversion cohort studies across Europe).

  Study EGAS00001000522

• Cryptic Relatedness in the Singapore Living Biobank Project

  The Singapore Living Biobank is a collection of healthy population-based Chinese and Malay individuals, for the purpose of phenotype recall study of high-impact variant carriers. These individuals are sampled from two studies: Multi-Ethnic Cohort (MEC), and the Singapore Health 2012 (SH2012). The MEC is a population-based cohort initiated in 2007 to investigate the genetic and lifestyle factors that affect the risk of developing chronic diseases such as diabetes and cardiovascular outcomes in the three ethnic groups (Chinese, Malays, and Indians). The SH2012 study is a population-based cross-sectional survey conducted in Singapore between 2012 and 2013, with over-sampling of Malays and Indians. Participants in MEC and SH2012 completed a similar set of questionnaire components, health examination, and biochemisty panels. Description of the MEC and SH2012 studies can be found at http://blog.nus.edu.sg/sphs/. We generated whole-exome sequencing data and Illumina OmniExpress array genotyping data for 1,299 Chinese and 1,229 Malays from the Singapore Living Biobank. This study includes a subset of 762 individuals that were found to be closely related (≤3rd degree), including 263 Chinese and 499 Malays.

  Study EGAS00001002619

• H3Africa - Identification and characterization of novel hereditary neurological disease genes in Mali.

  Despite the vast diversity of its populations, genetic studies in Africa have been limited. African populations, Malians in particular, have a high rate of intra-ethnic and consanguineous marriage, resulting in increased prevalence of autosomal recessive diseases. Family-based genetic studies can be limited in developed countries due to small sibships. The average fertility rate in Mali is over 6 births per woman, offering a unique opportunity to find new disease genes or mutations that can then be studied in other populations. Hereditary neurological diseases are very debilitating diseases, and developing countries, particularly in Africa, pay a high price in terms of disability-adjusted life years. Although most are currently untreatable, increasing awareness about hereditary neurological disorders can reduce this burden. This study will help to identify and characterize novel hereditary neurological disease genes in Mali. These genes are likely to be important in the normal function of the nervous system and to have important pathophysiological implications for African and other populations. This study will also train physicians and students in the characterization of neurodegenerative diseases as well as in genetic technology and molecular biology, and build a suitable research environment that will retain them.

  Study EGAS00001003016

• Genomic Characterization of Pediatric Low-Grade Gliomas

  Pediatric low-grade gliomas (PLGGs) are the most common pediatric brain-tumor, with more than ten histologic subtypes recognized by the World Health Organization. We performed a genomic analysis of 230 PLGGs of which 73 had whole genome/RNA sequencing performed and show that MYB-QKI fusions define the seizure associated tumor, Angiocentric Glioma (AG). MYB-QKI fusions present in AGs contribute to tumorigenesis through three mechanisms: MYB activation by truncation, enhancer translocation driving aberrant MYB-QKI expression, and hemizygous loss of QKI, a tumor suppressor gene. Such interplay between three oncogenic mechanisms has diagnostic and therapeutic implications in AGs, and illustrates the functional complexity associated with rearrangements in cancer.

  Study phs001054

• Transcriptomic Profiling of Peripheral Immune Cells in a Trial of Ruxolitinib with Nivolumab for Anti-PD1 Non-Responsive cHL

  Treatment with checkpoint inhibitors is effective in multiple cancer types. However, even in cancers with high response rates such as Hodgkin lymphoma, some patients fail to respond or relapse following an initial response to checkpoint inhibitors. In this study, we examined patients enrolled in a clinical trial of ruxolitinib with nivolumab in relapsed or refractory Hodgkin lymphoma (NCT03681561). Patients relapsed or refractory to anti-PD1 therapy received ruxolitinib for 8 days followed by nivolumab every 4 weeks and continued ruxolitinib twice daily. For this transcriptomic study, peripheral blood mononuclear cells (PBMCs) were collected at baseline and 8 days of ruxolitinib therapy and analyzed by single-cell and bulk RNA-sequencing.

  Study phs003601

• Tumor microenvironment study of ovarian granulosa cell tumors

  Adult-type granulosa cell tumors (aGCT) are rare ovarian sex cord tumors with few 41 effective treatments for recurrent disease. The objective of this study was to compare global gene expression profiles and characterize the tumor microenvironment (TME) of primary and recurrent aGCTs in order to identify correlates of disease recurrence. Total RNA sequencing was performed on 24 pathologically confirmed, cryopreserved aGCT samples, including 8 primary and 16 recurrent tumors. A total of 31 differentially expressed genes were identified between primary and recurrent aGCT. TME analysis demonstrated significantly higher fractions of neutrophils and macrophages in recurrent tumors in conjunction with significantly lower fractions of cancer-associated fibroblasts and endothelial cells.

  Study EGAS00001006478

• Single-cell RNA-sequencing of CD19 Chimeric Antigen Receptor (CAR) T-cells (CD19 CAR T-cells) from a Phase I clinical study in paediatric ALL: CARPALL

  Chimeric antigen receptor (CAR)-modified T-cells have become established as an effective treatment of haematological cancers. In the context of relapsed and refractory childhood pre-B cell acute lymphoblastic leukaemia (B ALL), CD19 targeting CAR T-cells often induce durable remissions. Previously, we generated a novel low-affinity CAR incorporating a CD19-specific single-chain variable fragment (scFV) called CAT, displaying a faster off-rate of interaction than the FMC63 CD19 binder used in prior clinical studies. Here, we systematically analysed CD19 CAR T-cells of ten children with relapsed or refractory B ALL enrolled in the CARPALL trial (NCT02443831). To characterize persisting CD19 CAR T-cells, we performed high throughput single-cell gene expression and T-cell receptor (TCR) sequencing of infusion products and serial blood and bone marrow samples up to five years post-infusion. We isolated CAR T-cells from peripheral blood or bone marrow by flow cytometry for CD3 and CAR expression, prior to single cell sequencing (Chromium 10X) platform.

  Dataset EGAD00001010018