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• Epigenetic Changes in Immune Response and Oncogenesis Related Genes Caused by Heavy Metal Long-Term Exposure

  Our study investigated methylation changes in CpG islands located in immune response and oncogenesis related genes in humans induced by long-term environmental heavy metal exposure. We assessed the methylation levels of 654 CpG sites located on NFKB1, CDKN2A, ESR1, APOA5 and IGF2/H19 genes by targeted bisulfite sequencing (target enrichment by 48.48 Access Array Integrated Fluidic Circuit (Fluidigm, USA) in a cohort of 40 subjects living near a metal mining area (the Kapan mining region, Armenia) and 40 unexposed subjects. We performed linear regression on our data to find differentially methylated positions with adjustment for gender, age, BMI class, smoking, and plasma concentrations of 21 essential and non-essential metals detected by ICP-MS. Our study showed hypomethylation of five CpG sites in the NFKB1 promoter region in the exposed group. According to our findings, the methylation changes of CpG sites in NFKB1, CDKN2A, IGF2 and ESR1 genes are associated with multiple and specific metal exposures. Targeted bisulfite sequencing data obtained for 80 subjects who participated in this study are available through dbGaP. The tables contain information about age, sex, BMI, smoking and exposure status, as well as race and ethnicity of the study participants.

  Study phs003392

• Molecular Characterization of Prostate Cancer Specimens by Bulk and Single Cell Analysis

  Version 1: We performed single-cell RNA-sequencing (scRNA-seq) of fresh biopsies from metastatic castration resistant prostate cancer. Additionally, where available, we performed matched bulk whole exome sequencing (WXS; tumor and normal paired) and whole transcriptome sequencing for the same individuals. We also performed bulk whole exome (WXS) and RNA-sequencing (RNA-Seq) from FFPE pre-treatment biopsies from patients with clinically localized high-risk prostate cancer.Version 2: We added data from a randomized phase 2 trial of radium-223 with or without pembrolizumab in patients with Metastatic Castration-Resistant Prostate Cancer (mCRPC) to bone. After enrollment, study participants underwent bone biopsy and were randomized 2:1 to receive radium-223 at 55 kBq/kg every 4 weeks + pembrolizumab at 200 mg every 3 weeks (Arm A, R223+P) or radium-223 at 55 kBq/kg every 4 weeks alone (Arm B, R223). Stratification factors were alkaline phosphatase ≥220 vs. Data generated includes bulk whole exome sequencing (WXS), ultra-low pass whole genome sequencing (WGS) at 0.1X coverage, and targeted-capture sequencing. The ultra-low pass sequencing was used as part of the selection criteria for the target capture sequencing. Note: Two subjects in this study are linked to phs001577 and phs000915 respectively.

  Study phs001988

• Early Detection of Malignant and Pre-Malignant Peripheral Nerve Tumors Using Cell-Free DNA Fragmentomics

  Early detection of neurofibromatosis type 1 (NF1) associated peripheral nerve sheath tumors (PNST) informs clinical decision-making, potentially averting deadly outcomes. Here, we describe a cell-free DNA (cfDNA) fragmentomic approach which distinguishes non-malignant, pre-malignant and malignant forms of NF1 PNST. Using plasma samples from a novel cohort of 101 NF1 patients and 21 healthy controls, we validated that our previous cfDNA copy number alteration (CNA)-based approach identifies malignant peripheral nerve sheath tumor (MPNST) but cannot distinguish among benign and premalignant states. We therefore investigated the ability of fragment-based cfDNA features to differentiate NF1-associated tumors including binned genome-wide fragment length ratios, end motif analysis, and non-negative matrix factorization deconvolution of fragment lengths. Fragmentomic methods were able to differentiate pre-malignant states including atypical neurofibromas (AN). Fragmentomics also adjudicated AN cases suspicious for MPNST, correctly diagnosing samples noninvasively, which could have informed clinical management. Overall, this study pioneers the early detection of malignant and premalignant peripheral nerve sheath tumors in NF1 patients using plasma cfDNA fragmentomics. In addition to screening applications, this novel approach distinguishes atypical neurofibromas from benign plexiform neurofibromas and malignant peripheral nerve sheath tumors, enabling more precise clinical diagnosis and management.

  Study phs003712

• Cardiovascular Health Study (CHS) - Imaging

  The Cardiovascular Health Study (CHS) is a prospective study of risk factors for development and progression of coronary heart disease (CHD) and stroke in people aged 65 years and older. The 5,888 study participants were recruited from four U.S. communities and have undergone extensive clinic examinations for evaluation of markers of subclinical cardiovascular disease. The original cohort, enrolled in 1989-90, totaled 5,201 participants. A supplemental cohort of 687 predominantly African-American participants was enrolled in 1992-93. Clinic examinations were performed at study baseline and at annual visits through 1998-1999, and again in 2005-2006. Examination components included medical and personal history, medication inventory, ECG, blood pressure, anthropometry, assessment of physical and cognitive function, and depression screening. Other components done less frequently included phlebotomy, spirometry, echocardiography, carotid ultrasound, cerebral magnetic resonance imaging, measurement of ankle-brachial index and retinal exam. Participants were contacted by telephone annually between exams to collect information about hospitalizations and potential cardiovascular events. Since 1999, participants have been contacted every six months by phone, primarily to identify cardiovascular events and to assess physical and cognitive health. Standard protocols for the identification and adjudication of events were implemented during follow-up. The adjudicated events are myocardial infarction, angina, heart failure (HF), stroke, transient ischemic attack (TIA), claudication, and mortality.

  Study phs003639

• Integrative Gene Regulatory Network Analysis Discloses Key Driver Genes of Fibromuscular Dysplasia

  Fibromuscular dysplasia (FMD) is a poorly understood vascular disease that can lead to hypertension, stroke, myocardial infarction and even death. In 2013 we initiated the DEFINE study (ClinicalTrials.gov Identifier: NCT01967511), which has now recruited > 440 subjects and which aims to unravel the pathobiological mechanisms of this disease. Here, by integrating DNA genotype and RNA sequence data from primary fibroblasts of 83 FMD patients and 71 matched healthy controls from the DEFINE study, and its precursor the CAUSE study, we inferred 18 gene regulatory co-expression networks, four of which were found to act together as an FMD-associated super network in the arterial wall. Molecular studies indicated that this super network, termed SN-A and with the top key driver gene UBR4, governs multiple aspects of vascular cell physiology and functionality, including collagen/matrix production. The effects of UBR4 knockdown were also investigated in commercially available aortic smooth muscle and fibroblast cell lines by RNA sequencing, and these results are included in these datasets.Note, that of the 154 subjects in this analysis, 62 did not provide consent to have their genomic data made publicly available. Therefore the human subject data available here is from the 92 study participants who provided written informed consent to share their deidentified genomic data publicly.

  Study phs003674

• NHLBI TOPMed - NHGRI CCDG: Atherosclerosis Risk in Communities (ARIC)

  Participants from the Atherosclerosis Risk in Communities (ARIC) Study, a large population-based longitudinal cohort study, have been included in this Project and whole genome sequencing will be performed to contribute to analyses of early-onset atrial fibrillation and venous thromboembolism. Additional phenotype and genotype data are available for these individuals on dbGaP and can be accessed through the parent ARIC Cohort accession (phs000280). The National Heart, Lung and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program is designed to generate scientific resources to enhance understanding of fundamental biological processes that underlie heart, lung, blood and sleep disorders (HLBS). It is part of a broader Precision Medicine Initiative, which aims to provide disease treatments that are tailored to an individual's unique genes and environment. TOPMed will contribute to this initiative through the integration of whole genome sequencing (WGS) and other -omics (e.g., metabolic profiles, protein and RNA expression patterns) data with molecular, behavioral, imaging, environmental, and clinical data. In doing so, this program seeks to uncover factors that increase or decrease the risk of disease, identify subtypes of disease, and develop more targeted and personalized treatments. The Whole Genome Sequencing (WGS) Project is part of NHLBI's TOPMed program and serves as an initial step for the larger initiative.

  Study phs001211

• Single cell RNAseq of stenotic, inflamed and non-inflamed transmural lesions from patients with Crohn's disease

  This dataset contains a gene-cell matrix derived from single-cell RNA sequencing (scRNA-seq) data of ileal tissue from Crohn's disease (CD) patients and colorectal cancer (CRC) patients. It includes: Crohn's Disease Patients: A trio of transmural lesions (stenotic, inflamed, and non-inflamed) from each patient. Colorectal Cancer Patients: Unaffected ileal tissue used as external non-inflamed control. Cell Level Metadata: The dataset includes relevant cell-level metadata such as cell type annotations used in the study. Experimental Details: Platform: 10x Genomics Chromium Single Cell 3' GEX Sequencing: Illumina NovaSeq Processing: Data processed with Cell Ranger software. Resulting count matrices were merged for downstream analysis, including integration and dimensionality reduction. Dataset Composition: Crohn's Disease Patients: 10 patients with 3 samples each (non-inflamed, inflamed, stenotic), totaling 30 samples. Colorectal Cancer Patients: 5 patients with 1 sample each of unaffected tissue, totaling 5 samples. Data Provided: Merged Raw Count Matrix: The final merged raw count matrix used for downstream analysis. Cell Metadata File: Contains details of sample, tissue, and patient for each cell in the count matrix. Barcodes File: Indicate each cell barcode which also encodes the sample, tissue, and patient details for each cell. CD.S_Inf: Stenotic Corhn's disease inflamed samples CD.S_Sten: Stenotic CD patient stenosis sample CD.S_Prox: Stenotic CD Patient - proximal non-inflamed sample CC.C_Prox: CRC Patient proximal unaffected sample eg: A barcode 'CC.C_1_Prox_AAGTCGTAGACCCTTA' indicates CRC Patient unaffected proximal sampe from CRC Patient no.1 and the nucleic acid sequence indicate a unique cell from this sample. Total Samples: Crohn's Disease (CD) Patients: 30 samples Colorectal Cancer (CRC) Patients: 5 samples Patient_no Sample Sample_type 1 CC.C_1 CC.C_1_Prox CC.C_Prox 2 CD.S_1 CD.S_1_Prox CD.S_Prox 3 CD.S_1 CD.S_1_Infl CD.S_Infl 4 CD.S_1 CD.S_1_Sten CD.S_Sten 5 CC.C_2 CC.C_2_Prox CC.C_Prox 6 CD.S_2 CD.S_2_Prox CD.S_Prox 7 CD.S_2 CD.S_2_Infl CD.S_Infl 8 CD.S_2 CD.S_2_Sten CD.S_Sten 9 CC.C_3 CC.C_3_Prox CC.C_Prox 10 CC.C_4 CC.C_4_Prox CC.C_Prox 11 CD.S_3 CD.S_3_Prox CD.S_Prox 12 CD.S_3 CD.S_3_Infl CD.S_Infl 13 CD.S_3 CD.S_3_Sten CD.S_Sten 14 CD.S_4 CD.S_4_Prox CD.S_Prox 15 CD.S_4 CD.S_4_Infl CD.S_Infl 16 CD.S_4 CD.S_4_Sten CD.S_Sten 17 CC.C_5 CC.C_5_Prox CC.C_Prox 18 CD.S_5 CD.S_5_Prox CD.S_Prox 19 CD.S_5 CD.S_5_Infl CD.S_Infl 20 CD.S_5 CD.S_5_Sten CD.S_Sten 21 CD.S_6 CD.S_6_Prox CD.S_Prox 22 CD.S_6 CD.S_6_Infl CD.S_Infl 23 CD.S_6 CD.S_6_Sten CD.S_Sten 24 CD.S_7 CD.S_7_Prox CD.S_Prox 25 CD.S_7 CD.S_7_Infl CD.S_Infl 26 CD.S_7 CD.S_7_Sten CD.S_Sten 27 CD.S_8 CD.S_8_Prox CD.S_Prox 28 CD.S_8 CD.S_8_Infl CD.S_Infl 29 CD.S_8 CD.S_8_Sten CD.S_Sten 30 CD.S_9 CD.S_9_Prox CD.S_Prox 31 CD.S_9 CD.S_9_Infl CD.S_Infl 32 CD.S_9 CD.S_9_Sten CD.S_Sten 33 CD.S_10 CD.S_10_Prox CD.S_Prox 34 CD.S_10 CD.S_10_Infl CD.S_Infl 35 CD.S_10 CD.S_10_Sten CD.S_Sten

  Dataset EGAD50000000559

• Center for Common Disease Genomics [CCDG] Neuropsychiatric: Autism Spectrum Disorder (ASD) – Whole Exomes

  The National Human Genome Research Institute (NHGRI) has funded a collaborative large-scale genome sequencing effort to comprehensively identify rare risk and protective variants contributing to multiple common disease phenotypes. Called the Centers for Common Disease Genomics (CCDG), this initiative will explore a range of diseases with the ultimate goal of 1) undertaking variant discovery for enough different examples of disease architectures and study designs to better understand the general principles of the genomic architecture underlying common, complex inherited diseases, 2) understanding how best to design rare variant studies for common disease, and 3) developing resources, informatics tools, and innovative approaches and technologies for multiple disease research communities and the wider biomedical research community. The initial focus of the CCDGs will be in cardiovascular disease (early-onset coronary artery disease, atrial fibrillation, hemorrhagic stroke), neuropsychiatric disease (epilepsy, autism), and autoimmune/inflammatory disease (type 1 diabetes, inflammatory bowel disease). The Broad Institute is one of four selected CCDG project centers. The goal of the Autism Spectrum Disorder (ASD) program is to work together to utilize dramatic new advances in DNA sequencing technology to reveal the genetic architecture of autism through comprehensive examination of the exotic sequence of all genes.

  Study phs002502

• Identifying New Genetic Subtypes in Follicular Lymphoma

  Follicular lymphoma (FL) exhibits considerable variability in biological features and clinical trajectories across patients. To dissect the diversity of FL, we utilized a Bernoulli mixture model to identify genetic subtypes in 713 pre-treatment tumor tissue samples. Our analysis revealed the existence of five subtypes with unique genetic profiles that correlated with clinicopathological characteristics. The clusters were enriched in specific mutations as follows: CS (CREBBP and STAT6), TT (TNFAIP3 and TP53), GM (GNA13 and MEF2B), Q (quiescent, for low mutation burden), and AR (mutations of mTOR pathway-related genes). The subtype Q was enriched for patients with stage I disease and was associated with a lower proliferative history compared to the other subtypes. The AR subtype was unique in its enrichment for IgM-expressing FL cases and was associated with advanced-stage and more than 4 nodal sites. The existence of subtypes was validated in an independent cohort of 418 samples from the GALLIUM trial. Notably, patients assigned to the TT subtype consistently experienced inferior progression-free survival when treated with immunochemotherapy. Collectively, our findings offer insight into core pathways distinctly linked with each FL cluster and are expected to be informative in the era of targeted therapies.

  Study EGAS50000000435

• Early detection of ovarian cancer using cell-free DNA fragmentomes and protein biomarkers

  Ovarian cancer is the leading cause of death from gynecological cancers worldwide. No effective screening methods exist, and tumors are commonly detected at advanced stages where treatment is much less effective. In this study, we used whole-genome cell-free DNA (cfDNA) fragmentome and protein biomarker (CA-125 and HE4) analyses to evaluate 591 women from the European Union or the United States with ovarian cancer, benign adnexal masses, or without ovarian lesions. Using a machine learning model that incorporated multi-analyte fragmentome data and protein measurements, we detected ovarian cancer with high specificity >99% and sensitivity of 72%, 69%, 87%, and 100% for stages I–IV, respectively (AUC=0.96, 95% CI: 0.94-0.99), including 90% of high grade serous ovarian cancers. At the same specificity, CA-125 alone detected 34%, 62%, 63%, and 100% of ovarian cancers for stages I–IV (p=0.001, two-sided test of equal proportions). Additionally, our approach distinguished benign masses from ovarian cancers with high accuracy (AUC of 0.88, 95% CI=0.83-0.92). These results were validated in an independent population. These findings show that integrated cfDNA fragmentome and protein analyses detect ovarian cancers with high performance, enabling a new accessible approach for noninvasive ovarian cancer screening and diagnostic evaluation.

  Study EGAS50000000484