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• Myocardial Infarction Genetics Exome Sequencing Consortium: Ottawa Heart Study

  The Ottawa Heart Study is a cross-sectional case-control study designed to identify genes that predispose to angiographically defined coronary artery disease. All exome sequencing was performed at the Broad Institute of Harvard and MIT; samples sequence capture was performed using Agilent SureSelect Human All Exon Kit v2 and sequencing was performed on an Illumina HiSeq 2000 or 2500.

  Study phs000806

• The Genomic Complexity of Primary Human Prostate Cancer

  Seven primary prostate cancers and their paired normal counterparts were DNA-sequenced on a massively parallel sequencing platform. This approach was taken to investigate the genomes for mutations and genomic alterations that would be undetectable by lower-resolution methods. As result, tumors containing chains of balanced rearrangements that occurred within or adjacent to known cancer genes were discovered.

  Study phs000330

• Integrating Circulating Tumor DNA Analysis and Radiomics for Dynamic Risk Assessment in Localized Lung Cancer

  DNA was isolated from pre-treatment and mid-treatment plasma samples and matched germline samples from patients undergoing chemoradiation therapy for stage IIB-IIIB non-small cell lung cancer. Sequencing libraries were hybrid captured using custom selector pools designed to target genes frequently mutated in non-small cell lung cancer prior to ultra-deep next generation sequencing.

  Study phs003947

• Whole blood transcriptomics analysis in Antiphospholipid syndrome in patients with Systemic Lupus Erythematosus

  We analyzed whole-blood RNA-sequencing data from 299 SLE patients (108 SLE-aPL-positive, including 67 SLE-APS; 191 SLE-aPL-negative) and 72 matched healthy controls (HC). Pathway enrichment analysis, unsupervised WGCNA analysis and machine learning were applied to distinguish disease endotypes. Deconvolution analysis was performed to characterize the peripheral blood immune cell profile.

  Study EGAS00001007750

• Systematic identification of long non-coding RNAs potentially involved in gastrointestinal carncer

  Recent work has suggested various important functions and molecular mechanisms for long non-coding RNAs (lncRNAs) and they are also thought to play critical roles in cancer. However the importance of lncRNAs in cancer biology is still unclear. In this study, we aim to comprehensively identify novel lncRNAs that are critically involved in tumorigenesis and progression in gastrointestinal cancer.

  Study JGAS000011

• Mutation screening in a large series of Japanese hearing loss patients using massively parallel DNA sequencing analysis.

  In the present study, mutation screening in a large series of Japanese hearing loss (HL) patients to clarify the prevalence and clinical characteristics of each deafness causative genes. Massively parallel DNA sequencing of 63 or 68 target genes were performed in 2969 unrelated Japanese HL patients to identify genomic variations responsible for HL.

  Study JGAS000490

• Mechanisms on relapse after allogeneic hematopoietic cell transplantation in CMML

  Disease relapse is a major cause of treatment failure after allogeneic hematopoietic cell transplantation (HCT), and mechanisms on relapse still remain to be elucidated. We experienced a patient with chronic myelomonocytic leukemia (CMML) who underwent haploidentical HCT from his daughter and developed relapse. To understand the mechanisms on relapse after HCT, we analyze blood samples at HCT and at relapse.

  Study JGAS000317

• Shallow whole genome sequencing of ctDNA samples from DETECT study

  A large-scale retrospective study in metastatic breast cancer patients using circulating tumour DNA and machine learning to predict treatment outcome and progression-free survival from the paper "A large-scale retrospective study in metastatic breast cancer patients using circulating tumour DNA and machine learning to predict treatment outcome and progression-free survival", by Beddowes et al. Mol.Onc.

  Study EGAS50000000911

• Variant analysis on FFPE specimen from NSCLC patients (OCAPlus)

  This study assessed the presence of somatic variants via the Oncomine Comprehensive Panel Plus panel (ThermoFisher) for commonly mutated cancer genes and measure tumor mutational burden using next-generation sequencing. It was performed on genomic DNA from FFPE tissue of tumor resections. Mutations were used to draw OncoPrints and to assess TMB in relation with response metrics.

  Study EGAS50000001136

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

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

  Study EGAS50000000997

• CLL_Cancer_Whole_Genome_Sequencing

  Genomic libraries (500 bps) will be generated from total genomic DNA derived from a range of cancer samples and subjected paired end sequencing on the llumina GA. Paired reads will be mapped to build 37 of the human reference genome to facilitate the generation of genome wide copy number information, and the identification of novel rearranged cancer genes and gene fusions.

  Study EGAS00001000014

• TMD_AMLK_Exome_Study

  Agilent whole exome hybridisation capture will be performed on genomic DNA derived from 20 Primary Acute Megakaryocytic Leukemia samples and matched normal DNA from the same patients. Three lanes of Illumina GA sequencing will be performed on the resulting 100 exome libraries and mapped to build 37 of the human reference genome to facilitate the identification of novel cancer genes

  Study EGAS00001000027

• μSeq: Universal mutation rate quantification via deep sequencing of a single clonal expansion

  We use patient-derived colorectal cancer organoids to introduce µSeq, a universal framework for inferring mutation rates in diverse biological systems. Our approach extracts mutation rates from deep sequencing of single clonal expansions, with a time gain of tenfold or more compared to a mutation-accumulation line, at the cost of three billion read whole-genome sequencing.

  Study EGAS50000001761

• Whole genome sequencing data of paediatric ETV6::RUNX1 acute lymphoblastic leukemia

  ETV6::RUNX1 (E::R) subgroup is the second most frequent form of B cell acute lymphoblastic leukemia (B-ALL) in childhood. This subgroup of ALL generally presents with low-risk features and responds well to chemotherapy with ensuing favorable prognosis. Some patients, however, have a slow response to induction treatment and carry increased risk for relapse.

  Study EGAS50000001599

• Fecal microbiome predicts treatment response after the initiation of semaglutide or empagliflozin uptake

  To investigate the effect of semaglutide and empagliflozin initiation on the gut microbiome of type 2 diabetes patients. In addition, to analyze whether the pre-treatment gut microbiome can predict the treatment efficacy. Gut microbiome fecal samples donated at four timepoints (Baseline, Month 1, Month 3; Month 12) were studied using 16S ribosomal RNA gene sequencing and analysis.

  Study EGAS50000000531

• Longread sequencing of selected 12q-amplified osteosarcomas

  Longread sequencing of selected 12q-amplified osteosarcomas for verification of SV data. This was carried out in order to verify findings from mate-pair sequencing regarding the structure of the chromosome 12q-amplicons and whether material from other chromosomes is also intertwined and amplified in a bid to further characterise these tumours beyond CDK4 and MDM2 amplification.

  Study EGAS50000000495

• RNA-seq of der(1;7)(q10;p10) & control MDS patients

  The study examined the RNA profiles of MDS cases. This study utilized BAM files of RNA-seq of der(1;7)(q10;p10) MDS cases, -7/del(7q) MDS cases, and OTHER MDS cases to analyze gene expression. In particular, the study profiled der(1;7)(q10;p10) MDS cases compared to non-der(1;7)(q10;p10) MDS cases.

  Study EGAS50000000705

• Subclonal variation in patients with pediatric T-lymphoblastic leukemia (T-ALL)

  Variations in TP53 and KRAS genes indicate a particularly poor prognosis in relapsed pediatric T-ALL. We hypothesized that these variations might be subclonally present at disease onset and contribute to relapse risk. To test this, we examined 386 children diagnosed with T-ALL, including more than 100 patients who relapsed as well as matched non-relapsing controls.

  Study EGAS50000000794

• sWGS data from 362 tumor with non muscle invasive bladder cancer and 30 blood samples (15 males and 15 females)

  A better understanding of the molecular landscape of non-muscle-invasive bladder cancer (NMIBC) is essential to improve risk assessment and identify potential therapeutic targets. Here, we perform a comprehensive genomic analysis of patients diagnosed with NMIBC based on whole-exome- (n=438), shallow whole-genome- (n=362), and total RNA-sequencing (n=414). This dataset contains 876 BAM files corresponding to the full WES dataset. This dataset contains 392 BAM files corresponding to the full sWGS dataset. Tumor samples were sequenced to median coverage of 2.14x (1.24-9.01).

  Dataset EGAD50000000732

• RNA sequencing data of pediatric ETV6::RUNX1 acute lymphoblastic leukemia

  ETV6::RUNX1 (E::R) subgroup is the second most frequent form of B cell acute lymphoblastic leukemia (B-ALL) in childhood. This subgroup of ALL generally presents with low-risk features and responds well to chemotherapy with ensuing favorable prognosis. Some patients, however, have a slow response to induction treatment and carry increased risk for relapse.

  Study EGAS50000001801

• A Prospective Multicenter Study of Exploring Genomic Correlates of Clinical Outcome in Patients with Metastatic Castration-Sensitive Prostate Cancer Receiving Enzalutamide.

  This study aims to characterize the somatic mutational landscape of metastatic castration-sensitive prostate cancer (mCSPC) in a Japanese population using whole-exome sequencing of tumor and matched germline DNA. The objective is to provide a comprehensive catalog of somatic mutations and a resource for understanding prostate cancer genomics and supporting future research.

  Study JGAS000902

• ER___HER2___PR__breast_Cancer_genome_sequencing

  Agilent whole exome hybridisation capture will be performed on genomic DNA derived from X triple negative breast cancers and matched normal DNA from the same patients. Three lanes of Illumina GA sequencing will be performed on the resulting X exome libraries and mapped to build 37 of the human reference genome to facilitate the identification of novel cancer genes.

  Study EGAS00001000197

• Whole-genome and transcriptome sequencing of primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma

  Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (pcAECyTCL) is a rare variant of cutaneous T-cell lymphoma with an aggressive clinical course and a very poor prognosis. We subjected tumor biopsies from patients with pcAECyTCL to whole-genome sequencing and RNA-sequencing to investigate genomic alterations and deregulated gene expression in the disease.

  Study EGAS00001004332

• Grey_Platelet_Syndrome__GPS_

  As part of the Bloodomics collaboration we have several categories of pedigrees with diseases/syndromes relevant to cardiovascular diseases (CVD). One such pedigree, Grey Platelet Syndrome (GPS) is a rare congenital bleeding disorder caused by a reduction or absence of alpha granules in platelets. Exome sequencing has been performed as part of a discovery program to ascertain potential causative variants of the clinical phenotype.

  Study EGAS00001000091

• HipSci HumanHT_12v4 Expression BeadChip analysis-Healthy volunteers

  The HipSci project brings together diverse constituents in genomics, proteomics, cell biology and clinical genetics to create a UK national iPS cell resource and use it to carry out cellular genetic studies. In this sub-study we performed Expression analysis using the Illumina HumanHT -12 Expression BeadChip on iPS cells generated from skin biopsies from healthy volunteers.

  Study EGAS00001000867

• The_International_1q_type_2_diabetes_consortium

  The aim of this project is to identify rare variants in the 1q region associated with type 2 diabetes. To this end 651 case samples and 651 control samples from six populations have been pooled (pool sizes range from 27-33 individuals), and are being sequenced. The hybridization solution being used captures the exons and UTRs of genes in the 1q region.

  Study EGAS00001000062

• Cancer_Exome_Resequencing

  Genomic libraries (500 bps) will be generated from total genomic DNA derived from a range of cancer samples and subjected paired end sequencing on the llumina GA. Paired reads will be mapped to build 37 of the human reference genome to facilitate the generation of genome wide copy number information, and the identification of novel rearranged cancer genes and gene fusions.

  Study EGAS00001000206

• Breast_Cancer_Exome_Sequencing

  Agilent whole exome hybridisation capture will be performed on genomic DNA derived from 100 breast cancers of all subtypes and matched normal DNA from the same patients. Three lanes of Illumina GA sequencing will be performed on the resulting 200 exome libraries and mapped to build 37 of the human reference genome to facilitate the identification of novel cancer genes.

  Study EGAS00001000211

• HipSci-Whole Exome sequencing-healthy volunteers

  The HipSci project brings together diverse constituents in genomics, proteomics, cell biology and clinical genetics to create a UK national iPS cell resource and use it to carry out cellular genetic studies. In this sup-study we perform whole exome sequencing using Agilent whole exome pulldown method on iPS cells generated from skin biopsies from healthy volunteers.

  Study EGAS00001000592

• Multiple Sclerosis ImmunoChip data

  The purpose of this study is to leverage the custom content of the ImmunoChip consortium; incorporating candidate loci from 12 autoimmune diseases, to both fine-map previously identified multiple sclerosis loci and identify new multiple sclerosis candidates. As a fine-mapping array, both common and rare variation are included within a subset of ~180 candidate loci across the genome.

  Study EGAS00001003219

• Prostate_Cancer_Whole_Genome_Validations

  We propose to definitively characterise the somatic genetics of Prostate cancer through generation of comprehensive catalogues of somatic mutations by high coverage genome sequencing. This study will aim to validate the findings of the whole genome study by re-sequencing regions of interest using a bespoke pulldown bait. See ICGC website for more information: http://icgc.org/icgc/cgp/70/508/71331

  Study EGAS00001000427

• SCAT_osteosarcoma_sequencing

  Agilent whole exome hybridisation capture will be performed on genomic DNA derived from 50 osteosarcoma cancers and matched normal DNA from the same patients. Three lanes of Illumina GA sequencing will be performed on the resulting 100 exome libraries and mapped to build 37 of the human reference genome to facilitate the identification of novel cancer genes

  Study EGAS00001000196

• Next Generation Children project - WGS study of patients in NICU and PICU and their families

  With growing evidence that rare single gene disorders present in the neonatal period, there is a need for rapid, systematic, and comprehensive genomic diagnoses in ICUs to assist acute and long-term clinical decisions. This study aimed to identify genetic conditions in neonatal (NICU) and paediatric (PICU) intensive care populations. Whole genome sequencing data.

  Study EGAS00001003002

• FAM50A_Disruption_in_TOV21G_Cells___RNAseq

  In this project we aimed to assess the transcriptional consequences of disrupting FAM50A in TOV21G cells in vivo. To do this we generated a dox inducible FAM50A gRNA allele such that we could conditionally inactivate FAM50A by feeding mice a diet containing doxycycline. Tumour masses were harvested from mice when they reached the ethical limit and RNA was extracted for RNA-Seq analysis.

  Study EGAS00001004156

• Molecular profiling of an AML case following treatment with a BCL2 inhibitor

  Molecular profiling of a single AML case. Exome sequencing was performed at diagnosis and after treatment with conventional chemotherapy and BCL2i. Some samples required whole genome amplification. Data will be made available to researchers upon completion of a data transfer agreement; use is restricted to ethically approved research focused on haematological malignancy, and precludes germline analysis.

  Study EGAS00001004841

• Molecular Phenotype of Constitutional TET2 Haploinsufficiency in Humans

  In this study, we observed the effects of constitutional heterozygous TET2 loss on blood DNA methylation, chromatin activity and gene expression in carriers of truncating TET2 germline mutations. To provide additional context to findings in TET2 mutation carriers, we analysed DNA methylation in four DNMT3A germline mutation carriers and their age-matched controls.

  Study EGAS00001003454

• Sputum bacterial microbiota in an overall healthy population in Guangdong province, China

  This repository contains raw sequencing data for sputum fungal microbiota in an overall healthy population in Guangdong province, China. The aim of the study is to provide a comprehensive insight on the multi-kingdom airway microbiome, how it may underlie the interplay between exposure and healthy outcomes, and whether it can be employed to inform airway health and diseases.

  Study EGAS00001006721

• Sputum fungal microbiota in an overall healthy population in Guangdong province, China

  This repository contains raw sequencing data for sputum fungal microbiota in an overall healthy population in Guangdong province, China. The aim of the study is to provide a comprehensive insight on the multi-kingdom airway microbiome, how it may underlie the interplay between exposure and healthy outcomes, and whether it can be employed to inform airway health and diseases.

  Study EGAS00001006720

• Whole genome sequencing of adult glioblastoma nuclei

  Nuclei were extracted from three primary adult glioblastoma samples and processed for scATAC-seq, and residual nuclei left over from these same samples were used to extract DNA and processed and sequenced for WGS. This WGS data was then used to cross-validate assessment of large-scale copy number alterations with scATAC-seq using the Copy-scAT tool.

  Study EGAS00001005256

• Amplified EPOR/JAK2 genes define a unique subtype of acute erythroid leukemia

  Acute erythroid leukemia (AEL) is a unique subtype of acute myeloid leukemia characterized by prominent erythroid proliferation, whose molecular basis is poorly understood. To elucidate the underlying mechanism of erythroid proliferation, we performed comprehensive genomic study. The aim of this study is to unveil genotype phenotype correlations and the feasible molecular targets for therapy of AEL.

  Study EGAS00001005810

• Somatic Inactivation of Breast Cancer Predisposition Genes in Tumours Associated with Pathogenic Germline Variants

  Breast cancers (BC) from susceptibility gene carriers, including BRCA1/2, PALB2 and RAD51C, have been shown to have bi-allelic loss in the respective genes and be associated with triple-negative (TN) BC and distinctive somatic mutational signatures. Tumour sequencing thus presents an orthogonal approach to assess the role of candidate genes in BC development.

  Study EGAS00001006532

• Whole genome analysis of pediatric patients with medulloblastoma

  Cancer genomes often contain structural variations (SVs) in non-coding regions, while its impact on tumorigenesis is still unclear. Our goal is to discover genome folding changes resulted from SVs using InfoGenomeR and InfoHiC frameworks, which may reveal novel therapeutic targets. We applied our frameworks to five pediatric patients with medulloblastoma, revealing 3D genome changes of medulloblastoma driver genes.

  Study EGAS00001006653

• The molecular landscape of homologous recombination deficient, end-stage, high grade serous ovarian cancer

  High grade serous ovarian cancer (HGSC) is frequently characterized by homologous recombination (HR) DNA repair deficiency, and while most such tumors are sensitive to initial treatment, acquired resistance is common. We undertook a multi-omics approach to interrogating mechanisms of resistance, using multiple autopsy samples collected from 15 women with HR-deficient HGSC.

  Study EGAS00001006789

• DNA methylation of peripheral blood leukocytes from patients with Li-Fraumeni syndrome

  Genomic DNA (~ 1 μg) from LFS patients was treated using sodium bisulfite (Qiagen) converting unmethylated cytosine to uracil but leaving methylated cytosine intact. These samples were then hybridized to the HumanMethylation450 BeadChip or HumanMethylationEPIC BeadChip from Illumina at the Centre for Applied Genomics (TCAG) at the Hospital for Sick Children using the manufacturer’s recommended protocol.

  Study EGAS00001007075

• LLDeep DAG2+: scRNA-seq in PBMCs

  Single cell transcriptomics of PBMCs of 47 donors from the Lifelines Deep cohort (general population, Northern part of the Netherlands). Cells of five or six different donors were pooled together in one sample pool, resulting in eight different sample pools. In total, 28.855 cells were captured and their transcriptomes were sequenced to an average depth of 74k. Genotype data was available for each donor, which allowed us to use the Demuxlet method that uses variable SNPs between the pooled individuals to determine which cell belongs to which individual. Since genotype information is lacking of 2 individuals, the transcriptome of only 45 individuals could be retrieved.

  Dataset EGAD00001003459

• ESGI-Identification of novel genes and mechanisms leading to Primary Ciliary Dyskinesia

  Approximately 80% of clinically clearly diagnosed patients suffering from primary ciliary dyskinesia (PCD) cannot be assigned to a specific gene defect. Despite extensive research on PCD and despite the increasing number of PCD genes and knowledge about their sites of action as e.g structural component or cytoplasmic pre-assembly factor, the biology of motile cilia and the pathomechanism leading to PCD is largely unknown. The aim of this study is to identify novel PCD related genes and processes relevant for motile cilia function.We will perform exome sequencing, aiming on the analysis of family trios. In these families, the diagnosis of PCD is secured, but the underlying gene defects has so far not been identified.

  Dataset EGAD00001001092

• Colorectal Adenoma Gene Screen

  A pilot to establish the feasability of using a custom Agilent targeted pulldown of 110 genes implicated in colorectal tumourigensis to sequence for driver mutations in a set of 30 FFPE colorectal adenomas. If successful, we propose to sequence an additional 350 adenomas as part of a MRC research study in order to define the pattern of driver mutations across the spectrum of pathological subtypes including coventional adenomas, serrated adenomas and hyperplastic polyps

  Dataset EGAD00001001879

• Targeted_sequencing_of_blood_DNA_from_Human_twins (2019-05-31)

  The goals of this study is to investigate the prevalence and heritability of age-related clonal haemopoeisis (ARCH) in healthy elderly individuals.We will use a bespoke bait set to pull down DNA regions of interest in whole blood samples combined with HiSeq at a deep level . By correlating findings from each individual to their respective twin we hope to elucidate whether heritable traits influence the development of ARCH. a. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/ . This dataset contains all the data available for this study on 2019-05-31.

  Dataset EGAD00001005055

• Transcriptomic profiling of RIRCD patient skeletal muscle, comparing muscle during affected phase to healthy control, and affected patient with and without additional EARS2 mutations.

  Illumina Nextseq total RNA sequencing profiles of skeletal muscle biopsies of 5 affected patients (F3/2M, F4/1F, F5/1M, F2/2F, F2/1M) compared to 6 control (Control040500, Control3509, Control3934, Control3949, Control4994, Control5106) and comparing 3 patients with additional EARS2 mutations (F2/2F, F2/1M, F5/1M) to 2 patients without (F3/2M, F4/1F). Illumina MiSeq total RNA sequencing profiles of skeletal muscle biopsies from patient F3/1M during affected disease phase (4 replicates: F3-1M_Affected_1, F3-1M_Affected_2, F3-1M_Affected_3, F3-1M_Affected_4) compared to recovered phase (F3-1M_Recovered_1, F3-1M_Recovered_2, F3-1M_Recovered_3, F3-1M_Recovered_4).

  Dataset EGAD00001006381

• Whole exome sequencing of normal CD34+ cells

  The Genomic DNA Clean & Concentrator kit (ZYMO Research) was used to remove EDTA from the DNA samples. Sample libraries were prepared using 100 ng of input according to the KAPA HyperPlus Kit (Roche) using Unique Dual Index adapters (Integrated DNA Technologies, Inc.). Exomes were captured using the SeqCap EZ MedExome (Roche Nimblegen) according to SeqCap EZ HyperCap Library v1.0 Guide (Roche) with the xGen Universal blockers – TS Mix (Integrated DNA Technologies, Inc.). The amplified captured sample libraries were paired-end sequenced (2x100 bp) on the Novaseq 6000 platform (Illumina) and aligned to the hg19 reference genome using the Burrows-Wheeler Aligner (BWA)3, v0.7.15-r1140.

  Dataset EGAD00001007645

• The Thrifty Microbiome: The Role of the Gut Microbiota in Obesity in the Amish

  Emerging evidence that the gut microbiota may contribute in important ways to human health and disease has led us and others to hypothesize that both symbiotic and pathological relationships between gut microbes and their host may be key contributors to obesity and the metabolic complications of obesity. Our "Thrifty Microbiome Hypothesis" poses that gut microbiota play a key role in human energy homeostasis. Specifically, constituents of the gut microbial community may introduce a survival advantage to its host in times of nutrient scarcity, promoting positive energy balance by increasing efficiency of nutrient absorption and improving metabolic efficiency and energy storage. However, in the presence of excess nutrients, fat accretion and obesity may result, and in genetically predisposed individuals, increased fat mass may result in preferential abdominal obesity, ectopic fat deposition (liver, muscle), and metabolic complications of obesity (insulin resistance, hypertension, hyperlipidemia). Furthermore, in the presence of excess nutrients, a pathological transition of the gut microbial community may occur, causing leakage of bacterial products into the intestinal lymphatics and portal circulation, thereby inducing an inflammatory state, further aggravating metabolic syndrome traits and accelerating atherosclerosis. This pathological transition and the extent to which antimicrobial leakage occurs and causes inflammatory and other maladaptive sequelae of obesity may also be influenced by host factors, including genetics. In the proposed study, we will directly test the Thrifty Microbiome Hypothesis by performing detailed genomic and functional assessment of gut microbial communities in intensively phenotyped and genotyped human subjects before and after intentional manipulation of the gut microbiome. To address these hypotheses, five specific aims are proposed: (1) enroll three age- and sex-matched groups from the Old Order Amish: (i) 50 obese subjects (BMI > 30 kg/m2) with metabolic syndrome, (ii) 50 obese subjects (BMI > 30 kg/m2) without metabolic syndrome, and (iii) 50 non-obese subjects (BMI < 25 kg/m2) without metabolic syndrome and characterize the architecture of the gut microbiota from the subjects enrolled in this study by high-throughput sequencing of 16S rRNA genes; (2) characterize the gene content (metagenome) to assess the metabolic potential of the gut microbiota in 75 subjects to determine whether particular genes or pathways are correlated with disease phenotype; (3) characterize the transcriptome in 75 subjects to determine whether differences in gene expression in the gut microbiota are correlated with disease phenotype, (4) determine the effect of manipulation of the gut microbiota with antibiotics on energy homeostasis, inflammation markers, and metabolic syndrome traits in 50 obese subjects with metabolic syndrome and (5) study the relationship between gut microbiota and metabolic and cardiovascular disease traits, weight change, and host genomics in 1,000 Amish already characterized for these traits and in whom 500K Affymetrix SNP chips have already been completed. These studies will provide our deepest understanding to date of the role of gut microbes in terms of 'who's there?', 'what are they doing?', and 'how are they influencing host energy homeostasis, obesity and its metabolic complications? PUBLIC HEALTH RELEVANCE: This study aims to unravel the contribution of the bacteria that normally inhabit the human gastrointestinal tract to the development of obesity, and its more severe metabolic consequences including cardiovascular disease, insulin resistance and Type II diabetes. We will take a multidisciplinary approach to study changes in the structure and function of gut microbial communities in three sets of Old Order Amish patients from Lancaster, Pennsylvania: obese patients, obese patients with metabolic syndrome and non-obese individuals. The Old Order Amish are a genetically closed homogeneous Caucasian population of Central European ancestry ideal for genetic studies. These works have the potential to provide new mechanistic insights into the role of gut microflora in obesity and metabolic syndrome, a disease that is responsible for significant morbidity in the adult population, and may ultimately lead to novel approaches for prevention and treatment of this disorder.

  Study phs000258

• Therapy-Induced APOBEC3A Drives Evolution of Resistance to Targeted Therapies in Non-Small Cell Lung Cancer

  The purpose of this study was to identify mechanisms of resistance and associated mutational signatures in non-small cell lung cancers (NSCLCs) treated with targeted therapies. Whole genome sequencing (WGS) and whole exome sequencing (WES) were performed on tumor tissue or cell lines derived from oncogene-driven NSCLCs before and after treatments with tyrosine kinase inhibitors. Somatic mutations were called and mutational signature analysis was performed, revealing enrichment of APOBEC mutational signatures mutational signatures in post-treatment tumors after the development to resistance to targeted therapies. The cohort includes WGS and WES data of tumor and normal tissues from patients with oncogene-driven NSCLCs harboring EGFR mutations, ALK fusions or NTRK1 fusions, who were treated with molecularly targeted therapies that target these oncogenes.

  Study phs003256

• Targeted Genomic Sequencing in Large Human Genes to Detect Induced Structural Variants

  Partial inhibition of DNA replication leads to de novo copy number variant (CNV) formation throughout the genome, especially at common fragile sites (CFSs). We previously showed that these hotspots for genome instability reside in late-replicating domains associated with large, transcribed genes. In this study, we performed targeted, error-corrected genomic sequencing of multiple large genes in several human cell lines. The svCapture pipeline was used to call novel structural variant junctions in co-analyzed samples. Multiple samples were analyzed from cell populations under different replication stresses, with suppression of DNA repair pathways, and in different cell cycle stages, to determine the mechanisms underlying CNV formation at these loci. Data are provided as raw genome sequencing reads and processed multi-sample VCF files with sequenced junctions encoded as breakends.

  Study phs003121

• Hereditary Gastric Cancer Syndromes: An Integrated Genomic and Clinicopathologic Study of the Predisposition to Gastric Cancer

  Gastric cancers are cancers of the stomach. Hereditary cancers are passed from parent to child. Researchers want to gather data about hereditary gastric cancers. Bulk RNA sequencing (RNA-seq) of signet ring cells (SRCs) and adjacent non-SRC epithelium (NEP) was performed on laser-capture microdissected (LCM) regions of interest found in risk-reducing total gastrectomy specimens from hereditary diffuse gastric cancer (HDGC) patients (Clinicaltrials.gov ID: NCT03030404). Twenty patients (6 male, 14 female) with confirmed HDGC were identified. Analysis of differentially expressed genes (DEGs) demonstrated upregulation of certain individual epithelial–mesenchymal transition (EMT) and proliferation genes. SRC regions had significant enrichment in pathways involved in T cell signaling. CIBERSORTx predicted significant increases in the presence of regulatory T cells (Tregs) specific to SRC regions.

  Study phs003422

• Single-Cell Sequencing Reveals Distinct Microenvironment Cell Types Associated with Response to High Dose Melphalan and Autologous Stem Cell Transplant in Multiple Myeloma

  The aim of this study is to understand the transcriptome of microenvironment cells in pre- and post- autologous stem cell transplantation (ASCT) samples between patients with complete response and partial response to transplant. Here, we studied immune cells from 40 multiple myeloma patients who have undergone ASCT. Samples were collected from 40 multiple myeloma patients before and after ASCT. Samples were sorted using magnetic activated cell sorting (MACS) and the non-tumor CD138- fraction underwent 3' single cell RNA-sequencing (scRNA-seq) or 5' scRNA-seq + 5' T cell receptor sequencing (TCRseq), to determine the scRNA transcriptome and TCR repertoire. This study includes 24 samples with 3' scRNA-seq, 56 samples with 5' scRNA-seq, and 56 samples with 5' TCRseq data.

  Study phs003219

• EGA synthetic data

  Synthetic Data One of the limitations in genomics research is that human genomics data is not openly available; access must be controlled according to participant consent agreements and data protection regulations such as GDPR. Obtaining authorization to access such data can sometimes take a long time, resulting in delays to important research work. In this context, synthetic genomic and phenotype data can be useful resources for researchers to avoid these delays. Synthetic data are artificially generated datasets, often created with algorithms, which can be used without the need for authorization to test new products and tools, build technical demonstrators, validate data models, and train AI models. The EGA provides access to synthetic cohort datasets augmented with rich synthetic metadata that overcomes these real data usage restrictions. Whilst synthetic datasets are not included in the general EGA mandate and services, we can consider such submissions and evaluate their acceptance on the basis of their unique use cases not already covered by existing synthetic datasets. Access to synthetic data studies is managed by the EGA Helpdesk Data Access Committee. Study ID Title Located in EGAS00001002472 CINECA synthetic cohort EUROPE UK1 referencing fake samples Central EGA EGAS00001005591 Synthetic data - Genome in a Bottle Central EGA EGAS00001005042 Test Study for EGA using data from 1000 Genomes Project - Phase 3 Central EGA EGAS00001005702 Human genomic and phenotypic synthetic data for the study of rare diseases Central EGA EGAS50000000190 EOSC4Cancer Synthetic Colorectal Cancer Genomic data Central EGA EGAS50000000086 Synthetic - FEGA Sweden Heilsa synthetic dataset December 2023 Federated EGA Sweden EGAS50000000678 Synthetic - GDI synthetic data Federated EGA Spain

  Documentation synthetic-data

• Low frequency and rare coding variation contributes to multiple sclerosis risk

  Multiple sclerosis is a common, complex neurological disease, where almost 20% of risk heritability can be attributed to common genetic variants, including >230 identified by genome-wide association studies. Multiple strands of evidence suggest that the majority of the remaining heritability is also due to the additive effects of individual variants, rather than epistatic interactions between these variants, or mutations exclusive to individual families. Here, we show in 68,379 cases and controls that as much as 5% of this heritability is explained by low-frequency variation in gene coding sequence. We identify four novel genes driving MS risk independently of common variant signals, which highlight a key role for regulatory T cell homeostasis and regulation, IFNγ biology and NFκB signaling in MS pathogenesis.

  Study EGAS00001003195

• Multiple migrations to the Philippines during the last 50,000 years

  A key link to understand human history in Island Southeast Asia is the Philippine archipelago and its poorly investigated genetic diversity. We collected and analyzed the most comprehensive set of population-genomic data for the Philippines, 1028 individuals covering 115 indigenous communities. We demonstrate that the Philippines were populated by at least five waves of human migration. The Cordillerans migrated into the Philippines prior to the arrival of rice agriculture, where some remain to be the least admixed East Asians carrying an ancestry shared by all Austronesian-speaking populations; thereby challenging an exclusive Out-of-Taiwan model of joint farming-language-people dispersal. Altogether, our findings portray Philippines as a crucial gateway, with a multilayered history, that ultimately changed the genetic landscape of the Asia-Pacific region.

  Study EGAS00001005083

• Open Targets 020 Epigenomes of Cell Lines (2018-10-23)

  There is currently a drive to establish cell based assay systems of greater human biological and disease relevance through the use of well characterised transformed cell lines, primary cells and complex cellular models (e.g. co-culture, 3D models). However, although the field is gaining valuable experience in running more non-standard & complex cell assays for target validation and compound pharmacology studies, there is the lack of a systematic approach to determine if this expansion in cell assay models is reflected in increased human biological and disease relevance. The increasing wealth of publically available transcriptomic, and epigenome (ENCODE and Epigenome Roadmap) data represents an ideal reference mechanism for determining the relationship between cell types used for target & compound studies to primary human cells and tissues from both healthy volunteers & patients. The CTTV020 epigenomes of cell line project aims to generate epigenetic and transcriptomic profiles of cell lines and compare these with existing and newly generated reference data sets from human tissue and cell types. The aim is to identify assay systems which will provide greater confidence in translating target biology and compound pharmacology to patients. Multiple cell types commonly used within research have been grouped according to biology. Examples include erythroid, lung epithelial, hepatocyte cell types and immortalised models of monocyte / macrophage biology. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute please see http://www.sanger.ac.uk/datasharing/ . This dataset contains all the data available for this study on 2018-10-23.

  Dataset EGAD00001004415

• Transcriptional Response to Hypoxia in iPSC-Derived Endothelial Cells from a High Altitude Adapted Population

  We established lymphoblastoid cell lines from 10 adult individuals of Tibetan ancestry living in the Chicago area. These lines were reprogrammed to induced pluripotent stem cells (iPSC). We validated genetic ancestry by genome-wide SNP array genotyping and population genetic analyses. After being subjected to standard quality control testing iPSCs were differentiated into endothelial cells. Following differentiation, endothelial cells were isolated via a pull down protocol using beads coated with an antibody for a canonical surface cell marker of the vascular endothelium (CD144). Purified vascular endothelial cells were cultured in parallel in normoxia (20% O2) and hypoxia (1% O2) for 48 hours prior to harvesting and processing for bulk RNA-sequencing. We provide imputed genotype data and bulk RNA-sequencing data in normoxia and in hypoxia for each of the 10 individuals. We also provide multiplexed scRNA-sequencing data for the 10 Tibetan individuals pooled with 10 CHB individuals from the 1000 Genome Project. Additionally, we provide scRNAseq data for the cardiomyocytes derived from the same iPSC lines from the Tibetan individuals pooled together with cardiomyocytes derived from iPSC lines of 10 CHB individuals from the 1000 Genome Project. Lymphoblastoid cell lines from the CHB were reprogrammed to iPSCs and differentiated to cardiomyocytes using the same protocols as used for the Tibetans. The batches of 4 lines were balanced by sex and population. These iPSC-derived cardiomyocytes were cultured in hypoxia (1% O2) for 48 hours and subjected to scRNAseq in pooled batches of 3 or 4 lines. The CHB individuals included in this analysis were: NA18528, NA18531, NA18557, NA18596, NA18606, NA18608, NA18614, NA18619, NA18633, and NA18748.

  Study phs003758

• Convergent evolution towards CD38 biallelic loss is a recurrent mechanism of resistance to anti-CD38 antibodies in multiple myeloma.

  Monoclonal antibodies directed against CD38 are a therapeutic mainstay in multiple myeloma (MM). While they have contributed to improved outcomes, most patients will still experience disease relapse. Despite their ubiquity, little is known about tumor-intrinsic mechanisms of resistance to these drugs. Antigen escape, whereby tumor cells alter expression of cell surface immunotherapy targets, has been proposed as a potential avenue, and has been seen with other immunotherapies in MM. Yet, it is unknown whether MM cells can develop permanent resistance to anti-CD38 antibodies by acquiring genomic events leading to biallelic disruption of the CD38 gene locus. Here, by using whole genome and whole exome sequencing data from 701 newly diagnosed patients, 72 patients at relapse with naivety to anti-CD38 antibodies, and 52 patients collected at relapse following anti-CD38 antibodies, we report biallelic inactivation of CD38 as a recurrent mechanism of resistance in 6% of patients, often via convergent evolution where distinct subclones are advantaged towards the same selective endpoint within the same patient. Monoallelic loss of the CD38 locus was seen in another 14% post-CD38-directed therapy. Three of the cases with biallelic events on CD38 presented with missense mutations and retained CD38 expression. Functional work demonstrated that two of these mutations decreased binding affinity and antibody-dependent cellular cytotoxicity of commercial antibodies Daratumumab and Isatuximab. However, the third mutation (R140G) provided relative resistance only towards one commercial product. Given that patients are often rechallenged with CD38 antibodies following disease progression, these data support the need for next generation sequencing to guide treatment selection.

  Study EGAS50000000709

• Response to Hepatitis B vaccine

  Approximately 5-10% of individuals, who are vaccinated with a hepatitis B (HB) vaccine designed based on the HBV genotype C, fail to acquire protective levels of antibodies. Host genetic factors behind low immune response to the HB vaccine were investigated by GWAS and HLA association tests. GWAS and HLA association tests were carried out using a total of 1,193 Japanese individuals including 107 low responders (HBsAb ?10 mIU/mL), 351 intermediate responders (10 mIU/mL< HBsAb <100 mIU/mL), and 735 high responders (HBsAb ?100 mIU/mL). Classical HLA class II alleles were statistically imputed using the genome-wide SNP typing data. GWAS identified independent associations of HLA-DRB1-DQB1 haplotypes, HLA-DPB1 alleles and BTNL2 gene with immune response to the HB vaccine designed based on the HBV genotype C. Five HLA-DRB1-DQB1 haplotypes and two DPB1 alleles showed significant associations with response to the HB vaccine in a comparison of three groups of 1,193 HB vaccinated individuals. When frequencies of DRB1-DQB1 haplotypes and DPB1 alleles were compared between low immune responders and HBV patients, significant associations were identified for three DRB1-DQB1 haplotypes, and no association was identified for any of DPB1 alleles. In contrast, no association for DRB1-DQB1 haplotypes and DPB1 alleles was identified in a comparison between high immune responders and healthy individuals. The findings in this study clearly show the importance of HLA-DR-DQ (i.e. recognition of a HB vaccine related HBsAg by specific DR-DQ haplotypes) and BTNL2 molecules (i.e. high immune response to the HB vaccine) for response to a HB vaccine designed based on the HBV genotype C.

  Study JGAS000341

• Development and validation of multivariate predictors of primary endocrine resistance to tamoxifen and aromatase inhibitors in luminal breast cancer reveal drug-specific differences

  Background: Endocrine therapy is highly effective in blocking the estrogen receptor pathway in HR+/HER2- early breast cancer (EBC). However, up to 40% of patients experience relapse during or after adjuvant endocrine therapy. Here, we investigate molecular mechanisms associated with primary resistance to endocrine therapy and develop predictive models. Results: TP53 mutations were prominently associated with primary resistance to both tamoxifen (TAM) and aromatase inhibitors (AI), with AI non-responders exhibiting resistance in up to 32% of cases. Additionally, we identified distinct DNA methylation patterns in TAM and AI non-responders, with TAM non-responders showing global DNA methylation loss, associated with KRAS signaling, apical junctions and epithelial-mesenchymal transition (EMT). Conversely, we observed methylation gain in AI non-responders affecting developmental transcription factors, hypoxia and estrogen signaling. TAM or AI resistance was associated with increased methylation-inferred proportions of immune cells and decreased proportions of endothelial cells. Based on these findings and patient age, we developed the Predictive Endocrine ResistanCe Index (PERCI). PERCI stratified NR and R cases in both treatment groups and cohorts with high accuracy (ROC AUC TAM discovery 93.9%, validation 83%; AI discovery 98.6%, validation 76.9%). A simplified PERCI efficiently predicted progression-free survival in the TCGA-BRCA sub-cohort (Kaplan-Meier log-rank p-value = 0.03 between low and high PERCI groups). Conclusions: We identified genomic and epigenomic features associated with primary resistance to TMA and AI. By combining information on genomic alterations, patient age, differential methylation and tumor microenvironment (TME) composition, we developed PERCI TAM and PERCI AI as novel predictors of primary resistance, with potential additional prognostic value. Applying PERCI in a clinical setting may allow patient-specific drug selection to overcome resistance.

  Study EGAS50000001102

• A Multifactorial Tumor and Immune Cell Profile Determines Response to Immune Checkpoint blockade in Melanoma

  The complex crosstalk between tumor and immune cells during immune checkpoint blockade mandates the development of integrated models that interpret the anti-tumor immune response and predict clinical outcome. We have integrated genome-wide sequence and structural alterations with pre and on-therapy transcriptomic and T cell repertoire features for a cohort of 64 immunotherapy-naïve melanomas treated with anti-PD1 monotherapy or combined anti-PD1 and anti-CTLA4 therapy. While tumor mutation burden (TMB) was associated with improved response to therapy, expressed mutation burden was superior to TMB in predicting outcome. An increased pre-existing T cell density differentiated responding from non-responding tumors independent of therapy. Importantly, T cell repertoire reshaping determined by T cell receptor (TCR) clonotypic regressions and expansions reflected response to therapy such that a more dynamic repertoire predicted improved clinical outcome. Through whole-transcriptome analyses, we discovered differential abundance of B cell subsets in responding tumors, which highlights the importance of the interplay between pre-existing T and B cell immunity in shaping therapeutic response. Tumor temporal trajectories during therapy revealed distinct patterns of molecular response related to expressed mutation elimination or retention that accurately interpreted clinical response. High-dimensional genomic, transcriptomic and immune repertoire data were integrated by both a machine learning and a censored regression approach, resulting in a harmonized multi-modal predictor of response to immune checkpoint blockade. B cell abundance, expressed mutation load and tumor aneuploidy were combined to identify patients at high risk for recurrence, such that high risk patients had a significantly shorter progression-free survival (HR=9.18, 95% CI: 3.14-26.85, p=3.4e-06) especially in the anti-PD1/anti-CTLA4 group (HR=20.34, 95% CI: 4.08-101.32, p=1.68e-06).

  Study EGAS00001004548

• Duplex sequencing

  A total of 387 buccal swab samples were subjected to error-corrected sequencing (duplex sequencing).

  Study EGAS50000000054

• T19_Yemen

  Sequencing of 50 individuals from Yemen to study the demographic history of the region

  Study EGAS00001002083

• T19_Chad_xten

  Sequencing of 8 individuals from Chad to study the demographic history of the region

  Study EGAS00001002082

• OAC scRNASeq

  Please see our related publication, 'Molecular profiling to predict immunochemotherapy outcomes in esophageal adenocarcinoma'

  Study EGAS00001006469

• National Cancer Institute (NCI) Genome Wide Association Study (GWAS) of Lung Cancer in Never Smokers

  A genomewide study of lung cancer in never smokers Abstract and specific aims In the United States, lung cancer incidence and mortality rates have been steadily declining over the past decade, following decline in the prevalence of tobacco smoking. However, lung cancer remains the leading cause of cancer death, killing more patients than breast, colon, and prostate cancers combined. Although tobacco smoke is the predominant risk factor for development of lung cancer, some patients develop the disease without a history of tobacco smoking. About 10 - 15% of all lung cancers occur in lilfetime never smokers. This figure will increase as the proportion of never smokers increases in the population. Even at present rates, lung cancer in never smokers, if considered a separate disease, is 6th to 8th top cause of cancer death. The growing number of never smokers in the USA and other countries emphasizes the importance of understanding the epidemiology and biology underlying lung cancer in this group. Genetic polymorphisms associated with the risk of lung cancer in never smokers are expected to overlap with those associated with the risk of lung cancer in ever smokers only partially. Epidemiological, molecular and clinical data suggest that molecular mechanisms of LC may differ in smokers and non-smokers, implying that lung cancer in never smokers is a different disease compared to the lung cancer in smokers. One can expect that there should be stronger genetic component in the control lung cancer in never smokers because effects of the genetic factors in never smokers are unmasked by the lack of tobacco smoke exposure. The genetic epidemiology of lung cancer in never smokers has not been well explored, largely because of difficulties in accruing the needed sample size for association studies. We propose a multicenter (total 14 sites from the US and Europe) genomewide association study of lung cancer in never smokers with the following specific aims: Aim 1: To identify candidate SNPs influencing risk for lung cancer in never smokers using Discovery sample. In the Discovery phase we will genotype 1256 Caucasian cases and 1365 age- and gender-matched never smoker controls using the Illumina Human660W-Quad platform. In addition, we will include in the analysis 284 cases and 175 matched controls already genotyped on the 610Quad platform. In this phase we will only include the study sites that have collected blood specimens (MDACC, Mayo Clinic, Karmanos Cancer Institute, The University of Liverpool Cancer research Centre, Institute of Cancer Research in Sutton, and Lunenfeld Research Institute in Toronto, Canada). All the samples will be sent to the independent lab for genotyping, to reduce site-specific technical artifacts. The final sample will consist of 1540 cases and 1540 controls matched by study site. Aim 2: To perform the second phase (validation) analysis of significant SNPs identified in aim 1 using an independent set of cases and controls. SNPs associated with risk at the significance level of 0.01 or below in the discovery set will be included in the replication phase. The proposed threshold guarantees an adequate power to retain SNPs with the typical effect size of 1.3. We plan to carry 6000-7000 SNPs for validation. The independent replication set will include 800 cases and 800 controls, mostly from sites that collected tissue (Mayo Clinic, Karmanos Cancer Institute, UT Southwestern) or buccal specimens (UCLA), but also blood samples (Imperial College London, University of Pennsylvana, German Cancer Research Center, Heidelberg, National Research Center for Environment and Health, Neuherberg, Carmel Medical Center, Haifa). We will then perform a joint analysis to test the significance of the SNPs identified in the first stage using a stringent critical p-value of 10-7. There will be 2340 cases and 2340 controls in the joint set. Based on our experience with GWAS in smokers and assuming that genetic component in lung cancer risk in never smokers can be higher than genetic component in smokers, we expect to identify about 5-10 candidate regions associated with lung cancer risk in never smokers. Aim 3: To identify and explore pathways associated with the risk of lung cancer in never smokers. Results of the number of studies on the molecular mechanisms and drug response suggest that lung cancer in never smokers is a different disease and different pathways will be associated with lung cancer risk in non-smokers and smokers. To identify pathways and molecular functions associated with lung cancer risk in never smokers we will apply Ingenuity and DAVID bioinformatics tools. We will use at least 300 top candidate genes identified in joint and discovery analysis. The reason why we select rather large number of candidate genes for functional annotation is two-fold: 1. Both algorithms are looking for enrichment of pathways and function by most significant genes and they produce statistically robust results only when number of genes is relatively high. 2. Despite the fact that this study will be largest possible for never smokers we still are underpowered to detect SNPs with relatively small effect size. But though those SNPs will not reach genome wide level of significance they will tend to be on the top of the list. In other words genes from the gray zone (significant on individual level and non-significant for genome wide level) are expected to be enriched by true discoveries. True discoveries are likely to be associated with limited number of pathways / functions while false positives are expected to be uniformly distributed across functions and pathways. Therefore significant clustering of the gene to a given function will suggest that that those genes are true discoveries. This is the first GWAS aiming at identifying the genetic control of susceptibility to lung cancer in Caucasian never smokers. We will combine the available resources from the multiple sites to achieve the sample size sufficient for this study. The study will identify genetic architecture of the predisposition to the lung cancer in never smokers.

  Study phs000634

• New England-Based Case-Control Study of Ovarian Cancer

  The case-control data provided to dbGaP were collected under NCI grant number CA54419 which had 3 enrollment phases: I (1992-1997), II (1998-2002) and III (2003-2008). Altogether, CA54419 funded 15 years of data and specimen collection, resulting in one of the longest running population based case-control studies of ovarian cancer. The study goal was to examine reproductive factors, lifestyle exposures, and genetic background in relation to ovarian cancer risk. The project recruited cases from Eastern Massachusetts and New Hampshire, and became known as the New England-based Case-Control study (NECC) of ovarian cancer. 3957 ovarian cancer cases diagnosed at ages 18-80 and residing in Eastern Massachusetts and New Hampshire were identified through tumor boards and registries. Of these, 3083 (78%) were eligible and among those eligible, 2203 (71%) were enrolled. After excluding 127 non-epithelial and 35 mixed mesodermal tumors, 2041 cases with epithelial tumors of ovarian, primary peritoneal, and fallopian tube origin, including borderline malignancies were included. On average, cases were interviewed 10 months after their diagnosis. A pathologist reviewed pathology reports and recorded histologic subtype, grade, and stage. Mixed ovarian cancers described as predominantly one type were classified as that type. Undifferentiated, transitional cell tumors, or mixed serous/transitional cell tumors were counted as serous. Other mixed epithelial, malignant Brenner, and unspecified epithelial tumors were classified as other. 2100 controls were identified through random digit dialing (RDD), driver-license lists, and town-resident lists. During the first funding phase from 1992 to 1997, 420 (72%) controls identified through RDD and 102 (51%) through town-resident lists agreed to participate. From 1998 to 2008, only town-resident lists were used to identify potential controls. 4366 controls were identified, of whom 1426 (33%) were ineligible if they had died, moved, or were seriously ill or if they did not have a working telephone, speak English, or have at least one ovary. Of eligible controls, 1362 (46%) declined to participate by phone or via &#39;opt-out&#39; postcard and 1578 (54%) were enrolled. Controls were frequency matched to cases by 5-year age groups and region of residence. In all phases, after written informed consent, demographic information, reproductive and medical history, and habits were assessed by in-person or telephone interview (in a few instances). All of the questions were framed with respect to a reference date defined as 1 year before the diagnosis date for women in the case group and the date of interview for those in the control group. This study was approved by institutional review boards at Dana Farber Harvard Cancer Center and Dartmouth Medical Center.

  Study phs001034

• Neoantigen-Targeted CD8+ T-Cell Responses 1 With PD-1 Blockade Therapy

  Background: The primary target of T-cell responses induced against cancer cells are peptides derived from non-synonymous mutations presented by HLA (neoantigens). However, the large diversity of HLA alleles and restricted availability of clinical samples have limited the study of the specificity and the evolution over time of the neoantigen-specific T cell responses induced after treatment with immune checkpoint blockade (ICB) immunotherapy. Methods: We applied a newly developed neoepitope-specific T cell isolation technology to perform a longitudinal landscape analysis of the neoepitope-specific T cells in peripheral blood and tumor from 11 patients with metastatic melanoma; 7 with response and 4 with no response to ICB. Briefly, first using computational prediction, the putative neoantigens in each patient were ranked based on affinity for the patient's HLA and expression levels. Then hundreds of barcoded capture reagents consisting of the patient HLA class I subtypes loaded with the corresponding predicted neoantigen were made and used to isolate neoepitope-specific T cells. Once isolated, the TCRs and the barcodes were sequenced. Finally, the tumor reactivity of the isolated neoepitope-specific TCRs (neoTCRs) was assessed upon co-culture of autologous melanoma cell lines from each patient with primary human T cells expressing the neoTCRs generated using a CRISPR-based non-viral gene editing to replace the endogenous TCRs. Results: The tumor mutation burden ranged between 3507 and 177 for patients with response to therapy and 977 to 31 for patients without response to therapy. We screened a median of 172 predicted neoantigen-HLA per patient across their 6 HLA molecules and isolated neoTCRs in all 11 patients. The number of mutations targeted ranged between 13 and 1. We assessed the neoTCR-tumor reactivity in samples from 3 patients with response and 3 patients without response. 39 of the 62 neoTCRs demonstrated specific recognition and cytotoxicity to patient-matched melanoma cell lines. Multiple T cell clonotypes recognized a limited number of mutations in 7 patients with response (median of 41 different neoTCR clonotypes per patient), and the T cell specificities were recurrently detected in the blood and the tumor over time. Samples from 4 patients without response to therapy also demonstrated neoepitope-specific T cell responses in blood and tumor to a similarly restricted number of mutations, but lacked TCR polyclonality (median 6.5 neoTCR clonotypes per patient) and were not recurrently detected in sequential samples. Conclusion: Effective ICB therapy is associated with polyclonal neoepitope-specific T-cell responses in the tumor and blood that recognize a limited number of immunodominant mutations and are recurrently detected over time.

  Study phs003153

• Heart Failure Network Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy - (HFN ATHENA-BioLINCC)

  ObjectiveTo assess whether high-dose spironolactone treatment for patients with acute heart failure lowers natriuretic peptide levels and improves outcomes better than usual care.BackgroundAcute heart failure (AHF) accounts for more than a million hospitalizations in the United States annually. The role of low-dose mineralocorticoid receptors antagonists (MRAs) therapy as a neurohormonal antagonist is well established for the treatment of chronic heart failure and reduced ejection fraction. However, the role of high-dose MRA therapy in AHF remained uncertain. A previous clinical trial suggested that the benefits of high-dose MRA therapy in AHF included lower natriuretic peptide levels, less congestion, better renal function, and less need for an intravenous diuretic. The use of intravenous loop diuretics can intensify secondary hyperaldosteronism among AHF patients, and hyperaldosteronism directly contributes to diuretic resistance in AHF. Elevated aldosterone levels in AHF are associated with an increased risk of cardiovascular mortality and HF readmission. Hospitalizations for heart failure are associated with increased risk of mortality and/or readmission.The HFN-ATHENA trial was conducted to determine if mineralocorticoid receptor antagonists administered at high doses relieved congestion, decreased diuretic resistance, and mitigated the effects of adverse neurohormonal activation in AHF.SubjectsThe ATHENA trial enrolled 360 participants. Of these, 178 participants were randomized to usual care treatment (placebo or low-dose spironolactone) and 182 participants were randomized to high-dose spironolactone.DesignThe study intervention was initiated within 24 hours of patients receiving the first dose of intravenous diuretics. Participants not taking spironolactone at enrollment were randomized to 100 mg spironolactone or a placebo. Participants taking low-dose spironolactone before their hospital admission were randomized to 100 mg or 25 mg per day in the usual care treatment arm. Prescription of all other medications, including diuretics, was left at the discretion of the treating physician. The study drug was discontinued after 96 hours and further MRA use was left to the treating physician's discretion. The primary end point was the proportional change in the log NT-proBNP levels from randomization to 96 hours (or at the hospital discharge if the discharge occurred earlier than 96 hours). Secondary endpoints included: (1) a clinical congestion score; (2) dyspnea relief; (3) daily cumulative net urine output for up to 96 hours; (4) net weight change from baseline to 96 hours or discharge (whichever came first); (5) furosemide equivalents of the loop diuretic dosage at discharge; and (6) the development of in-hospital worsening HF, with signs and symptoms requiring additional therapy.ConclusionsThere was no significant difference in the primary or secondary endpoints between the high-dose treatment arm and the usual care treatment arm.

  Study phs003506

• Patient Registry for Primary Pulmonary Hypertension (PPH Registry-BioLINCC)

  Data Access NOTE: Please refer to the "Authorized Access" section below for information about how access to the data from this accession differs from many other dbGaP accessions. Objectives Establish a patient registry to evaluate the natural history, etiology, pathogenesis and treatment of primary pulmonary hypertension. Specific aims included the characterization of the demographic, medical history, family history, physical and laboratory findings of patients at time of diagnosis, and to characterize the survival duration of patients by traits evaluated at diagnosis and by medical interventions. Background There are several known causes of pulmonary hypertension: chronic obstructive pulmonary disease, congenital heart disease, mitral stenosis, left ventricular dysfunction and recurrent pulmonary emboli. Primary Pulmonary Hypertension is a disorder of unknown etiology which is diagnosed only after the known causes of pulmonary hypertension have been eliminated. Prior to the PPH registry, little was known regarding the epidemiology, etiology, natural history or ultimate survival among patients with PPH. In 1973, the WHO met to review the current state of knowledge on PPH and proposed the establishment of a multicenter collaborative study. The NHLBI PPH registry enrolled patients in the registry from 1981 to 1985. Participants Participants were enrolled into the registry from 32 medical centers throughout the US. Pulmonary hypertension was defined as a mean pulmonary arterial pressure of >25 mmHg at rest or 30 mmHg with exercise at catheterization. The diagnosis of primary pulmonary hypertension was only accepted after the following secondary causes of pulmonary hypertension had been excluded: pulmonary hypertension within the first year of life, congenital abnormalities of the heart, lungs, or diaphragm, pulmonary thromboembolic disease, diagnosis of sickle cell anemia, history of intravenous drug abuse, obstructive lung disease, interstitial lung disease, arterial hypoxemia, collagen vascular disease, parasitic disease affecting the lungs, pulmonary artery or valve stenosis, or pulmonary venous hypertension. Baseline and follow-up data collected on participants include demographic characteristics, chest radiograph, pulmonary function tests, lung perfusion scan or pulmonary angiogram, intracardiac left-to-right shunt, pulmonary hemodynamics, as well as a history, physical findings and other laboratory measurements. Participants were followed for approximately 5 years. Conclusions There were 1.7 females for each male in the registry, and females tended to present with more severe symptoms. The mean time from onset of symptoms to diagnosis was 2 years. Right ventricular hypertrophy was found in 87% of participants and right atrial pressure was elevated in 72% of participants. The estimated median survival was 2.8 years with single year survival rates of: 1 year, 68%; 3 years, 48%; and 5 years, 34%. (Ann Intern Med, 1987; 107:216-23, Ann Intern Med, 1991; 115:343-49).

  Study phs004275

• Reference single cell SNP array dataset from Coriell for training and validation of method for accurate single cell genotyping

  This dataset contains DNA from B-lymphocytes from 2 Coriell families and 4 individuals hybridized to HumanKaryomap BeadChip Array. Single cells from subjects GM12878 and GM7228 were amplified using multiple displacement amplification (SureMDA) according to Infium Karyomapping Assay Guide. Bulk DNA was processed and hybridized to an array for subject GM12878, GM07224 and GM07225.

  Dataset EGAD00001006376

• Genomic Characterization CS-MATCH-0007 Arm N

  The CS-MATCH-0007 protocol is part of a collaboration between the Center for Cancer Genomics (CCG) and the Division of Cancer Treatment and Diagnosis (DCTD) to perform whole-exome sequencing, RNA sequencing and if possible, whole-genome, methylation and miRNA sequencing using pre-and post-treatment tumor biopsy specimens from patients enrolled on a treatment arm of the NCI-MATCH clinical trial (EAY131). The goal of this study is to identify the molecular basis for response and resistance to targeted therapies that are matched to specific genomic alterations found in their cancers. Arm N is one of the treatment sub-protocols within the NCI-MATCH Clinical Trial (EAY131) where patients with PTEN mutation, or deletion with PTEN expression on IHC, are treated with the drug GSK2636771. This subprotocol is one of the treatment arms included in the CS-MATCH-0007 protocol and will provide specimens for the program including DNA from tumor tissue and whole blood.

  Study phs002151

• A Genome-wide Association Study (GWAS) of Risk for Osteosarcoma

  This is a genome-wide association study (GWAS) of osteosarcoma, the most common primary bone malignancy. Osteosarcoma typically occurs in adolescents and young adults. It occurs at increased frequency in several inherited cancer predisposition syndromes but the genetic contribution to sporadic osteosarcoma is largely unexplored. The objective of this study was to identify genetic risk factors for osteosarcoma by conducting a genome-wide association study. We developed collaborations with multiple institutions in order to attain the necessary sample size required to discover novel loci in the genome associated with osteosarcoma using the GWAS approach. Genomic DNA (either blood or buccal in source) derived from osteosarcoma cases was obtained from each participating institution or research group. De-identified blood or buccal cell DNA samples from osteosarcoma cases were derived from existing biobanks at the collaborative institutions. Control subjects were derived from existing NCI cohorts and matched by gender and ethnicity.

  Study phs000734

• Cell-Type Specific Effects of Genetic Variation on Chromatin Accessibility During Human Neuronal Differentiation

  Common genetic risk for neuropsychiatric disorders is enriched in regulatory elements active during cortical neurogenesis. However, the mechanisms mediating the effects of genetic variants on gene regulation are poorly understood. To determine the functional impact of common genetic variation on the non-coding genome longitudinally during human cortical development, we performed a chromatin accessibility quantitative trait loci (caQTL) analysis in neural progenitor cells and their differentiated neuronal progeny from 92 donors. We identified significant genetic effects on 988/1,839 neuron/progenitor regulatory elements, with highly cell-type and temporally specific effects. A subset (~30%) of caQTLs were also associated with changes in gene expression. Motif-disrupting alleles of transcriptional activators generally led to decreases in chromatin accessibility, whereas motif-disrupting alleles of repressors led to increases in chromatin accessibility. By integrating cell-type specific caQTLs and brain-relevant genome-wide association data, we were able to fine-map and identify regulatory mechanisms underlying non-coding neuropsychiatric disorder risk loci.

  Study phs001958

• Reproductive Health in Men and Women with Vasculitis

  The purpose of this study is to learn about reproductive health, including fertility and pregnancies, in people with vasculitis. All patients enrolled in the Vasculitis Clinical Research Consortium&#39;s Contact Registry will be invited via email to participate in this study. The Contact Registry includes people who self-identify as having one of 11 vasculities: Beh&#231;et&#39;s disease, central nervous system vasculitis, drug-induced vasculitis, eosinophilic granulomatosis with polyangiitis (Churg-Strauss), giant cell arteritis, granulomatosis with polyangiitis (Wegener&#39;s), Henoch-Schoenlein purpura, Kawasaki disease, microscopic polyangiitis, polyarteritis nodosa, or Takayasu arteritis. People voluntarily enroll in this Registry with the understanding that they will receive information about clinical studies for which they might be eligible. The introductory email included basic information about the study and all of the required elements for informed consent in a brief format. Once participants agreed to participate in the study, they were directed to an online questionnaire.

  Study phs001382

• NIDCD Otitis Media Genetic Susceptibility and Middle Ear Microbial Shifts

  The study funded by R01 DC015004 aims to: (1) Identify rare OM susceptibility variants within families and in probands; and (2) Identify differences in the middle ear microbiome due to OM susceptibility variants. This study will also elucidate mechanisms responsible for the formation and growth of cholesteatoma, and bony erosion and complications due to cholesteatoma e.g. intracranial, hearing/vestibular loss, facial nerve palsy. A better understanding of cholesteatoma pathogenesis will potentially reveal novel drug targets, which can lead to new non-surgical therapies for cholesteatomatous OM. Our specific aims for this administrative supplement are: Aim 1 -- Perform RNA-sequencing using cholesteatoma samples collected from Filipino and Colorado patients who will be screened for FUT2, SPINK5 and A2ML1 variants; and Aim 2 -- Using network analysis, identify bone-expressed proteins potentially interacting with FUT2, SPINK5 or A2ML1, then test protein expression in archival human temporal bone in direct contact with cholesteatoma.

  Study phs001941

• Intervention with Micronutrients and Long-Term Impact in Brazil-RECODISA

  Intervention with Micronutrients and Long-Term Impact in Brazil, a partnership between the Federal University of Cear&#225;, Brazil and the University of Virginia, USA, enrolled infants in the age group of 2-36 months to investigate trends in gastrointestinal infections and their effects on growth and development and to identify genetic factors contributing to these diseases.A total of 1044 children from six urban communities in Brazil's semiarid region, were enrolled during active surveillance; those with diarrhea (three or more liquid stools in the last 24 hours at enrollment) were defined as a cases and matched with controls having no diarrhea during the past two weeks (at enrollment) to evaluate their growth and development. A subset of 664 children with their genetic and associated phenotypic data is included in this submission. More information on this project and its related projects can be found here: Studies of diarrheal susceptibility, growth, and development, in pediatric populations in Northeastern Brazil

  Study phs003174

• Idiopathic Multicentric Castleman Disease Whole Genome Sequencing Project

  Multicentric Castleman disease (MCD) is a rare lymphoproliferative disorder driven by excessive production of inflammatory cytokines. Patients can exhibit a wide range of clinical features from mild flu-like symptoms to multiple organ failure and death. Human herpesvirus-8 (HHV-8) is a well-established cause of MCD in individuals who are immunosuppressed due to human immunodeficiency virus infection or other causes. On the other hand, it is not known what causes MCD in otherwise healthy individuals with no evidence of exposure to HHV-8 (idiopathic MCD or iMCD). Although iMCD is most common in 40-60 years old adults, it affects people of all ages and early-onset (childhood or young adulthood) cases have been reported. Germline mutations may underlie iMCD in such cases. Patients with early-onset iMCD and their family members were enrolled in the study. To identify germline mutations that may underlie iMCD, whole-genome sequencing was performed in patients and their biological parents from whom DNA samples were available.

  Study phs001706

• Single-Cell Analysis of Human Adipogenesis

  The data in this study consists of RNA sequencing reads and read counts from single-cell and single-nuclei RNA sequencing experiments performed on two cell lines to investigate the transcriptional landscape of human adipogenesis in both the brown and white adipose tissue lineage. The two cell lines are human preadipocytes collected and isolated from a defined anatomical location in the neck of a single individual. This depot is known to harbor white adipose tissue (WAT) and brown adipose tissue (BAT). These white and brown preadipocytes were immortalized for the purposes of studying human adipogenesis in vitro. In this study we induced differentiation of these two preadipocyte lines and performed RNA sequencing on over 135,000 single cells spanning a 20-day time course from unperturbed preadipocytes to mature adipocytes from both brown and white lineages. Additionally, we performed both single-cell and single-nuclei RNA sequencing to comprehensively compare the advantages and disadvantages of either technique.

  Study phs002461

• Integrated Analysis of Multimodal Single-Cell Datasets for SARS-CoV-2 Vaccination

  The study aimed to explore immune responses during a time course of BNT162b2 mRNA vaccination. To better characterize these responses, we utilize a suite of multi-modal single-cell sequencing technologies to identify and characterize antigen-specific CD8+ T cells. We leverage an integrative analysis strategy to characterize five molecular modalities in these cells. Our dataset enables the discovery of new subpopulations, molecular signatures, and developmental regulators of these cells. Moreover, we identify these cells in SARS-CoV-2 infected patients and demonstrate their positive predictive value for subsequent clinical recovery. The sequence data of CITE-seq, ASAP-seq and ECCITE-seq experiments are deposited in dbGaP. Peripheral blood mononuclear cell (PBMC) samples for CITE-seq and ASAP-seq were collected from six healthy donors at four time points: immediately before (Day 0) vaccination, after primary vaccination (Day 2, Day 10), and seven days after boost vaccination (Day 28). PBMC samples for ECCITE-seq were collected from eight healthy donors on Day 28.

  Study phs003322

• RNA-Seq of PBMC's from rUTI Patients and Healthy Controls

  Recurrent urinary tract infections (rUTIs) are a major health burden worldwide, with history of infection being a significant risk factor. While the gut is a known reservoir for uropathogenic bacteria, the role of the microbiota in rUTI remains unclear. We conducted a year-long study of women with and without history of rUTIs, from whom we collected urine, blood and monthly fecal samples for multi-omic interrogation. The rUTI gut microbiome was significantly depleted in microbial richness and butyrate-producing bacteria compared to controls, reminiscent of other inflammatory conditions, though Escherichia coli gut and bladder dynamics were comparable between cohorts. Blood samples revealed signals of differential systemic immunity, leading us to hypothesize that rUTI susceptibility is in part mediated through a syndrome involving the gut-bladder axis, comprising gut dysbiosis and differential immune response to bacterial bladder colonization, manifesting in symptoms. This work highlights the potential for microbiome therapeutics to prevent and treat rUTIs.&nbsp; (Reprinted from medrxiv.org&nbsp;)&nbsp;

  Study phs002728

• A Comprehensive Platform for Analyzing Longitudinal Multi-Omics Data

  PALMO (Platform for Analyzing Longitudinal Multi-omics data) is a platform for analyzing longitudinal data from bulk as well as single cell. It allows to identify inter-, intra-donor variations in genes over longitudinal time points. The analysis can be done on bulk expression dataset without known cell type information or single cell with cell type or user defined groups. It allows to infer stable and variable features in a given donor and each cell type or a user defined group. The outlier analysis can be performed to identify technical/biological perturbed samples in a donor or a participant. Further, differential analysis can be performed to decipher time-wise changes in gene expression in a cell type. The data that is available in the dbGaP is the demo longitudinal samples used in the study, which includes hashed raw fastq files for single-cell RNA-sequencing (scRNA-seq) and non-hashed fastq files for single-cell ATAC-sequencing (scATAC) experiment.

  Study phs003203

• iRHOM2 Deficiency Causes Environmentally Directed Immunodysregulatory Disease

  We have conducted a study of two kindreds each with a unique mutation in the gene RHBDF2 that encodes the protein iRHOM2. Whole exome (kindred 1) and whole genome sequencing (kindred 2) have uncovered the first human loss-of-function mutations of RHBDF2 in 4 individuals. The affected patients are all children, 8 years old or younger, and were brought to our attention initially due to their suffering recurrent infections. Sequencing of their family members revealed parents with heterozygous RHBDF2 mutations, and heterozygous and wild type siblings &#8211; all of which were unaffected by this disease. A comprehensive investigation of this gene mutation through in vivo and in vitro experiments revealed that a loss of the protein iRHOM2 impairs the activity of the protease ADAM17 and subsequently compromises immune responses. This condition leads to the afflicted patients becoming vulnerable to different infections based on their unique environment and presenting with diverse clinical phenotypes.&nbsp;

  Study phs002478

• Whole Genome, Exome, Transcriptome and Validation Sequencing of an Acute Lymphoblastic Leukemia

  We used massively parallel sequencing technology to profile the genomic DNA and RNA of tumor cells (leukemic bone marrow) and normal cells (skin biopsy) obtained from a single patient with Acute Lymphoblastic Leukemia (ALL), referred to throughout this study as &#39;ALL1&#39;. Included in this study are samples obtained from a primary tumor, first relapse, second relapse and several intermediate timepoints. We identified somatic mutations present in each tumor by analysis of whole genome (WGS) and exome sequence data. Single nucleotide variants (SNVs) and small insertions and deletions were identified in both the exome and WGS data. Large copy number variations (CNVs) and structural variants (SVs) were identified in the WGS data. A custom capture reagent was designed to target most variants and used to generate deep validation sequence data. The expression status of all somatic variants was assessed by RNA-seq. The RNA-seq data was also used for gene expression analysis and gene fusion detection.

  Study phs001066

• Starting Treatment with Agonist Replacement Therapies (START): A Randomized Trial of Methadone vs Buprenorphine/Naloxone for the Treatment of Opioid Dependence

  The Starting Treatment with Agonist Replacement Therapy (START) study was a 24-week, open-label, randomized trial of methadone versus Suboxone (buprenorphine/naloxone) for the treatment of opioid dependence. Patients were over the age of 18 and met DSM-IV qualifications for opioid dependence. The primary goal of the study was to determine if either medicine was associated with liver toxicity issues in this vulnerable patient population. Liver enzymes were measured at four time points. Urinalysis for opioids, cocaine, cannabis, benzodiazepines, and methamphetamine were performed on a weekly basis. A flexible dosing scheme was used during which physicians could alter medication dose based on withdrawal symptoms and urinalysis results. Neither medication was found to be associated with liver enzyme levels. In version 2 of this study, a text file containing 7704 SNPs with large allele frequency discrepancy as compared to 1000 Genomes is included. Users have the option to exlude these 7704 SNPs.

  Study phs001135

• Transcriptome study of differential expression in schizophrenia

  Schizophrenia is a common and severe psychotic disorder. While some common SNPs and rare copy number variants have been identified as being significantly associated with disease risk, the biological mechanisms remain undefined. To identify gene expression abnormalities in schizophrenia, we generated whole-genome gene expression profiles using microarrays on lymphoblastoid cell lines from a total of 413 cases and 446 controls. Regression analysis identified 95 transcripts differentially expressed by affection status at a genome-wide false discovery rate of 0.05, while simultaneously controlling for confounding effects. These transcripts represented 89 genes with functions such as neurotransmission, gene regulation, cell cycle progression, differentiation, apoptosis, and immunity. The observed differential expression of extended major histocompatibility complex region genes converges with the genetic evidence from schizophrenia genome-wide association studies, which find the same region to be the most significant schizophrenia susceptibility locus. Our analysis also provides novel candidate genes for further study to assess their potential contribution to schizophrenia.

  Study phs000775

• Somatic Mutations and Cell Lineage in the Human Brain

  Genetic mutations causing human disease are conventionally thought to be inherited from one's parents and present in all somatic (body) cells. Increasingly however, somatic mutations are implicated in neurological diseases. Somatic mutations that arise during the cell divisions of prenatal brain development are inherited in clonal fashion and can cause neurodevelopmental diseases, even when present at low levels of mosaicism. In this study we use whole genome, RNA, and ATAC sequencing of single cells and bulk tissue to identify somatic mutations in control, and some disease, brains to: 1) identify and catalogue the mutations which shape the somatic neuronal genome; 2) perform a cell lineage analysis of the human brain using clonal somatic mutations in cortical neurons; 3) determine patterns of somatic mutations at different ages and in aging related disease phenotypes; and 4) relate cell lineage patterns to cell phenotype in the human brain through cell type-specific analyses.

  Study phs001485

• Rare Mendelian Disease in Old Order Amish and Mennonite Patients

  The Clinic for Special Children (CSC) has integrated biochemical and molecular methods into a rural pediatric practice serving Old Order Amish and Mennonite (Plain) children. Among the Plain people, we have used single nucleotide polymorphism (SNP) microarrays to genetically map recessive disorders to large autozygous haplotype blocks (mean = 4.4 Mb) that contain many genes (mean = 79). For some, uninformative mapping or large gene lists preclude disease-gene identification by Sanger sequencing. Seven such conditions were selected for exome sequencing at the Broad Institute; all had been previously mapped at the CSC using low density SNP microarrays coupled with autozygosity and linkage analyses. Using between 1 and 5 patient samples per disorder, we identified sequence variants in the known disease-causing genes SLC6A3 and FLVCR1, and present evidence to strongly support the pathogenicity of variants identified in TUBGCP6, BRAT1, SNIP1, CRADD, and HARS. Our results reveal the power of coupling new genotyping technologies to population-specific genetic knowledge and robust clinical data.

  Study phs000623

• Genomic Analysis of Paired Endometrial Cancer Primaries and Metastases

  Formation of metastases is the major cause of cancer related deaths. Recent studies have sequenced primary endometrial carcinomas yielding data for a single entity in the progression from the birth of a progenitor tumor cell to metastatic disease. However, the progression of these tumors to metastases has not been characterized. We performed whole-exome sequencing of 98 tumor biopsies including complex atypical hyperplasias, primary tumors and paired abdominopelvic metastases to survey the evolutionary landscape of endometrial cancer. We expanded and reanalyzed TCGA-data, identifying novel recurrent alterations in primary tumors, including mutations in the estrogen receptor cofactor NRIP1 in 12% of patients. We found that likely driver events tended to be shared by primary and metastatic tissue-samples, with notable exceptions such as ARID1A mutations. Phylogenetic analyses in cases with multiple metastases indicated these metastases typically arose from one lineage of the primary tumor. These data indicate extensive genetic heterogeneity within endometrial cancers and relative homogeneity across metastatic sites.

  Study phs001127

• Structurally Complex Osteosarcoma Genomes Exhibit Limited Heterogeneity within Individual Tumors and across Evolutionary Time

  A key characteristic of osteosarcoma is extensive and complex genomic rearrangements. However, published models explaining how these genomic rearrangements occur disagree about if these rearrangements occur early in tumor progression and then are stable afterwards, or if there is ongoing genomic instability. Previous studies have employed bulk sequencing technologies to characterize genomic alterations. A limitation of this approach is that it averages all changes within the bulk sample, essentially masking intra-sample heterogeneity and making evaluation of ongoing genomic instability difficult. To overcome this limitation and compliment previous work, we utilized single-cell whole genome sequencing to quantify somatic copy number alterations (SCNA). By interrogating individual cells within a sample, we were able to examine intra-sample heterogeneity. We found that the SCNA patterns between cells within a single sample were remarkably consistent, which supports the concept that the genomes of osteosarcoma tumors are relatively stable after early genome fragmentation events.

  Study phs003209

• Genetic Analysis of Latin American Cervical Cancer

  HPV16 is the most oncogenic type of human papillomaviruses (HPV). Integration of HPV into the human genome is an important mechanism of carcinogenesis but is absent in at least 30% of HPV16+ tumors. We applied long-read whole-genome sequencing (WGS) to cervical cancer cell lines and tumors to characterize HPV16 carcinogenesis in the absence of integration. WGS of HPV16+ cervical tumor samples from Latin America revealed that 11/20 tumors with only episomal HPV (EP) had intact monomer episomes. The remaining 9 EP tumors had multimer and rearranged HPV genomes. The majority (80%) of the HPV rearrangements and deletions disrupted the E1 and E2 genes, and EP tumors overexpressed the E6 and E7 viral oncogenes, a similar profile to tumors with HPV integration. Tumors with putative multimer HPV integrations display HPV multimers and concatemers of human and viral sequences. Our data uncovered a novel mechanism for HPV16 to cause cancer without integration through aberrant episomal replication, and forming rearranged, mutated, and multimer episomes.

  Study phs002810

• Multi-Ethnic Study of Atherosclerosis (BioLINCC)

  The Multi-Ethnic Study of Atherosclerosis (MESA) is a study of the characteristics of subclinical cardiovascular disease (disease detected non-invasively before it has produced clinical signs and symptoms) and the risk factors that predict progression to clinically overt cardiovascular disease or progression of the subclinical disease. MESA researchers study a diverse, population-based sample of 6,814 asymptomatic men and women aged 45-84. Thirty-eight percent of the recruited participants are white, 28 percent African-American, 22 percent Hispanic, and 12 percent Asian, predominantly of Chinese descent. Data available for request include phenotypic data previously released on BioLINCC as well as raw images (E.g. Echocardiogram) and raw tracing data files (e.g. Electrocardiogram). These new data are intended to be made available to interested researchers via BioData Catalyst, will include participants irrespective of participation in genetics (i.e. the full MESA cohort), and may be merged with currently posted (to dbGaP) phenotype and molecular datasets (WGS, GWA, RNA Seq, Methylation, Metabolomics, and Proteomics).

  Study phs003288

• Genomics and Methylation of Neuroendocrine Prostate Cancer from cfDNA (Cornell/Trento 2019)

  A subset of castration resistant prostate cancers develop small cell neuroendocrine prostate cancer (NEPC) as a mechanism of treatment resistance. Metastatic tissue biopsies to evaluate for NEPC transformation are invasive and challenging to perform serially. We performed whole exome and whole genome bisulfite sequencing of plasma cfDNA and matched tumor biopsy samples from 62 patients with metastatic prostate cancer along the disease spectrum to evaluate for NEPC associated genomic and epigenomic features. Multiple tissue biopsies and/or plasma time points were included for a subset of patients to characterize disease heterogeneity and dynamic changes. Computational analysis of clonality and allele specific quantification allowed for detailed comparison of matched tumor tissue and cfDNA data (CLONET v2). Methylation profiles detected from tissue and plasma data were compared and NEPC specific alterations were evaluated in cfDNA. The study supports the feasibility of a plasma based assay for the detection of NEPC.

  Study phs001752

• Spatial Transcriptomics Reveals Discrete Tumor Microenvironments and Autocrine Loops Within Ovarian Cancer Subclones

  Ovarian masses from patients with high grade serous ovarian carcinoma undergoing debulking surgery were subjected to spatial transcriptomics profiling using the 10x Genomics Visium (fresh frozen) platform. Copy number inference using inferCNV predicted the presence of subclones with mutually exclusive copy number alterations (CNAs) in 5 of the 8 patient samples studied. In one patient, 3 subclones were predicted. For this patient sample, a serial section of the same tumor was used to microdissect regions corresponding to each of these subclones, and a 'normal' region predicted to contain only fibroblasts and no tumor cells. These microdissected regions were processed for low pass whole genome sequencing (WGS) and CNAs recorded using ichorCNA. An oral biopsy lacking tumor cells from an unrelated donor was used as a negative control for CNA inference. The CNAs predicted by inferCNV for the three subclones were validated by the low pass WGS and no CNAs were observed in the normal region containing fibroblasts.

  Study phs003561

• MP2PRT: Genomic and Molecular Characterization of Biomarkers Associated with Tumor Angiogenesis, DNA Repair, and Immunologic Tolerance using Samples from the NRG Oncology Phase 3 Randomized Trial, GOG-0240 (NCT00803062)

  The Molecular Profiling to Predict Response to Treatment (MP2PRT) program is part of the NCI's Cancer Moonshot Initiative. The aim of this program is the retrospective characterization and analysis of biospecimens collected from completed NCI-sponsored trials of the National Clinical Trials Network and the NCI Community Oncology Research Program. This study is one of the selected studies under this program. For this study, genomic characterization (WGS, WXS, Total RNAseq, miRNAseq) has been performed on cervical tumor tissue from patients with advanced disease (persistent, recurrent, and metastatic) and matching germline samples. It is hypothesized that the characterization of these tissues using next generation sequencing will lead to the identification of relevant novel genetic aberrations within the immunologic, DNA repair, and tumor angiogenesis domains that dichotomize the study population into exceptional responders and non-responders to systemic therapy, with a spectrum of response manifesting between the two extremes.

  Study phs002293

• Role of Microglia Somatic Mutations in Neurodegenerative Diseases

  Somatic genetic heterogeneity resulting from post-zygotic DNA mutations is widespread in human tissues and can cause diseases, however few studies have investigated its role in neurodegenerative processes such as Alzheimer&#39;s Disease (AD). Here we report the selective enrichment of microglia clones carrying pathogenic variants, that are not present in neuronal, glia/stromal cells, or blood, from patients with AD in comparison to age-matched controls. Notably, microglia-specific AD-associated variants preferentially target the MAPK pathway, including recurrent CBL ring-domain mutations. These variants activate ERK and drive a microglia transcriptional program characterized by a strong neuro-inflammatory response, both in vitro and in patients. Although the natural history of AD-associated microglial clones is difficult to establish in human, microglial expression of a MAPK pathway activating variant was previously shown to cause neurodegeneration in mice, suggesting that AD-associated neuroinflammatory microglial clones may contribute to the neurodegenerative process in patients.

  Study phs002213

• Multi-Omic Investigation of Beckwith-Wiedemann Syndrome Hepatoblastoma

  Hepatoblastoma (HB) is the most common malignant liver tumor diagnosed in children under 5 years of age. One of the most common HB predisposition syndromes is Beckwith-Wiedemann Syndrome (BWS, OMIM 130650), which affects approximately 1/10,000 live births. In this study, we perform Whole Exome Sequencing (WES), DNA methylation array, messenger RNA-Sequencing (mRNA-Seq), and microRNA-Sequencing (miRNA-Seq) to examine the genomic, methylomic, and transcriptomic signature of BWS HB. We analyzed five tumor-normal paired samples, two BWS tumor only samples, and five non-BWS control samples to identify a predisposition and oncogenic signature of BWS HB development. To further understand the new impact of 11p15 changes, specifically in the liver, we performed single-nucleus RNA sequencing (snRNA-seq) and single-nucleus assay for transposase-accessible chromatin with sequencing (snATAC-seq) to generate paired, cell-type-specific transcriptional and chromatin accessibility profiles of both BWS-liver and nonBWS-liver nontumorous and tumor tissues.

  Study phs002614