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• Diagnostic utility of whole genome sequencing in adults with B-other acute lymphoblastic leukemia

  Genomic profiling at diagnosis of B-cell precursor Acute Lymphoblastic Leukemia (BCP-ALL) in adults is used to guide disease classification, risk stratification and treatment decisions. Patients for which diagnostic screening fails to identify disease defining or risk stratifying lesions are classified as B-other ALL. We screened a cohort of 652 BCP-ALL cases enrolled in UKALL14 to identify and perform whole genome sequencing (WGS) on paired tumor-normal samples. For 52 B-other patients we compared WGS findings to data from clinical and research cytogenetics. WGS identifies a cancer associated event in 51/52 cases, this includes an established subtype defining genetic alteration in 5/52 that were previously missed by standard-of-care genetics. Of the 47 true B-other ALL we identified a recurrent driver in 87% (41).  Complex karyotype by cytogenetics emerges as a heterogeneous group, underlied by distinct genetic alterations associated with either favorable (DUX4-r) or poor outcomes (MEF2D-r, IGK::BCL2). For a subset of 31 cases, we integrate findings from RNA-sequencing (RNA-seq) analysis to include fusion gene detection, and classification by gene expression. Compared to RNA-seq, WGS was sufficient to detect and resolve recurrent genetic subtypes, however RNA-seq can provide orthogonal validation of findings. In conclusion, we demonstrate that WGS can identify clinically relevant genetic abnormalities missed by standard-of-care testing and identify leukemia driver events in virtually all cases of B-other ALL.

  Dataset EGAD00001009304

• Transcriptomic profiling of circulating regulatory T cells from follicular lymphoma patients before and after Lenalidomide treatment

  Lenalidomide has demonstrated a favorable efficacy profile in follicular lymphoma (FL) in combination with anti-CD20 antibodies. However, in vivo administration of Lenalidomide in FL patients triggers a proliferation of functional regulatory T cells (Tregs), and a high percentage of Tregs before and along the course of treatment with Lenalidomide/anti-CD20 combination is of poor prognosis. In this study, we evaluated the impact of Lenalidomide on circulating Treg in 3 FL patients using single cell RNA sequencing (scRNAseq). For this purpose, we took advantage of the GALEN clinical trial (NCT01582776), where Lenalidomide was initiated one week before starting the anti-CD20 antibody Obinutuzumab, allowing us to compare the transcriptomic profile of immune cells before (D0) and at day 7 (D7) of treatment by Lenalidomide alone.

  Study EGAS50000001048

• Biomarker Screen for Efficacy of Oncolytic Virotherapy in Patient-derived Pancreatic Cancer Cultures

  Pancreatic ductal adenocarcinoma (PDAC) is a tumour entity with unmet medical need. To assess the therapeutic potential of oncolytic virotherapy (OVT) against PDAC, different oncolytic viruses (OVs) are currently investigated in clinical trials. However, systematic comparisons of these different OVs in terms of efficacy against PDAC and biomarkers predicting therapeutic response are lacking. We screened fourteen patient-derived PDAC cultures for their sensitivity to five clinically relevant OVs, namely serotype 5 adenovirus Ad5-hTERT, herpes virus T-VEC, measles vaccine strain MV-NIS, reovirus jin-3, and protoparvovirus H 1PV using live cell analysis, quantification of viral genome/gene expression, cell viability as well as cytotoxicity assays. Sensitivity was correlated with transcriptome profiles to identify potential predictive biomarkers for response to OVT. Patient-derived PDAC cultures showed individual response patterns to OV treatment. Twelve of fourteen cultures were responsive to at least one OV, with no single OV proving superior or inferior across all cultures. Known host factors for distinct viruses were retrieved as potential biomarkers. Compared to the basal-like molecular subtype, the quasi-mesenchymal subtype of PDAC was more sensitive to H-1PV, jin-3, and T-VEC. Expression of viral entry receptors did not correlate with sensitivity to OV treatment. Rather, cellular pathways controlling immunological, metabolic, and proliferative signalling appeared to determine outcome. For instance, high baseline expression of interferon-stimulated genes (ISGs) correlated with relative resistance to oncolytic measles virus, whereas cGAS expression was associated with exceptional response. Combination treatment of MV-NIS with a cGAS inhibitor improved tumour cell killing in several PDAC cultures.

  Study EGAS00001007001

• Upper cortical layer-driven network impairment in schizophrenia

  Schizophrenia is one of the most wide-spread and complex mental disorders. To characterize the impact of schizophrenia, we performed single nucleus RNA sequencing (snRNA-seq) of >220,000 neurons from the dorsolateral prefrontal cortex of patients with schizophrenia and matched controls. Additionally, >115,000 neurons were analyzed topographically by immunohistochemistry. Compositional analysis of snRNA-seq data revealed a reduction in abundance of GABAergic neurons and a concomitant increase in principal neurons, most pronounced for upper cortical layer subtypes, which was substantiated by histological analysis. Many neuronal subtypes showed extensive transcriptomic changes, the most dramatic - in upper layer GABAergic neurons, including downregulation in energy metabolism and upregulation in neurotransmission. Transcription factor network analysis demonstrated a developmental origin of transcriptomic changes. Finally, Visium spatial transcriptomics further corroborated upper layer neuron vulnerability in schizophrenia. Overall, our results point towards general network impairment within upper cortical layers as a core substrate associated with schizophrenia symptomatology. Study is available on bioRxiv (https://doi.org/10.1101/2020.11.17.386458) and in upcoming publication.

  Study EGAS00001006495

• Molecular profiling of blastic plasmacytoid dendritic cell neoplasm (BPDCN) as compared to acute myeloid leukemia (AML)

  Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, male-predominant myeloid malignancy that is characterized by the malignant proliferation of precursor plasmacytoid dendritic cells (pDCs) with morphologic and molecular similarities to acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) in its presentation within the bone marrow and peripheral blood. To identify disease-specific molecular features of BPDCN, we profiled bone marrow, peripheral blood and serum samples from primary patient samples using an in-house hematologic malignancy panel (“T300” panel), transcriptome microarray, and serum multiplex immunoassays and compared results to a cohort of AML patients.

  Study EGAS00001003453

• Rheumatoid Arthritis Finger Stick RNA Sequence Data

  This is a longitudinal study of 355 blood samples collected weekly from 5 patients with Rheumatoid Arthritis with varying disease activity over the course of one to five years. Blood samples were self collected from finger sticks and mailed from home. RNA was extracted, purified and sequenced.

  Study phs003179

• Progression to AML is predictable and distinct from age related clonal hematopoiesis

  To examine the occurrence of somatic mutations prior to the development of acute myeloid leukemia, we undertook deep ECS (estimated limit of detection 1 mutation in 2500 cells) of 261 AML associated genes in 96 pre-AML cases and 420 age and gender-matched healthy controls of an average of 3853 unique DNA molecules covering each of the 1.19M bases spanning the target gene panel. The findings suggest that the development of clonal hematopoiesis and accumulation of somatic mutations is distinct and accelerated in pre-AML cases compared to healthy individuals

  Study EGAS00001002570

• Sequence data to study genomic CNVs that drive apoptotic resistance and relapses on immune checkpoint inhibitors

  This project investigates the genomic mechanisms underlying acquired resistance to immune checkpoint inhibitors (ICIs) across tumor types, addressing the critical clinical problem of treatment relapses where the molecular basis remains poorly understood. Through integrative genomic analyses of longitudinal clinical melanomas, functional CRISPR-Cas9 screens, and human and murine melanoma models, the study demonstrates that copy-number variant (CNV)-driven subclonal evolution is a primary driver of clinical relapses. The research identifies resistance-driver genes targeted by CNVs, including pro-apoptotic gene deletions and anti-apoptotic gene amplifications, which collectively downregulate apoptotic priming in resistant cells. The findings establish that modulating the apoptotic threshold can prevent or reverse ICI resistance, positioning CNV evolution as a key driver of acquired resistance and identifying apoptotic regulation as a therapeutic target to combat resistance evolution.

  Study EGAS50000001055

• Gut Microbiome and Types of Colorectal Polyps

  Colorectal cancer is a heterogeneous disease arising from at least two precursors-the conventional adenoma and the serrated polyp. This dataset was used to test the relationship of the gut microbiota to specific colorectal polyp types. We included samples from two independent study populations based at colonoscopy clinics: the Centers for Disease Control and Prevention (CDC) Study of In-home Tests for Colorectal Cancer (SIT), and the New York University (NYU) Human Microbiome and Colorectal Tumor study. Gut microbiota were assessed in 667 colonoscopy-screened adults by 16S rRNA gene sequencing of stool samples, of which 540 were included in our analysis. Participants were categorized as conventional adenoma cases, serrated polyp cases, or polyp-free controls. CA cases were further classified as proximal or distal and as non-advanced or advanced. Serrated polyp cases were further classified as hyperplastic polyp or sessile serrated adenoma. Our results show associations between gut microbiome composition and presence of conventional adenomas, including reduced diversity and alterations in taxon abundance.

  Study phs001381

• Proteomic predictors of individualized nutrient-specific insulin secretion in health and disease

  Population level variation and molecular mechanisms behind insulin secretion in response to carbohydrate, protein, and fat remain uncharacterized despite ramifications for personalized nutrition. We now define prototypical insulin secretion dynamics in response to the three macronutrients in islets from 140 cadaveric donors, including those diagnosed with type 2 diabetes. We leverage the insulin response heterogeneity and use transcriptomics and proteomics to identify molecular pathways of specific nutrient responsiveness. Surprisingly, we find robust insulin secretion to fatty acid stimulus in ~8% of donors, challenging the idea that fat has negligible effects on insulin release. Distinct islet proteomes with differences in metabolic signalling networks convey this hyper-responsiveness to fat relative to carbohydrate. By comparing human islets to human embryonic stem cell-derived islet clusters, we show that, unlike glucose-responsiveness, fat hyper-responsiveness is equivalent and may be a hallmark of functionally immature cells. Our study represents the first comparison of dynamic responses to nutrients and multi-omics analysis in human insulin secreting cells. Responses of different people’s islets to carbohydrate, protein, and fat lay the groundwork for personalized nutrition.

  Dataset EGAD50000000519

• NOWAC blood-based breast cancer case-control study

  Tumor-host interactions extend beyond the local microenvironment and cancer development largely depends on the ability of malignant cells to hijack and exploit the normal physiological processes of the host. Although abnormalities in a host’s systemic immunity are associated with increased cancer susceptibility, the functional interplay between tumor cells and circulating immune cells in regulating tumorigenic responses is unclear. We employed the Norwegian Women and Cancer study, a large prospective population-based cohort study, to identify gene expression changes in blood cells that provide a robust and reproducible diagnostic signal specific to breast cancer patients. We further show that circulating blood cells in breast cancer patients are enriched in genes involved in systemic immunosuppression and the motility, metabolism, growth, and proliferation of immune cells. By mining of the cancer-associated blood transcriptome, we identified immune mediators or biomarkers that could permit early detection of breast cancer and open avenues to novel targeted immunotherapies.

  Study EGAS00000000134

• PTEN homozygous deletion is a negative prognostic factor in Tumor Treating Fields-treated glioblastoma, IDH wildtype patients

  This study investigates genomic determinants of outcome in glioblastoma, IDH-wildtype patients treated with Tumor Treating Fields (TTFields) in addition to standard radiochemotherapy. Tumor tissue from primary glioblastoma at initial diagnosis was profiled using the Illumina TruSight Oncology 500 (TSO500) targeted sequencing panel to characterise somatic alterations. The overarching goal is to provide exploration of genomic determinants of survival and treatment response in TTFields-treated glioblastoma, IDH-wildtype.

  Study EGAS50000001469

• Transcriptional characterization of human innate lymphoid cells (ILCs) and natural killer (NK) cells from fresh umbilical cord blood

  The heterogenicity of cord blood ILCs (ILC1, ILC2, ILC3) and NK cells in humans has so far not been assessed. In this study, we sorted from fresh cord blood the respective cell types from 3 donors and performed single-cell transcriptome analysis. To achieve high resoluation, each sorted population was labelled individually via multiplexing antibodies and subsequent Abseq staining before pooling. To determine single-cell transcriptomes the BD Rhapsody pipeline was performed. This is the first data set to characterize human ILCs and NK cells at such depth.

  Study EGAS50000001204

• Phase II Therapeutic Trial of Mexiletine in Non-Dystrophic Myotonia (IND #77,021)

  Non-dystrophic myotonias are a group of rare muscle disorders caused by abnormalities in different muscle cell membrane proteins. Patients experience delayed muscle relaxation that causes impaired physical activity, stiffness, and pain. Mexiletine has been shown to be beneficial for symptoms of myotonia in case reports of patients with non-dystrophic myotonia, however, current management of these patients primarily depends on individual practitioners' preference. This study is a placebo-controlled, double-blind, cross-over treatment trial using mexiletine in non-dystrophic myotonias. The results, if positive, will permit the identification of mexiletine as an effective therapy for myotonia, making it a first-line therapy for patients with non-dystrophic myotonia. The specific aim of this proposal is to perform a randomized, double-blind, placebo-controlled cross-over study to assess whether mexiletine improves both quantitative and qualitative measures of myotonia in patients with non-dystrophic myotonia. Given the rarity of non-dystrophic myotonia, large randomized controlled treatment trials in these disorders have not been feasible in the past. Primary Outcome Measure: Patient-assessed symptom: stiffness as measured by an Interactive Voice Response Diary (IVR). Secondary Outcome Measures: a) patient-assessed pain, weakness, and fatigue as measured by IVR; b) clinical myotonia assessment; c) quality of life as measured by INQoL, SF36; d) a quantitative measure of grip myotonia; e) measurement of CMAP after short and long exercise; f) grading of myotonia on needle EMG.

  Study phs001311

• RNA Expression in Diverse Donor Derived Dermal Fibroblasts Correlates with Reprogramming to Pluripotency

  The cohort used in this study includes 36 African American (17 female, 19 male) and 36 White American (19 female, 17 male) individuals. The total cohort has a median age of 32 years, with a range of 20-64 years. The African American cohort has a median age of 34, with a range of 21-52 years. The White American cohort has a median age of 31, with a range of 20-64 years. Primary dermal fibroblast lines were derived from skin biopsies obtained from adult individuals at the NIEHS under institutional review board approved protocol human subjects 10-E-0063, "Sample Collection Registry for Quality Control of Biological and Environmental Specimens and Assay Development and Testing protocol" (ClinicalTrials.gov #NCT01087307). All participants gave written informed consent for tissue donation. Donor sex, age, and ancestry were voluntarily self-reported. Fibroblast cells were reprogrammed via lentiviral transduction using six transcription factors contained in three plasmids (ADDGENE/PSIN4-EF2-N2L, ADDGENE/PSIN4-EF2-O2S and ADDGENE/PSIN4-CMV-K2M). Reprogramming efficiency was determined by alkaline phosphatase staining of triplicate 10cm reprogrammed dishes containing colonies, which were then scanned. The saved images were analyzed with ImageJ 1.51h (Wayne Rasband, National Institutes of Health, USA) to count colonies, using color threshold adjusted and binary converted images of each dish. Triplicate plates were averaged and reported as colony counts or percent reprogramming efficiency ((# of colonies/250,000) x100). The African American cohort had reprogramming efficiencies ranging from 0.06-1.37%, with a median of 0.655%. The White American cohort had reprogramming efficiencies ranging from 0.02-1.13%, with a median of 0.455%. Our goal was to define transcriptomic heterogeneity that could be contributing to differences in reprogramming efficiency between individuals and between groups. Total RNA was obtained from dermal fibroblasts and matched iPSCs. For each sample, 500 ng total RNA was used as input for preparation of whole transcriptome rRNA depleted libraries. An adapter-ligated library was prepared with the KAPA HyperPrep Kit (KAPA Biosystems, Wilmington, MA) using Bioo Scientific NEXTflex™ DNA Barcoded Adapters (Bioo Scientific, Austin, TX, USA) according to KAPA-provided protocol. Sequencing was performed using an Illumina HiSeq 2500 following Illumina-provided protocols for 2x150 bp paired-end sequencing. Each transcriptome was sequenced to a target depth of 125 million reads. The following mean raw reads were obtained: African American dermal fibroblasts= 129,571,450; White American dermal fibroblasts= 131,939,505; African American iPSCs= 132,501,335; White American iPSCs= 134,394,164. Raw reads were aligned to hg19 using the STAR alignment tool (https://github.com/alexdobin/STAR). The following mean aligned reads were obtained: African American dermal fibroblasts= 123,315,343; White American dermal fibroblasts= 125,178,035; African American iPSCs= 123,148,312; White American iPSCs= 123,886,992. Reprinted from L. C. Mackey et al., Epigenetic Enzymes, Age, and Ancestry Regulate the Efficiency of Human iPSC Reprogramming. Stem Cells 36, 1697-1708 (2018), with permission from Wiley. Reprinted from L. S. Bisogno et al., Ancestry-dependent gene expression correlates with reprogramming to pluripotency and multiple dynamic biological processes. Science Advances 6 (47) (2020) (PMID: 33219026), with permission from AAAS.

  Study phs002341

• Context-specific regulatory genetic variation in MTOR dampens neutrophil-T cell crosstalk in pneumonia-associated sepsis, modulating disease

  Sepsis is a heterogeneous clinical syndrome with a high mortality, requiring personalised stratification strategies. Here, we characterise genetic variation that modulates MTOR, a critical regulator of metabolism and immune responses in sepsis. The effects are highly context specific, involving a regulatory element that affects MTOR expression in activated T cells with opposite direction of effect in neutrophils. We show that the G-allele of the lead variant, rs4845987, associated with decreased risk of T2D, reduces MTOR expression in T cells and improves survival in sepsis due to pneumonia, with effects specific to sepsis endotype. Using ex vivo models, we demonstrate that activated T cells promote immunosuppressive sepsis neutrophils through released cytokines, a process dampened by hypoxia and the mTOR inhibitor rapamycin. Our work demonstrates a novel epigenetic mechanism that fine-tunes MTOR transcription and T cell activity via the variant-containing regulatory element, which further exhibits an allelic effect upon vitamin C treatment. These findings reveal how genetic variation interacts with disease state to modulate immune cell-cell communication, providing a patient stratification strategy to inform more effective sepsis treatment.

  Study EGAS50000000894

• Evolution of Chromatin Architecture and Transcriptional Regulation in Mammals

  Changes in gene expression are a critical force driving the evolution of form and function. As a result, the mechanisms by which gene expression evolves have become a subject of intense interest. A number of investigators have measured evolutionary changes in gene expression at the chromatin, mRNA, and protein levels, leading to new insights about how species evolve. However, studies of different stages in gene expression have not always been in agreement. For example, the extremely rapid rates of evolutionary changes that have been widely observed at enhancers appear to conflict with the slower rates observed in mRNA abundance. We recently completed a major comparative study in primates showing that this disparity between enhancer and mRNA evolution, in part, reflects extensive compensation at enhancers that jointly determine transcription at target genes. Likewise, related findings have demonstrated that post-transcriptional changes buffer protein abundance to relatively more common differences in mRNA expression. Together, these recent findings demonstrate that evolutionary changes affecting multiple stages of transcriptional regulation often have interdependent effects on gene expression. Here we propose to determine how stages early during transcriptional regulation work in concert, either to conserve gene expression through compensatory changes across stages, or, in rare cases, to change mRNA in ways that alter organism phenotypes. Our central hypothesis is that interactions between stages are common, especially at long evolutionary time-scales. To test this hypothesis we propose an ambitious plan to collect rich genomic data profiling distinct stages of gene expression in two cell types and three tissues from nine mammalian species. We have focused our study on several early rate-limiting steps in mRNA production, using molecular assays selected to provide orthogonal sources of information about chromatin architecture (Hi-C/Hi-ChIP), accessibility (ATAC-seq), transcription (PRO-seq), and mRNA levels (RNA-seq). This project will produce the largest resource of genomic data uniformly collected across mammals to date. We will integrate genomic data using a suite of new computational tools, which together will provide a new understanding of how distinct regulatory stages work in concert during regulatory evolution.

  Study phs002146

• Fecal microbiome subtype affects the clinical and genomic aberrations of colorectal cancer

  Colorectal cancers (CRCs) have been categorized based on histopathological characteristics or genomic abnormalities, such as gene expression. These classifications have gained widespread acceptance and application in clinical practice. It has become evident in recent times that there is a connection between gut bacteria and CRC. However, the extent to which the diversity of CRC and the gut microbiota are linked has not been extensively investigated. We conducted a comprehensive analysis that integrated whole genome and whole transcriptome data of CRC tissues, along with stool-derived whole genome metagenome analysis. Our approach to accurately stratify CRC involved the utilization of explainable AI, which allowed us to classify the disease into four distinct subtypes based on the composition of gut microbiota.

  Study JGAS000696

• WES of probands in KLB project

  These are the vcf files of exome sequencing of the two probands who were found to harbor mutations in KLB. Sample: EGAN00001564799 is the proband 1; Sample: EGAN00001564800 is the proband 11 in the KLB paper. Exome capture was performed using the SureSelect All Exon capture (Agilent Technologies, Santa Clara, CA USA) and sequenced on the HiSeq2500 (Illumina, San Diego CA USA).

  Dataset EGAD00001003463

• Resequencing candidate genes for male spermatogenic impairment

  This study aims to identify novel candidate variants from human Y-chromosomal genes DAZ, BPY2 and CDY1/2 by resequencing the coding regions of these genes from male patients with spermatogenic impairment. The coding regions of the genes plus a selection of phylogenetically informative Y-chromosomal markers have been amplified by standard PCR, amplicon lengths range from 178 to 486 bp. Amplicons were quantified by gel electrophoresis and pooled in approx. equimolar concentrations per patient. For each of the 480 submitted samples, approx. 1 microgram of amplified DNA pool was provided in a total volume of 120 microlitres. The samples were indexed and libraries prepared for PE250bp Illumina MiSeq runs. 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/ .

  Dataset EGAD00001006784

• Timing and trajectory of BCR-ABL1 driven chronic myeloid leukaemia

  Mutation of some genes provide fitness advantages that drive uncontrolled cell proliferation, leading to clinical manifestations of cancer. The discovery of the Philadelphia chromosome in chronic myeloid leukaemia (CML) provided the very first such genetic link to cancer and the hypothesis that this lesion provided an abnormal growth advantage to cells. However, little is known about the trajectory to CML, the rate of BCR::ABL1 driven clonal expansion, and how this impacts on disease presentation. Here, using whole-genome sequencing of 1013 single-cell-derived colonies from patients with CML, we reconstruct phylogenetic trees of haematopoiesis in 9 patients aged 22 to 81 years at diagnosis. The expected intronic breaks in BCR and ABL1 were not always observed, and out-of-frame exonic breakpoints in BCR, requiring exon skipping to derive BCR::ABL1 fusion transcripts, were noted in several patients. Apart from ASXL1 and RUNX1 mutations, additional somatic mutations in myeloid genes were generally present only in wild-type cells and did not contribute to the CML clone. Using phylogenetic analysis, we infer sustained explosive growth attributed to BCR::ABL1 fusion, with clonal expansions beginning 3-14 years (Cl 2-16 years) before diagnosis and annual growth rates exceeding 70,000% per year in some young patients with the most recent and rapid clonal expansions. Mutation rate was higher in BCR::ABL1-positive cells than in wild-type counterparts, together with markedly shorter telomere lengths, reflecting their excessive cell division history. Clonal expansion rates inferred from phylogenetic trees were in line with mutational signature patterns and telomere attrition, and inversely correlated with the time to diagnosis. Whole genome sequencing of advanced phase CML was characterised by genomic evolution within BCR::ABL1-positive cells. Our findings highlight the oncogenic potency of a single BCR::ABL1 fusion and its capacity to drive fast clonal outgrowth to cancer. These data contrast with the early-in-life, slow, and sequential clonal trajectories typical of most cancers, such as Philadelphia-negative myeloproliferative neoplasms, solid organ malignancies, and patterns of clonal expansion in healthy tissue ageing.

  Dataset EGAD00001015473

• A genome scan for genes underlying adult body size differences between Central African hunter-gatherers and farmers.

  The evolutionary and biological bases of the Central African pygmy phenotype, a characteristic of rainforest huntergatherers defined by reduced body size compared with neighboring farmers, remain largely unknown. Here, we perform a joint investigation in Central African hunter-gatherers and farmers of adult standing height, sitting height, leg length, and body mass index (BMI), considering 358 hunter-gatherers and 169 farmers with genotypes for 153,798 SNPs. In addition to reduced standing heights, hunter-gatherers have shorter sitting heights and leg lengths and higher sitting/standing height ratios than farmers and lower BMI for males. Standing height, sitting height, and leg length are strongly correlated with inferred levels of farmer genetic ancestry, whereas BMI is only weakly correlated, perhaps reflecting greater contributions of non-genetic factors to body weight than to height. Single- and multi-marker association tests identify one region and eight genes associated with hunter-gatherer/farmer status, and 24 genes associated with the height-related traits. Many of these genes have putative functions consistent with roles in determining their associated traits and the pygmy phenotype, and they include three associated with standing height in non-Africans (PRKG1, DSCAM, MAGI2). We find evidence that European height-associated SNPs or variants in linkage disequilibrium with them contribute to standing- and sitting-height determination in Central Africans, but not to the differential status of hunter-gatherers and farmers. These findings provide new insights into the biological basis of the pygmy phenotype, and they highlight the potential of cross-population studies for exploring the genetic basis of phenotypes that vary naturally across populations. Pemberton et al. Human Genetics 2018 https://doi.org/10.1007/s00439-018-1902-3

  Study EGAS00001002975

• HTAN MCL Pre-Cancer Atlas Pilot Project - Targeted Sequencing Development Study

  The HTAN-MCL Pre-Cancer Atlas Pilot Project (PCAPP) is the result of a collaboration between the seven members of the MCL consortium. Across four organ types, PCAPP's goal is to collect and profile pre-malignant lesions for gene expression, DNA mutations, single-cell gene expression and immune-environment. Most PML are small in size and only available come from formalin fixed paraffin embedded archived tissue. The primary goal of PCAPP is to 1) understand the logistical challenges of PML specimen collection, 2) document technical limitations of the assays that are specific to the PML and 3) overcome them to support the generation of a more comprehensive Pre-Cancer Atlas in the future. The current upload provides RNA and DNA sequencing from participants with DCIS who were studied at the University of San Diego and the University of Vermont. Description of the overall study: A. Background/Significance One of the critical barriers to developing new approaches for cancer detection and prevention is the lack of understanding of the key molecular and cellular changes that cause cancer initiation and progression. Unlike the extensive work that has been done profiling advanced stage tumors, few studies have comprehensively profiled the molecular alterations found in precancerous tissues. Premalignant lesions are currently characterized by histologic changes that precede the development of invasive carcinoma1,2.These lesions can often be identified in regions surrounding an invasive tumor or in biopsies taken from patients undergoing diagnostic evaluation for suspicion of cancer. Currently, limited metrics exist to identify lesions that will likely progress to carcinoma and require intervention from those that will naturally regress or remain stable3,4. Characterization of the molecular alterations in premalignant lesions and the corresponding changes in the microenvironment would hasten the development of biomarkers for early detection and risk stratification as well as suggest preventive interventions to reverse or delay the development of cancer. Our pilot study will establish the feasibility of transcriptomic, genomic and immune profiling of FFPE premalignant lesions from multiple organ sites, collected and profiled with uniform SOPs across multiple institutions within the MCL consortium. We will characterize the molecular alterations in precancerous lesions and the corresponding microenvironment in four major organ sites, in order to uncover the molecular and cellular determinants of premalignancy, and establish standardized sequencing and immunohistochemistry protocols on FFPE precancerous tissue. We will also evaluate the technical feasibility of single nuclei sequencing of small FFPE pre-cancer lesions. Successful completion of the proposed pilot study will set the stage for expansion and development of a comprehensive Pre-Cancer Atlas (PCA) as part of the NCI's moonshot.B. Specific Aims Aim 1: Collect premalignant lesions (PML) and their associated microenvironment via LCM from FFPE tissue across four organ sites (breast, lung, pancreas & prostate). Aim 2: Perform bulk RNA and DNA seq on premalignant FFPE samples (and flash frozen tissue where available) and compare the genomic/transcriptomic alterations within and across organ sites. C. ApproachAim 1: Collect premalignant lesions (PML) and their associated microenvironment via LCM from FFPE tissue across four organ sites (breast, lung, pancreas & prostate). MethodsI. Patient Population/Sample Collection: Overview of the sites collecting PML tissue from the respective organs is provided in Table 1 and a full description of the biospecimens to be obtained is described in detail for each organ type below. Table 1. Breakdown of cohort by tissue type and collection site.Organ siteBreastLungPancreasProstateType of PMLDCISAAH, Squamous Dysplasia/CISIPMNsPINCollection of PatientsUCSF/UCSDUVMBU*/UCLAVanderbilt/MoffittMDACC*JHUStanford*# of Patients201920 (10 of each type)20 (10 of each type)242020Total patients per Organ39402440Note: single nuclei/cell RNA-Seq will be performed on 4-5 FFPE samples from each of the organ types 1. DCIS lesions from breast tissue: DCIS lesions will be collected from 39 patients (20 from UCSF/UCSD & 19 from UVM) with primary low or high-grade DCIS diagnosed from a breast core biopsy. Subsequent resected lumpectomy or mastectomy tissues will be prospectively sampled in the vicinity of the prior biopsy site using multiple approaches: 1) Live cells (heterogeneous mix) will be obtained as a cell scrape slurry from the lesion surface or by fine needle aspirate (FNA); 2) For a subset of specimens where size is sufficient, a block of breast tissue with DCIS will be fresh-frozen; 3) The remainder of the specimen will be taken for routine formalin-fixation and paraffin-embedding (FFPE). The FFPE sample will be annotated to identify the matched FFPE tissue block adjacent to the fresh-frozen sample and will be sectioned for use in bulk and single nuclei sequencing . We will dissect DCIS, adjacent normal and when available, associated carcinoma. In addition, when possible, normal tissue will be collected from a tissue block lacking lesions as well as collection of blood. A subset of patients (n = 5 | FFPE, flash frozen and fresh) will be sent to the Broad Institute for single nuclei/cell sequencing.2. AAH and squamous dysplastic/CIS lesions from airway and lung tissue: For squamous cell lung cancer, we will collect endobronchial biopsies from abnormal airway regions identified on autofluroscence bronchoscopy or identify PMLs in the margins of resected lung tissue. We will study 20 patients (5 each from BU/UCLA/Vanderbilt/Moffitt) with pre-invasive squamous lesions (moderate-severe dysplasia or carcinoma in situ (CIS)) identified on pathologic examination. LCM of the premalignant region and adjacent normal epithelium will be performed as well as the invasive tumor for those collected from the resection margin (n=5 from UCLA). On a subset of lesions collected at bronchoscopy (n=5), we will collect additional biopsies that will be flash frozen and fresh for single nuclei and cell sequencing, respectively, performed at the Broad Institute. In parallel to the work at the Broad, BU will perform single cell RNA-seq on these freshly cell sorted tissues (n = 5). Blood will be collected on all patients for genomic studies. For lung adenocarcinoma, we will collect resected FFPE lung tissues from 20 patients (10 from UCLA and 10 from Vanderbilt/Moffitt) with early stage lung adenocarcinoma that harbor atypical adenomatous (AAH) premalignant lesions in the resection margin. We will LCM multiple AAH regions (3-5 per patient) as well as adjacent regions of normal epithelium and invasive adenocarcinoma. In addition, blood will be collected on all patients for genomic studies. 3. IPMNs from pancreatic tissue: For pancreatic cancer PML, we will collect low and high grade lesions from 24 patients representing macroscopic Intraductal Papillary Mucinous Neoplasms (IPMN) (n=24) from surgically resected specimens along with blood samples. Archival FFPE specimens of microscopic PanIN lesions, occurring multi-focally adjacent to invasive PDAC, and archival IPMN lesions (with or without associated invasive cancer), along with the adjacent normal tissue, will undergo LCM and utilized for bulk DNA and RNA sequencing. If matched frozen tissues are available for a subset of these FFPE samples, we will bank for comparison of profiles. Because IPMNs are macroscopic lesions, they provide an opportunity for obtaining the samples fresh and therefore can be used for single cell sequencing (in contrast to PanINs). Therefore, 5 freshly obtained IPMNs will be used for the single cell RNA sequencing studies performed at both the Broad Institute and MDACC, and the matched FFPE and/or frozen sections from these lesions (obtained from the adjacent PML) will be sent to Broad Institute as a pilot to assess "single nuclei" RNA sequencing.4. PINs from prostate tissue: For prostate cancer PML, there will be 40 samples of Prostatic Intraepithelial Neoplasia (PIN) collected between the Stanford and JHU sites (20 cases per site). At the Stanford site, 20 prostate specimens detected by PSA screening who have/will undergo surgery (radical prostatectomy) for clinically localized disease will make up the final cohort. The age range of the participants would be 40-75, and we anticipate that 18 will be Caucasian, 1 Asian and 1 Latino or African American based on the practice demographics practice at Stanford. Clinical and MRI data will also be collected for these samples. We will collect low grade (e.g. Gleason score of 6/Grade group 1; n=10) and high grade (Gleason score 4+3=7 or higher/Grade group 3 or higher; n=10) PINs from FFPE samples that have prostate carcinoma. In addition to obtaining LCM archival samples of low and high grade PIN, we will also obtain normal prostatic epithelial from the peripheral, central and transition zones as well as multiple samples of prostate carcinoma in order to obtain the spectrum of Gleason grades in the carcinoma as needed. LCM samples will be used for bulk DNA and RNA sequencing. In addition, single cells will be dissected from FFPE samples to prepare single cell RNA seq libraries using techniques developed at Stanford, and FFPE tissue will be sent to the Broad for single nuclei sequencing. When available, flash frozen and fresh samples from these prostates will be archived and prepared for single nuclei and cell sequencing, respectively, at the Broad Institute and at Stanford (single cell only). JHU will also capture 10 cases (5 grade group 1 and 5 grade group 2) of high grade PIN, normal and invasive adenocarcinoma using frozen sections from fresh frozen tissues. When possible these will be from the same patients as the FFPE samples. Since frozen sections can be quite challenging to morphologically determine high grade PIN from normal epithelium, for these samples we will perform a number of additional tissue-based characterizations. These will include a multicolor combined basal cells (p63 and CK903) and PIN/carcinoma markers (AMACR) referred to in the cocktail as "PIN4", c-MYC (referred to as MYC) protein5, by IHC and mRNA by in situ hybridization (AM De Marzo, Q Zheng unpublished observations), telomere length by in situ hybridization6 and the 5'ETS/45S rRNA7. For these slides, the whole slides will be scanned with a Hammamatsu Nanozoomer with a 40x objective and regions of interest will be annotated as a guide for LCM.II. Laser-capture microdissection (LCM): FFPE tissue blocks will be sectioned at 7μm thickness and serial sections will be stained with H&E. LCM will be performed utilizing standard LCM systems, such as Leica LMD7000 and ArcturusXT at each site. Regions of premalignancy will be dissected and RNA/DNA will be extracted from microdissected cells using the Qiagen All Prep DNA/RNA FFPE Kit. Aim 2: Perform bulk RNA and DNA seq on premalignant FFPE samples and compare the genomic/transcriptomic alterations within and across organ sites. Rationale: There have been limited studies characterizing the genomic and transcriptomic landscape of premalignant lesions associated with breast, pancreatic, lung or prostate cancers. Characterizing the molecular determinants of premalignant disease that are unique and shared across multiple organs will enable new candidate biomarkers for early detection and novel therapeutic strategies for early intervention. MethodsBulk RNA-seq of LCM FFPE tissue: All participating sites will perform bulk RNA-seq in accordance with SOPs developed at BU. In brief, total RNA will be isolated from LCM'd lesion and associated microenvironment tissue using the Qiagen All Prep DNA/RNA FFPE Kit and quality will be assessed with the Agilent Bioanalyzer. Libraries will be generated with the Illumina TruSeq Access kit (for FFPE samples). They will be sequenced on the Illumina HiSeq2500 with 75base-pair paired-end reads. Quality of FASTQ files will be assessed with FastQC. Reads will be aligned to the human genome with STAR and gene-level and isoform-level expression will be quantified with RSEM. Splice junction saturation, transcript integrity, and biotype distributions will be calculated for each sample with RSeQC. DESeq2 and EdgeR will be used to identify associations between gene expression profiles and clinical variables while controlling for confounding covariates. BU will serve as an RNA-seq Core to assess reproducibility of FFPE RNA-seq methods across sites. We will perform RNA-seq according to the SOP listed above on a subset of samples for each organ type (total n ~ 20). Bulk seq of DNA from FFPE tissue: All participating sites will perform targeted or whole exome-seq (WES) in accordance with SOPs. In brief, DNA from laser captured material will be isolated using the Qiagen All Prep DNA/RNA FFPE Kit and undergo stringent quality control to ensure high quality input material for genomic profiling. Purified DNA (ideally 100-200 ng) will be used for library preparation and amplification, followed by next generation sequencing using standard protocols distributed by CDMG. Exome-seq methods are considered standardized, thus we will not need a DNA-seq Core to assess reproducibility across sites. We anticipate local centers will use Illumina paired end reads, following the following general approach. 1) DNA library preparation: Paired-end libraries will be prepared following the manufacturer's protocols (Illumina and Agilent), fragmented to 150-200 bp 2) Capture of targeted exome: Whole exome capture will be carried out using the protocol for Agilent's SureSelect Human All Exon kit. Purified capture products will be amplified using the SureSelect GA PCR primers (Agilent) for 12 cycles. 3) Sequencing will be carried out for the captured libraries using at least 100 bp paired-end reads. To achieve high level sensitivity and accuracy for detecting all the mutations in the whole exome, each sample will be sequenced at 200X mean depth. 4) Read mapping and alignment and variant analysis: Sequence short reads will be aligned to a reference genome (NCBI human genome assembly build 38) using BWA-MEM. Local realignment of aligned reads will be performed using Genome Analysis Toolkit (GATK).Data QC: To ensure scientific rigor and consistency among sites in RNA and DNA processing we will include a preliminary analysis of steps in processing and analysis. Protocols for extraction of high quality RNA and DNA from formalin fixed paraffin embedded (FFPE) tissues, which will be used extensively in these studies continue to improve and may have variable implementation among the sites participating in this study. To evaluate consistency of preliminary steps in processing and downstream analyses, we will initially distribute slides from one large FFPE fixed cancer of origin from prostate, breast, lung and pancreatic cancer. Analysis of these samples will allow us to review the DNA and RNA characteristics (yield, purity and strand length) among sites. Downstream analysis of these same samples will also allow us to compare among sites the consistency of variant calls among centers. We will be able to identify if there are some times of calls (such as small insertion deletions) that are more variable among centers versus other types of calls (such as relative gene expression or single base pair substitutions) that we expect to be less variable and to characterize the reliability of findings across sites. We are also including a 5% blind duplicate analysis of RNA sequencing. Samples will be analysed by the participating genomics cores without knowledge of the phenotype. RNA seq and CNA analyses are normalized for batch effects. We will also compare the observed sex to the self-reported sex as based on RNA profiles and exome sequencing of X chromosome genes as another check for processing accuracy and sample management. D. References 1. Wacholder, S. Precursors in Cancer Epidemiology: Aligning Definition and Function. Cancer Epidemiol. Prev. Biomark. 22, 521-527 (2013). PMID: 23549395.2. Berman, J. J. Precancer: The Beginning and the End of Cancer. (Jones & Bartlett Learning, 2011).3. Nasiell, K., Nasiell, M. & Vaćlavinková, V. Behavior of moderate cervical dysplasia during long-term follow-up. Obstet. Gynecol. 61, 609-614 (1983). PMID: 6835614.4. Merrick, D. T. et al. Persistence of Bronchial Dysplasia Is Associated with Development of Invasive Squamous Cell Carcinoma. Cancer Prev. Res. (Phila. Pa.) 9, 96-104 (2016). PMID: 26542061.5. Gurel, B. et al. Nuclear MYC protein overexpression is an early alteration in human prostate carcinogenesis. Mod. Pathol. Off. J. U. S. Can. Acad. Pathol. Inc 21, 1156-1167 (2008). PMID: 18567993.6. Meeker, A. K. et al. Telomere shortening is an early somatic DNA alteration in human prostate tumorigenesis. Cancer Res. 62, 6405-6409 (2002). PMID: 12438224.7. Guner, G. et al. Novel Assay to Detect RNA Polymerase I Activity In Vivo. Mol. Cancer Res. MCR 15, 577-584 (2017). PMID: 28119429.

  Study phs002225

• Transcription Factor Analysis of SLE

  Background: Systemic lupus erythematosus (SLE) is an autoimmune disease with protean manifestations. This study identifies two histone marks of activation and the binding of p300 genome-wide in three cell types and three clinical subsets to better understand cell-specific effects and differences across clinical subsets. Results: We examined 20 patients with SLE and 8 controls and found the TNF, IL-2/STAT5, and KRAS pathways were identified across multiple cell types and ChIP data sets. Patients with cutaneous lupus and lupus nephritis generally had less dramatically altered chromatin than the general SLE group. Conclusions: NFkB and classical inflammatory pathways were strongly associated with increased peak heights across all cell types but were the highest-ranking pathway for all three antibodies in monocytes according to fgsea analysis. IL-6 Jak/STAT3 signaling was the most significant pathway association in T cells marked by H3K27ac change. Therefore, each cell type experiences the disease process distinctly although in all cases there was a strong theme of classical inflammatory pathways. These studies define important cell type differences and emphasize the breadth of the inflammatory effects in SLE.

  Study phs003713

• Pathologically Expanded Peripheral B Cell-Helper T Cells in Rheumatoid Arthritis

  PROSET-HD aims to identify and study immune cell populations altered in patients with autoimmune and inflammatory diseases. We have identified a population of PD-1hi CXCR5- 'peripheral helper' T (Tph) cells that are expanded in the joints and circulation of patients with seropositive rheumatoid arthritis. This T cell population uniquely combines potent B cell-helper function with a migratory program that directs homing to inflamed tissues. RNA sequencing was performed on sorted memory CD4+ T cell subpopulations to compare the global gene expression profiles of PD-1hi CXCR5- CD4+ T cells, PD-1hi CXCR5+ follicular helper T cells, and other T cell populations obtained from blood of rheumatoid arthritis patients.

  Study phs001262

• C3 SNPs and outcome after lung transplantation

  Background: Development of chronic rejection is still a severe problem and causes high mortality rates after lung transplantation (LTx). Complement activation is important in the development of acute rejection (AR) and bronchiolitis obliterans syndrome, with C3 as a key complement factor. Methods: Since a single nucleotide polymorphism (SNP) in the C3 gene (rs2230199) is associated with long-term outcome after solid organ transplantation, we investigated this SNP in relation to LTx. In addition, we looked at local production of C3 by analyzing bronchoalveolar lavage fluid (BALF) of LTx patients using isoelectric focusing (IEF). Results: We demonstrated the presence of C3 in BALF and showed that this is produced by the donor lung based on the genotype of SNP rs2230199. We also analyzed donor and patient SNP configurations and observed a significant association between the SNP configuration in patients and episodes of AR during 4-years follow-up. Survival analysis showed a lower AR-free survival in homozygous C3 slow patients (p=0.005). Furthermore, we found a significant association between the SNP configuration in donors and BOS development. Patients receiving a graft from a donor with at least one C3 fast variant for rs2230199 had an inferior BOS-free survival (p=0.044). Conclusions: In conclusion, our data indicate local C3 production by donor lung cells. In addition, a single C3 SNP present in recipients affects short-term outcome after LTx, while this SNP in donors has an opposite effect on long-term outcome after LTx. These results could contribute to an improved risk stratification after transplantation.

  Study EGAS00001003843

• UCSF Pediatric Bithalamic Glioma Genome Project

  Targeted next-generation sequencing of 13 pediatric bithalamic diffuse gliomas. BAM files of targeted next-generation DNA sequencing data of 13 pediatric gliomas, with multi-region sequencing data from 2 of these cases (17 total tumor samples). Genomic DNA was extracted from formalin-fixed, paraffin-embedded blocks of tumor tissue from using the QIAamp DNA FFPE Tissue Kit (Qiagen). Capture-based next-generation DNA sequencing was performed at the University of California, San Francisco Clinical Cancer Genomics Laboratory, using an assay that targets all coding exons of 480 cancer-related genes, select introns of 47 genes, and TERT promoter with a total sequencing footprint of 2.8 Mb (UCSF500 Cancer Panel). Sequencing libraries were prepared from genomic DNA, and target enrichment was performed by hybrid capture using a custom oligonucleotide library (Nimblegen SeqCap EZ Choice). Captured libraries were sequenced as paired-end 100 bp reads on an Illumina HiSeq 2500 instrument. Duplicate sequencing reads were removed computationally to allow for accurate allele frequency determination and copy number calling.

  Dataset EGAD00001005499

• NIDA Genetic Epidemiology of Opioid Dependence in Bulgaria (GEODB)

  The study was conducted in Bulgaria as a collaboration between the Molecular Medicine Center (Medical University, Sofia), the Bulgarian Addictions Institute (Sofia), the Initiative for Health Foundation (Sofia) and Washington University School of Medicine (Saint Louis, MO, USA). This is a case-population control study. Participants (N=2,499 interviews; N=1,995 with GWAS data) in our study are primarily active heroin users (78%) aged 18 and over, with a median 8.9 years of daily heroin use (minimum of 12 months). Virtually all participants (99.1%) qualified for a lifetime DSM-IV diagnosis of dependence, symptom endorsement probabilities ranging from 77% to 99.3%; and 61% endorsing all symptoms. 85% were heroin injectors and 97% reported using (or having used) heroin daily. Anonymized, population-representative control samples (no phenotypic data, N = 1,062 with GWAS data) were drawn from the MMC repository. Unlike other studies, where samples are clinically ascertained (e.g., from ORT programs), our participants are primarily untreated. PTSD, major depression, suicidality, mania, alcohol, nicotine and substance dependence (separating heroin and opioids) were assessed using the MAGIC (Todd et al., 2003, PMID: 14627881), a broad semi-structured psychiatric assessment tool with good reliability and prospective stability. The onset of (any) illicit drug use in this sample is not particularly remarkable (age~16), but the age of onset of heroin use is much lower than in the USA: 25% by age 16; 50% by age 19, with no differences between ethnicities or gender. This is consistent with findings from other studies in Bulgaria. In contrast, in 2008, SAMHSA estimated an average age of 23.4 for new heroin initiates in the USA. Further, progression from first use to regular use appears to be more rapid, with the majority of participants reporting onset of dependence problems within one year of initiation. Another unique aspect of this study population are the comparatively low levels of polysubstance use (outside of nicotine and alcohol). This early-use, fast-transition and monosubstance heroin pattern stands in sharp contrast to what is reported in many studies in the Western World. In our study, 47% of Ethnic Bulgarians and 66% of Roma used only opioids, even years after the onset of drug use. 15.4% of Ethnic Bulgarians and 66.2% of Roma reported heroin as the very first illicit drug used. Lifetime, 12.5% of Ethnic Bulgarians and 52.8% of Roma report never having used another illicit drug other than heroin more than five times. While both Roma and Ethnic Bulgarians certainly experiment with other drugs, abuse/dependence rates for these drugs are low in Ethnic Bulgarians (from 8.4% for inhalants to 28% for stimulants) and in the Roma population (from 1.3% for hallucinogens to 11.2% for stimulants).

  Study phs001804

• UK10K NEURO IMGSAC

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches.The IMGSAC cohort is an international collection of families containing children ascertained for ASDs (autism spectrum disorders). The affected individuals are have been phenotyped, including using the ADI-R and ADOS instruments. Individuals with a past or current medical disorder of probable etiological significance or TSC have been excluded. Where possible, karyotyping has been performed on one affected individual per family to exclude Fragile X syndrome. Many of the samples have been genotyped, using the Affymetrix 10k and Illumina 1M platforms. All samples to be included in the current study are of UK origin.For further information on this cohort please contact Jeremy Parr (jeremy.parr@newcastle.ac.uk).

  Study EGAS00001000120

• Targeted sequencing (paired) of HR genes in primary and metastatic patient-derived xenografts (PDXs) of colorectal cancer (CRC)

  The dataset includes DNA targeted paired-wise (2 FASTQ per sample) sequencing of a manually curated panel of 44 genes with a documented role in homologous recombination (HR), a pathway of DNA damage response. Sequencing was conducted in 69 tumors from patients with metastatic colorectal cancer after serial passaging in mice (patient-derived xenografts, PDXs). For each PDX model profiled for HR gene mutations, therapeutic annotation of response to FOLFIRI (a chemotherapeutic regimen consisting of the combination of 5-fluorouracil and irinotecan) is available.

  Dataset EGAD50000000107

• Latency and interval therapy affect the evolution in metastatic colorectal cancer

  While comparison of primary tumor and metastases has highlighted genomic heterogeneity in colorectal cancer (CRC), previous studies have focused on a single metastatic site or limited genomic testing. Combining data from whole exome and ultra-deep targeted sequencing, we explored possible evolutionary trajectories beyond the status of these mutations, particularly among patient-matched metastatic tumors. Our findings confirm the persistence of known clinically-relevant mutations (e.g. those of RAS family of oncogenes) in CRC primary and metastases, yet reveal that latency and interval systemic therapy affect the course of evolutionary events within metastatic lesions. Specifically, our analysis of patient-matched primary and multiple metastatic lesions, developed over time, showed a similar genetic composition for liver metastatic tumors, which were 21-months apart. This genetic makeup was different from those identified in lung metastases developed before manifestation of the second liver metastasis. These results underscore the role of dormancy in the evolutionary path of metastatic CRC.

  Study EGAS00001003646

• Transcriptomic analysis of Acute Myeloid Leukemia stem cells

  Acute Myeloid Leukemia (AML) is characterized by the accumulation of clonal myeloid blast cells unable to differentiate into mature leukocytes. Chemotherapy induces remission in the majority of patients, but relapse rates are high and lead to poor clinical outcomes. Since this is primarily caused by chemotherapy-resistant leukemic stem cells (LSCs), it is essential to eradicate LSCs to improve patient survival. LSCs have predominantly been studied at the transcript level, thus lacking information about post-transcriptionally regulated genes and associated networks. Here we extend our previous report on LSC proteomes to healthy age-matched hematopoietic stem and progenitor cells (HSPCs) and correlate the proteomes to the corresponding transcriptomes. By comparing LSCs to leukemic blasts and healthy HSPCs, we validate candidate LSC markers and highlight novel and potentially targetable proteins that are absent or only lowly expressed in HSPCs. In addition, our data provides strong evidence that LSCs harbor a characteristic energy metabolism, adhesion molecule composition, as well as RNA processing properties. Furthermore, correlating proteome and transcript data of the same individual samples highlights the strength of proteome analyses, which are particularly potent in detecting alterations in metabolic pathways. In summary, our study provides a comprehensive proteomic and transcriptomic characterization of functionally validated LSCs, blasts and healthy HSPCs, representing a valuable resource helping to design LSC-directed therapies.

  Study EGAS00001004402

• Genetics and Pathophysiology of Autoinflammatory Disorders

  In this study, patients with suspected disorders of inflammation and innate immune system dysregulation will undergo whole exome sequencing. This will involve both family studies (often trios or multiplex families including affected and unaffected individuals) and sporadic cases. The overall objective is to discover rare/novel high-penetrance mutations in genes that have not yet been implicated as the cause of monogenic autoinflammatory diseases. The aim also includes discovery of variants associated with inflammatory disease susceptibility.

  Study phs001860

• Sarcopenia related to Head and Neck squamous cell carcinomas: transcriptome modifications of muscle cells induced by distant malignant cells

  The biological mechanisms of sarcopenia are still very poorly understood, particularly in the case of Head and Neck Squamous Cell Carcinomas (HNSCC). However, there is good reason to believe that diffusible factors originating from tumor cells exert a distant deleterious effect on muscle cells. To test this hypothesis we implemented a dual approach based both on experiments carried out in vitro and on the study of muscle fragments from patients.

  Study EGAS50000000669

• SOFT_study___sequencing_premenopausal_breast_cancer

  Our project will examine the role of PIK3CA mutations and their sensitivity to endocrine therapies and its role, with the addition of complete ovarian suppression. We plan to test our hypotheses using tumour samples collected from patients enrolled in the SOFT/IBCSG24-02 clinical study (Suppression of Ovarian Function Trial – (NCT00066690). SOFT is a phase III trial that randomised 3066 premenopausal women to evaluate if adding ovarian suppression to adjuvant endocrine therapy will improve clinical outcomes.

  Study EGAS00001000983

• Whole Genome Sequences of 18th century African descended individuals from Charleston, South Carolina.

  This study presents Whole Genome Sequencing results from the Anson Street African Burial Ground Project, which is a community-based initiative aimed at understanding the histories of 37 Ancestors in Charleston, South Carolina. Here we report fastq files for all 37 Ancestors. DNA was extracted at the University of Tennessee-Knoxville following Dabney et al. 2013, and dual index libraries prepared using a modified NEBNext Ultra II kit with partial USER enzyme digestion. Libraries were then enriched for human genomic DNA (MyBaits) and sequenced on Illumina Platforms.

  Dataset EGAD00001009643

• Chordoma_Sequencing_Project_RNAseq

  This is a continuation of the Chordoma Sequencing Project. All cancers arise due to somatically acquired abnormalities in DNA sequence. Systematic sequencing of cancer genomes allows acquisition of complete catalogues of all classes of somatic mutation present in cancer. These mutation catalogues will allow identification of the somatically mutated cancer genes that are operative and characterise patterns of somatic mutation that may reflect previous exogenous and endogenous mutagenic exposures. In this application, we aim to perform whole genome sequencing on 10 chordoma matched genome pairs. RNA Sequencing/Methylation and SNP6 and an additional sequencing of three cancer cell lines will be added to this work.

  Study EGAS00001000410

• FLG LoF Variants are Associated with Atopic Dermatitis in an Early-Life Prospective Cohort

  We performed targeted sequencing of the FLG gene in 438 children with physician-diagnosed Atopic Dermatitis (AD), identified Loss-of-Function (LoF) variants, and tested the association of having one or more of these variants (binary composite) variants with AD-associated outcomes. We found that having a LoF variant was associated with moderate-severe AD compared to mild AD, food allergy at the first visit, and higher transepidermal water loss (TEWL) in both lesional and non-lesional skin in these children.

  Study phs003489

• Whole Exome and Targeted Sequencing in Tourette Syndrome Multiplex Families

  This study consists of 771 individuals from 15 extended, multi-generational Tourette Syndrome (TS) pedigrees collected by the Tourette Syndrome Association International Consortium for Genetics (TSAICG), 213 of whom are affected either with TS or its broader, genetically related phenotype, chronic tic disorder (CT). Prior microsatellite linkage analysis, including 624 individuals from these families, has identified a genome-wide significant TS/CT susceptibility locus on chromosome 2p21-24 with two additional loci meeting criteria for suggestive linkage on chromosomes 6p12-21 and 17p11-q11. Subsequent joint linkage and association analysis, incorporating genome-wide SNP genotyping on the Illumina Hap610 platform from 221 individuals, has strengthened the evidence for a major TS/CT locus on chromosome 2p but did not refine the locus further. In addition, haplotype analyses suggest that multiple TS/CT loci may exist on the short arm of chromosome 2. The goal of the current sequencing study is to use exon-focused sequencing, supplemented with targeted sequencing of additional known functional elements on chromosome 2p, to identify susceptibility variants contributing to the highly penetrant TS/CT phenotype in these families.

  Study phs000415

• Mayo-Perlegen LEAPS (Linked Efforts to Accelerate Parkinson's Solutions) Collaboration

  We performed a two-tiered, whole-genome association study of Parkinson disease (PD). For tier 1, we individually genotyped 198,345 uniformly spaced and informative single-nucleotide polymorphisms (SNPs) in 443 sibling pairs discordant for PD. For tier 2a, we individually genotyped 1,793 PD-associated SNPs (P<.01 in tier 1) and 300 genomic control SNPs in 332 matched case-unrelated control pairs. We identified 11 SNPs that were associated with PD (P<.01) in both tier 1 and tier 2 samples and had the same direction of effect. For these SNPs, we combined data from the case-unaffected sibling pair (tier 1) and case-unrelated control pair (tier 2) samples and employed a liberalization of the sibling transmission/disequilibrium test to calculate odds ratios, 95% confidence intervals, and P values. A SNP within the semaphorin 5A gene (SEMA5A) had the lowest combined P value (P=7.62E-6). The protein encoded by this gene plays an important role in neurogenesis and in neuronal apoptosis, which is consistent with existing hypotheses regarding PD pathogenesis. A second SNP tagged the PARK11 late-onset PD susceptibility locus (P=1.70E-5). In tier 2b, we also selected for genotyping additional SNPs that were borderline significant (P<.05) in tier 1 but that tested a priori biological and genetic hypotheses regarding susceptibility to PD (n=941 SNPs). In analysis of the combined tier 1 and tier 2b data, the two SNPs with the lowest P values (P=9.07E-6; P=2.96E-5) tagged the PARK10 late-onset PD susceptibility locus. Independent replication across populations will clarify the role of the genomic loci tagged by these SNPs in conferring PD susceptibility. Note: The following instruments were used: 1)clinical assessments form and manual; 2) sibling screening form and manual; 3) unrelated control screening and manual; and 4) risk factors questionnaire and manual. All cases underwent #1, as did sibling controls screening positive (see below). Unrelated controls were not examined. All siblings underwent #2. All unrelated controls underwent #3. All subjects (cases, sibling controls, and unrelated controls) underwent #4. Any publications using the data are to cite the original American Journal of Human Genetics article (Maraganore et al., 2005). Investigators using the data collection instruments are to acknowledge Drs. Maraganore and Rocca, and cite grants ES-10751 and NS-33978.

  Study phs000048

• The British Autozygosity Populations BioResource (2022-04-26)

  This data set contains whole exome sequences of individuals from 8086 (mostly British Pakistani/British Bangladeshi, mostly self-reported parentally related) individuals from the following studies: 1. 5236 British Pakistani/British Bangladeshi adults from East London Genes & Health, now known as Genes & Health 2. 2624 British South Asian mothers from Born in Bradford (mostly Pakistani) 3. 1061 British South Asian adults from Birmingham (mostly Pakistani) This dataset contains all the exome sequence data available for this study on 2022-04-26

  Dataset EGAD00001008736

• Transcriptomic profiles of chronic lymphocytic leukemia before and after frontline therapy: 5-year results from the randomized CLL14 study

  CLL14 (NCT02242942) is a multinational, open-label Phase III study designed to compare venetoclax-obinutuzumab (Ven-Obi) versus chlorambucil-obinutuzumab (Clb-Obi) in previously untreated patients with CLL and co-existing conditions. Between Aug 7, 2015, and Aug 4, 2016, 432 patients were enrolled and randomly assigned to receive either venetoclax plus obinutuzumab (Ven-Obi, n=216) or chlorambucil plus obinutuzumab (Clb-Obi, n=216). In both study arms, patients received fixed-duration treatment of overall 12 cycles, each cycle 28 days long, and entered subsequent post-treatment surveillance. Peripheral blood samples were collected before the start of therapy, as well as every 3-6 months during and after therapy, including at the time of disease progression. The primary endpoint of the study was progression-free survival, secondary endpoints included overall response rate, minimal residual disease response, and overall survival. The primary read-out was conducted after a median follow-up of 28.1 months, when the primary endpoint was met with 30 primary end-point events (disease progression or death) in the Ven-Obi arm and 77 in the Clb-Obi arm (hazard ratio, 0.35; 95% confidence interval [CI], 0.23 to 0.53;P<0.001). Follow-up is ongoing until 9 years after the last patient enrollment. In an exploratory analysis, bulk RNAseq was conducted with CD19-enriched blood from patients before start of therapy (418 patients) and at first relapse (44 patients).

  Study EGAS00001006596

• Single-cell/single-nucleus RNA-seq of Embryonal Tumor with Multilayered Rosettes (ETMR)

  Embryonal tumor with multilayered rosettes (ETMR) is a pediatric brain tumor with dismal prognosis. We analyzed eleven ETMR patient samples using single-cell transcriptomics. We reveal a spatially distinct cellular hierarchy that spans highly proliferative neural stem-like cells and more differentiated neuron-like cells. C19MC is predominantly expressed in stem-like cells and controls a transcriptional network governing stemness and lineage commitment. Systematic analysis of receptor-ligand interactions between malignant cell types reveals FGFR and NOTCH signaling as oncogenic pathways. Our study provides fundamental insights into ETMR pathobiology and a powerful rationale for more effective targeted therapies.

  Study EGAS50000000937

• shallow WGS and deep targeted panel on ctDNA in rhabdomyosarcomas

  The genomic spectrum of rhabdomyosarcoma (RMS) progression from primary to relapse is not fully understood. In this study we investigate 35 patients with relapsed RMS from two contributing institutions, 18 fusion-positive (FP-RMS) and 17 fusion-negative RMS (FN-RMS). Targeted DNA or whole exome sequencing (WES) was used to detect alterations in paired primary/relapsed samples. In 10 cases, circulating tumor DNA (ctDNA) from multiple timepoints through clinical care and progression was analyzed for feasibility of liquid biopsy in monitoring treatment response/relapse. ctDNA alterations were evaluated using a targeted custom RMS panel (36 genes) at high coverage for single nucleotide variation and fusion detection, and a shallow whole genome sequencing for copy number variation. FP-RMS had a stable genome with relapse, with the most common secondary alterations : CDKN2A/B, MYCN and CDK4 alterations, being already present at diagnosis and impacting overall survival. FP-RMS lacking major secondary events at baseline acquired recurrent MYCN and AKT1 alterations. FN-RMS acquired a higher number of new alterations, most commonly SMARCA2 missense mutations. ctDNA analyses detected pathognomonic variants in all RMS patients at diagnosis, regardless of FP/FN or type of alterations, while at relapse selected alterations were confirmed in 86% of FP-RMS and 100% FN-RMS. Moreover, a higher number of fusion reads was detected with increased disease burden and at relapse in patients following a fatal outcome. These results underscore patterns of tumor progression within a relatively stable genomic landscape and provide rationale for using liquid biopsy to monitor treatment response.

  Study EGAS00001007399

• Whole Transcriptome Sequencing of Resectable Stage III/IV Melanoma Evaluated After Starting Hu14.18-IL2 Predicts Outcome

  Background: We analyzed whole transcriptome sequencing in tumors from 23 patients with stage III or IV melanoma from a pilot trial of the anti-GD2 immunocytokine, hu14.18-IL2, to identify predictive immune and/or tumor biomarkers in melanoma patients at high risk for recurrence. Methods: Patients were randomized to receive the first of 3 monthly-courses of hu14.18-IL2 immunotherapy either before (Group A) or after (Group B) complete surgical resection of all known disease. Tumors were evaluated by histology and whole transcriptome sequencing. Results: We report here that tumor infiltrating lymphocyte (TIL) levels directly associate with relapse-free survival (RFS) and overall survival (OS) in resected tumors from Group A, where early responses to the immunotherapy agent could be assessed. TIL levels directly associated with a previously reported immune signature which associated with RFS and OS, particularly in Group A tumors. In Group A tumors there were decreased cell cycling gene RNA transcripts, but increased RNA transcripts for repair and growth genes. We found that outcome (RFS and OS) was directly associated with several immune signatures and immune-related RNA transcripts and inversely associated with several tumor growth-associated transcripts, particularly in Group A tumors. Most of these associations were not seen in Group B tumors. Conclusion: We interpret these data to signify that both immunologic and tumoral cell processes, as measured by RNAseq analyses detected shortly after initiation of hu14.18-IL2 therapy are associated with long term survival and could potentially be used as prognostic biomarkers in tumor resection specimens obtained after initiating neoadjuvant immunotherapy. Note: RNA sequences and expression data can be found at NCBI GEO GSE133713

  Study phs001947

• Similarity and diversity of the tumor microenvironment in multiple metastases: critical implications for overall and progression-free survival of high-grade serous ovarian cancer.

  The tumor microenvironment is pivotal in influencing cancer progression and metastasis. Different cells co-exist with high spatial diversity within a patient, yet their combinatorial effects are poorly understood. We investigate the similarity of the tumor microenvironment of 192 local metastatic lesions in 61 ovarian cancer patients. An ecologically inspired measure of microenvironmental diversity derived from multiple metastasis sites is correlated with clinicopathological characteristics and prognostic outcome. We demonstrate a high accuracy of our automated analysis across multiple sites. A low level of similarity in microenvironmental composition is observed between ovary tumor and corresponding local metastases (stromal ratio r = 0.30, lymphocyte ratio r = 0.37). We identify a new measure of microenvironmental diversity derived from Shannon entropy that is highly predictive of poor overall (p = 0.002, HR = 3.18, 95% CI = 1.51-6.68) and progression-free survival (p = 0.0036, HR = 2.83, 95% CI = 1.41-5.7), independent of and stronger than clinical variables, subtype stratifications based on single cell types alone and number of sites. Although stromal influence in ovary tumors is known to have significant clinical implications, our findings reveal an even stronger impact orchestrated by diverse cell types. Quantitative histology-based measures can further enable objective selection of patients who are in urgent need of new therapeutic strategies such as combinatorial treatments targeting heterogeneous tumor microenvironment.

  Study EGAS00001002065

• DPY30 ChIP-seq

  H9 human embryonic stem cells (hESCs) were cultured in feeder-free chemically-defined conditions in medium containing 10ng/ml Activin A and 12ng/ml FGF2 (Vallier L. 2011, Methods in Molecular Biology, 690: 57-66). Chromatin immunoprecipitation was performed as described in Brown S. et al. 2011. Stem Cells 29: 1176-85 by using 5ug of anti-DPY30 antibody (Sigma, cat. number HPA043761). This protocol was performed in control hESCs (expressing a scrambled shRNA) and in hESCs stably expressing an shRNA against DPY30 (Sigma, clone n. TRCN0000131112).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/

  Dataset EGAD00001001268

• Adoptive Cell Therapy of Autologous T cell Receptor-Engineered T Cells Targeting the p53 Neoantigens in Human Solid Tumors

  Adoptive T cell therapy (ACT) using T cell receptor (TCR)-engineered T cells can mediate regression of advanced human cancers. How TCR-transduced T cells change post-ACT in vivo is currently not well understood. We screened 78 patients for TP53 mutations by whole exome sequencing and whole transcriptome sequencing. Of the 78 patient samples, 49 patient samples were previously reported (phs001003) and 2 additional patients were reported in phs002735. In this accession we report the sequencing data of remaining 23 patients and include 6 additional samples from previously published patients. Additionally, we treated a patient with chemo-refractory breast cancer that expressed mutant p53 R175H with autologous T cells transduced with an allogeneic TCR targeting p53 R175H with human leukocyte antigen (HLA) restriction of A*02. The patient had a partial response for 6 months with 55% tumor regression. The T cells from the infusion product and the peripheral blood T cells at 6 weeks post-ACT were analyzed using 10X single cell transcriptome analysis.

  Study phs002928

• JAK Inhibitor Withdrawal Causes a Transient Proinflammatory Cascade: A Potential Mechanism for Major Adverse Cardiac Events

  This is a study of mesenchymal stromal cells (MSCs) from salivary glands. The salivary glands were derived from participants who had dry eye or dry mouth symptoms but did not have evidence of systemic autoimmune disease (sicca controls). The aim of the study was to determine the effects of Type I and Type II Janus kinase (JAK) inhibitors (JAKinibs) withdrawal on these cells in vitro. The MSCs were treated in vitro with a) IFN-gamma (10 ng/mL) for the entire duration, b) IFN-gamma (10 ng/mL) and withdrawal of ruxolitinib (1 µM), c) IFN-gamma (10 ng/mL) and withdrawal CHZ-868 (1 µM), and d) IFN-gamma (10 ng/mL) and ruxolitinib (1 µM) for the entire duration. For the drug (CHZ-868 and ruxolitinib) conditions, after IFN-gamma treatment for 48 hours, we washed the cells with PBS and treated them with standard growth media with 0.01% DMSO, 10 ng/mL IFN-gamma + 0.01% DMSO, or 10 ng/mL IFN-gamma + JAKinib for 48 hours. For withdrawal conditions, we washed the cells twice and then treated them with standard growth media with either 0.01% DMSO or with 10 ng/mL IFN-gamma + 0.01% DMSO for 24 hours before harvest.

  Study phs003915

• Pharmacogenomic Analysis Reveals New Therapeutic Options for Pleural Mesothelioma

  Background: Pleural mesothelioma (PM) urgently requires novel effective treatments. Drug repurposing is a relevant strategy to discover new therapeutic options among well-known drugs used in clinical practice. This study aimed to identify new therapies in the context of molecular heterogeneity of PM. Methods: We performed a multi-omics study of the largest cohort of patient-derived primary PM cell lines (n=58) to date, using whole exome sequencing, RNA sequencing and methylome analysis. We also conducted a large-scale drug screening of over 1300 compounds on a subset of cell lines (n=11), as well as an extension screen (n=48) for selected drugs of interest. The best candidates were validated using 3D culture and mouse models. Results: We demonstrated that the molecular landscape of the cell lines cohort recapitulates the main findings in tumours and revealed new specific features of PM. The large-scale drug screening and subsequent validations highlighted notably strong sensitivity to entinostat and fluvastatin. Importantly, both compounds displayed same efficacy in 2D and 3D culture models and single treatment prolonged survival in vivo similarly or even better than standard chemotherapy. Strikingly, combining entinostat treatment with anti-PD1 led to cures in some mice and immunized them against tumour cells. Conclusions: Among several candidates, we identified entinostat, notably in combination with immune checkpoint inhibitor, and to a lesser extent fluvastatin, as promising therapeutic options for patients. We believe our study provides a valuable resource that could contribute to advances in the field and warrants further clinical investigation.

  Study EGAS00001007866

• Study on the proliferation history of colorectal adenomas

  Mismatch repair (MMR) deficient colorectal adenomas are composed of transformed cells that descend from a common founder and progressively accumulate genomic alterations but their proliferation history is still largely unknown. Here we rebuilt the proliferation history of four MMR deficient colorectal adenomas from male individuals by deep sequencing the X chromosome and mapping the somatic mutations that were progressively acquired during tumor growth. We developed a novel method to call high and low frequency mutations, to cluster them according to their frequencies and rebuild the proliferation trees directly from these mutation clusters using a recursive algorithm. The trees of all four lesions were formed of a dominant subclone that coexisted with other genetically heterogeneous subpopulations of cells. Despite this similar hierarchical organization, however, the growth dynamics varied among and within tumors, likely depending on a combination of tumor-specific genetic and environmental factors. Our study provides insights into the biological properties of individual MMR deficient colorectal adenomas that may influence their growth and also the response to therapy. Extended to other solid tumors, our approach could inform on the mechanisms of cancer progression, thus providing insight into the best choice of cancer treatment methods.

  Study EGAS00001000883

• Longitudinal single-cell transcriptomic study in patient-derived xenografts of pediatric T-ALL

  In this study, we conducted single cell full length total RNA sequencing (VASA-seq) on 13 matched pediatric T-ALL PDX samples at initial diagnosis and relapse, along with 5 non-relapsing PDX samples collected at initial diagnosis. We identified a subpopulation of T-ALL cells with stem-like cell features that expands substantially at relapse indicating resistance to first-line therapy. Chemotherapy resistance was further validated through functional testing: Two samples were subjected to in-vitro drug testing, treated with Cytarabine for three days, followed by single-cell transcriptomic analysis using 10x Genomics. Additionally, in-vivo drug testing was conducted on one sample, involving re-engraftment into mice and treatment with a combination of Vincristine, Doxorubicin, and Dexamethasone. Single-cell transcriptomic analysis using 10x Genomics was performed after 0, 15 and 30 days of treatment.

  Study EGAS50000000582

• Genomic characterization of co-existing biliary tract intraepithelial neoplasia and carcinoma lesions reveals distinct evolutionary paths of gallbladder cancer

  Gallbladder carcinoma is the most common cancer of the biliary tract with dismal survival largely due to delayed diagnosis. Biliary tract intraepithelial neoplasia (BilIN) is the common benign tumor that is suspected to be precancerous lesions. However, the genetic and evolutionary relationships between BilIN and carcinoma remain unclear. Here we performed whole-exome sequencing of coexisting low-grade BilIN (adenoma), high-grade BilIN, and carcinoma lesions, and normal tissues from the same patients.

  Dataset EGAD00001007792

• Mind Body Study: A Sub-Study on Psychosocial Factors and Microbiomes of Nurses in the Nurse's Health Study II

  The Mind-Body Study is a sub-study of the Nurses' Health Study II (NHSII) which investigated associations between biomarkers and psychosocial factors. The prevalences of clinically meaningful depressive symptoms, mild-to-severe anxiety symptoms, experiencing major-life discrimination, and food addiction were 19%, 21%, 30%, and 5% respectively. These participants were more likely to have experienced childhood abuse and take psychotropic medications but less likely to have chronic conditions such as diabetes and hypertension than participants in the larger NHSII cohort. Participants (n = 213, mean age = 60.6) provided one or two separate stool samples for microbiome profiling between 2013 and 2014, and completed two online psychosocial assessments 10 months apart. The participants also completed two 30-day FFQs around the two microbiome collections. There was excellent reproducibility of psychosocial factors over 1 year. Moderate-to-strong positive correlations were observed between markers of distress and between positive psychosocial factors such as mindfulness and optimism. Here, the subjects' metadata including phenotypic and diet covariates have been provided. Microbial DNA sequence data from the stool microbiome collections is provided via Sequence Read Archive (SRA).

  Study phs003786

• WES Elucidation of Pathogenetic Mechanisms for Immune System Disorders and NIAID Pilot of Genetic Incidental Finding Management

  Background: - There are many types of immune disorders. These range from rare immune deficiencies to allergies to autoimmune disease like rheumatoid arthritis. Genes are the instructions our body uses to work and develop. A new technology called whole exome sequencing may help find the cause of these disorders. Whole exome sequencing is a way to look at many genes at once for errors. Researchers hope to find new gene changes that lead to immune disorders. Additionally, researchers are interested in finding the best way to manage unexpected but important findings by whole exome sequencing. Objectives: - To better understand genetic causes of immune system disorders. Also, to better understand people s thoughts and feelings about immune system disorders and new genomic testing. Eligibility: - People ages 0 100 with an immune disorder or a relative with an immune disorder. People must be at least 2 to be evaluated at the NIH clinical center. People must be at least 12 to do the survey/interview portion of the study. Design: Participants will have their genes sequenced. They may be asked for a new sample of blood. If participants cannot come for a study visit, they can have a blood sample collected by their local lab or doctor and sent by mail. Researchers may or may not find the cause of the participant s immune disorder. Participants will learn that information. Some participants may be asked to return to NIH to get results and have more tests. Researchers may share information with other studies. The data will be anonymous. For the survey part of the study, participants will answer questions about their or their relative s immune disorder. They will also answer about their thoughts and feelings about genomic testing. Some participants will be asked for a brief interview to ask more about the survey topics. There may be more follow-up after several months. From clinicaltrials.gov

  Study phs001561

• Pediatric Papillary Thyroid Carcinoma Whole Exome Sequencing

  BACKGROUND: Pediatric papillary thyroid carcinoma (PPTC) is distinct from adult-onset disease. Despite higher rates of regional and distal metastases and more frequent recurrence, there is, paradoxically, a highly favourable prognosis. Historically, only 40-50% of childhood PTC are driven by genomic variants common to adult PTC, while the oncogenic drivers in the remainder are unknown. METHODS: Fifty-two PPTCs were genotyped by candidate gene testing, followed, in a subset (n=32), by whole exome (WES) and transcriptome sequencing (RNASeq) to identify oncogenic variants in driver-unknown tumors and to explore gene expression patterns. FINDINGS: Thirty-one tumors (60%) carried variants identified by candidate gene testing, specifically: BRAFV600E(22%), NRASQ61R(2%), RET-CCDC6(19%), RET-NCOA4(15%) and PAX8-PPARG. Among the 21 remaining tumors with negative first-line genotyping, oncogenic variants were identified in 19 (90%). These were enriched with oncogenic fusions, with 11 non-recurrent fusion transcripts identified, including two that had not been previously described: STRN-RET and TG-PBF. Most fusions were associated with 3’ receptor tyrosine kinase (RTK) moieties: RET, MET, ALK and NTRK3. Gene expression analysis defined three distinct clusters, which demonstrated differing expression of genes involved in thyroid differentiation and MAPK signaling. INTERPRETATION: Exome and transcriptome-wide sequencing identify genomic drivers of PPTC in 98% of tumors, whereas conventional genotyping leaves many tumors genetically unexplained. PPTC is driven, in the majority of cases, by oncogenic fusion transcripts involving one of a limited number of RTKs. These observations have broad implications for diagnostic testing and for therapeutic options in children with advanced disease.

  Study EGAS00001005187

• Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile

  The Multiple Myeloma Research Foundation (MMRF) CoMMpass (Relating Clinical Outcomes in MM to Personal Assessment of Genetic Profile) trial (NCT01454297) is a longitudinal observation study of 1000 newly diagnosed myeloma patients receiving various standard approved treatments that aim at collecting tissue samples, genetic information, Quality of Life (QoL) and various disease and clinical outcomes over 10 years.

  Study phs000748

• The evolutionary steps from primary to metastatic prostate cancer are largely uncharted, and the ability to use DNA present in body fluids as correlates of aggregate metastatic status is under-examined. We reconstructed phylogenies in ten prostate cancer patients with fatal disease using deep targeted sequencing of the prostate, adjacent and distant organs, as well as plasma, serum, and cerebrospinal fluid at various time points. A total of 163 samples are studied.

  The evolutionary steps from primary tumor to metastasis in prostate cancer are largely uncharted, and the ability to use serum, plasma, and cerebrospinal fluid as a correlate of aggregate metastatic tumor genomic status has not been tested. We used deep targeted sequencing to reconstruct tumor evolution in ten prostate cancer patients with fatal disease encompassing examination of the prostate and adjacent and distant organs, as well as plasma, serum, and cerebrospinal fluid at various time points. We show that there is substantial evolution from a common ancestor within the prostate that results in branching to multiple lineages which form an intermixed multi-clonal primary tumor mass. After the occurrence of key driver aberrations, one of these lineages will metastasize to multiple sites in a sequential fashion. These metastatic sites are then susceptible to being populated by cells from other intra-prostatic lineages or from other metastases. Genomic representation of metastases in body fluids is not uniform. Cerebrospinal fluid analysis can detect lineages not detected in circulating DNA, suggesting possible clinical utility.

  Study EGAS00001003848

• Inherited Genetic Variation and Predisposition to Testicular Germ Cell Tumor: UPenn Local TGCT Study

  Testicular germ cell tumors (TGCT) are the most common cancer in men ages 20-40. The incidence of TGCT has more than doubled over the past forty years, without clear etiology. Both genetic effects and environmental exposures, specifically during the pre-natal period, are likely to play an important role in determining TGCT susceptibility. TGCT is known to develop from primordial germ cells (PGCs). We hypothesize that variation in genes that impact upon the differentiation and maturation of PGCs will be important determinants of TGCT susceptibility and based on this hypothesis have selected three important pathways for study, i) male germ cell development, ii) androgen and estrogen biosynthesis and metabolism, and iii) IGF signaling. The proteins involved in early male germ cell development, normally only expressed in PGCs, are markers of and are overexpressed in TGCT. Markers of increased exposure to estrogen (or relatively decreased exposure to androgen) in utero and exogenous estrogen exposures, such as endocrine disruptors, have been associated with TGCT case status in multiple studies. IGF signaling is necessary for testis differentiation and maturation in mice and interacts synergistically with the estrogen signaling pathway. Additionally, we are interested in examining genetic factors predisposing to TGCT in an unbiased fashion, and thus will conduct a Genome Wide Association Study. As well disease susceptiblity, genetics are likely to play a role in disease progression, disease outcomes and response to treatement. We will also assess association of inherited genetics with these outcomes. We will analyze the contribution of genetic variants in these pathways to TGCT risk using a population-based case-control study in the Philadelphia metropolitian area. Our goal is the collection of 550 TGCT cases and 1100 age, race and cell phone use matched controls without a history of TGCT, which will yield 500 and 1000 white cases and controls, respectively, available for final analyses. All cases will be enumerated through the New Jersey and Pennsylvania state cancer registries. We will use a two-tiered approach for case recruitment: hospital clinic-based followed by registry-based. Hospital based cases will be identified within the Univeristy of Pennsylvania Health System and the University of Pennsylvania Cancer Network. All cases identified through this mechanism will be recruited irregardless of diagnosis date. The remaining cases will be identified through the New Jersey and Pennsylvania cancer registries and contacted following their protocols. Controls will be identified through random digit dialing and address based sampling. Both cases and controls will complete a questionnaire addressing known, presumed, and hypothesized risk factors for TGCT and provide a biospecimen. Pathological slides will be reviewed to cases to confirm diagnostic sub-type of TGCT. Haplotypes and functional SNPs will be typed in the genes of interest, as well as throughout the genome. Analyses will be conducted for specific variants, common haplotypes, alone and in conjunction with each other and exposure data after appropriate adjustment for potential confounders. The findings from this study will greatly contribute to our understanding of determinants of TGCT susceptibility.

  Study phs001307

• Somatic mutant selection is altered by prior NOTCH1 mutation in ageing esophageal epithelium

  Authors: Charlotte King1, Emilie Abbie1, Joanna C. Fowler1, Irina Abnizova1, Roshan K. Sood1, Swee Hoe Ong1, Michael W. J. Hall1,2, Faye Lynch-Williams3, Benjamin A. Hall4, Philip H. Jones1,2,5 Abstract: In cancer evolution, genome alterations often occur in a specific order, implying selection depends on the prior clonal genotype 1-3. It is unknown if similar constraints operate in normal epithelia. Here, we mapped mutations in normal mid-esophagus of aged UK subjects. Mutant NOTCH1 clones colonized most of the epithelium by age 60 and above 70 tissue was saturated with mutants under strong competitive selection. Mutant TP53 was more strongly selected in donors over 60 years of age. Samples predominantly mutant for NOTCH1 showed increased selection of NOTCH2 mutants and weaker selection of mutant TP53 compared with samples that were mostly NOTCH1 wild type. In mouse esophagus lacking Notch1 we observed strong selection of mutant Notch2 and other genes not selected in wild type esophagus. In normal ageing esophagus, the first driver mutation may change the trajectory of subsequent somatic evolution by altering mutant selection.

  Dataset EGAD00001015256

• Somatic mutant selection is altered by prior NOTCH1 mutation in ageing esophageal epithelium

  Authors: Charlotte King1, Emilie Abbie1, Joanna C. Fowler1, Irina Abnizova1, Roshan K. Sood1, Swee Hoe Ong1, Michael W. J. Hall1,2, Faye Lynch-Williams3, Benjamin A. Hall4, Philip H. Jones1,2,5 Abstract: In cancer evolution, genome alterations often occur in a specific order, implying selection depends on the prior clonal genotype 1-3. It is unknown if similar constraints operate in normal epithelia. Here, we mapped mutations in normal mid-esophagus of aged UK subjects. Mutant NOTCH1 clones colonized most of the epithelium by age 60 and above 70 tissue was saturated with mutants under strong competitive selection. Mutant TP53 was more strongly selected in donors over 60 years of age. Samples predominantly mutant for NOTCH1 showed increased selection of NOTCH2 mutants and weaker selection of mutant TP53 compared with samples that were mostly NOTCH1 wild type. In mouse esophagus lacking Notch1 we observed strong selection of mutant Notch2 and other genes not selected in wild type esophagus. In normal ageing esophagus, the first driver mutation may change the trajectory of subsequent somatic evolution by altering mutant selection.

  Dataset EGAD00001015257

• Somatic mutant selection is altered by prior NOTCH1 mutation in ageing esophageal epithelium

  Authors: Charlotte King1, Emilie Abbie1, Joanna C. Fowler1, Irina Abnizova1, Roshan K. Sood1, Swee Hoe Ong1, Michael W. J. Hall1,2, Faye Lynch-Williams3, Benjamin A. Hall4, Philip H. Jones1,2,5 Abstract: In cancer evolution, genome alterations often occur in a specific order, implying selection depends on the prior clonal genotype 1-3. It is unknown if similar constraints operate in normal epithelia. Here, we mapped mutations in normal mid-esophagus of aged UK subjects. Mutant NOTCH1 clones colonized most of the epithelium by age 60 and above 70 tissue was saturated with mutants under strong competitive selection. Mutant TP53 was more strongly selected in donors over 60 years of age. Samples predominantly mutant for NOTCH1 showed increased selection of NOTCH2 mutants and weaker selection of mutant TP53 compared with samples that were mostly NOTCH1 wild type. In mouse esophagus lacking Notch1 we observed strong selection of mutant Notch2 and other genes not selected in wild type esophagus. In normal ageing esophagus, the first driver mutation may change the trajectory of subsequent somatic evolution by altering mutant selection.

  Dataset EGAD00001015258

• Somatic mutant selection is altered by prior NOTCH1 mutation in ageing esophageal epithelium

  Authors: Charlotte King1, Emilie Abbie1, Joanna C. Fowler1, Irina Abnizova1, Roshan K. Sood1, Swee Hoe Ong1, Michael W. J. Hall1,2, Faye Lynch-Williams3, Benjamin A. Hall4, Philip H. Jones1,2,5 Abstract: In cancer evolution, genome alterations often occur in a specific order, implying selection depends on the prior clonal genotype 1-3. It is unknown if similar constraints operate in normal epithelia. Here, we mapped mutations in normal mid-esophagus of aged UK subjects. Mutant NOTCH1 clones colonized most of the epithelium by age 60 and above 70 tissue was saturated with mutants under strong competitive selection. Mutant TP53 was more strongly selected in donors over 60 years of age. Samples predominantly mutant for NOTCH1 showed increased selection of NOTCH2 mutants and weaker selection of mutant TP53 compared with samples that were mostly NOTCH1 wild type. In mouse esophagus lacking Notch1 we observed strong selection of mutant Notch2 and other genes not selected in wild type esophagus. In normal ageing esophagus, the first driver mutation may change the trajectory of subsequent somatic evolution by altering mutant selection.

  Dataset EGAD00001015259

• Somatic mutant selection is altered by prior NOTCH1 mutation in ageing esophageal epithelium

  Authors: Charlotte King1, Emilie Abbie1, Joanna C. Fowler1, Irina Abnizova1, Roshan K. Sood1, Swee Hoe Ong1, Michael W. J. Hall1,2, Faye Lynch-Williams3, Benjamin A. Hall4, Philip H. Jones1,2,5 Abstract: In cancer evolution, genome alterations often occur in a specific order, implying selection depends on the prior clonal genotype 1-3. It is unknown if similar constraints operate in normal epithelia. Here, we mapped mutations in normal mid-esophagus of aged UK subjects. Mutant NOTCH1 clones colonized most of the epithelium by age 60 and above 70 tissue was saturated with mutants under strong competitive selection. Mutant TP53 was more strongly selected in donors over 60 years of age. Samples predominantly mutant for NOTCH1 showed increased selection of NOTCH2 mutants and weaker selection of mutant TP53 compared with samples that were mostly NOTCH1 wild type. In mouse esophagus lacking Notch1 we observed strong selection of mutant Notch2 and other genes not selected in wild type esophagus. In normal ageing esophagus, the first driver mutation may change the trajectory of subsequent somatic evolution by altering mutant selection.

  Dataset EGAD00001015260

• Somatic mutant selection is altered by prior NOTCH1 mutation in ageing esophageal epithelium

  Authors: Charlotte King1, Emilie Abbie1, Joanna C. Fowler1, Irina Abnizova1, Roshan K. Sood1, Swee Hoe Ong1, Michael W. J. Hall1,2, Faye Lynch-Williams3, Benjamin A. Hall4, Philip H. Jones1,2,5 Abstract: In cancer evolution, genome alterations often occur in a specific order, implying selection depends on the prior clonal genotype 1-3. It is unknown if similar constraints operate in normal epithelia. Here, we mapped mutations in normal mid-esophagus of aged UK subjects. Mutant NOTCH1 clones colonized most of the epithelium by age 60 and above 70 tissue was saturated with mutants under strong competitive selection. Mutant TP53 was more strongly selected in donors over 60 years of age. Samples predominantly mutant for NOTCH1 showed increased selection of NOTCH2 mutants and weaker selection of mutant TP53 compared with samples that were mostly NOTCH1 wild type. In mouse esophagus lacking Notch1 we observed strong selection of mutant Notch2 and other genes not selected in wild type esophagus. In normal ageing esophagus, the first driver mutation may change the trajectory of subsequent somatic evolution by altering mutant selection.

  Dataset EGAD00001015261

• Epiclomal: probabilistic clustering of sparse single-cell DNA methylation data

  We present Epiclomal, a probabilistic clustering method arising from a hierarchical mixture model to simultaneously cluster sparse single-cell DNA methylation data and infer their corresponding hidden methylation profiles. Using synthetic and published single-cell CpG datasets we show that Epiclomal outperforms non-probabilistic methods and is able to handle the inherent missing data feature which dominates single-cell CpG genome sequences. Using a recently published single-cell 5mCpG sequencing method (PBAL), we show that Epiclomal discovers sub-clonal patterns of methylation in aneuploid tumour genomes, thus defining epiclones. We show that epiclones may transcend copy number determined clonal lineages, thus opening this important form of clonal analysis in cancer.

  Study EGAS00001003504

• The genomic landscape of cutaneous squamous cell carcinoma from immunosuppressed and immunocompetent patients reveals common drivers and a novel mutational signature associated with chronic azathioprine exposure

  Cutaneous squamous cell carcinoma (cSCC) has a high tumour mutational burden (50 mutations per megabase DNA pair). Combining whole exome analyses from 40 primary cSCC tumours, comprising 20 well differentiated and 20 moderately/poorly differentiated tumours, with accompanying clinical data from a longitudinal study of immunosuppressed and immunocompetent patients, coupled with integration of independent gene expression studies has allowed the identification of commonly mutated genes and altered pathways and processes. Mutational signature analysis revealed the presence of a novel signature (signature 32), which was found exclusively in the tumours from immunosuppressed patients who had been exposed to azathioprine. Characterisation of a panel of 15 keratinocyte cancer cell lines derived from tumours from immunocompetent and immunosuppressed patients reveals that they accurately reflect the mutational signatures and genomic alterations of primary tumours and provide a resource for the validation of tumour drivers and therapeutic targets.

  Study EGAS00001002612

• Genome-Wide Association Study of Breast Cancer in the African Diaspora - the ROOT study

  The paucity of data on the genetic epidemiology of breast cancer for racial/ethnic groups other than those of European ancestry hinders the development of innovative interventions to reduce health disparities. Women in the African Diaspora experience a disproportionate burden of pre-menopausal breast cancer in comparison to all other races for reasons that remain unknown and understudied. This higher proportion of early-onset breast cancer might suggest a stronger genetic component in these populations. Genome-wide association studies (GWAS) have revealed several genetic loci that confer risk of breast cancer. Because all GWAS started the discovery stage in women of European ancestry and replicated mainly in women of European ancestry, we propose a novel approach for a GWAS in indigenous African women to identify alleles associated with breast cancer risk which will then be replicated in other populations. This innovative design builds on our current understanding of the etiologic heterogeneity in breast cancer and the distribution of breast cancer molecular subtypes which differ between women of African ancestry and women of European ancestry. The major objective of the proposed studies is to get to the "root" causes of breast cancer by identifying breast cancer risk alleles in a pooled sample of women of African ancestry and to replicate our findings in other populations. To achieve this objective, we conducted a case control study of breast cancer in women of African ancestry, including Africans living in Nigeria, African Americans and African Barbadians. We will genotype ~3800 individuals using the Illumina HumanOmni2.5-Quad platform. We will conduct both standard and novel genetic analyses of the data to map genes associated with breast cancer susceptibility, verify genotyping and carry out fine-mapping studies in genes or regions showing association with breast cancer risk, and replicate in other African American and non-African American populations. By pooling unique resources from studies throughout the African Diaspora, this study has the potential to identify risk alleles in several genes that contribute to increased breast cancer risk and may have implications for early detection, prognosis and treatment of breast cancer in ALL women. This should ultimately lead to improved outcomes for those who suffer a disproportionate burden of early-onset breast cancer.

  Study phs000383

• Brain Cell Type-Specific Enhancer-Promoter Connectivity Maps and Disease Risk Association

  These studies map the epigenetic landscape of microglia, neurons, astrocytes and oligodendrocytes. The initial study compared acutely isolated microglia to cultured microglia from the same donors, to identify changes that occur when microglia are removed from the brain microenvironment. In collaboration with the Rady Children's Hospital, we obtained brain tissue samples from pediatric patients representing putative normal tissue resected to gain access to brain tumors as well as tissue resected to remove epileptic foci. We assayed microglia isolated from these samples using RNA-seq, ATAC-seq and ChIP-seq for PU.1, H3K4me2, and H3K27ac. For patients from whom a sufficient cell number was obtained, we additionally cultured their microglia for up to 7 days and subjected these to the same suite of assays. In a follow-up study, we obtained brain tissue from a comparable cohort of pediatric epilepsy patients from Rady Children's Hospital. We isolated nuclei from microglia, neurons, astrocytes and oligodendrocytes, and assayed for ATAC-seq, ChIP-seq for H3K4me3, and H3K27ac, and PLAC-seq (Proximity Ligated ChIP-seq). We isolated microglia from human fetal and postnatal sample and assayed for bulk RNA-seq, bulk ATAC-seq, bulk H3K27ac ChIP-seq, single-cell RNA-seq (scRNA-seq) and single-cell ATAC-seq. For these studies, human microglia are defined by signature genes/proteins, such as P2RY12, SALL1, and CX3CR1.

  Study phs001373

• Cell-free DNA analysis reveals POLR1D-mediated resistance to bevacizumab in colorectal cancer

  Bevacizumab is an approved anti-angiogenic drug for patients with metastasized colorectal cancer (mCRC) targeting VEGF. The survival benefit of anti-VEGF therapy in mCRC patients is limited to a few months and acquired resistance mechanisms are greatly unknown. Using plasma DNA, we studied the evolution of tumor genomes in a cohort of patients with mCRC (n=150) and observed a recurrent focal amplification (8.7% of cases) on chromosome 13q12.2. Analysis of TCGA data (n=619) suggested an association with later stages, which we confirmed by longitudinal plasma analyses. We defined the minimally amplified region and studied the mechanistic consequences of copy number gain of the involved genes. The amplification of one gene, POLR1D, impacted cell proliferation, resulting in upregulation of VEGFA, an important regulator of angiogenesis which has been implicated in the resistance to bevacizumab. In several patients, we observed the emergence of this 13q12.2 amplicon under bevacizumab treatment, which was invariably associated with evolution of therapy resistance. Hence, we describe a novel resistance mechanism against a widely applied treatment in mCRC patients which will impact clinical management

  Study EGAS00001003791

• RNA-seq, WGS and WES of Hepatocellular carcinomas, enriched in fibrolamellar carcinomas

  DNAJB1-PRKACA fusion is a specific driver event in fibrolamellar carcinoma (FLC), a rare subtype of hepatocellular carcinoma (HCC) occurring in adolescents and young adults. In older patients, molecular determinants of HCC with mixed histological features of HCC and FLC (mixed-FLC/HCC) remain to be discovered.This study aims to molecularly caracterize mixed fibrolamellar hepatocellular carcinoma (mixed FLC/HCC) within the molecular liver tumors diversity, in respect of pure FLC and different HCC subtypes. This study reunites WGS data (n=3, Tumoral/Non-Tumoral pairs), WES data (n=43, Tumoral/Non-Tumoral pairs) and RNAseq data (n=66, Tumoral only). On a trascriptomic level, most of the mixed-FLC/HCC RNAseq clustered in a robust subgroup of tumors all showing mutation or translocation inactivating BAP1 that codes for the BRCA1 associated protein-1.

  Study EGAS00001003837

• E05-Bioenvironmental Psychiatry

  The Bio-Environmental Psychiatry Group is made up of a group of clinical (psychiatry, neuroradiology) and basic (biology) researchers. The objective of our activity is the identification of determinants of mental disorders with the aim of devising interventions that improve the quality of life of patients with mental disorders. Our fields are the prediction of mental disorder, the premorbid and precise diagnosis of mental disorder, the identification of bio-environmental markers and the personalization of treatments. We also work with specific disorders such as Delusional Disorder, OCD, depression and personality disorders.

  Dac EGAC50000000222

• National Eye Institute (NEI) Genetic Epidemiology of Age-Related Macular Degeneration in the Old Order Amish

  Identifying genetic risk loci for Age-Related Macular Degeneration is important. Most of the loci identified to date have been found through the interrogation of common variants. This study initiates the identification of rare variants in a founder population, the Amish, and will use genotyping of known risk loci and ultimately use the whole exome chip to assess the association of Age-related Macular Degeneration with coding variants. We will further refine the Age-Related Macular Degeneration phenotype through the use of modern imaging, the OCT, to visualize the early anatomic signs of Age-Related Macular Degeneration. We hypothesize there are endophenotypes associated with specific genotypes that can be used to determine Age-related Macular Degeneration progression. These endophenotypes are hypothesized to be influenced by a combination of common and rare variants. We will relate these endophenotypes to genotypes to define the role of genetics in the progression of Age-Related Macular Degeneration and a new risk profile incorporating genotypic information.

  Study phs001361

• RNA-seq FASTQ files from newborn screening dried blood spot samples

  Paired-end RNA-seq FASTQ files from 21 newborn screening dried blood spot (DBS) samples. These DBS samples were obtained from extremely low gestional age newborns, where 10 of them were affected by a fetal inflammatory response (FIR) before birth, and 11 were unaffected. Total RNA was sequenced using an Illumina NextSeq-500 instrument. The sample preparation protocol included the depletion of rRNA and globin mRNA using the Globin Zero Gold rRNA Removal Kit from Illumina. Libraries were prepared using the NebNext Ultra TM II Directionl RNA LIbrary Prep Kit (New England Biolabs). Each sample was sequenced in 4 lanes, leading to 8 FASTQ files per sample and a total of 21x8=168 FASTQ files. There is an additional number of 8 FASTQ files corresponding to sample BS13, which was downsampled to 1/4 of its original depth (see BS13_README file for details).

  Dataset EGAD00001004991

• The landscape of somatic mutation in normal colorectal epithelial cells

  The colorectal adenoma-carcinoma sequence has provided a paradigmatic framework for understanding the successive somatic genetic events and consequent clonal expansions leading to cancer. As for most cancer types, however, understanding of the earliest phases of colorectal neoplastic change, which may occur in morphologically normal tissue, is comparatively limited because of the difficulty of detecting somatic mutations in normal cells. Each colorectal crypt is a small clone of cells derived from a single recently-existing stem cell. Here, we sequenced hundreds of normal crypts from 42 individuals. Signatures of multiple mutational processes were revealed, some ubiquitous and continuous, others only found in some individuals, in some crypts or during some phases of the cell lineage from zygote to adult cell. Likely driver mutations were present in ~1% of normal colorectal crypts in middle-aged individuals, indicating that adenomas and carcinomas are rare outcomes of a pervasive process of neoplastic change across morphologically normal colorectal epithelium.

  Dataset EGAD00001004193

• PROGRESS/ELEMENT DNA Methylation Study

  An extension to the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) birth cohort of Mexico City, the Programming Research in Obesity, GRowth, Environment and Social Stress (PROGRESS) Cohort is an ongoing longitudinal pre-birth cohort, established in 2006 in Mexico City, partnering Icahn School of Medicine at Mount Sinai with Harvard University and the National Institute of Public Health in Mexico, which was designed to study the effects of prenatal exposure to toxic metals, air pollution, phthalates, and stress on childhood development. Pregnant women of 18 years of age and older, pregnant for less than 20 weeks of gestation, had no documentation of heart or kidney disease, no use of steroids or anti-epilepsy drugs, no daily alcohol consumption, had telephone access, and planned to live in Mexico city for the following 3 years, and receiving care through the Mexican Social Security System were initially enrolled (n=1,054). In addition to clinical, demographic and exposure data collected, cord blood was collected to interrogate DNA methylation across the genome for over 300 mother-child dyads. Clinical assessments and exposures were captured during several life stages, including prenatal, infant (0-1 year), youth (1-18 years), and adulthood (mother). The PROGRESS cohort added well-documented phenotyping of children for obesity, metabolic dysfunction, respiratory outcomes, and cardiovascular outcomes, as well as measures of air pollutant, personal care/consumer product, non-chemical stress, and metal mixture exposures. No clinical trials were conducted in this cohort. The data collected in this study should provide a unique resource to investigate DNA methylation as it relates to several environmental exposures and adverse cardiometabolic and neurocognitive health in mothers and children from a prospective birthing cohort. For access to demographic, clinical, and exposure data please directly contact study principal investigators.

  Study phs002754

• RNA-sequencing of mechanical stress induced osteoarthritis-like damage in aged human cartilage explants treated with the anti-deiodinase iopanoic acid

  The current study aimed to confirm chondroprotective effects of the D2 inhibitor iopanoic acid (IOP) in an ex vivo aged human osteochondral explant model in which injurious mechanical stress is applied to inflict OA-like damage. This dataset contains RNA-seq (Illumina HiSeq X ten) of osteochondral explant cartilage from aged human patients that underwent a joint replacement surgery due to OA (N=10 donors; n=21 explants).

  Study EGAS00001006242

• GWAS on covid-19 severity and susceptibility in the province of Bergamo, Italy

  This is a case-control GWAS that involved the voluntary recruitment of inhabitants of the Bergamo province via an online questionnaire. We collected detailed clinical data and verified all information through personal interviews. Cases (severe COVID-19; G1) and controls (mild or asymptomatic COVID-19, G2; non-infected, G3) were matched by age, sex and risk factors

  Study EGAS00001007310

• GEX CITE-Seq performance dataset

  To understand the impact of enzymatic treatments on gene expression and epitope preservation on major immune cell populations, skin dissociation (SkinD) and solid soft tumor dissociation (TumorD) were tested on three healthy PBMC samples in triplicate (D1, D2, D3), against an untreated control. CITE-seq performance was assessed on a solid biopsy cohort of 11 samples (5 healthy skin samples, 3 primary melanoma samples, 3 melanoma metastasis samples) as well as on a liquid biopsy PBMC cohort consisting of three healthy donors and three immunotherapy-treated melanoma patients. This dataset contains the GEX data for each sample. Data is provided in the form of pooled BAM files. Linkage between samples, BAM files and hashtags is provided in a separate linkage file.

  Dataset EGAD00001008418

• ADT/SPEX CITE-Seq performance dataset

  To understand the impact of enzymatic treatments on gene expression and epitope preservation on major immune cell populations, skin dissociation (SkinD) and solid soft tumor dissociation (TumorD) were tested on three healthy PBMC samples in triplicate (D1, D2, D3), against an untreated control. CITE-seq performance was assessed on a solid biopsy cohort of 11 samples (5 healthy skin samples, 3 primary melanoma samples, 3 melanoma metastasis samples) as well as on a liquid biopsy PBMC cohort consisting of three healthy donors and three immunotherapy-treated melanoma patients. This dataset contains the ADT/SPEX data for each sample. Data is provided in the form of pooled BAM files. Linkage between samples, BAM files and hashtags is provided in a separate linkage file.

  Dataset EGAD00001008419

• Toxigenic Clostridium perfringens isolated from at-risk pediatric inflammatory bowel disease patients

  With the goal of studying mucosal-associated bacteria and products detrimental to inflammatory bowel disease (IBD) patients, we directly cultured bacterial communities from mucosal biopsies and examined for detrimental traits. Focusing on red blood cell lysis, a virulence trait, communities from 5 of 9 patients exhibited hemolytic activity. Clostridium perfringens was isolated from each hemolytic community, and whole-genome sequencing confirmed presence of hemolytic toxins – alpha toxin in all 5 strains, perfringolysin O (PFO) in 4 strains, alveolysin in 2 strains – and absence of enterotoxins. In vitro cytotoxicity experiments demonstrated strain supernatants were toxic to various cell types located beneath the intestinal epithelial barrier, including endothelial, neuroblasts, and neutrophils, while impact on epithelial cells was less pronounced. These findings suggest C. perfringens may be damaging particularly when intestinal barrier integrity is compromised, such as in IBD patients. Further characterization using purified toxins and genetic insertion mutants confirmed PFO toxin was sufficient for cell toxicity. C. perfringens supernatants also induced activation of neuroblast and dorsal root ganglion (DRG) neuron cells in vitro, suggesting C. perfringens in inflamed mucosal tissue may directly contribute to abdominal pain, a frequent IBD symptom. Strikingly, C. perfringens was detected in biopsies of 8 of 9 pediatric patients while not in all corresponding stool samples, and in other datasets, C. perfringens was in stool samples of IBD adults (18.7-27.1%) much more frequently versus healthy (5.1%). Our findings showcase C. perfringens may have an important pathogenic impact on IBD patients. Similar to Clostridioides difficile, routine monitoring of C. perfringens and PFO toxins in patients may be beneficial.

  Study EGAS50000000334

• Multi-omics analysis of cocaine use disorder in postmortem brain tissue of the ventral striatum [Proteomics data to study EGAS50000000623]

  We performed a multi-omics analysis of cocaine use disorder in postmortem human brain tissue of the ventral striatum in N=41 individuals (N=20 CUD cases, N=21 non-affected individuals). From the postmortem brain tissue samples, we generated miRNA-seq, RNA-seq, proteomics, and snRNA-seq data. The miRNA-seq, RNA-seq and snRNA-seq datasets can be found in the EGA under study ID EGAS50000000623. Proteomics data is deposited under study ID EGAS00001007945 (this study). The proteomic dataset was obtained using TMT-labeling. Measurement was performed on an Orbitrap Fusion Lumos device.

  Study EGAS00001007945

• Analysis of IDHwt-glioblastoma samples from paired primary and recurrent tumor samples

  IDHwt-glioblastomas rapidly recur after initial treatment. To study genetic evolution in glioblastoma, we analyzed whole genomes of 21 pairs of primary and recurrent tumor samples using next generation sequencing. In addition we sequenced RNA from 16 tumor pairs and a panel of 50 glioma-associated genes in tumor pairs from 43 patients (including 14 of the 21 patients included in the WGS discovery set). Glioblastoma subtypes were determined using 450k/EPIC methylation arrays. This study was supported within the e:med program of the German Ministry of Education and Research (BMBF) by the collaborative research project ‘SYS-GLIO - Systems-based prediction of the biological and clinical behavior of gliomas’ (https://www.sys-med.de/de/demonstratoren/sys-glio/) This study is part of the Heidelberg Center for Personalized Oncology - HIPO-043

  Study EGAS00001003184

• Platelets contain a repertoire of DNA fragments that map over the human nuclear genome, including tumour-derived DNA in patients with active malignancy.

  This dataset consists of WGS from six patients with a recent diagnosis of gastrointestinal adenocarcinoma. DNA-Seq libraries were prepared from platelet DNA (pDNA) and plasma cfDNA obtained from the same peripheral blood sample. pDNA was size selected into 2 groups (small, s-pDNA: less than 600 bp and long, b-pDNA: greater than 600 bp). The short fragments were further cleaned to remove <100 bp fragments and large platelet fragments were fragmented via sonication. Libraries were then prepared using the NEBNext Ultra II DNA Sample Preparation Kit for Illumina according to the manufacturer’s protocol and sequenced on an Illumina NextSeq 500 (300 cycle PE) at low-pass (0.1X) for all samples, and 10X for the cfDNA and s-pDNA, using four lanes in each sample.

  Dataset EGAD00001009856

• Genome-Wide Association Study of Endometrial Cancer in the Epidemiology of Endometrial Cancer Consortium (E2C2)

  Endometrial cancer, the most common gynecological malignancy in the United States, has both an environmental and genetic component. To this end, we conducted a genome-wide association study to identify genes involved in endometrial cancer using studies from the NCI-supported Epidemiology of Endometrial Cancer Consortium (E2C2). For the discovery stage we included samples from 6 cohort and 7 case control studies through 2007. The total number of cases genotyped were 2,307, white women of European descent, and 2,307 matched controls using the Illumina HumanOmniExpress platform. We conducted the replication using the Infinium HumanExome BeadChip, which successfully genotyped 177,139 variants in 1055 cases and 1778 controls from four ethnically diverse studies that are part of the Epidemiology of Endometrial Cancer Consortium (E2C2). The overall goal is to determine whether certain genotypes are predictive of future endometrial cancer risk, and whether the genotypes interact with established endometrial risk factors.

  Study phs000893

• Expression array

  The whole study comprises of two patient cohorts. Screening cohort: 40 patients of Germany; validation cohort: 40 patients from Asia. Further, bile duct and CCA cell lines have been analyzed.
This dataset contains expression array data for 32 patients of the screening cohort with 8 of them having paired normal tissue plus an additional relapse tumor/normal pair of one of those 8 patients and a patient only with normal tissue. Data was generated on a HumanHT-12 v4 Bead Array (Illumina) and is stored in IDAT file format.

  Dataset EGAD00010002596

• Fusion gene analysis using multiplex single primer extension-based RNA-sequencing

  The whole study comprises of two patient cohorts. Screening cohort: 40 patients of Germany; validation cohort: 40 patients from Asia. Further, bile duct and CCA cell lines have been analyzed. This dataset contains fusion gene analysis using multiplex single primer extension-based RNA-sequencing for a subset of 25 patients of the screening cohort. Data was generated on Illumina NexSeq 550 device in paired-end mode and is stored in compressed FASTQ file format.

  Dataset EGAD00001011326

• Single-Cell Multi-Omic Analysis of the Vestibular Schwannoma Ecosystem Uncovers a Nerve Injury-Like State

  Vestibular schwannomas are benign tumors that can lead to significant morbidity, including hearing loss, facial nerve paralysis and obstructive hydrocephalus. The genomic landscape of vestibular schwannomas is relatively bland and the molecular pathophysiology of vestibular schwannomas is poorly understood. Therefore, we performed single cell RNA sequencing on 15 sporadic vestibular schwannomas, with paired single cell ATAC sequencing (n = 6) and whole exome sequencing (n = 12) to perform a detailed characterization of the vestibular schwannoma tumor microenvironment at the transcriptional and epigenetic level. We validated our results by analyzing bulk RNA sequencing data from 22 newly sequenced vestibular schwannomas and 173 previously sequenced bulk RNA sequencing data from 195 vestibular schwannomas. Data available in dbGaP include whole exome sequencing of 12 tumors and matched blood samples. Matching single cell RNA sequencing and single cell ATAC sequencing data is available via NCBI GEO.

  Study phs003318

• Characterization of the cellular microenvironment in fibrostenotic Crohn’s disease

  Crohn's disease (CD) is marked by recurring intestinal inflammation and tissue injury, often resulting in fibro-stenosis and bowel obstruction, necessitating surgical intervention with high recurrence rates. To elucidate to the mechanisms underlying fibro-stenosis in CD, we analysed the transcriptome of cells isolated from the transmural ileum of CD patients, including a trio of lesions from each patient: non-affected, inflamed, and stenotic ileum samples, and compared them with samples from non-CD patients. Our computational analysis revealed that pro-fibrotic signals from a subset of monocyte-derived cells induced a disease-specific fibroblast population, resulting in chronic inflammation and tissue fibrosis. Our findings suggest that the myeloid-stromal axis may offer a promising therapeutic target to prevent fibro-stenosis in CD.

  Study EGAS50000000382

• NHLBI TOPMed: Children's Health Study (CHS) Integrative Genetic Approaches to Gene-Air Pollution Interactions in Asthma (GAP)

  The Integrative Genetic Approaches to Gene-Air Pollution Interactions in Asthma (GAP) study was proposed to use an innovative genetics approach in mice and humans to identify novel variants that interact with traffic-related pollutant exposures to affect lung function phenotypes and the risk of childhood asthma. The study participants were enrolled from the original southern California Children's Health Study (CHS). In the TOPMed project, seven Hispanic White participants who did not have asthma history were included in the WGS analysis.

  Study phs001602

• A biobank of patient-derived pediatric brain tumor models

  Brain tumors are the leading cause of cancer-related death in children. Genomic studies have provided insights into molecular subgroups and oncogenic drivers of pediatric brain tumors that may lead to novel therapeutic strategies. To evaluate new treatments, better preclinical models adequately reflecting the biological heterogeneity are needed. Through the Children’s Oncology Group ACNS02B3 study, we have generated and comprehensively characterized 30 patient-derived orthotopic xenograft models and 7 cell lines representing 14 molecular subgroups of pediatric brain tumors. Patient-derived orthotopic xenograft models were found to be representative of the human tumors they were derived from in terms of histology, immunohistochemistry, gene expression, DNA methylation, copy number, and mutational profiles. In vivo drug sensitivity of targeted therapeutics was associated with distinct molecular tumor subgroups and specific genetic alterations. These models and their molecular characterization provide an unprecedented resource for the cancer community to study key oncogenic drivers and to evaluate novel treatment strategies.

  Study EGAS00001002536

• Activation of Wnt/β-catenin signalling by mutually exclusive FBXW11 and CTNNB1 hotspot mutations drives salivary gland basal cell adenoma - WES

  Wnt signalling must be 'just right' to promote tumour growth. Basal cell adenoma (BCA) and basal cell adenocarcinoma (BCAC) of the salivary gland are rare tumours that can be difficult to distinguish from each other and other salivary gland tumour subtypes. Due to their rarity, the genomic profiles of BCA and BCAC have not been explored. Using whole-exome and transcriptome sequencing of BCA and BCAC cohorts, we identify a novel recurrent FBXW11 missense mutation (p.F517S) in BCA, that was mutually exclusive with the previously reported CTNNB1 p.I35T gain-of-functon (GoF) mutation. These driver events collectively accounted for 94% of BCAs. In vitro, mutant FBXW11 had a dominant negative affect, characterised by defective binding to β-catenin and the accumulation of β-catenin in cells. This was consistent with the nuclear expression of β-catenin observed in BCA cases harbouring the FBXW11 p.F517S mutation and activation of the Wnt/β-catenin pathway and defines a novel mechanism of Wnt pathway control. The genomic profiles of BCAC were distinct from BCA, with hotspot DICER1 and HRAS mutations and putative driver mutations affecting PI3K/AKT and NF-κB signalling pathway genes. A single BCAC, which may represent a malignant transformation of BCA, harboured the recurrent FBXW11 mutation. These findings have important implications for the diagnosis and treatment of BCA and BCAC, which, despite histopathologic overlap, may be unrelated entities.

  Dataset EGAD00001015365

• Activation of Wnt/β-catenin signalling by mutually exclusive FBXW11 and CTNNB1 hotspot mutations drives salivary gland basal cell adenoma - RNA

  Wnt signalling must be 'just right' to promote tumour growth. Basal cell adenoma (BCA) and basal cell adenocarcinoma (BCAC) of the salivary gland are rare tumours that can be difficult to distinguish from each other and other salivary gland tumour subtypes. Due to their rarity, the genomic profiles of BCA and BCAC have not been explored. Using whole-exome and transcriptome sequencing of BCA and BCAC cohorts, we identify a novel recurrent FBXW11 missense mutation (p.F517S) in BCA, that was mutually exclusive with the previously reported CTNNB1 p.I35T gain-of-functon (GoF) mutation. These driver events collectively accounted for 94% of BCAs. In vitro, mutant FBXW11 had a dominant negative affect, characterised by defective binding to β-catenin and the accumulation of β-catenin in cells. This was consistent with the nuclear expression of β-catenin observed in BCA cases harbouring the FBXW11 p.F517S mutation and activation of the Wnt/β-catenin pathway and defines a novel mechanism of Wnt pathway control. The genomic profiles of BCAC were distinct from BCA, with hotspot DICER1 and HRAS mutations and putative driver mutations affecting PI3K/AKT and NF-κB signalling pathway genes. A single BCAC, which may represent a malignant transformation of BCA, harboured the recurrent FBXW11 mutation. These findings have important implications for the diagnosis and treatment of BCA and BCAC, which, despite histopathologic overlap, may be unrelated entities.

  Dataset EGAD00001015366

• Somatic Copy Number Analysis of Endometrial Carcinomas

  Endometrial cancer (EC) is the most commonly diagnosed gynecologic malignancy in the United States and is the sixth leading cause of cancer death amongst American women. The purpose of this study was to identify somatic (tumor-specific) copy number alterations in 7 clear cell ECs, 31 serous ECs, 17 endometrioid ECs, and the clear cell components of 2 endometrioid/clear cell ECs. To this end, DNAs from de-identified primary endometrial tumors and matched non-tumor tissues or blood were hybridized to high-density Illumina Infinium HumanHap650Y Beadchips or to high-density Human660W-Quad Beadchips and the data analyzed to annotate somatic copy number alterations throughout the genome.

  Study phs001690

• High-resolution testing of ctDNA dynamics predicts survival in metastatic NSCLC

  One of the great challenges of therapeutic oncology is determining who might achieve survival benefit from a particular therapy. Circulating tumor DNA (ctDNA) provides real-time assessments of patient prognosis and response to treatment using a simple blood draw. While ctDNA positivity is established as a poor prognostic factor, studies on longitudinal ctDNA dynamics have been small and non-randomized, with ctDNA assessments done at disparate time points. To address this, we performed high-sensitivity longitudinal ctDNA testing in 466 patients across 5 time points (1,954 samples total) in a randomized phase III study comparing different chemotherapy-immunotherapy combinations. We leverage machine learning to jointly model multiple ctDNA metrics to predict overall survival in a training/testing framework. _ . Treatment initiation correlated with reductions in ctDNA levels, and training of our machine learning model suggests that assessment of ctDNA dynamics at C3D1 (cycle 3 day 1) of chemo-IO treatment may be optimal to predict OS. The model performs well in the hold-back test data, enabling stratification of patients with Stable Disease (SD) into high-risk vs low-intermediate-risk (HR = 3.2 [2.0-5.3], p <0.001; median 7.1 versus 22.3 months respectively); similarly, the model stratifies patients with a Partial Response (PR) (HR =3.3 [1.7-6.4], p <0.001; median 8.8 versus 28.6 months). Importantly, the model validates well in an external cohort of patients in a different treatment setting and assayed with a different ctDNA technology, in which model predictions similarly identified high-risk patients (OS HR=3.73 [1.83-7.60], logrank p=0.00012). Simulations of clinical trial scenarios employing our ctDNA model further suggest that early ctDNA testing outperforms early radiographic imaging for predicting trial outcomes (increasing the rate of ‘True Go’ decisions by 5.2 - 22.8% depending on the drug combination). Overall, we show that measuring ctDNA dynamics during the course of therapy dramatically improves patient risk stratification, and may provide a means to differentiate between competing therapies at an early time point during clinical trials.

  Study EGAS00001006703

• Single-Cell Genomic and Transcriptomic Analysis of the Aging Human Brain

  We studied human brain aging using single-cell whole genome sequencing and single-nucleus RNA sequencing of the pre-frontal cortex from 19 donors ranging in age from 0.4 years to 104 years. All donors were free of neuropathology and none received a clinical neurological diagnosis prior to death. snRNA-seq libraries were prepared in batches that always included old and young donors to mitigate batch effects in the preparations. Neurons for single-cell WGS were collected from the same tissue region as the snRNA-seq for each donor but represent independent cells. Multiplexed error-robust fluorescent in-situ hybridization (MERFISH) data was also collected from pre-frontal cortex samples of a subset of the 19 donors. Transcriptomic results identified infant-specific cell clusters, and common-down regulation of cell-essential genes involved in ribosomes, transport, homeostasis and metabolism during aging, across all cell types. scWGS identified two-age associated mutational signatures, as well as gene-length and expression-level dependent somatic mutation rates in neurons. Raw sequencing data in fastq format for single-nucleus RNA-seq and single-cell DNA-seq, as well as cell and gene count matrix, transcript metadata, and cell metadata for MERFISH will be available in dbGaP.

  Study phs003445

• Transcriptome analysis of human longitudinal whole blood samples from PCR-positive and PCR-negative adults following controlled inoculation with Influenza A (H3N2) virus.

  Transcriptome analysis of influenza A (H3N2) human challenge samples. Understanding of the transcriptomic profile of individuals in early influenza infection is limited. To investigate this, longitudinal whole-blood samples (n=178) were taken from adult participants following controlled inoculation with Influenza A H3N2 virus (sampling at baseline (0) and days 1, 2, 3, 7, 10 and 14 post-challenge). Most participants became influenza PCR-positive; a minority remained PCR-negative. Total RNA was extracted from PAXgene tubes before undergoing globin and rRNA depletion. DNA libraries were constructed using the NEBNext® Ultra™ II Directional RNA Library Prep Kit for Illumina. All samples were then sequenced using Illumina NovaSeq 6000.

  Study EGAS50000000679

• Detection of ctDNA in Plasma of Patients with Clinically Localised Prostate Cancer is Associated with Rapid Disease Progression

  Purpose: DNA originating from degenerate tumour cells can be detected in the circulation in many tumour types, where it can be used as a marker of disease burden as well as to monitor treatment response. Although circulating tumour DNA (ctDNA) measurement has prognostic/predictive value in metastatic prostate cancer, its utility in localised disease is unknown. Patients and Methods: We performed whole genome sequencing of tumour-normal pairs in eight patients with clinically localised disease undergoing prostatectomy, identifying high confidence genomic aberrations. A bespoke DNA capture and amplification panel against the highest prevalence, highest confidence aberrations for each individual was designed and used to interrogate ctDNA isolated from plasma prospectively obtained pre- and post- (24 hours and 6 weeks) surgery. In a separate cohort (n=189) we identified the presence of ctDNA TP53 mutations in pre-operative plasma in a retrospective cohort, and determined its association with biochemical- and metastasis-free survival. Results: Tumour variants in ctDNA were positively identified pre-treatment in two of eight patients, which in both cases remained detectable postoperatively. Patients with tumour variants in ctDNA had extremely rapid disease recurrence and progression compared to those where variants could not be detected. In terms of aberrations targeted, single nucleotide and structural variants outperformed indels and copy number aberrations. Detection of ctDNA TP53 mutations was associated with a significantly shorter metastasis-free survival (6.2 vs. 9.5 years (HR 2.4; 95% CIs 1.2-4.8, p = 0.014)). Conclusions: CtDNA is uncommonly detected in localised prostate cancer but its presence portends more rapidly progressive disease.

  Study EGAS00001004636

• NHLBI TOPMed: Genetic Epidemiology Network of Arteriopathy (GENOA)

  The Genetic Epidemiology Network of Arteriopathy (GENOA) is one of four networks in the NHLBI Family-Blood Pressure Program (FBPP). GENOA's long-term objective is to elucidate the genetics of target organ complications of hypertension, including both atherosclerotic and arteriolosclerotic complications involving the heart, brain, kidneys, and peripheral arteries. The longitudinal GENOA Study recruited European-American and African-American sibships with at least 2 individuals with clinically diagnosed essential hypertension before age 60 years. All other members of the sibship were invited to participate regardless of their hypertension status. Participants were diagnosed with hypertension if they had either 1) a previous clinical diagnosis of hypertension by a physician with current anti-hypertensive treatment, or 2) an average systolic blood pressure = 140 mm Hg or diastolic blood pressure = 90 mm Hg based on the second and third readings at the time of their clinic visit. Only participants of the African-American Cohort were sequenced through TOPMed. The Family Blood Pressure Program (FBPP), GENOA's parent program, is an unprecedented collaboration to identify genes influencing blood pressure (BP) levels, hypertension, and its target-organ damage. This program has conducted over 21,000 physical examinations, assembled a shared database of several hundred BP and hypertension-related phenotypic measurements, completed genome-wide linkage analyses for BP, hypertension, and hypertension associated risk factors and complications, and published over 130 manuscripts on program findings. The FBPP emerged from what was initially funded as four independent networks of investigators (HyperGEN, GenNet, SAPPHIRe and GENOA) competing to identify genetic determinants of hypertension in multiple ethnic groups. Realizing the greater likelihood of success through collaboration, the investigators created a single confederation with program-wide and network-specific goals. Comprehensive phenotypic data for GENOA study participants are available through dbGaP phs001238.

  Study phs001345

• Targeted Validation Samples

  The dataset consists of targeted sequencing data obtained from an independent cohort of 11 patients to validate discriminative DMRs (differentially methylated regions) for Acute coronary syndrome (ACS) subtypes. The cohort includes 2 healthy subjects, 4 STEMI (ST-segment elevation myocardial infarction), 3 NSTEMI (non-ST-segment elevation myocardial infarction), and 2 UA (unstable angina) patients. The sequencing panel targeted 18,831 CpGs for analysis, reaching at least 5 reads coverage for 75% of the targeted CpGs in each sample. The sequencing was performed using the NEBNext Enzymatic Methyl-seq Module and the Nonacus Cell3TMTarget: Library Preparation kit, followed by probe hybridization, capture enrichment, and sequencing on the Novaseq 6000 platform, generating 400 million reads. The dataset is in raw fastq format.

  Dataset EGAD00001010934