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• Recursive splicing in long vertebrate genes

  Recent studies have shown that expression of many genes with exceptionally long introns in the mammalian brain can be perturbed by regulatory factors linked to neurodevelopmental or neurodegenerative disorders1-3, suggesting unique regulatory mechanisms. Here we identify functional recursive splice sites (RSS) in long introns of genes expressed in the brain. These RSS are highly conserved in genes with extreme length across diverse vertebrate species and permit step-wise removal of long introns via recursive splicing. Recursive splicing requires initial definition of a “recursive exon” that is located downstream of RSS, and most often contains premature stop codons. Moreover, we show that RSS create a splicing switch driven by splice site competition in order to distinguish primary mRNA isoforms from alternative isoforms that are prevalent in long genes. The recursive exon is not detectable in the dominant mRNA isoform due to recursive splicing, but is completely included when cryptic promoters or other cryptic exons are used. Thus, by coupling inclusion of recursive exons with the use of cryptic elements, RSS act to distinguish new mRNA isoforms emerging from long genes.

  Study EGAS00001001170

• Cell-free DNA TAPS for early cancer detection

  Multimodal, genome-wide characterization of epigenetic and genetic information in circulating cell-free DNA (cfDNA) could enable more sensitive early cancer detection. However, due to technological challenges associated with DNA methylation sequencing in low input cfDNA samples, most studies have been limited by DNA damage caused by bisulfite sequencing, or the qualitative nature of enrichment-based sequencing. Recently, we developed TET-assisted Pyridine Borane Sequencing (TAPS), which is a mild, bisulfite-free method for base-resolution direct DNA methylation sequencing. Here we optimized TAPS for cfDNA (cfTAPS) to provide high-quality and high-depth whole-genome cell-free methylomes. We applied cfTAPS to 85 cfDNA samples from patients with hepatocellular carcinoma (HCC) or pancreatic ductal adenocarcinoma (PDAC) and non-cancer controls. From just 10 ng cfDNA (1-3 mL of plasma), we generated the most comprehensive cfDNA methylome to date. We demonstrated that cfTAPS provides multimodal information about cfDNA characteristics, including DNA methylation, tissue of origin, and DNA fragmentation. Integrated analysis of these epigenetic and genetic features enables accurate identification of early HCC and PDAC.

  Study EGAS00001004962

• NHLBI TOPMed: Walk-PHaSST Sickle Cell Disease (SCD)

  Walk-PHaSST study is a multi-center clinical trial to evaluate the effects of sildenafil on Sickle Cell Disease (SCD) population with low exercise capacity associated with an increased Doppler-estimated pulmonary artery systolic pressure (as assessed by the tricuspid regurgitant velocity (TRV)). It is a double-blind, placebo-controlled trial to assess the safety, tolerability, and efficacy of sildenafil in patients with SCD who had both an elevated TRV and decreased exercise capacity. The screening phase of the study enrolled 720 subjects and 74 of them were randomized for the clinical trial. For the screening cohort, we have collected general demographics and race/ethnicity, hemoglobin genotype, physical examination, laboratory screening, transthoracic Doppler echocardiography, and 6 minute walk test in 9 US and 1 UK site. The walk-PHaSST biorepository have banked samples from 610 of the screening subjects. A total of 592 subjects from the screening phase are included in the TOPMed program for WGS.

  Study phs001514

• 1000 Genomes Used for Cloud Testing

  WARNING: This is a test data set. The phenotype data was not checked to match 1000 Genomes project. Use with caution.This study provides public access to a demonstration subset of 1000 genomes sequence data in dbGaP. It is intended to be used by software developers who design, implement and validate pipelines for dbGaP data. While this project distributes only public data, it uses dbGaP security mechanisms which include a project-specific security key and a decryption password. Since the data are public, the key and password for this project will be included by SRA into public demonstration packages that permit users to test and validate the security of their computational pipelines. Note that all public users of this data will be logged under the same project and account ID. The datasets attached to this project must be restricted to 1000 Genomes data identical to the project's public FTP site. To access these test data using SRA toolkit use prj_phs710EA_test.ngc.

  Study phs000710

• Rna-Seq Leiomyosarcoma subtypes

  Leiomyosarcomas (LMS) are genetically heterogeneous tumors differentiating along smooth muscle lines. Currently, LMS treatment is not informed by molecular subtyping and is associated with highly variable survival. While disease site continues to dictate clinical management, the contribution of genetic factors to LMS subtype, origins, and timing are unknown. Here we analyzed 70 genomes and 130 transcriptomes of LMS, including multiple tumor regions and paired metastases. Molecular profiling highlighted the extremely early origins of LMS. Three specific subtypes of LMS develop from distinct lineages of smooth muscle cells. Of these, dedifferentiated LMS with high immune infiltration and tumors primarily of gynaecological origin acquired the highest burden of genomic mutation and are associated with worse survival. Homologous recombination defects lead to genome-wide mutational signatures, and a corresponding sensitivity to PARP and other DNA damage response inhibitors, suggesting a novel therapeutic strategy for LMS. Finally, by phylogenetic reconstruction, we present evidence that clones seeding lethal metastases arise decades prior to LMS diagnosis.

  Study EGAS00001004783

• Heart Failure Network: Diuretic Optimization Strategies Evaluation in Acute Heart Failure (HFN DOSE-BioLINCC)

  ObjectivesThe DOSE study sought to evaluate the most effective dosing (high vs. low) and administration (continuous infusion vs. intermittent boluses) combination of the diuretic Furosemide in the treatment of patients with acute decompensated heart failure.BackgroundAcute decompensated heart failure is the most common cause of hospital admissions among patients older than 65 years of age and is responsible for more than 1 million hospitalizations annually in the United States. Intravenous loop diuretics are an essential component of current treatment and are administered to approximately 90% of patients who are hospitalized with heart failure. Despite decades of clinical experience with these agents, prospective data to guide the use of loop diuretics are sparse, and current guidelines are based primarily on expert opinion. As a result, clinical practice varies widely with regard to both the mode of administration and the dosing.SubjectsA total of 308 patients were enrolled between March 2008 and November 2009 at 26 clinical sites in the United States and Canada. DesignThe DOSE study was a prospective, randomized, double-blind, controlled trial with a 2-by-2 factorial design. Patients were randomly assigned to either a low-dose strategy (total intravenous furosemide dose equal to their total daily oral loop diuretic dose in furosemide equivalents) or a high-dose strategy (total daily intravenous furosemide dose 2.5 times their total daily oral loop diuretic dose in furosemide equivalents) and to administration of furosemide either by intravenous bolus every 12 hours or by continuous intravenous infusion.The study treatment, with group assignments concealed, was continued for up to 72 hours. At 48 hours, the treating physician had the option of adjusting the diuretic strategy on the basis of the clinical response. An assessment of biomarkers, including creatinine, cystatin C, and N-terminal pro-brain natriuretic peptide, was performed at a central core laboratory at baseline, 72 hours, and 60 days. Patients were followed for clinical events to day 60. The coprimary end points were patients' global assessment of symptoms, quantified as the area under the curve (AUC) of the score on a visual-analogue scale over the course of 72 hours, and the change in the serum creatinine level from baseline to 72 hours.ConclusionsAmong patients with acute decompensated heart failure, there were no significant differences in patients' global assessment of symptoms or in the change in renal function when diuretic therapy was administered by bolus as compared with continuous infusion or at a high dose as compared with a low dose. (Felker et. al., 2011, PMID: 21366472)

  Study phs003524

• 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

• HGSOC genome-wide SNP (project ITH)

  SNP array genotyping of multi-site HGSOC samples

  Dataset EGAD00010002482

• Melanoma multi site metastases

  These are caveman, pindel, battenberg and brass calls for index patients' metastatic melanoma genomes within this study.

  Dataset EGAD00001005483

• NIH RECOVER: A Multi-Site Observational Study of Post-Acute Sequelae of SARS-CoV-2 Infection in Adults

  The NIH Researching COVID to Enhance Recovery (RECOVER) initiative comprises a set of three combined retrospective and prospective, longitudinal, observational meta-cohort studies with nested case-control studies designed to define and characterize the epidemiology, natural history, clinical spectrum, and underlying mechanisms of post-acute effects of SARS-CoV-2 infection (PASC or Post-COVID syndrome) in a diverse study population representative of the general COVID-19 population in the US. Enrolled patients with and without known SARS-CoV-2 infection will be observed for clinical signs and symptoms of PASC and will be assessed for risk and resiliency factors and potential mediating factors associated with the severity and progression of PASC. The objective of the RECOVER initiative is to enhance knowledge of recovery from SARS-CoV-2 infections in order to support development of novel diagnostic and therapeutic interventions. Overarching scientific objectives are as follows: Characterize the incidence and prevalence of sequelae of SARS-CoV-2 infection. Characterize the spectrum of clinical symptoms, subclinical organ dysfunction, natural history, and distinct phenotypes identified as sequelae of SARS-CoV-2 infection.Define the biological mechanisms underlying pathogenesis of the sequelae of SARS-CoV-2 infection. The RECOVER observational studies comprise three cohorts across the lifespan (adult, pediatric, and tissue pathology (autopsy)). The data collection and data analysis plans for each cohort have been harmonized to use common data elements where feasible. Brief descriptions of each cohort are provided in the following paragraphs:1) NIH RECOVER: A Multi-site Observational Study of Post-Acute Sequelae of SARS-CoV-2 Infection in Adults (this study)The RECOVER adult cohort study is a combined retrospective and prospective, longitudinal, observational meta-cohort of individuals who will enter the cohort with and without SARS-CoV-2 infection and at varying stages before and after infection. Individuals with and without SARS-CoV-2 infection and with or without PASC symptoms will be followed to identify risk factors and occurrence of PASC. This study will be conducted in the United States and subjects will be recruited through inpatient, outpatient, and community-based settings. Study data including age, demographics, social determinants of health, medical history, vaccination history, details of acute SARS-CoV-2 infection, overall health and physical function, and PASC symptom screen will be reported by subjects or collected from the electronic health record using a case report form at specified intervals. Biologic specimens will be collected at specified intervals, with some tests performed in local clinical laboratories and others performed by centralized research centers or banked in the Biospecimen Repository. Advanced clinical examinations and radiologic examinations will be performed at local study sites with cross-site standardization. A summary of information available by request in the RECOVER Adult Cohort (this study) can be reviewed via the "Adult Cohort Dataset Release Notes" and the "REDCap Codebook for the Adult Cohort" documents.2) The RECOVER Post Acute Sequelae of SARS-CoV-2 (PASC) Pediatric Cohort Study: A Multi-Center Observational Study (data not yet released)The RECOVER pediatric study is a combined retrospective and prospective, longitudinal, observational meta-cohort of individuals ages newborn-25 years who will enter the cohort with and without SARS-CoV-2 infection at varying stages before and after infection. Individuals with and without SARS-CoV-2 infection and with or without PASC symptoms will be followed to identify risk factors and occurrence of PASC. This study recruit participants inpatient, outpatient, and community-based settings in the United States. Study data including age, demographics, social determinants of health, medical history, vaccination history, details of acute SARS-CoV-2 infection, overall health and physical function, and PASC symptoms will be reported by participants or collected from the electronic health record using a case report form at specified intervals. Biologic specimens will be collected at specified intervals, with some tests performed in local clinical laboratories and others performed by centralized research centers or banked in the Biospecimen Repository. Advanced clinical and radiologic examinations will be performed at local study sites with cross-site standardization.3) NIH RECOVER: A Multi-site Pathology Study of Post-Acute Sequelae of SARS-CoV-2 Infection (data not yet released)The RECOVER tissue pathology study is a cross-sectional study designed to define and characterize the epidemiology, natural history, clinical spectrum, and underlying mechanisms of post-acute effects of SARS-CoV-2 infection in a diverse population representative of the general COVID-19 population in the US. The autopsy study will characterize the pathology of PASC in (i) non-hospitalized patients who die 30 days or later from symptom onset of COVID-19, and (ii) hospitalized patients who die 30 days or later after discharge from a hospitalization for COVID-19. The study will include decedents who had previously fully recovered from SARS-CoV-2 infection (i.e., >30 days from onset in non-hospitalized, or >30 days from discharge in hospitalized patients), and decedents who meet clinical criteria of PASC as defined by the recent World Health Organization publication (see Section 5.4 below). The autopsy study will also explore the pathology of acute SARS-CoV-2 infection in a smaller subset of patients who died 15-30 days from symptom onset. This protocol defines the common set of clinical data elements, autopsy procedures for tissue collection, core measures, pathology protocols, shared pathology tissues, data elements, and methodology. Each investigator site is expected to perform autopsies on the decedents to address the pathophysiology of the potential long-term effects of SARS-CoV-2 infection on human health. The Consortium analysis plan aims to address research questions by incorporating: 1) tissue obtained from autopsies performed at each Phase II participant's site; and 2) tissue available from other pathology investigators/autopsy sites within the Consortium.

  Study phs003463

• Molecular Analysis of Alliance A031201 Study

  This is the first study examining the relationship between clonal hematopoiesis and clinical outcomes in prostate cancer patients. We used a targeted gene sequencing panel to identify patients in the A031201 clinical trial with and without clonal hematopoiesis. We found that clonal hematopoiesis did not affect overall or progression free survival in A031201 but was associated more adverse cardiac events.

  Study phs003717

• The Genomic Map of Poland in Open Access

  The main goal is to prepare and share WGS/WES of Polish population In this project NGS (next generation sequencing) was performed using Illumina NOVASEQ 6000 and Illumina DRAGEN aligner was used. Shared BAM and BAM.BAI files Library Construction Protocol: Illumina DNA PCR-Free Prep, Tagmentation. Reference Genome: GRCh37.

  Study EGAS50000000091

• Sequencing of cancer autopsies and ctDNA

  Tumor heterogeneity is a major obstacle for precision oncology strategies. To characterize inter-lesion heterogeneity in pre-treated cancers, we performed genetic and transcriptomic profiling of synchronous lesions from ten rapid autopsies comprising six cases of breast cancer, three of cholangiocarcinoma and one lung cancer case. For nine patients, we studied mutation representation in circulating cell-free DNA (cfDNA).

  Study EGAS00001005109

• Patient Microbiome and Surgical Site Infection in Spine Surgery

  Single center, prospective cohort study on the contribution of the preoperative patient microbiome and resistome to surgical site infection (SSI) and resistance to surgical antibiotic prophylaxis in spine surgery. The samples in this entry comprise a subset of patients for whom paired preoperative microbiome samples and postoperative wound culture isolates were obtained. These samples were analyzed by Illumina-based sequencing of metagenomic libraries enriched for the SSI pathogen of interest using the GenCap-Seq methodology (PMID: 36121157) to identify instances of endogenous infection with strains present in the preoperative microbiome.

  Study phs003358

• Whole Exome Sequencing in Alopecia Areata Identifies Rare Mutations in KRT82

  Alopecia areata (AA) is an autoimmune disorder, in which the body's own immune cells attack hair follicels resulting in hair loss. It is a complex genetic disease with 14 associated loci previously identified in our genome-wide association study (GWAS). In the study, we performed the whole-exome sequencing (WES) on 849 AA patients with the aim to identify the novel rare variants in genes contributing to AA susceptibility. We performed gene-collapsing analyses and identified keratin 82 (KRT82 Gene ID: 3888) as the highest associated AA gene in the three rare damaging collapsing models with p<6.7E-07 in one of the models. The KRT82 gene is a hair-specific type II keratin expressed in the hair shaft cuticle during the anagen phase of the hair cycle. We reported the lower expression of KRT82 in AA hair follicles, compared to controls, and the KRT82 expression is absent from the bulb region, the site of AA immune attack. This study emphasizes the significance of using WES and gene collapsing analyses to identify rare variation in a functionally relevant risk gene using a moderate sample size.  

  Study phs002632

• PEVOsq

  The PEVOData PEVOsq basket trial is an open-label, multi-center, phase II trial investigating the combination of pembrolizumab (an immune checkpoint inhibitor) with vorinostat (a histone deacetylase inhibitor). This trial focuses on treating patients with recurrent or metastatic squamous carcinomas, including cancers of the cervix, head and neck, anus, vulva/vagina, penis, and lung. The aim is to evaluate the efficacy and safety of this combination, with pembrolizumab administered every 3 weeks and vorinostat daily. Outcomes include overall response rate and progression-free survival.

  Study EGAS50000000731

• Systematic evaluation of NIPT aneuploidy detection software tools with clinically validated NIPT samples

  Non-invasive prenatal testing (NIPT) is a powerful screening method for fetal aneuploidy detection, relying on laboratory and computational analysis of cell-free DNA. Although several published computational NIPT analysis tools are available, no comprehensive and direct accuracy evaluations of these tools is published. Here, we evaluate and determine the precision of five commonly used computational NIPT aneuploidy analysis tools, considering diverse sequencing depth (coverage), arbitrary sequencing read placement, and fetal DNA fraction on clinically validated NIPT samples.

  Study EGAS00001005323

• cfDNAme allows early prediction of PE

  Preeclampsia (PE) is a leading cause for peripartal morbidity, especially if developing early in gestation. To enable prophylaxis to prevent PE, it is essential that pregnancies at risk of PE are identified early, in the first trimester. To identify patients at risk, we profiled methylomes of plasma-derived cell-free DNA (cfDNA) from pregnant women. We detected DNA methylation differences between control and PE pregnancies that enable risk stratification of patients, at PE diagnosis but also presymptomatically, around 12 weeks of gestation.

  Study EGAS00001007071

• Data Quality Control

  Data Quality Control High-throughput sequencing techniques have become the leading method to study, decode and discover the genomic origins of biological phenomenons. EGA provides a secure archival of such identifiable genomics data with the purpose of data-upcycling, i.e. to re-use these data for research. High-quality data standards are essential to ensure the quality and credibility of the research. Moreover, a quality check report can assure a researcher beforehand about the data that they will request access, therefore saving time and effort. The EGA has developed a File Quality Control Report (QC Report) to provide generic quality control reports for Fastq, SAM/BAM/CRAM, and VCF files deposited at EGA. This QC Report will allow users to get information regarding the files submitted within a specific dataset. The data requesters will obtain information such as the quality of reads, mapped reads, number of variants, and other features before starting the requesting process, which will save the efforts and time.Accessing file quality control reportsIn each dataset page, the user can explore the files that it contains by clicking the "files" tab. The Quality Control report of a file has two sections. The first one, contains general information about the file, such as the inferred assembly, total reads, the dataset or study where it comes from, etc. The second section contains plots that summarise interesting information about the file, for example, the base coverage distribution, base quality or mapped reads. The description of each plot is accessible by clicking the "i" button at the top-right corner of each plot box. Technical Description For analysing the fastq, SAM/BAM/CRAM and VCF files, the EGA applies a set of tools widely used in the bioinformatics community. FASTQ: FastQC, recognised as the gold standard tool by the community.Per base sequence quality, per sequence quality scores, per base sequence content, per sequence GC content, sequence duplication levels, etc.SAM/BAM/CRAM: samtools, also the gold standard, generates results plots useful to get an overall idea of the quality of the file.base coverage distribution, base quality, % of mapped reads, % of both mates mapped, singletons, duplicates, etc.VCF: vcftools and bcftools, combined with a custom script to infer the genome assembly.site frequency distribution, Ts/Tv, base changes, indel distribution, etc.

  Documentation access/request-data/quality-control-reports

• Genome-wide cell-free DNA biological patterns in patients with cancer

  The structure of cell-free DNA (cfDNA) is altered in the blood of cancer patients. From whole genome sequencing we retrieved the cfDNA fragment-end composition using a new software (FrEIA), as well as the cfDNA size and tumor fraction in three independent cohorts (n=925 cancer from >10 types and 321 control samples). At 95% specificity, we detect 72% of cancer samples using at least one cfDNA measure, including 64% of early-stage cancer (n=220). cfDNA detection correlates with a shorter overall (p=0.018) and recurrence-free (p=0.006) survival in patients with resectable esophageal adenocarcinoma. Integrating cfDNA measures with machine learning in an independent test set (n=396 cancer, 90 controls) achieve a detection accuracy of 82% and AUROC of 96%. In conclusion, harnessing the biological features of cfDNA can improve at no-extra cost the diagnostic performance of liquid biopsies.

  Study EGAS00001007400

• Genotyping_of_additional_Inflammatory_Bowel_Disease_cases___2014

  Both internal and external funding has enabled 5000 inflammatory bowel disease cases to be whole genome sequenced (CD @4X, UC @2X). The Anderson and Barrett groups are currently generating genotypes across these samples for comparison to 4000 population controls sequenced as part of UK10K. The UK10K project has shown that imputing sequenced genetic variation into previously GWASed samples greatly increases power to detect association. Given that our study has been designed to detect association to low frequency variation (0.5% and above) these gains in power are especially important. Overall, the UKIBDGC has GWAS data for around 1800 CD samples (Affy 500K) and 3000 UC samples (Affy6), though some of these samples have also been whole genome sequenced. Here, we apply to get all remaining non-GWAS and non-WGS IBD cases in the UKIBDGC (N=X) genotyped genotyped on the Illumina Core Exome Array

  Study EGAS00001000924

• Plasma mutation profile of precursor lesions and colorectal cancer using the Oncomine Colon cfDNA Assay

  Colorectal cancer (CRC) is the second leading cause of cancer death worldwide. Early detection of precursor lesions or early-stage cancer could hamper cancer development or improve survival rates. Liquid biopsy, which detects tumor biomarkers, such as mutations, in blood, is a promising avenue for cancer screening. To assess the presence of genetic variants in plasma cell-free tumor DNA from patients with precursor lesions and colorectal cancer using the commercial Oncomine Colon cfDNA Assay. Cell-free DNA (cfDNA) samples from the blood plasma of 52 Brazilian patients were analyzed. Eight patients did not have any significant lesions (five normal colonoscopies and three hyperplastic polyps), 24 exhibited precursor lesions (13 nonadvanced adenomas, ten advanced adenomas, and one sessile serrated lesion), and 20 patients with cancer (CRC). The mutation profile of 14 CRC-associated genes were determined by next-generation sequencing (NGS) using the Oncomine Colon cfDNA Assay in the Ion Torrent PGM/S5 sequencer.

  Study EGAS50000000471

• Non-invasive prenatal diagnosis by genome-wide haplotyping of cell-free plasma DNA

  This dataset contains a total of 10 families and 51 samples presented in 'Non-invasive prenatal diagnosis by genome-wide haplotyping of cell-free plasma DNA' study, in which 9 of them are cfDNA samples and the rest of samples are gDNA samples. All the samples are targeted sequencing data with a custom 45Mb capture library . Raw pair-end fastq files for each sample is available.

  Dataset EGAD00001004989

• Genome-Wide Association Study of HCC in Non-Asian USA Population

  This GWAS of HCC relied on existing biological and data resources from 7 USA sites and one Canadian site which allows for the integration of genetic and environmental data. Total of 2199 case patients and 1103 non cancer controls were genotyped. Case patients are defined as patients with pathological or radiological diagnosis of HCC with and without chronic hepatitis C virus infection. Study was restricted to Caucasian population without prior infection with chronic HBV infection. All DNA samples were extracted from peripheral blood. Study population of the participated sites are: Site-1: University of Texas MD Anderson Cancer Center A hospital based-case-control study was initiated at UT MD Anderson Cancer Center in 2000 and approved by the Institutional Review Board of The University of Texas M. D. Anderson Cancer Center. Study design was previously described in detailed (1-3). Written informed consent for an interview and for a biological sample was obtained from each participant. At time of diagnosis prior to treatment exposure. Case patients were recruited from the population of patients with newly diagnosed HCC who were evaluated and treated at the institution's gastrointestinal medical and surgical oncology outpatient clinics. Inclusion criteria were as follows: a pathologically confirmed diagnosis of HCC, U.S. residency, and the ability to communicate in English. Patients with concurrent or past history of other types of cancers were excluded. Control subjects were healthy spouses of patients with cancers other than liver, gastrointestinal, lung, or head and neck (smoking-related cancers) undergoing treatment at our institution. Eligibility criteria for control subjects were the same as those for patients, except that control subjects could not have ever had cancer. A short, structured questionnaire was used to screen potential control subjects on the basis of eligibility criteria. Control subjects and patients were recruited simultaneously. Case patients and control subjects were interviewed by well-trained interviewers who followed a written protocol to guide ascertainment and reduce surveillance, interviewer, and recall bias. No proxy interviews were conducted. The interviewers used a structured and validated questionnaire to collect information about demographic characteristics and potential risk factors for HCC such as personal smoking history, alcohol use, medical history, occupational history, and family history of cancer. Blood samples from cases and controls were tested for HBV and HCV. HCV antibodies, hepatitis B surface antigen, and antibodies to hepatitis B core antigen were detected by use of a third-generation enzyme-linked immunosorbent assay (ELISA) (Abbott Laboratories, North Chicago, IL). Important clinical information were retrieved from patients' medical records. Total of 1188 case patients and 278 controls from MD Anderson study were genotyped. Site-2: Mayo Clinic Case patients and controls included in the study from Mayo clinic were recruited as part of Mayo International Hepatobiliary Neoplasia Register and Biorepository. Only USA patients and controls were participated. All cases and controls signed informed consent indicating their willingness to participate in genetic studies. Epidemiological and clinical data were collected from participants and retrieved from medical records. Total of 522 HCC case patients and 182 controls were genotyped in this study. Site-3: Toronto University Molecular Epidemiology of Hepatobiliary Tumors (HBT study, CAPCR 09-0289) is a hospital-based study that includes 1710 patients diagnosed with liver, bile duct or gallbladder adenocarcinoma (Hepatocellular carcinoma - HCC; cholangiocarcinoma - CCA; and gall bladder adenocarcinoma -GBCa) recruited at University Health Network (UHN) between 2009 and 2018. HBT study is a prospective study of cancer patients that collects self-reported demographic and epidemiological data, medical records/clinical information and blood samples for research purposes. Eligible patients recruited between 2009 and March 15 2016 were selected to participate in the Genome-Wide Association Study in Patients with Hepatocellular Carcinoma (GWAS in HCC, CAPCR 15-9943-CE), a sub-study of the HBT study. Eligible prospective patients recruited after March 15 2016 signed the Addendum to the HBT consent form and became eligible to participate in the GWAS in HCC study. Total of 271 cases and 21 controls were genotyped from Toronto University Site-4: University of Pittsburgh The design of the study has been described previously (4-6). Briefly, this population-based study enrolled 120 HCC patients and 230 matched controls from black, Hispanic, and non-Hispanic white residents of Los Angeles County who were between 18 and 74 years of age at diagnosis from January 1995 through December 2001. HCC Cases were identified through the Los Angeles County Cancer Surveillance Program. We sought to recruit up to two control subjects per case from the neighborhoods where HCC patients resided at the time of diagnosis, who were matched to the index case by sex, age (within 5 years), and race (Hispanic white, non-Hispanic white, black). Blood samples (plasma and buffy coat), medical and lifestyle factors were collected from all consenting participants. Total of 65 cases and 60 controls were genotyped in this study Site-5: South Western Dallas Under IRB approval, HCC Cases and controls were prospectively collected since 2015 from the outpatient Liver clinics from Parkland Health and Hospital System and UT Southwestern Medical Center, two large health systems in Dallas TX. A Total of 31 cases and 29 controls were genotyped from site 5. Site-6: Columbia University HCC patients from Columbia are those recruited as part of the Herbert Irving Comprehensive Cancer Center Database Shared Resource which seeks to recruit all cancer patients for potential future studies. The PI is Dr. Katherine Crew AAAL5871. This resource collects sociodemographic, lifestyle and clinical data on patients as well as a blood sample. Those who indicated on their consent form that they would participate in genetic studies were included. Total of 79 case patients with HCC were genotyped from Columbia University. Site-7: University of Michigan The study population included from University of Michigan were included from a prospective study of with chronic HCV infection recruited in Ann Arbor Patients who had under- gone liver transplantation, known coinfection with HIV, life expectancy <12 months due to extra-hepatic illnesses, or were receiving HCV treatment at enrolment, were excluded. Protocol, surveys, and data forms were developed where each enrolled patient completed the same questionnaire All patients provided written informed consent before enrolment in the study. The study was approved by the institutional review board or ethics committee at the University of Michigan. Detailed study description was previously published (7). Total of 44 cases and 347 controls were genotyped Site-8: Veteran Administration Medical Center in Houston This research including written informed consent form was jointly approved by Institutional Review Boards for the Baylor College of Medicine and the Michael E. DeBakey VA Medical Center in Houston, Texas. Study details have been previously published (8). Briefly, we prospectively recruited consecutive HCV-infected veterans prior to their previously scheduled HCV clinic visit at a large tertiary care VA medical center between May 1, 2009 and December 31, 2012. Patients completed a research assistant (RA) administered survey interrogating medical and risk factor history including lifetime alcohol use, had anthropometric measurements taken, and completed a fasting venipuncture for performance of the FibroSure-ActiTest as a measure of hepatic pathology. We restricted our current analysis to individuals who were: (1) White male veterans between 18 and 70 years; (2) had no history of HCC, liver transplant, decompensated liver disease including ascites, dementia, or psychosis; (3) were serologically-confirmed to have chronic HCV and to be negative for both HIV and active HBV infection; (4) were not currently receiving anti-HCV pharmacotherapy; and (5) had FibroSURE testing shown F3/F4 fibrosis consistent with cirrhosis.

  Study phs001744

• Whole genome sequencing data of paediatric KMT2A-rearranged acute lymphoblastic leukemia

  Pediatric KMT2A-rearranged leukemia is an aggressive subtype of leukemia commonly seen in infants (less tha 1 year old) and young children. It involves rearrangements of the KMT2A gene (formerly MLL) on chromosome 11q23, resulting in fusion genes that drive uncontrolled cell growth. This subtype is most often found in acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) and is associated with a poor prognosis. In infants, the 5-year event-free and overall survival rates are around 35–40%. Despite intensive chemotherapy, outcomes remain challenging, prompting ongoing research into targeted therapies and novel treatment strategies.

  Study EGAS50000001079

• Whole-exome sequencing of intravascular large B-Cell lymphoma

  Intravascular large B-cell lymphoma (IVLBCL) is a unique form of diffuse large B-cell lymphoma (DLBCL) characterized by extranodal cell growth especially in small vessels without systemic lymphadenopathy. The limitation in obtaining sufficient tumor materials hampers understanding the molecular pathogenesis of IVLBCL. We performed whole-exome sequencing of IVLBCL using plasma-derived cell-free DNA (cfDNA) and patient-derived xenograft (PDX) samples.

  Study EGAS00001003970

• A Genome-Wide Association Study in Patients Experiencing Breast Events While Receiving Adjuvant Aromatase Inhibitors for Early Breast Cancer on NCIC CTG Trial MA.27

  Source of patients:The source of the patients for this genome-wide case-control study was MA.27, which was conducted as a multi-cooperative group effort under the auspices of the NCI Breast Cancer Intergroup of North America. The NCIC Clinical Trials Group (CTG) serves as the coordinating group, with participation by the NCI-sponsored North Central Cancer Treatment Group, Eastern Cooperative Oncology Group (ECOG), Southwest Oncology Group, and Cancer and Leukemia Group B (CALGB). MA.27 involved postmenopausal women with histologically confirmed and completely resected invasive breast cancer with surgical margins clear of invasive carcinoma in the following TMN categories (AJCC Version 6): pT1, pT2, pT3; pNx, pN0, pN1, pN2, pN3 (only when the sole basis is presence of 10 or more involved axillary nodes); MO. The primary tumor must have been estrogen receptor (ER) and/or progesterone receptor positive. Patients were stratified by lymph node status at diagnosis, prior adjuvant chemotherapy, and trastuzumab use and were randomized to 5 years of adjuvant therapy with anastrozole or exemestane. The trial was activated on May 26, 2003, and reached its accrual objectives on July 31, 2008, after the randomization of 6827 North American patients, with the majority (79%) providing DNA and consent for genetic testing. Non-North American patients were also entered by the International Breast Cancer Study Group but they did not contribute DNA. From 2003 to December 21, 2004, patients also underwent a second randomization to celecoxib 400 mg twice daily or placebo but, after the entry of 1,622 patients, this treatment was discontinued because of reports of increased cardiovascular risk associated with celecoxib. The final results of this study have been published, see Goss et al., 2013 (23358971). The patients in this analysis came from three cohorts: Cohort 1 consisted of 870 patients genotyped on the Illumina Human610-Quad BeadChip studied in a GWAS with the phenotype of musculoskeletal adverse event, see Ingle et al., 2010 (20876420), Cohort 2 consisted of 882 patients genotyped on the Illumina OmniExpress platform studied in a GWAS with the phenotype of fragility fractures, see Liu et al., 2014 (25148458), and the remaining 2913 patients were genotyped with the Illumina OmniExpressExome platform.

  Study phs001043

• The Gene Partnership (TGP) - eMERGE Data

  The Gene Partnership (TGP) is a prospective longitudinal registry at Boston Children's Hospital (BCH) to study the genetic and environmental contributions to childhood health and disease, collect genetic information on a large number of children who have been phenotyped, and implement the Informed Cohort and the Informed Cohort Oversight Board (ICOB). The term "The Gene Partnership" reflects a partnership between researchers and participants. Children seen at BCH are offered enrollment, as are their parents and siblings. DNA is collected on all enrollees. BCH has a comprehensive EMR system, and virtually all inpatient and outpatient data are captured electronically. Clinical data in the BCH EMR is loaded in the i2b2 data warehouse which is available to investigators. Cases, phenotypes, and covariates are ascertained using the i2b2 database. Participants at BCH in TGP have consented to receive any research result and/or incidental finding that arises from studies using TGP that is approved by the Informed Cohort Oversight Board (ICOB) and is in accordance with the participants' preferences; results are returned through the Personally Controlled Health Record (PCHR). BCH and Cincinnati Children's Hospital Medical Center (CCHMC) have partnered as the Pediatric Alliance for Genomic and Electronic Medical Record (EMR) Research (PAGER) site for the eMERGE Phase II network for pediatric institutions, and the cohort for eMERGE at BCH is TGP.

  Study phs000495

• Targeted sequencing of 72 prostate cancer driver in 712 plasma cell free DNA samples

  Dataset contains targeted sequencing data of 712 plasma cell free DNA samples and 428 white blood cell samples collected from 428 men with metastatic prostate cancer. Target capture was performed using a hydridization-based custom Roche SeqCap EZ Choice kit, designed to capture all exons of 72 prostate cancer driver genes. Cell free DNA was extracted from 10 mL blood samples. Libraries were sequenced using Illumina HiSeq 2500 or Illumina MiSeq instruments to a median coverage of 750x. 62% of samples had ctDNA fraction above 2% of total cfDNA. Note that "Dataset type" is erroneously listed as "Amplicon sequencing", because "Captured-based targeted sequencing" or "Hybridization-based targeted sequencing" were not available options in EGA at the time of submission.

  Dataset EGAD00001004208

• scRNA-seq of total bone marrow and T cells from multiple myeloma long-term survivors

  scRNA This dataset contains 50 scRNA-seq samples from bone marrow aspirates of 11 multiple myeloma patients experiencing long-term survival and 3 healthy donors. For each donor, total bone marrow and CD3+ T cells were sequenced. For multiple myeloma patients, paired samples were collected at initial diagnosis and between 7-17 years after first-line therapy. Bone marrow mononuclear cells were isolated by Ficoll density gradient centrifugation. For sorting of total bone marrow cells singlet, live cells were gated and sorted, for sorting of T cells CD45+, CD3+ cells were gated and sorted on either FACSAria Fusion or FACSAria II. Single-cell RNA sequencing were generated using 10x Genomics single-cell RNAseq technology (Chromium Single Cell 3’ Solution v2) according to the manufacturer’s protocol and sequenced on an Illumina HiSeq4000 (paired end, 26 and 74 bp). Bulk RNA Singlet, live CD3+CD4- CXCR3+CD8+ and CD3+CD4- CXCR3-CD8+ cells were sorted from 7 bone marrow and 3 peripheral blood samples of 7 multiple myeloma patients using a FACSAria Fusion machine. Bulk-RNA sequencing libraries were generated using the SMART Seq Stranded Total RNA-Seq kit (Takara) and sequenced using the Illumina NovaSeq 6000 platform (2 x 100 bp).

  Dataset EGAD00001010025

• Influence of the Microbiome on Epigenetic Mechanisms in IBD

  Live CD4 T cells were sorted from inflamed and non-inflamed tissue samples of IBD patients or from healthy and IBD blood samples. ATAC-Seq libraries were generated from live CD4 T cells sorted from i) inflamed and non-inflamed tissue samples, ii) healthy and IBD blood samples, or from iii) CD4 T cell subsets polarised from healthy blood samples. After isolating crude nuclei, live CD4+ T cells were treated with Tagment DNA buffer and Tagment DNA Enzyme (Nextera DNA Library Prep Kit, Illumina), and then the DNA was purified by MinElute PCR Purification Kit (Qiagen). Transposed DNA fragments were amplified using specific adapters followed by purification with MinElute PCR Purification Kit (Qiagen). Fragments from 240-360pb were selected in the PippinHT system (Sage Science). The quality of the library and its DNA concentration were assessed by Bioanalyzer instruments (Agilent Technologies) and ultimately submitted for sequencing using Illumina HiSeq 2500 sequencer, V4 chemistry. On the other hand, single cell RNA-Seq libraries were generated exclusively from inflamed and non-inflamed tissue samples of Crohn’s disease patients. Briefly, live CD4 T cells were captured and encapsulated before cDNA amplification using the 10X Genomics Chromium Platform. Samples were prepared as outlined by 10x genomics Single Cell 3’ Reagent Kits v2 user guide. Samples were sequenced on a HiSeq 2500 with the following run parameters: Read 1 – 26 cycles, read 2 – 98 cycles, index 1 – 8 cycles.

  Dataset EGAD00001011066

• Genome-wide NanoRCS of cfDNA from plasma of healthy individuals

  Levels of circulating tumor DNA (ctDNA) in liquid biopsies may serve as a sensitive biomarker for real-time, minimally-invasive tumor diagnostics and monitoring. However, detecting ctDNA is challenging, as much fewer than 5% of the cell-free DNA in the blood typically originates from the tumor. To detect lowly abundant molecules, extremely sensitive sequencing methods are required. We adapted a new technique, NanoRCS, which is based on Oxford Nanopore sequencing of concatenated copies of a single DNA molecule for genome-wide sequencing, and applied this to plasma of healthy controls.

  Study EGAS50000000695

• Childhood Cancer Model Atlas

  we establish a single-site collection of 243 cell lines, including 207 paediatric cancer cell lines representing 14 distinct extracranial and brain childhood tumour types. We subjected 164 paediatric cancer cell lines to multi-omic analyses across three dimensions (DNA-sequencing, RNA-sequencing, DNA methylation) to classify them based on clinically relevant molecular subtypes.

  Study EGAS00001006320

• cell-free Nucleosome ChIP-seq

  Dataset includes cell-free ChIP-seq data of 268 samples (from 61 self-declared healthy donors, four patients with acute myocardial infarction, 29 patients suffering from autoimmune, metabolic, or viral liver diseases and 56 metastatic colorectal carcinoma (CRC) patients). DNA libraries preparation is documented in the methods section. Libraries were paired end sequenced by Illumina NextSeq 500 and aligned to the human genome (hg19) using bowtie2 (2.3.4.3) with ‘no-mixed’ and ‘no-discordant’ flags. This dataset includes fastq and BAM files of all samples.

  Dataset EGAD00001006811

• NIH RECOVER-Pediatric: Understanding the Long-Term Impact of COVID on Children and Families

  The NIH Researching COVID to Enhance Recovery (RECOVER) initiative comprises a set of three combined retrospective and prospective, longitudinal and observational meta-cohort studies with nested case-control studies designed to define and characterize the epidemiology, natural history, clinical spectrum, and underlying mechanisms of post-acute effects of SARS-CoV-2 infection (PASC or Post-COVID syndrome) in a diverse study population representative of the general COVID-19 population in the US. Enrolled patients, with and without known SARS-CoV-2 infection, will be observed for clinical signs and symptoms of PASC and will be assessed for risk and resiliency factors and potential mediating factors associated with the severity and progression of PASC. The objective of the RECOVER initiative is to enhance knowledge of recovery from SARS-CoV-2 infections in order to support development of novel diagnostic and therapeutic interventions. Overarching scientific objectives are as follows:Characterize the incidence and prevalence of sequelae of SARS-CoV-2 infection.Characterize the spectrum of clinical symptoms, subclinical organ dysfunction, natural history, and distinct phenotypes identified as sequelae of SARS-CoV-2 infection. Define the biological mechanisms underlying pathogenesis of the sequelae of SARS-CoV-2 infection. The RECOVER observational studies comprise three cohorts across the lifespan (adult, pediatric, and tissue pathology (autopsy)). The data collection and data analysis plans for each cohort have been harmonized to use common data elements where feasible. Brief descriptions of each cohort are provided in the following paragraphs: 1) NIH RECOVER: A Multi-site Observational Study of Post-Acute Sequelae of SARS-CoV-2 Infection in Adults (see phs003463)The RECOVER adult cohort study is a combined retrospective and prospective, longitudinal, observational meta-cohort of individuals who will enter the cohort with and without SARS-CoV-2 infection and at varying stages before and after infection. Individuals with and without SARS-CoV-2 infection, and with or without PASC symptoms, will be followed to identify risk factors and occurrence of PASC. This study will be conducted in the United States and subjects will be recruited through inpatient, outpatient, and community-based settings. Study data including age, demographics, social determinants of health, medical history, vaccination history, details of acute SARS-CoV-2 infection, overall health and physical function, and PASC symptom screen will be reported by subjects or collected from the electronic health record using a case report form at specified intervals. Biologic specimens will be collected at specified intervals, with some tests performed in local clinical laboratories and others performed by centralized research centers or banked in the Biospecimen Repository. Advanced clinical examinations and radiologic examinations will be performed at local study sites with cross-site standardization. 2) A Multi-Center Observational Study: The RECOVER Post Acute Sequelae of SARS-CoV-2 (PASC) Pediatric Cohort Study (this study)The RECOVER pediatric study is a combined retrospective and prospective, longitudinal, observational meta-cohort of individuals ages newborn-25 years who will enter the cohort with and without SARS-CoV-2 infection at varying stages before and after infection. Individuals with and without SARS-CoV-2 infection and with or without PASC symptoms will be followed to identify risk factors and occurrence of PASC. This study recruit participants inpatient, outpatient, and community-based settings in the United States. Study data including age, demographics, social determinants of health, medical history, vaccination history, details of acute SARS-CoV-2 infection, overall health and physical function, and PASC symptoms will be reported by participants or collected from the electronic health record using a case report form at specified intervals. Biologic specimens will be collected at specified intervals, with some tests performed in local clinical laboratories and others performed by centralized research centers or banked in the Biospecimen Repository. Advanced clinical and radiologic examinations will be performed at local study sites with cross-site standardization. 3) NIH RECOVER: A Multi-site Pathology Study of Post-Acute Sequelae of SARS-CoV-2 Infection The RECOVER tissue pathology study is a cross-sectional study designed to define and characterize the epidemiology, natural history, clinical spectrum, and underlying mechanisms of post-acute effects of SARS-CoV-2 infection in a diverse population representative of the general COVID-19 population in the US. The autopsy study will characterize the pathology of PASC in (i) non-hospitalized patients who die 30 days or later from symptom onset of COVID-19, and (ii) hospitalized patients who die 30 days or later after discharge from a hospitalization for COVID-19. The study will include decedents who had previously fully recovered from SARS-CoV-2 infection (i.e., >30 days from onset in non-hospitalized, or >30 days from discharge in hospitalized patients), and decedents who meet clinical criteria of PASC as defined by the recent World Health Organization publication (see Section 5.4 below). The autopsy study will also explore the pathology of acute SARS-CoV-2 infection in a smaller subset of patients who died 15-30 days from symptom onset. This protocol defines the common set of clinical data elements, autopsy procedures for tissue collection, core measures, pathology protocols, shared pathology tissues, data elements, and methodology. Each investigator site is expected to perform autopsies on the decedents to address the pathophysiology of the potential long-term effects of SARS-CoV-2 infection on human health. The Consortium analysis plan aims to address research questions by incorporating: 1) tissue obtained from autopsies performed at each Phase II participant's site; and 2) tissue available from other pathology investigators/autopsy sites within the Consortium.

  Study phs003461

• Nasal MicroRNA during Bronchiolitis and Age 6y Asthma: MARC-35 Cohort

  We analyzed data from the 35th Multicenter Airway Research Collaboration (MARC-35) study to examine the relationship between nasal airway microRNAs (miRNAs) and the risk of developing childhood asthma. MARC-35 is a multicenter prospective cohort study which enrolled infants (age Structured interviews of the parents/guardians were performed by site investigators and clinical details were collected via emergency department and hospital inpatient chart reviews. Following the index hospitalization, trained study personnel conducted telephone interviews with parents/legal guardians at six-month intervals. Participants also underwent nasal swab sampling conducted by trained site personnel during the index bronchiolitis hospitalization and during an in-person follow-up examination at about age 6 years. Total RNA was extracted from nasal swab specimens using Trizol LS reagent (ThermoFisher Scientific, Waltham, MA) and the Direct-zol RNA Miniprep Kit (Zymo Research, Irvine, CA). Small RNA-seq was performed using the PerkinElmer NEXTFLEX® small RNA-seq v3 kit with Unique Dual Indexes (PerkinElmer, Waltham, MA) and sequenced on an Illumina NovaSeq6000 sequencer using an S2 50bp PE Flowcell (Illumina, San Diego, CA). Through dbGaP, limited de-identified phenotypic data (e.g., demographics) and RNA-seq FASTQ files will be made available. Among a cohort of infants hospitalized with bronchiolitis, we applied a small RNA sequencing approach and found miRNAs were associated with asthma risk factors, and highly expressed in lung tissue and immune cells (e.g., TH cells, neutrophils). They also played key roles in mechanisms relating to asthma, such as innate immunity, airway remodeling, and IgE regulation.

  Study phs003564

• Center for Common Disease Genomics [CCDG] - Cardiovascular ATVB: Atherosclerosis Thrombosis and Vascular Biology

  Italian Atherosclerosis Thrombosis and Vascular Biology study is a prospective, nationwide, case-control study involving 125 coronary care units in Italy. The cases were patients who were hospitalised for a first MI before the age of 45 years and underwent coronary angiography. Acute MI was defined as resting chest pain lasting more than 30 minutes, accompanied by persistent electrocardiographic changes, and confirmed by an increase in total creatine kinase or in the MB fraction to more than twice the upper normal limits. The controls were healthy subjects without a history of thromboembolic disease who were unrelated to the patients, but individually matched with them by age, gender and geographical origin. They were enrolled from among the blood donors or staff of the same participating hospitals. Recruitment of cases and controls took place between 1994 and 2007. This site hosts data from ~60 whole exomes.

  Study phs001592

• Childhood Cancer Data Initiative (CCDI): Pediatric In Vivo Testing Program - Neuroblastoma

  The goal of NCI's Pediatric In Vivo Testing Consortium (PIVOT) is to advance the development of effective treatments for pediatric cancers through preclinical in vivo testing of novel therapeutic agents. To design impactful experiments that can be rapidly translated to the clinic, PIVOT investigators require comprehensive genomic characterization of the patient-derived xenograft (PDX) models used across the consortium. This robust experimental design enhances collaboration with industry partners by providing proof-of-concept data for drugs in development. As part of this effort, neuroblastoma PDX models are being molecularly characterized to identify promising therapeutic candidates. The molecular profiling includes whole exome sequencing (WES), RNA-seq, MethylEPIC array, CytoSNP array, and DNA fingerprinting for quality control. Additionally, demographic and clinical data (e.g., diagnosis, disease site, disease status) are shared. These characterized PDX models, matched with patient tumors, guide model selection for preclinical drug testing.

  Study phs003163

• Genetic Discovery and Application in a Clinical Setting: Continuing a Partnership (eMERGE Phase II)

  The electronic Medical Records and Genomics (eMERGE) Network is a consortium of ten participating sites funded by the NHGRI to investigate the use of electronic medical record systems for genomic research. The goal of eMERGE is to conduct genome-wide association studies in approximately 19,000 individuals using EMR-derived phenotypes and DNA from linked Biorepositories. The eMERGE Network brings together researchers with a wide range of expertise in genomics, statistics, ethics, informatics, and clinical medicine from leading medical research institutions across the country. Each center participating in the consortium is uniquely situated to provide critical resources to this highly collaborative and productive network. Each site combines a biobank or study cohort with extensive genomic data and access to clinical data derived from electronic medical records. Sites are geographically dispersed and have diverse patient populations, including two sites focusing specifically on pediatrics. The eMERGE Network is comprised of 9 sites and one coordinating center. Each site maintains its own biorepository where DNA specimens are linked to phenotypic data contained within EMRs. Children's Hospital of Pennsylvania, PI: Hakon Hakonarson, MD, PhD Cincinnati Children's Medical Center with Boston Children's Hospital, PI: John Harley, MD, PhD - CCHMC and Ingrid Holm, MD, MPH - BCH Geisinger Health System, PI: David Carey, PhD and Marc Williams, MD Group Health Cooperative with University of Washington, PI: Eric Larson, MD, MPH - GHC and Gail Jarvik, MD, PhD - UW Marshfield Clinic with Essentia Institute of Rural Health, PI: Catherine McCarty, PhD, MPH - Essentia and Murray Brilliant, PhD - Marshfield Mayo Clinic, PI: Christopher Chute, MD, DrPH and Iftikhar Kullo, MD Icahn School of Medicine at Mount Sinai, PI: Erwin Bottinger, MD Northwestern University, PI: Rex Chisholm, PhD and Maureen Smith, MS Vanderbilt University, PI: Dan Roden, MD eMERGE Coordinating Center - Vanderbilt University, PI: Paul Harris, PhD Using electronic phenotyping methods, the consortium used DNA samples from all participating sites to explore the genetic determinants of red cell indices, white blood count (WBC) differential, diabetic retinopathy, height, serum lipid levels, specifically total cholesterol, HDL (high density lipoprotein), LDL (low density lipoprotein), and triglycerides, and autoimmune hypothyroidism as well as using the phenome-wide association study (PheWAS) paradigm to replicate and discover relationships between targeted genotypes with multiple phenotypes.

  Study phs000948

• Cell-Free, Methylated DNA in Blood Samples Reveals Tissue-Specific, Cellular Damage from Radiation Treatment

  Radiation therapy is an effective cancer treatment, although damage to surrounding healthy tissues can also occur. Cell-type specific DNA methylation patterns can be used to decode the cellular origins of cell-free DNA fragments, allowing for minimally-invasive monitoring of tissue damage. To evaluate whether changes in cell-free DNA methylation can indicate damages to tissues in patients treated with radiation, we collected serum samples from 15 breast cancer patients at three timepoints during their standard-of-care radiation therapy after surgery. A baseline sample was taken for each patient before onset of radiation therapy and a second End-Of-Treatment (EOT) sample was taken 30 minutes after the last treatment fraction. Finally, a recovery sample was taken one month after completion of radiation therapy. From serum samples, cell-free DNA was isolated and bisulfite capture-sequencing DNA methylation data were generated. Bisulfite capture-sequencing DNA methylation data were also generated from buffy coat and tissue-specific endothelial gDNA samples as well as from serum/plasma samples of healthy controls. The analysis of serum samples from breast cancer patients undergoing radiation treatment revealed distinct tissue-specific epithelial and endothelial responses to radiation across multiple organs. In conclusion, as a proof of concept we show that cell-type specific methylation signatures can be applied to detect cellular injury from radiation treatment using minimally invasive cell-free DNA in blood samples.

  Study phs003290

• Multi-site tumor sampling highlights molecular intra-tumor heterogeneity in malignant pleural mesothelioma

  Background:Malignant pleural mesothelioma (MPM) is a heterogeneous cancer. Better knowledge of molecular and cellular intra-tumor heterogeneity throughout the thoracic cavity is required to develop efficient therapies. This study focuses on molecular intra-tumor heterogeneity using the largest series to date in MPM and is the first to report on the multi-omics profiling of a substantial series of multi-site tumor samples. Methods:Intra-tumor heterogeneity was investigated in 16 patients from whom biopsies were taken at distinct anatomical sites. The paired biopsies collected from apex, side wall, costo-diaphragmatic or highest metabolic sites as well as 5 derived cell lines were screened using targeted sequencing. Whole exome sequencing, RNA sequencing, and DNA methylation were performed on a subset of the cohort for deep characterization. Molecular classification, recently defined histo-molecular gradients, and cell populations of the tumor microenvironment were assessed. Results:Sequencing analysis identified heterogeneous variants notably in NF2, a key tumor suppressor gene of mesothelial carcinogenesis. Subclonal tumor populations were shared among paired biopsies, suggesting a polyclonal dissemination of the tumor. Transcriptome analysis highlighted dysregulation of cell adhesion and extracellular matrix pathways, linked to changes in histo-molecular gradient proportions between anatomic sites. Methylome analysis revealed contribution of epigenetic mechanisms in two patients. Finally, significant changes in the expression of immune mediators and genes related to immunological synapse, as well as differential infiltration of immune populations in the tumor environment were observed and led to a switch from a hot to a cold immune profile in three patients. Conclusions:This comprehensive analysis reveals patient-dependent spatial intra-tumor heterogeneity at the genetic, transcriptomic and epigenetic levels and in the immune landscape of the tumor microenvironment. Results support

  Study EGAS00001005328

• STAMPEED: Cardiovascular Health Study (CHS) GWAS to identify genetic variants associated with aging and CVD risk factors and events

  The primary aim of the study is to conduct a genome-wide association study to identify genetic variants associated with the incidence of myocardial infarction (MI), stroke, and heart failure (HF) among participants enrolled in the Cardiovascular Health Study (CHS) who were free of clinical cardiovascular disease at baseline. The secondary aim is to conduct genome-wide association study of other phenotypes in CHS. The study is an ancillary study to CHS. CHS is a population-based cohort study of risk factors for heart disease and stroke among older adults recruited at 4 US sites in 1989-1990. Subjects underwent an extensive baseline examination, and annual follow-up examinations through 1988-1999.

  Study phs000226

• Investigation of mutational signatures associated with DNMT3A deficiency (2019-04-03)

  Mutational signatures have been shown to be attributable to specific genetic contexts, such as mutations in DNA repair genes. DNMT3A is a DNA methyltransferase that helps maintain the DNA methylation pattern in a site-specific manner and may participate in DNA repair or the stress response. We have identified an adult individual who is a germline mosaic for a DNMT3A mutation. We have obtained clonal lymphoblastoid cells (LCLs) from the subject representing both WT and mutant lines grown in the same individual for >50 years. These clones represent a unique opportunity to examine the mutational impact of the DNMT3A mutation in a well-controlled setting. Our goal is to perform WGS on whole blood, representing the pool, as well as several WT and several mutant clones, in order to investigate the contribution of DNMT3A to mutation rates and signatures. . This dataset contains all the data available for this study on 2019-04-03.

  Dataset EGAD00001004889

• Multi-site tumor sampling highlights molecular intra-tumor heterogeneity in malignant pleural mesothelioma

  Dataset EGAD00001007762

• A comprehensive characterization of the cell-free transcriptome reveals tissue- and subtype-specific biomarkers for cancer detection

  Cell-free RNA (cfRNA) is a promising analyte for cancer detection. However, a comprehensive assessment of cfRNA in individuals with and without cancer has not been conducted. We performed the first transcriptome-wide characterization of cfRNA in cancer (stage III breast [n=46], lung [n=30]) and non-cancer (n=89) participants from the Circulating Cell-free Genome Atlas (NCT02889978). Of 57,820 annotated genes, 39,564 (68%) were not detected in cfRNA from non-cancer individuals. Within these low-noise regions, we identified tissue- and cancer-specific genes, defined as "dark channel biomarker" (DCB) genes, that were recurrently detected in individuals with cancer. DCB levels in plasma were correlated with tumor shedding rate and RNA expression in matched tissue, suggesting that DCBs with high expression in tumor tissue could enhance cancer detection in patients with low levels of circulating tumor DNA. Overall, cfRNA provides a unique opportunity to detect cancer, predict the tumor tissue of origin, and determine the cancer subtype.

  Study EGAS00001004704

• Metastatic Adrenocortical Carcinoma Displays Higher Mutation Rate and Tumor Heterogeneity than Primary Tumors

  We have analyzed 33 human metastatic adrenocortical tumors from 14 patients with advanced metastases and performed whole exome sequencing to identify novel signatures in these tumors. We observed tumor heterogeneity in these tumors coming from the same metastatic tissue site across different patients while the different metastatic tumor sites coming from the same patient are more homogenous in nature.

  Study phs001658

• Melanoma_multi_site_metastases

  Despite multiple large-scale sequencing studies offering substantial insight into the genomic landscape of cutaneous melanoma, the molecular events surrounding disease progression and the resulting molecular heterogeneity between metastases have not been fully elucidated. We have been applying whole genome and transcriptome sequencing across metastases collected during post mortem as well as to multi-site metastases during treatment

  Study EGAS00001001348

• Ischemic Stroke Genetics Study (ISGS)

  The third leading cause of death in the United States, stroke is an acute neurological event leading to death of neural tissues. Although the majority of strokes are ischemic strokes, meaning there is oxygen deprivation to the brain, almost 20% of strokes are hemorrhagic, resulting from bleeding into the brain. Stroke is a complex disorder and likely multigenic in nature, resulting from a combination of genetic and environmental factors. These well characterized risk factors that contribute to the incidence of stroke include hypertension, cardiac disease, sickle cell disease, hyperhomocysteinemia, family history of stroke and smoking. ISGS aim is to perform a prospective genetic association study of ischemic stroke focusing on the hemostatic system. ISGS is a 5-center case-control study of first-ever ischemic stroke cases and concurrent controls individually matched for age, sex and recruitment site. This data includes that from subjects both banked in the NINDS repository with biologicals publicly available, and those whose samples are not banked/not available. Important links to apply for individual-level data Data Use Certification Requirements (DUC) Apply here for controlled access to individual level data Participant Protection Policy FAQ --> This study utilized the NINDS Repository Cerebrovascular/Stroke Study, and neurologically normal controls from the sample population which are banked in the National Institute of Neurological Disorders and Stroke (NINDS Repository) collection for a first stage whole genome analysis.

  Study phs000102

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  Documentation cookies

• Panel sequencing of endocrine-resistant breast cancer

  Patients with endocrine-resistant breast cancer in Stockholm Sweden. DNA obtained from patients primary and relapse tumors, and tumor-free lymph nodes used as germline control. DNA was extracted from formalin-fixed paraffin-embedded tissue and sequenced by 370-gene panel-based sequencing with Kapa HyperPlus library preparation and Twist Bioscience hybrid capture. Custom bait sets (panels) from Twist Bioscience. Paired end 2x150 bp using NovaSeq X. The data is presented as fastq-files.

  Study EGAS50000000236