1756 results for "prix credit fc 26 Visitez le site Buyfc26coins.com Achat de FC 26 coins sans stress et livraison express.6lio"

in 31.86 milliseconds.

• CRLF2 sequencing project Exomes

  CRLF2 sequencing project Exomes

  Dataset EGAD00001000077

• Whole Exome and Target Sequencing Data in 75 Samples from 5 Hepatocellular Carcinoma Patients.

  Whole Exome and Target Sequencing Data in 75 Samples from 5 Hepatocellular Carcinoma Patients. The sequencing was performed by Illumina HiSeq 4000. Background and aims: Intratumoral heterogeneity (ITH) challenges identifying mutations with target therapy potential whereas circulating cell-free DNAs (cfDNAs) could reflect nearly the entire mutation spectrum in given tumors. We investigated how to minimize the limit of ITH for profiling hepatocellular carcinoma (HCC).Methods: Thirty-two multi-regional HCC samples from five patients were subjected to whole exome sequencing (WES) and targeted deep sequencing (TDS). ITH extent was measured by the average percentage of non-ubiquitous mutations (present in parts of tumor regions). Matched cfDNAs were also analyzed by WES and TDS. Profiling efficiencies of single tumor specimen and cfDNA were compared and the one better depicted mutational landscape was selected to screen therapeutic targets.Results: We found variable extents of ITH in HCCs and observed branched and parallel evolution patterns. ITH level decreased at higher sequencing depth of TDS than that measured by WES (28.1% vs 34.9%, P < 0.01) but it remained unchanged upon additional samples analyzed. TDS of single tumor specimen detected an average of 70% the total mutations in HCC. Although more mutations were detected in cfDNA under TDS than WES, an average of 47.2% total HCC mutations uncovered by cfDNA suggested tissue outperform cfDNA and the latter may serve as alternative in profiling HCC genome. Consequently, TDS of single tumor tissue in 66 patients and cfDNAs in four unresectable HCCs identified 38.6% (26/66 and 1/4) patients bearing therapeutic targets.Conclusions: TDS of single tumor specimen could largely circumvent ITH to uncover mutations indicative of target therapy in HCC.

  Dataset EGAD00001003278

• Clonal selection after gene therapy in sickle cell disease

  While gene therapy (GT) provides a potentially curative treatment option for patients with sickle cell disease (SCD), the occurrence of myeloid malignancies in clinical trials has prompted concern. To interrogate potential mechanisms underlying increased cancer risk, we used hematopoietic stem cell (HSC) clonal tracking by whole genome sequencing (WGS) to map the somatic mutation and clonal landscape of 2,592 gene modified as well as unmodified single stem and progenitor cells from six SCD patients undergoing gene therapy (7-26 years old, average 12.7× depth). Pre-GT phylogenetic trees in SCD were highly polyclonal and mutation burdens per cell were elevated in some, but not all, patients. Post-GT, no clonal expansions were identified. However, an increased frequency of driver mutations associated with myeloid neoplasms or clonal hematopoiesis (DNMT3A- and EZH2-mutated clones in particular) were seen in both genetically modified and unmodified cells suggested positive selection of mutant clones during gene therapy. This work sheds light on the mutation landscape and HSC clonal dynamics in gene therapy for SCD and highlights enhanced fitness of some HSCs harboring pre-existing driver mutations following gene therapy. Future studies should define the long-term fate of mutant clones including any contribution to expansions associated with myeloid neoplasms.

  Dataset EGAD00001010914

• Stress and Treatment Response in Puerto Rican and African American Children with Asthma (STAR)

  The Stress and Treatment Response in Puerto Rican and African American Children with Asthma Study (STAR) was a 6-week study of response to inhaled corticosteroids (ICS) in youth aged 8-20 years recruited at the University of Puerto Rico Medical Center and UPMC Children's Hospital of Pittsburgh from June 5, 2018 to May 16, 2022. At a baseline visit, participants completed questionnaires and underwent collection of nasal specimens. After nasal sampling, participants were treated with daily medium-dose inhaled Mometasone for 6 weeks, with adherence measured using a dose-counter. Spirometry and fractional exhaled nitric oxide (FeNO) measurements were conducted at baseline and after 6 weeks of ICS. STAR was approved by the institutional review boards (IRBs) of the University of Puerto Rico and the University of Pittsburgh. Written parental consent and assent were obtained from participants

  Study phs004052

• Dissociation of solid tumour tissues with cold active protease for single-cell RNA-seq minimizes conserved collagenase-associated stress responses

  Background Single-cell RNA sequencing (scRNAseq) is a powerful tool for studying complex biological systems, such as tumour heterogeneity and tissue microenvironments. However, the sources of technical and biological variation in primary solid tumour tissues and patient-derived mouse xenografts for scRNAseq, are not well understood. Here, we used low temperature (6°C) protease and collagenase (37°C) to identify the transcriptional signatures associated with tissue dissociation across a diverse scRNAseq dataset comprising 128,481 cells from patient cancer tissues, patient-derived breast cancer xenografts and cancer cell lines.Results We observe substantial variation in standard quality control (QC) metrics of cell viability across conditions and tissues. From FACS sorted populations gated for cell viability, we identify a sub-population of dead cells that would pass standard data filtering practices, and quantify the extent to which their transcriptomes differ from live cells. We identify a further subpopulation of transcriptomically “dying” cells that exhibit up-regulation of MHC class I transcripts, in contrast with live and fully dead cells. From the contrast between tissue protease dissociation at 37°C or 6°C, we observe that collagenase digestion results in a stress response. We derive a core gene set of 512 heat shock and stress response genes, including FOS and JUN, induced by collagenase (37°C), which are minimized by dissociation with a cold active protease (6°C). While induction of these genes was highly conserved across all cell types, cell type-specific responses to collagenase digestion were observed in patient tissues. We observe that the yield of cancer and non-cancer cell types varies between tissues and dissociation methods.Conclusions The method and conditions of tumour dissociation influence cell yield and transcriptome state and are both tissue and cell type dependent. Interpretation of stress pathway expression differences in cancer single cell studies, including components of surface immune recognition such as MHC class I, may be especially confounded. We define a core set of 512 genes that can assist with identification of such effects in dissociated scRNA-seq experiments.

  Study EGAS00001003753

• Jackson Heart Study (JHS) Cohort

  The Jackson Heart Study (JHS) is a large, community-based, observational study whose participants were recruited from urban and rural areas of the three counties (Hinds, Madison and Rankin) that make up the Jackson, MS metropolitan statistical area (MSA). Participants were enrolled from each of 4 recruitment pools: (1) random, 17%, (2) volunteer, 30%, (3) currently enrolled in the Atherosclerosis Risk in Communities (ARIC) Study, 31%, and (4) secondary family members, 22%. The final cohort of 5,306 participants included 6.59% of all African American Jackson MSA residents, aged 35-84, during the baseline exam (N-76,426, US Census 2000). Among these, approximately 3,600 gave consent that allows genetic research and deposition of data into dbGaP. Major components of three clinic examinations (see study history) include medical history, physical examination, blood/urine analytes, and interview questions on areas such as physical activity, stress, coping and spirituality, racism and discrimination, socioeconomic position, and access to health care. Extensive clinical phenotyping includes anthropometrics, electrocardiography, carotid ultrasound, ankle-brachial blood pressure index, echocardiography, CT chest and abdomen for coronary and aortic calcification, liver fat, and subcutaneous and visceral fat measurements, and cardiac MRI. At 12-month intervals after the baseline clinic visit (Exam 1), participants have been contacted by telephone to update information, confirm vital statistics, document interim medical events, hospitalizations and functional status, and obtain additional sociocultural information. Questions about medical events, symptoms of cardiovascular disease and functional status are repeated annually. Ongoing cohort surveillance includes abstraction of medical records and death certificates for relevant International Classification of Diseases (ICD) codes and adjudication of nonfatal events and deaths. CMS data are currently being incorporated into the dataset. Note: Regarding date variables warehoused in the Jackson Heart Study (JHS) Cohort on dbGaP, the coordinating center has developed an algorithm that will systematically review and de-identify any of the (nearly 100) date-related variable types stored in the data package. To simultaneously minimize (i) de-identifiability of the data and (ii) impact on analyses utilizing sensitive data elements, a participant-level random number was generated to avoid the necessity of sharing any potentially sensitive data. The coordinating center maintains an archived linkage of these data in their raw form and regularly reviews ad hoc requests to utilize the raw data on a project-by-project basis. The JHS Cohort is utilized in the following dbGaP substudies. To view genotypes, other molecular data, and derived variables collected in these substudies, please click on the following substudies below or in the "Substudies" section of this top-level study page phs000286 JHS Cohort. phs000402 ESP Heart GO JHS phs000498 JHS Allelic Spectrum Seq phs000499 JHS CARephs001069 MI Gen JHS phs001098 T2D GENES Exome Seq phs001356 Exome Chip phs002256 Cardiometabolic Renal Proteomics phs002369 Metabolomics Insulin Resistance

  Study phs000286

• Childhood Cancer Model Atlas

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

  Study EGAS00001006320

• Whole_genome_sequence_of__third_generation_family_member__SFHS_

  Previously we performed deep WGS on 6 parents and 13 children from 3 large families from the Scottish Family Health Study to identify de novo mutations. This prelim is cover the additional sequencing of one grandchild from one of these three families. The inclusion of a third generation individual will provide additional experimental validation for the de novo mutations found in the initial trio. As in the previous study, the DNA will be WGS to a depth of approximately 25X to achieve this purpose.

  Study EGAS00001000429

• Genetic landscape of relapsed DLBCL

  Diffuse large B-cell lymphoma is a heterogenous malignancy that can arise de novo or can result from histologic transformation from indolent lymphomas. Considerable sequencing effort has been placed on determining the mutations that are common at the time of diagnosis in DLBCL but little is known about the nature of relapsed disease. We have sequenced tumour and matched normal exomes of 38 rrDLBCL patients including 25 de novo DLBCLs and 13 transformed lymphomas to identify somatic mutations and copy number alterations associated with relapse.

  Study EGAS00001001553

• Cell type mapping of inflammatory muscle diseases highlights selective myofiber vulnerability in inclusion body myositis

  Inclusion body myositis (IBM) is the most prevalent inflammatory muscle disease in older adults with no effective therapy available. In contrast to other inflammatory myopathies like subacute immune-mediated necrotizing myopathy (IMNM), IBM follows a chronic disease course with both inflammatory and degenerative features of pathology. Moreover, causal factors and molecular drivers of IBM progression are largely unknown. Therefore, we paired single-nucleus RNA sequencing with spatial transcriptomics from patient muscle biopsies to map cell type-specific drivers underlying IBM pathogenesis compared to IMNM muscles and non-inflammatory skeletal muscle samples. In IBM muscles, we observed a selective loss of type 2 myonuclei paralleled by increased levels of cytotoxic T and cDC1 cells. IBM myofibers were either characterized by upregulation of cell stress markers featuring GADD45A and NORAD, or protein degradation markers including RNF7 associated with p62 aggregates. GADD45A upregulation was preferentially seen in type 2A myofibers associated with severe tissue inflammation. We also noted IBM-specific upregulation of ACHE encoding acetylcholinesterase, which can be regulated by NORAD activity and result in functional denervation of myofibers. Our results provide promising insights into possible mechanisms of myofiber degeneration in IBM and suggest a selective type 2 fiber vulnerability linked to genomic stress and denervation pathways.

  Study EGAS50000000310

• Human liver NPCs single cell project

  Independent of their inflammatory phenotype, macrophages are key orchestrators of hepatic metabolism. Non-alcoholic fatty liver disease (NAFLD) often occurs in obese individuals and is among the most common causes of cirrhosis, the terminal chronic liver disease that may necessitate liver transplantation. While multiple populations of macrophages have been described in the human liver, their function and turnover in obese patients at high risk of developing NAFLD and cirrhosis is currently unknown. Herein we identified a specific human population of resident liver myeloid cells that protects against the metabolic impairment associated with obesity. By studying the turnover of liver myeloid cells in individuals undergoing liver transplantation using markers of donor-recipient mismatch, we made the novel discovery that liver myeloid cell turnover differs between humans and mice. Using single cell techniques and flow cytometry we determined that the proportion of the protective resident liver myeloid cells, denoted liver myeloid cells 2 (LM2), decreases during obesity. Functional validation approaches using human 2D and 3D cultures revealed that the presence of LM2 ameliorates the oxidative stress associated with obese conditions. Our study indicates that resident myeloid cells could be a therapeutic target to decrease the oxidative stress associated with NAFLD.

  Study EGAS00001007194

• Multi-focal genomic dissection of synchronous primary and metastatic tissue from de novo metastatic prostate cancer

  De novo metastatic prostate cancer is highly aggressive, but the paucity of routinely-collected tissue in this setting has hindered genomic stratification and jeopardizes precision oncology efforts. Here, we leveraged a rare study of surgical intervention in 43 de novo metastatic prostate cancers to assess somatic genotype across 607 synchronous primary and metastatic tissue foci plus circulating tumor DNA. Intra-prostate heterogeneity was pervasive and impacted clinically-relevant genes, resulting in frequent discordance between select primary-restricted foci and synchronous metastases. Additional complexity was driven in several instances by polyclonal metastatic seeding from the reservoir of phylogenetically-related primary populations. When simulating standard clinical practice relying on a single tissue focus, genomic heterogeneity plus highly variable per-sample tumor fraction caused false genotyping of dominant disease. However, in silico modeling demonstrated that analysis of multiple biopsy cores can rescue misassigned somatic genotypes. Our results define the relationship between synchronous treatment-naive primary and metastatic lesions in de novo metastatic prostate cancer and provide a framework for implementing genomics-guided patient management.

  Study EGAS00001006466

• Whole exome sequencing of 69 trios with bipolar disorder

  We performed whole exome sequencing to trios with bipolar disorder to elucidate genetic architecture of bipolar disorder including de novo mutations and transmitted variants.

  Study JGAS000273

• Novel genes for Intellectual Disability identified using whole genome sequence and pathway analysis

  Intellectual Disability (ID) is one of the most common global disorders. However for ~30% of patients with ID no cause is identified, despite a clinical diagnostic odyssey that includes genome wide clinical microarray (CMA). We carefully selected 8 trios, each composed of a child with ID and brain structural defect, and both normal parents for whole genome sequencing (WGS). We conducted WGS on the trio and filtered out de novo single nucleotide variants (SNVs) and then used a pathway-based refinement to select candidates. We confirmed a de novo pathogenic SNV in ARID1B, and likely pathogenic SNVs in CACNB3, SPRY4, PHF6, SQSTM1 and UPF1 in 5 of the 8 children. All genes except ARID1B and PHF6 are previously unreported for ID. We analysed our WGS data using 4 independent algorthims for copy number and structural variation including using de novo whole genome assembly. We confirmed one likely contributory 165kb de novo CNV (missed by CMA). We conducted a validation study of over 2000 exomes for our novel candidate genes and also present a strategy to analyze the non-coding sequence space. This study provides an extensive analysis of WGS in the context of ID and yielded causative variants in >60% of cases.

  Study EGAS00001001386

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

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

  Study phs001658

• Melanoma_multi_site_metastases

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

  Study EGAS00001001348

• Oncogenic cooperation in a human de novo T-ALL model

  We previously modelled T-cell acute lymphoblastic leukemia (T-ALL) by over-expressing four oncogenes (activated NOTCH1, LMO2, TAL1, and BMI1) in healthy human umbilical cord blood cells through lentiviral transduction (Kusakabe et al, Nat Commun 10, 2913 (2019). https://doi.org/10.1038/s41467-019-10510-8). We have now tested individual effects of the four oncogenes by transducing human cells with all possible combinations of one, two, three, and four oncogenes. We also tested the effects of additional known T-ALL oncogenes including HOXA9, LYL1, MEF2C, NXK2.1, TLX1, and TLX3. In addition to culture in vitro on OP9-DL1 feeders, we also injected transduced cells into immunodeficient NSG mice. We observed differing abilities of the various oncogene combinations to support growth in vitro and frank leukemia in vivo. This study includes RNA-seq data from samples of transduced cells cultured in vitro as well as cells harvested from clinically moribund mice after development of leukemia in vivo.

  Study EGAS00001006055

• Searching for variants associated with endometriosis

  We explored regulatory mechanism of a SNP on chromosome 9p21 associated with endometriosis by leveraging “allele-specific” functional genomic approaches. By re-sequencing 1.29 Mb of 9p21 region and scrutinizing DNase-seq data from the ENCODE project, we prioritized rs17761446 as a candidate functional variant that was in perfect linkage disequilibrium with the original GWAS SNP (rs10965235) and located on DNase I hypersensitive site. Chromosome conformation capture followed by high-throughput sequencing revealed that the protective G allele of rs17761446 exerted stronger chromatin interaction with ANRIL promoter. We demonstrated that the protective allele exhibited preferential binding affinities to TCF7L2 and EP300 by bioinformatics and chromatin immunoprecipitation (ChIP) analyses. ChIP assays for histone H3 lysine 27 acetylation and RNA polymerase II reinforced the enhancer activity of the SNP site. The allele specific expression analysis for eutopic endometrial tissues and endometrial carcinoma cell lines showed that rs17761446 was a cis-regulatory variant where G allele was associated with increased ANRIL expression.

  Study EGAS00001001741

• CTCF-dependent enhancer hijacking by the EVI1 oncogene in leukemia

  Chromosomal rearrangements are a frequent cause of oncogene deregulation in human malignancies. Overexpression of EVI1 is found in a subgroup of acute myeloid leukemia (AML) with 3q26 chromosomal rearrangements which are often therapy resistant. In a cohort of primary t(3;8)(q26;q24) AML samples we observed the translocation of a MYC super-enhancer to EVI1. We generated a patient-based t(3;8)(q26;q24) model in vitro using CRISPR-Cas9 technology and demonstrated hyper-activation of EVI1 by the hijacked MYC super-enhancer. One MYC super-enhancer element in particular, which recruits early hematopoietic regulators, is critical for EVI1 expression and enhancer-promoter interaction. This interaction is facilitated by a CTCF-bound motif upstream of the EVI1 promoter that acts as an enhancer-docking site in t(3;8) AML. Genomic analyses of 3q26-rearranged AML samples point to a common mechanism by which EVI1 uses this CTCF-bound enhancer-docking site to hijack early hematopoietic enhancers.

  Study EGAS00001004808

• Clinical and Genetic Analysis of Costa Rican Patients with Parkinson's Disease

  This study is a pilot study designed to describe the clinical and genetic landscape of Parkinson's disease in Costa Rica. While most genetic studies have been conducted on Europeans, few have examined Parkinson's disease in Costa Ricans. 118 patients and 97 controls were recruited at the Movement Disorders Unit of the Department of Neurology, Hospital San Juan de Dios, Caja Costarricense de Seguro Social, Costa Rica. Familial Parkinson's disease genes were sequenced using Next-Generation Sequencing. We also measured and obtained different sociodemographic and clinical information.

  Study phs002495

• Mapping and phasing of structural variation in patient genomes using nanopore sequencing

  We whole genome sequence 2 patients with congenital abnormalities and known complex de novo chromosomal rearrangements using the Nanopore MinION. We show how we can detect most previoulsy detected de novo rearrangements as well as uncover a few new ones. Furthermore, we perform genome-wide analyses showing the accuracy of SV detection and of phasing, using long reads. The files uploaded here are the whole genome Nanopore data for each of the two patients used, as well as the corresponding whole genome illumina data, used in our comparisons.

  Study EGAS00001002333

• Genetics causes of male infertility in 185 patient-parent trios from Netherlands and UK

  In this, whole exome sequencing was performed on 185 patients suffering from Azoospermia or severe oligozoospermia and on their respective fertile parents in order to investigate de novo and inherited genetic variants likely to be the cause of infertility in these men. After bioinformatic analysis and comprehensive variant interpretation several de novo point mutations and copy number variations were identified as well as multiple homozygous and compound heterozygous mutations in recessive genes that are likely influencing the infertility phenotypes observed in the patients.

  Study EGAS00001005417

• Caregiving as a Natural Stressor in Studies of the Role of Genes That Affect Serotonin Function in Regulating Risk Factors for Coronary Heart Disease (CAREGIVER)

  The burden of caregiving for an ill relative has been shown to interact with existing comorbidities to increase risk of several health outcomes including metabolic syndrome and blood pressure reactivity. The CAREGIVER study was developed to compare cardiometabolic risk factors in caregivers and controls. These risk factors include physiologic measures, psychologic measures, neighborhood characteristics, and genetic and genomic factors. DNA and plasma were collected and used for examination of cardiometabolic and stress biomarkers, genotyping and methylation analysis.

  Study phs001747

• Transcriptome of CD4+ T cells and CD8+ T cells in glioblastoma multiforme

  Patients included in this study were over 18 years of age and had a histology-confirmed diagnosis of glioblastoma multiforme (GBM). Exclusion criteria were the previous administration of any anti-tumor therapy including radiation therapy. All patients gave written informed consent. The study was approved by the local ethics committee (TUM Medical school) and conducted following the Declaration of Helsinki. During resection of the tumors, tumor tissue and tissue from normal appearing brain within the operative channel was collected. Blood was drawn during the surgical procedure. Single cell suspensions were prepared from the tumor tissue, the normal appearing brain, and the blood. CD4+ T cells and CD8+ T cells were sorted by flow cytometry. Only patients with a complete set of specimens (CD4+ tumor infiltrating lymphocytes (TIL), CD8+ TIL, CD4+ T cells from normal appearing brain, CD8+ T cells from normal appearing brain, blood-derived CD4+ and CD8+ T cells) containing a minimum of 1000 cells in each sorted sample were further analyzed (n=9). Total RNA was isolated from sorted cell populations using the RNAeasy Plus micro kit (Qiagen, 74034). Quality and integrity of total RNA was controlled on a Bioanalyzer 2100 (Agilent Technologies). Library preparation for bulk-sequencing of poly(A)-RNA was done as described previously (Parekh et al., 2016). Briefly, barcoded cDNA of each sample was generated with a Maxima RT polymerase (ThermoFisher Scientific, EP0742) using oligo-dT primer containing barcodes, unique molecular identifiers (UMIs) and an adaptor. Ends of the cDNAs were extended by a template switch oligo (TSO) and full-length cDNA was amplified with primers binding to the TSO-site and the adaptor. NEB UltraII FS kit was used to fragment cDNA. After end repair and A-tailing, a TruSeq adapter was ligated and 3'-end-fragments were finally amplified using primers with Illumina P5 and P7 overhangs. In comparison to previous descriptions (Parekh et al., 2016), the P5 and P7 sites were exchanged to allow sequencing of the cDNA in read 1 and barcodes and UMIs in read 2 to achieve a better cluster recognition. The library was sequenced on a NextSeq 500 (Illumina) with 59 cycles for the cDNA in read 1 and 16 cycles for the barcodes and UMIs in read 2. Data were processed using the published Drop-seq pipeline (v1.0) to generate sample- and gene-wise UMI tables (Macosko et al., 2015). Reference genome (GRCh38) was used for alignment. Transcript and gene definitions were used according to the Genecode Annotation Version 35.

  Dataset EGAD50000000226

• Sant Joan de Déu Research Institute (IRSJD)

  Sant Joan de Déu Research Institute (IRSJD) institutional Data Access Committee. The objective of the DAC is to manage, review and assess datasets access requests. The DAC is managed by the Knowledge Management Unit, and an adhoc committee per dataset will be formed to take into consideration each access request. Contact the Knowledge Management Unit at gestio.coneixement@sjd.es

  Dac EGAC50000000253

• Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations

  It is well established that autism spectrum disorders (ASD) have a strong genetic component; however, for at least 70% of cases, the underlying genetic cause is unknown. Under the hypothesis that de novo mutations underlie a substantial fraction of the risk for developing ASD in families with no previous history of ASD or related phenotypes-so-called sporadic or simplex families-we sequenced all coding regions of the genome (the exome) for parent-child trios exhibiting sporadic ASD, including 189 new trios and 20 that were previously reported. Additionally, we also sequenced the exomes of 50 unaffected siblings corresponding to these new (n = 31) and previously reported trios (n = 19), for a total of 617 individual exomes from 209 families deposited in dbGaP. Here we show that de novo point mutations are overwhelmingly paternal in origin (4:1 bias) and positively correlated with paternal age, consistent with the modest increased risk for children of older fathers to develop ASD. Moreover, 39% (49 of 126) of the most severe or disruptive de novo mutations map to a highly interconnected beta-catenin/chromatin remodelling protein network ranked significantly for autism candidate genes. In proband exomes, recurrent protein-altering mutations were observed in two genes: CHD8 and NTNG1. Mutation screening of six candidate genes in 1,703 ASD probands identified additional de novo, protein-altering mutations in GRIN2B, LAMC3 and SCN1A. Combined with copy number variant (CNV) data, these results indicate extreme locus heterogeneity but also provide a target for future discovery, diagnostics and therapeutics.

  Study phs000482

• Directeur de Recherches

  Dac EGAC00001002511

• POT1_splice_site_mutant_analysis

  We are interested in the contribution mutations in the Shelterin complex protein POT1 may have to the development of melanoma. We have identified a patient who carries a splice site mutation in POT1 and as part of our analysis of this gene we aim to sequence the transcriptome of this patient to see how this mutation influences splicing. RNA has been obtained from lymphocytes collected from the patient.

  Study EGAS00001000571

• Abnormal foetal development exome trios

  This project is to explore the contribution of de novo mutations to severe structural malformations diagnosed prenatally using ultrasound. These malformations include heart, CNS, renal and GI abnormalities. In this pilot project we aim to exome sequence 30 parent-foetus trios to ~50X mean coverage and identify de novo functional variants using an algorithm developed in the Hurles group

  Dataset EGAD00001001442

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

  Dataset EGAD00001007762

• Transcriptomic analyisis of 54 samples of AC16 cells exposed to trastuzumab

  Data of 54 samples with their 54 paired fastaq files that were sequenced in a Novaseq 6000 platform. Samples correspond to the three biological replicates of AC16 cells (i.e. AC16, C1, C2). Each biological replicate was edited to carry either of the three different genotypes of the rs1136201 variant (i.e. AA, AG, GG) and each genotype was enriched to express HER2 protein in three levels (i.e. low, medium and high expression) as selected by FACS. Additionally, treatment of each sample was performed and sequenced in duplicates (i.e. 1 and 2)

  Dataset EGAD50000001705

• OpACIN-neo – A Multicenter Phase 2 Study to identify the Optimal neo-Adjuvant Combination scheme of Ipilimumab and Nivolumab – Whole exome sequencing

  The outcome of patients with macroscopic stage III melanoma is poor. Neoadjuvant treatment with ipilimumab plus nivolumab at the standard dosing schedule induced pathological responses in a high proportion of patients in two small independent early-phase trials. However, toxicity of the standard ipilimumab plus nivolumab dosing schedule was high, preventing its broader clinical use. The aim of the OpACIN-neo study (NCT02977052) to identify a dosing schedule of ipilimumab plus nivolumab that is less toxic but equally effective. 86 patients with macroscopic stage III melanoma were randomised to one of three dosing schedules: arm A, two cycles of ipilimumab 3 mg/kg plus nivolumab 1 mg/kg once every 3 weeks; arm B, two cycles of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg once every 3 weeks; or arm C, two cycles of ipilimumab 3 mg/kg once every 3 weeks directly followed by two cycles of nivolumab 3mg/kg once every 2 weeks. Within the first 12 weeks, grade 3–4 immune-related adverse events were observed in 12 (40%) of 30 patients in group A, six (20%) of 30 in group B, and 13 (50%) of 26 in group C. Pathological responses occurred in 24 (80%) patients in group A, 23 (77%) in group B, and 17 (65%) in group C. The 2-year estimated relapse-free survival was 84% for all patients, 97% for patients achieving a pathologic response and 36% for nonresponders (p<0.001). High tumor mutational burden (TMB) and high interferon-gamma-related gene expression signature score (IFN-γ score) were associated with pathologic response and low risk of relapse; pathologic response rate (pRR) was 100% in patients with high IFN-γ score/high TMB, patients with high IFN-γ score/low TMB or low IFN-γ score/high TMB had pRRs of 91% and 88%; while patients with low IFN-γ score/low TMB had a pRR of only 39%. These data demonstrate long-term benefit in patients with a pathologic response and show the predictive potential of TMB and IFN-γ score.

  Study EGAS00001004832

• OpACIN-neo – A Multicenter Phase 2 Study to identify the Optimal neo-Adjuvant Combination scheme of Ipilimumab and Nivolumab – RNA sequencing

  The outcome of patients with macroscopic stage III melanoma is poor. Neoadjuvant treatment with ipilimumab plus nivolumab at the standard dosing schedule induced pathological responses in a high proportion of patients in two small independent early-phase trials. However, toxicity of the standard ipilimumab plus nivolumab dosing schedule was high, preventing its broader clinical use. The aim of the OpACIN-neo study (NCT02977052) to identify a dosing schedule of ipilimumab plus nivolumab that is less toxic but equally effective. 86 patients with macroscopic stage III melanoma were randomised to one of three dosing schedules: arm A, two cycles of ipilimumab 3 mg/kg plus nivolumab 1 mg/kg once every 3 weeks; arm B, two cycles of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg once every 3 weeks; or arm C, two cycles of ipilimumab 3 mg/kg once every 3 weeks directly followed by two cycles of nivolumab 3mg/kg once every 2 weeks. Within the first 12 weeks, grade 3–4 immune-related adverse events were observed in 12 (40%) of 30 patients in group A, six (20%) of 30 in group B, and 13 (50%) of 26 in group C. Pathological responses occurred in 24 (80%) patients in group A, 23 (77%) in group B, and 17 (65%) in group C. The 2-year estimated relapse-free survival was 84% for all patients, 97% for patients achieving a pathologic response and 36% for nonresponders (p<0.001). High tumor mutational burden (TMB) and high interferon-gamma-related gene expression signature score (IFN-γ score) were associated with pathologic response and low risk of relapse; pathologic response rate (pRR) was 100% in patients with high IFN-γ score/high TMB, patients with high IFN-γ score/low TMB or low IFN-γ score/high TMB had pRRs of 91% and 88%; while patients with low IFN-γ score/low TMB had a pRR of only 39%. These data demonstrate long-term benefit in patients with a pathologic response and show the predictive potential of TMB and IFN-γ score.

  Study EGAS00001004833

• The Nurses' Health Study (NHS) GWAS of Mammographic Density

  The Nurses' Health Study is an on-going prospective cohort study of women that was initiated in 1976. This specific study was part of a larger study to advance our knowledge of breast cancer etiology, expand the current knowledge of mammographic density, and clarify the relationship between mammographic density and breast cancer risk. We conducted a nested case control study of breast cancer among women who provided a blood sample. We then targeted our mammogram collection to participants that were selected as part of this nested case-control study (i.e. those who had provided a blood sample). The mammogram closest to the date of blood draw (~1989-1990) was used. We assessed mammographic breast density from digitized film images using a computer assisted thresholding method (Cumulus). The women in this study were genotyped using the Illumina Omni Express Platform.

  Study phs000975

• Exploring Extracellular Vesicle microRNAs in Usher Syndrome Type 1B: Tear-Derived EVs as Indicators of Retinal Health

  The goal of this study was to explore extracellular vesicles (EVs) from human tears and iPSC-derived RPE cells as biomarkers for Usher syndrome type 1B (USH1B), a rare inherited disorder causing deafness and retinitis pigmentosa. Researchers found that tear EVs showed higher levels and diversity of miRNAs, making them a promising non-invasive source for diagnosing USH1B. In contrast to patient-derived RPE cells, which did not express MYO7A protein despite similar expression levels in controls, the study identified specific microRNA signatures associated with retinal degeneration in both tear EVs and RPE-derived EVs. The findings suggest that tear EVs can serve as a useful biomarker for USH1B diagnosis, monitoring, and therapeutic development. Overall, this research aims to contribute to our understanding of disease mechanisms and identify potential targets for treatment in patients with Usher syndrome type 1B.

  Study EGAS50000001200

• Pomalidomide for the Treatment of Bleeding in HHT (PATH-HHT)

  Data Access NOTE: Please refer to the "Authorized Access" section below for information about how access to the data from this accession differs from many other dbGaP accessions.Objectives: To determine efficacy (reduction in severity of epistaxis), tolerability, and improvement in quality of life of pomalidomide compared to placebo after 24 weeks of treatment.Background: This study addresses the efficacy of pomalidomide in the treatment of epistaxis in patients with Hereditary Hemorrhagic Telangiectasia (HHT) who have anemia and/or require blood transfusion or iron infusion for treatment of bleeding-induced anemia and iron deficiency. HHT (also known as Osler-Weber-Rendu disease) is an inherited bleeding disorder. Over 95% of patients develop recurrent epistaxis, which may be severe and result in chronic anemia, need for iron infusions and blood transfusions, substantial psychiatric comorbidity (including depression and post-traumatic stress disorder) and reduction in health-related quality of life (HRQoL). HHT is clinically diagnosed using the Curacao criteria, which consists of 1) spontaneous and recurrent epistaxis, 2) telangiectasias at characteristic sites, 3) visceral arteriovenous malformations (AVMs) or telangiectasias, and 4) a first degree relative with HHT (inheritance is usually autosomal dominant). Patients with three criteria are considered to have definite HHT, and those with 2 criteria probable HHT. HHT affects approximately 1 in 3,800 individuals. Significant manifestations of HHT often do not appear until the third or fourth decades, sometimes later.Participants: 144 patients from 11 clinical centers were enrolled.Design: This is a multi-center, double blind, randomized placebo-controlled trial that investigated the efficacy and safety of pomalidomide in patients with HHT and chronic epistaxis leading to iron-deficiency anemia or requiring intravenous iron infusions or blood transfusion.Screening evaluation included the Epistaxis Severity Score (ESS) with three-month recall, which reflected the patient's history of epistaxis and bleeding over the prior three months, as well as detailed review of iron infusion and red cell transfusion over the preceding six months. Eligible patients were provided a diary to record the duration of each epistaxis event that occurred during the 4 weeks prior to the baseline visit, and then returned for the baseline randomization visit, at which time patients underwent genetic testing, if this had not been previously performed, and completed an ESS with 4-week recall and quality of life assessments. Patients were randomized 2:1, stratified by study site, to either pomalidomide 4 mg/day or matching placebo during each of six 28 day cycles (24 weeks). Patients were seen every four weeks during treatment, and at a 4-week post-treatment follow-up visit to measure the ESS (with 4-week recall), laboratory assessments including iron stores and need for iron infusion, CBC, and metabolic profile. Patients were assessed for adverse events (AE) throughout the study. Treatment dosage could be reduced, or temporarily or permanently discontinued following AE-specific guidelines related to fatigue, cytopenias or other toxicities.Quality of life assessments were completed at baseline, and the 12- and 24-week visits, and the 4-week post-treatment follow-up visit using validated NIH instruments of 1) Neuro-QOL satisfaction with social roles and activities, 2) PROMIS emotional distress – depression, and 3) PROMIS fatigue, and the HHT-specific quality of life instrument developed specifically for this study. The effect of pomalidomide on duration of epistaxis was assessed via diary between weeks 8-12, 20-24 and the 4-week post-treatment period.Conclusions: Among patients with HHT, pomalidomide treatment resulted in a significant, clinically relevant reduction in epistaxis severity. No unexpected safety signals were identified (Al-Samkari et al., 2024; PMID: 39292928)

  Study phs003948

• HV31 - De novo assembly of eight immune system regions

  De novo assembly of eight immune system regions for individual HV31, generated using a multi-platform pipeline. A full description of the generation of these assemblies can be found at https://doi.org/10.1101/2021.02.03.429586.

  Dataset EGAD00001007050

• Transcriptomic predictors of survival for palbociclib + endocrine therapy vs. capecitabine in aromatase inhibitor-resistant breast cancer from GEICAM/2013-02 PEARL

  We examined transcriptomic tumor features associated with survival from GEICAM/2013-02 PEARL, a phase III trial of palbociclib + ET vs. capecitabine in aromatase inhibitor-resistant HR+/HER2- MBC. PAM50 intrinsic subtype predicted PFS differences between palbociclib + ET and capecitabine, and lower B-cell-associated gene expression predicted longer OS with palbociclib + ET vs. capecitabine. These features may help identify HR+/HER2- tumors resistant to further ET-based treatment with CDK4/6 inhibitors.

  Study EGAS00001008177

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

  The RECOVER tissue pathology study is a cross-sectional study designed to define and characterize the epidemiology, natural history, clinical spectrum, and underlying mechanisms of post-acute effects of SARS-CoV-2 infection in a diverse population representative of the general COVID-19 population in the US. The autopsy study will characterize the pathology of PASC in decedents who die more than 60 days after initial onset or after hospital discharge, whether in-hospital or out-of-hospital at time of death, and who meet the working definition of PASC as defined by the recent World Health Organization publication given in Section 5.4. The autopsy study will also explore the pathology of acute SARS-CoV-2 infection in a smaller subset of decedents who died between15-60 days from symptom onset. This protocol defines the common set of clinical data elements, autopsy procedures for tissue collection, core measures, pathology protocols, shared pathology tissues, data elements, and methodology. Each investigator site is expected to perform autopsies on the decedents to address the pathophysiology of the potential long-term effects of SARS-CoV-2 infection on human health. The Consortium analysis plan aims to address research questions by incorporating: 1) tissue obtained from autopsies performed at each Phase II participant's site; and 2) tissue available from other pathology investigators/autopsy sites within the Consortium.

  Study phs003768

• Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study

  Study population The WECARE Study is an international multicenter population-based case-control study of cases with asynchronous contralateral breast cancer (CBC) and individually matched controls with unilateral breast cancer (UBC). Recruitment and data collection for the WECARE Study were conducted in two phases, herein referred to as WECARE I (2001–2004) and WECARE II (2009–2012). The study design of the first phase (WECARE I) has been described in detail elsewhere [Bernstein JL, et al 2004, PMID: 15084244]; the second phase (WECARE II) employed a nearly identical approach [Langballe R, et al 2016, PMID: 27400983]. Participants in each phase were identified through eight population-based cancer registries, including six in the United States that contribute to the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program: Los Angeles County Cancer Surveillance Program; Cancer Surveillance System of the Fred Hutchinson Cancer Center (Seattle region, WA); State Health Registry of Iowa; Cancer Surveillance Program of Orange County/San Diego-Imperial Organization for Cancer Control (Orange County/San Diego, CA); the Greater Bay Area Cancer Registry (San Francisco Bay Area region and Santa Clara region, CA); and the Sacramento and Sierra Center Registry (Sacramento region, CA). Participants were additionally identified using the Ontario Cancer Registry (Canada) and the Danish Breast Cancer Cooperative Group Registry, supplemented by data from the Danish Cancer Registry. The study protocol was approved by the institutional review or regulatory ethics boards at each study site. Data collection Study participants were interviewed by telephone using a structured questionnaire aimed at evaluating known or suspected breast cancer risk factors, including personal demographics, medical history, menstrual and reproductive history, family history of cancer, use of hormones, smoking, and alcohol intake. Risk factor status was assessed during the period prior to first diagnosis, as well as between first diagnosis and reference date (i.e., the at-risk period for CBC). Detailed data on treatment and tumor characteristics were obtained directly from cancer registry records or by abstracting medical records, including pathology and surgical reports, radiation oncology clinic notes, and systemic adjuvant treatment data. Complete medical treatment history information was collected, and for all women who received radiotherapy, the radiation dose to the contralateral breast was reconstructed using radiotherapy records and radiation measurements. Biospecimens were collected from study participants for genotyping: blood collected from WECARE I women; and saliva collected from WECARE II women.

  Study phs003945

• Long-read-transcriptome-sequencing of CLL and MDS patients uncovers common molecular effects of SF3B1 mutations

  Mutations in SF3B1 occur frequently in patients with chronic lymphocytic leukemia (CLL) and myelodysplastic syndromes (MDS), and a full-length transcriptome approach can expand our current knowledge on SF3B1 mutation effects on RNA splicing. We applied long-read-transcriptome-sequencing (LRTS) to 44 MDS and CLL patients with and without SF3B1 mutations and found a large fraction (>60%) of novel isoforms. Furthermore, we revealed that mutation effects on alternative splicing were largely common in both cancer types and specifically altered the usage of introns as well as 3’-splice-sites. We combined the LRTS with genome-wide SF3B1-RNA binding maps and show multimodal binding at 3’-splice-sites highlighting a window of 12-21nt upstream of the canonical 3’-splice-site in which a dynamic switch in splice site usage is observable in patients carrying SF3B1 mutations. Our work presents the hitherto most complete LRTS study in CLL and MDS and provides a resource for further research on aberrant splicing in cancer.

  Study EGAS50000000053

• Service de Génétique,Hôpital Européen Georges Pompidou

  Dac EGAC00001000224

• Detection and phasing of single base de novo mutations in biopsies from human in vitro fertilized embryos by advanced whole-genome sequencing

  Current methods available for pre-implantation genetic diagnosis (PGD) of in vitro fertilized (IVF) embryos do not detect de novo. Detection of these types of mutations requires whole genome sequencing (WGS). In this study advanced massively parallel WGS was performed on three 5-10 cell biopsies from two blastocyst-stage embryos. Overall, greater than 95% of each genome was called and experimentally derived haplotypes and barcoded read data were used to detect and phase up to 82% of de novo single base mutations with a false positive rate of ~1 error per Gb. These results suggest that phased WGS using barcoded DNA could be used in the future as part of the PGD process to maximize comprehensiveness in detecting disease causing mutations and reduce the incidence of genetic diseases.

  Study phs000858

• Circulating tumour DNA abundance and potential utility in de novo metastatic prostate cancer

  We set out to determine ctDNA abundance at de novo mCSPC diagnosis and whether ctDNA provides complementary clinically relevant information to a prostate biopsy. We collected and sequenced 77 plasma cell-free DNA samples from 53 newly diagnosed patients with mCSPC. Targeted sequencing was also performed on DNA from 48 diagnostic prostate tissue samples.

  Dataset EGAD00001004526

• De novo mutations in cell-free foetal DNA - Pulldown experiment

  A pulldown experiment with Agilent SureSelect probes designed on regions that were more likely to contain de novo mutations. 266 candidate sites were selected based on whole genome sequencing data. The probes also included the exons of genes that have been identified as neurodevelopmental disorder genes in DDD (the DDG2P genes) 1,336 targets. In addition, the design included the standard iPLEX sites.

  Dataset EGAD00001002265

• Spatial heterogeneity of follicular lymphoma

  Follicular lymphoma (FL) is an incurable B cell malignancy characterized by advanced stage disease and a heterogeneous clinical course. Recent genomic studies have focused on profiling “single” FL biopsies over several time-points, however, multi-site sampling in solid cancers has demonstrated profound spatial intra-tumor heterogeneity (ITH) with implications for precision medicine based initiatives. This study examined the extent of spatial heterogeneity in FL by whole exome sequencing 22 synchronously removed spatially separated biopsies from 9 patients. We observed significant differences in the extent of ITH across cases, with two distinct patterns of high and low spatial heterogeneity emerging. Site-specific alterations in genes with biological, prognostic or therapeutic relevance included, TNFRSF14, PIK3CD, TNFAIP3, PTEN, EP300 and XBP1. In depth characterization of these variants using deep-sequencing techniques confirmed their discordant nature, suggesting on-going genetic diversification driving evolution after widespread tumor dissemination. There was evidence of tumors comprising multiple competing subclones, with distinct clusters of mutations demonstrating differential expansions within spatially-separated sites. For cases where spatial tumors were examined at two time-points (FL and transformation to diffuse large B cell lymphoma (DLBCL)), the degree of heterogeneity increased with transformation. Collectively, our results demonstrate that spatial ITH is prevalent in FL. The existence of site-specific aberrations suggests that a single biopsy may not be sufficient in all patients to capture the full genomic complexity present and these spatial variations need to be considered in biomarker-led clinical studies.

  Dataset EGAD00001003553

• Translational Oncology Instituto de Medicina Molecular DAC

  Dac EGAC00001002108

• How are we funded?

  How are we funded? The EGA is provided infrastructure, administrative support, advisory input, and other relevant and necessary aspects by: CRG The EGA at the CRG is funded and supported by “La Caixa Foundation”, The Generalitat de Catalunya (Catalan Government), the Spanish Ministerio de Asuntos Económicos y Transformación Digital (Spanish Government) and the Instituto de Salud Carlos III. The Generalitat de Catalunya contributes with funding to the CRG and to the Barcelona Supercomputing Centre (BSC). The Barcelona Supercomputing Center is decisively contributing to EGA by providing the required compute, storage and networking resources, as well as key personnel for shared operations of EGA infrastructure. EMBL-EBI As part of the European Molecular Biology Laboratory (EMBL), the EGA at EMBL’s European Bioinformatics Institute receives funding from the governments of EMBL’s member states. The UK government, via UK Research and Innovation, also continues to support EMBL-EBI technical infrastructure, with EMBL supporting operational costs. A major source of funding for the EGA both at CRG and EMBL-EBI are competitive projects.The EGA resource continues to be funded through strategic engagement in collaborative partnerships and projects. Please see our projects page for more information. Other funders include the European Commission, the US National Institutes of Health, the Wellcome Trust, UK Research Councils, and our Industry Programme partners. Last updated on October, 2024.

  Documentation about/projects-and-funders/funders

• Environmental Influences on Child Health Outcomes (ECHO) - PATHWAYS - Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE)

  Pregnant women are exposed daily to multiple chemical and non-chemical stressors, including air pollutants, phthalates, and psychosocial stress. The Developmental Origins of Health and Disease model (DOHaD) states that exposure to these stressors in pregnancy affects fetal development in a manner that impacts offspring health across the life course. Yet epidemiologic data in these areas is limited, particularly with U.S. samples. It is also poorly understood whether these exposures prenatally affect childhood neurodevelopment and airway health in an independent or combined manner, and likely moderators of effects, such as the sex of the child, are infrequently addressed. We propose to unify three diverse extant pregnancy cohorts: TIDES (N=717, 2010-12), GAPPS (N=1133, 2012-16), and CANDLE (N=1385, 2007-11), for a combined sample size of 3235 mother-child dyads in the PATHWAYS study. PATHWAYS will investigate how chemical (air pollutants and phthalates) and non-chemical (psychosocial stress) exposures during pregnancy are related to placental gene expression (transcriptome) and childhood neurodevelopment and airway health (at ages 4-6, 8-9, and 10-11 years). Each cohort has rich resources of prenatal data and banked specimens (urine, blood, and placenta) that will be harmonized for the PATHWAYS study and will contribute to the ECHO consortium. We will develop a national model with high spatiotemporal resolution of key air pollutants and assess urinary markers of maternal exposure. A composite measure will capture multilevel maternal psychosocial stress across pregnancy, and urinary phthalate and blood stress hormone [Corticotropin-releasing hormone (CRH)] levels in the second and third trimesters will provide individual assessment of those exposures in potential critical periods. We will characterize the placental transcriptome using RNA sequencing (RNA-Seq) and will assess neurodevelopment and airway health prospectively into middle childhood. PATHWAYS will examine how these prenatal exposures are related to the placental transcriptome and child health outcomes in main effect and interactive models, with emphasis on sex-specific associations. For both neurodevelopment and airway health, we propose to measure both phenotypic precursors of health outcomes (i.e. fluid cognition, lung function growth), which yield dimensional tests of proposed associations, as well as clinically meaningful and policy relevant outcomes (i.e. asthma, mental health). Our study is powered to assess interactive effects of chemical and non-chemical stressors and will be the first study to characterize how prenatal environmental exposures relate to placental transcriptome pathways in relation to childhood health outcomes. This represents a significant scientific advance in testing DOHaD hypotheses. Major contributions to the ECHO Consortium include: 1) the development of a state of the art national model of air pollution, 2) a large, diverse pregnancy cohort with extensive biorepositories and extant prenatal and postnatal biomarkers, placental transcriptome, psychosocial and environmental data, and 3) an experienced, interdisciplinary team that will contribute meaningfully to the ECHO program of work.The sequencing data in this submission pertains only to the 794 subjects from the CANDLE study for whom placental tissue transcriptomics was performed.

  Study phs003619

• Environmental Influences on Child Health Outcomes (ECHO) - PATHWAYS - Global Alliance to Prevent Prematurity and Stillbirth (GAPPS)

  Pregnant women are exposed daily to multiple chemical and non-chemical stressors, including air pollutants, phthalates, and psychosocial stress. The Developmental Origins of Health and Disease model (DOHaD) states that exposure to these stressors in pregnancy affects fetal development in a manner that impacts offspring health across the life course. Yet epidemiologic data in these areas is limited, particularly with U.S. samples. It is also poorly understood whether these exposures prenatally affect childhood neurodevelopment and airway health in an independent or combined manner, and likely moderators of effects, such as the sex of the child, are infrequently addressed. We propose to unify three diverse extant pregnancy cohorts: TIDES (N=717, 2010-12), GAPPS (N=1133, 2012-16), and CANDLE (N=1385, 2007-11), for a combined sample size of 3235 mother-child dyads in the PATHWAYS study. PATHWAYS will investigate how chemical (air pollutants and phthalates) and non-chemical (psychosocial stress) exposures during pregnancy are related to placental gene expression (transcriptome) and childhood neurodevelopment and airway health (at ages 4-6, 8-9, and 10-11 years). Each cohort has rich resources of prenatal data and banked specimens (urine, blood, and placenta) that will be harmonized for the PATHWAYS study and will contribute to the ECHO consortium. We will develop a national model with high spatiotemporal resolution of key air pollutants and assess urinary markers of maternal exposure. A composite measure will capture multilevel maternal psychosocial stress across pregnancy, and urinary phthalate and blood stress hormone [Corticotropin-Releasing Hormone (CRH)] levels in the second and third trimesters will provide individual assessment of those exposures in potential critical periods. We will characterize the placental transcriptome using RNA sequencing (RNA-Seq) and will assess neurodevelopment and airway health prospectively into middle childhood. PATHWAYS will examine how these prenatal exposures are related to the placental transcriptome and child health outcomes in main effect and interactive models, with emphasis on sex-specific associations. For both neurodevelopment and airway health, we propose to measure both phenotypic precursors of health outcomes (i.e., fluid cognition, lung function growth), which yield dimensional tests of proposed associations, as well as clinically meaningful and policy relevant outcomes (i.e., asthma, mental health). Our study is powered to assess interactive effects of chemical and non-chemical stressors and will be the first study to characterize how prenatal environmental exposures relate to placental transcriptome pathways in relation to childhood health outcomes. This represents a significant scientific advance in testing DOHaD hypotheses. Major contributions to the ECHO Consortium include: 1) the development of a state of the art national model of air pollution, 2) a large, diverse pregnancy cohort with extensive biorepositories and extant prenatal and postnatal biomarkers, placental transcriptome, psychosocial and environmental data, and 3) an experienced, interdisciplinary team that will contribute meaningfully to the ECHO program of work.The sequencing data in this submission pertain only to the 408 subjects from the GAPPS study for whom placental tissue transcriptomics was performed.

  Study phs003620

• Regulatory Genomics of Human Embryonic Development

  We used epigenetic profiling to map active enhancers in the developing human limb and cortex as described in two published studies: Cotney J, Leng J, Yin J, Reilly SK et al. The evolution of lineage-specific regulatory activities in the human embryonic limb. Cell 2013;154(1):185-96. Reilly SK, Yin J, Ayoub AE, Emera D et al. Evolutionary changes in promoter and enhancer activity during human corticogenesis. Science 2015;347(6226):1155-9. We also used ChIP-seq to map binding sites for the chromatin modifier CHD8 in the developing human brain, as described in one published study: Cotney J, Muhle RA, Sanders SJ, Liu L et al. The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment. Nat Commun 2015;6:6404. We are also depositing primary human sequence reads related to processed datasets in the Gene Expression Omnibus under the following accession numbers: GSE42413 (Cotney et al. 2013); GSE63649 (Reilly et al. 2015); GSE57369 (Cotney et al. 2015).

  Study phs001226

• DAC for de-methylation of the FOXP3-TSDR study

  Dac EGAC00001001902

• Andersen-Tawil Syndrome: Genotype-phenotype correlation and longitudinal study

  Andersen-Tawil Syndrome (ATS) is a rare, genetic disorder that causes episodes of muscle weakness, potentially life-threatening changes in heart rhythm, and developmental abnormalities. Disease symptoms can vary, the cause of some ATS cases remains unknown, and no specific treatment has been identified. The purpose of this multi-site study is to better characterize ATS, establish whether symptoms change over time, and determine if symptoms are related to a mutation in the KCNJ2 gene.

  Study phs001289

• The PUWMa (

  The PUWMa GWAS of ADHD is a multi-site collaboration initiated to conduct a family-based association study from existing research samples. The source sample of ADHD families was ascertained at Massachusetts General Hospital (MGH, N=309 trios), Washington University at St. Louis (WASH-U, N=272 trios), and University of California at Los Angeles (UCLA, N=156 trios). All offspring met criteria for DSM-IV-TR attention-deficit hyperactivity disorder with childhood onset.

  Study phs000358

• Understanding Determinants of Racial Disparities in Lung Cancer Incidence

  This is a nested case-control study designed to evaluate the association between common genetic variants and the risk of lung cancer. The study included 1258 cases and 1252 controls selected from the Southern Community Cohort Study (SCCS), a large, prospective observational cohort. Cases were identified from cancer registries across the catchment area of the SCCS. Cases and controls were frequency matched on age, sex, race, and enrollment site (community health center vs general population).

  Study phs003789

• HGG panel sequencing

  NGS panel sequencing of pediatric high-grade gliomas (HGG), including diffuse midline gliomas and hemispheric HGG. This is a population-based dataset from the Hospital for Sick Children (Toronto, Canada), of patients <18 years of age at diagnosis, and diagnosed between 2000-2022. The goal of the study was to define the genetic drivers in pediatric HGG, including the rates of different genetic drivers, such as H3 and BRAF mutations, in a single-site population based cohort.

  Study EGAS50000000221

• RNAseq of 76 samples from Uveal Melanoma tumors

  Hotspot mutations in the spliceosome gene SF3B1 are reported in 20% of uveal melanomas. SF3B1 is involved in 3'-splice site (3'ss) recognition during RNA splicing; however, the molecular mechanisms of its mutation have remained unclear. Here we show, using RNA-Seq analyses of uveal melanoma, that the SF3B1 R625/K666 mutation results in deregulated splicing at a subset of junctions, mostly by the use of alternative 3'ss

  Study EGAS00001002932

• Single nuclei RNAseq data from HGSOC primary tumour samples

  As described in Burdett et al, snRNAseq was performed on primary HGSOC tumour samples that had previously undergone bulk WGS and RNAseq as described in Patch et al 2015 Nature.

  Study EGAS50000000249

• A new beta-globin mutation responsible of a beta-thalassemia (HbVar database ID 2928) was observed in 8 unrelated French families. The mutation carriers originated from Nord-Pas-de-Calais, a Northern French region where the chief town is Lille.5 unrelated mutation carriers were genotyped for a set of 12 microsatellites from chromosome 11, around the beta-globin gene. Among the 5 mutation carriers, 4 were genotyped for 97 European Ancestry Informative SNPs (EAIMs). 32 controls from Nord-Pas-de-Calais were genotyped for the microsatellites and SNPs.

  Dac EGAC00001000245

• Germline

  This study is part of the &#39;First 1,000 Days of Life and Beyond&#39; study at the Inova Translational Medicine Institute. Whole-genome sequencing data from 1,291 parent-offspring trios was used to study the properties of clustered de novo mutations. The maternal clusters were found to be enriched in regions with accelerated maternal mutation rate and show distinct mutational signatures. For additional details, please refer to: "Germline de novo mutation clusters arise during oocyte aging in genomic regions with increased double-strand break incidence". Jakob M. Goldmann, Vladimir B. Seplyarskiy, Wendy S.W. Wong, Thierry Vilboux, Pieter B. Neerincx, Dale L. Bodian, Benjamin D. Solomon, Joris A. Veltman, John F. Deeken, Christian Gilissen, John E. Niederhuber. Nature Genetics.

  Study phs001522

• Diagnostic Exome Sequencing in Persons with Severe Intellectual Disability

  Intellectual disability is a common condition that carries lifelong severe medical and developmental consequences. The causes of intellectual disability (ID) remain unknown for the majority of patients due to the extensive clinical and genetic heterogeneity of this disorder. De novo mutations may play an important role in ID as most individuals with ID present as isolated cases without family history and/or clear syndromic indication. In addition, the involvement of such mutations have recently been demonstrated in a small number of individuals with ID. Here we evaluate the diagnostic potential and role of de novo mutations in a cohort of 100 patients with ID of unknown cause using family-based exome sequencing.

  Study EGAS00001000287

• Temporal Lobe Epilepsy and Retrotransposons

  Idiopathic (cryptogenic) epilepsy is a common, chronic group of brain disorders, affecting 1-2% of the US population, creating a significant public health problem because of the associated morbidity and mortality. One subtype of this complex group of brain disorders, temporal lobe epilepsy (TLE), is particularly burdensome, because a substantial fraction of patients do not respond to anticonvulsant medications. If the seizure focus can be localized by imaging and/or EEG, the TLE patient often elects to have a partial resection of the affected temporal lobe, because they have daily seizures, despite multiple pharmacotherapy regimens. Although genetic risk is thought to play a role in TLE, identification of common risk alleles has had limited success. In the past 5 years, data have accumulated to prove that neuronal embryogenesis is accompanied by activation of LINE1 (L1) retrotransposons (RTPs) to an unexpected degree, such that developing neurons may accumulate de novo L1 insertions. This results in a substantial mosaicism within populations of CNS neurons. While most of these somatic de novo L1s will have little effect on neuronal function (perhaps because they occur in gene deserts or in large introns or in genes not required for that cell&#39;s function), some may interfere with normal neuronal activity because they have inserted into a gene needed by that particular neuron for normal function. If one or more functional de novo L1s occur early in CNS development, all the daughter neurons that derive from that neuronal precursor will also carry the L1 insertion, perhaps leading to a dysfunctional population of neurons destined to become an epileptic focus. This study leveraged CNS tissue (obtained at craniotomy) from patients with intractable TLE, who have undergone a therapeutic partial resection of one temporal lobe. Using fluorescence-assisted cell sorting of temporal lobe neuronal nuclei, followed by high-throughput sequencing and alignment to the reference genome, detection of de novo L1s will be done. In this manner, it is expected that de-novo intragenic L1s, contributing to idiopathic TLE, will be discovered.

  Study phs002067

• scRNA-seq dataset to study interactions between HSPCs, BMSCs and immune microenvironment

  Mechanisms of clonal evolution in myeloid neoplasms remain incompletely understood. Darwinian theory predicts that the (micro)environment of clone-propagating stem cells may contribute to clonal selection. Here, we provide data fitting this model, establishing a relationship between stromal niche inflammation, inflammatory stress in HSPCs, clonal resistance and leukemic evolution in human MDS.

  Dataset EGAD00001015770

• Transcriptomic analysis of liver CD8+ T cells

  Sorted single CD8+T cells expressing CD14 from human liver for SMARTSeq2. Livers processed: Kucykowicz et al STAR Prot 2022:pubmed.ncbi.nlm.nih.gov/35516846/ Published: Pallett et al Nature 2022 Tissue CD14+CD8+T-cells are reprogrammed by myeloid cells and modulated by LPS The liver is bathed in bacterial products including LPS transported from the intestinal portal vasculature, but maintains a state of tolerance exploited by persistent pathogens and tumours1,2,3,4. The cellular basis mediating this tolerance, yet allowing a switch to immunity or immunopathology, needs to be better understood for successful immunotherapy of liver diseases. Here we show that a variable proportion of CD8+T-cells compartmentalised in the human liver co-stain for CD14 and other prototypic myeloid membrane proteins; CD14+CD8+T-cells preferentially accumulate within the donor pool in liver allografts, amongst hepatic virus-specific and tumour-infiltrating responses, and in cirrhotic ascites. CD14+CD8+T-cells exhibit increased turnover, activation and constitutive immunomodulatory features with high homeostatic IL-10/IL-2 production directly ex vivo, and an enhanced capacity to rapidly produce antiviral/anti-tumour cytokines upon TCR engagement. This CD14+CD8+T-cell profile can be recapitulated by acquisition of membrane proteins, including the LPS receptor complex, from mononuclear phagocytes, resulting in augmented tumour killing by TCR-redirected T-cells in vitro. CD14+CD8+T-cells express integrins and chemokine receptors favouring interactions with the local stroma, which can promote their induction through CXCL12. LPS can also increase the frequency of CD14+CD8+T-cells in vitro and in vivo, and skew their function towards the production of chemotactic and regenerative cytokines. Thus, bacterial products in the gut-liver axis and tissue stromal factors can tune liver immunity by driving myeloid instruction of CD8+T-cells with immunomodulatory capacity. For the analysis of the single cell transcriptome two intrahepatic perfusate samples were isolated and frozen at -80 'C for storage prior to transportation to Newcastle, UK. Once thawed in pre-warmed HBSS containing 0.001% DNaseI, intrahepatic leukocytes were sorted by FACS to index classical mononuclear phagocytes (MNP) defined as Singlets, CD3-CD56-CD19-CD14hiHLA-DR+ or CD14± CD8+T-cells as follows: Singlets, CD3+CD56-CD19-CD4-CD8+V7.2- and split in to CD14± based on an isotype control. Single cells were sorted into 96-well skirted LoBind plates (Eppendorf) containing 5 µL lysis buffer (TCL buffer [Qiagen], supplemented with 1% b-mercaptoethanol [Sigma Aldrich; Merck]) on a BD Bioscience FACSFusion. The sorted plates were subsequently immediately sealed, centrifuged, and placed on dry ice to flash-freeze the cell lysate and stored at -80 'C. A modified SMART-seq2 protocol57 was performed on the single flow cytometry sorted-cells as previously described58. After cDNA generation, libraries were prepared (384 cells per library) using the Illumina Nextera XT kit (Illumina). Each library was sequenced to achieve a minimum depth of 1-2 million raw reads per cell using an Illumina HiSeq 4000 using v. 4 SBS chemistry to generate 75-bp paired-end reads.

  Study EGAS00001006885

• Supraphysiologic MDM2 Expression Impacts P53-Independent Chromatin Networks and Therapeutic Responses in Sarcoma

  We collected multiple liposarcoma samples from different patients, including different subtypes (DD, WD) and normal adipose tissue as control. This study provides the biggest liposarcoma cohort to date, and examined the molecular regulatory circuits associated with MDM2 overexpression. To this end, we obtained not only RNA-seq data, but also ChIP-seq from Jun, RUNX, MDM2, P53 and H3K27ac, as well as hiChIP from tumor samples and cell lines. We found that MDM2 binds to thousands of genes involved in cellular growth and stress response in a P53-independent manner. Furthermore, we described these active genes engaged in multi-way topological interactions that resemble transcriptional hubs.

  Study phs003272

• Maternal and Developmental Risks from Environmental and Social Stressors (MADRES) Center for Environmental Health Disparities

  MADRES is a prospective pregnancy cohort based in urban Los Angeles, recruiting predominantly low income Hispanic mothers-to-be as part of a children's health study, funded by Environmental Influences on Child Health Outcomes (ECHO). Participants were measured for a number of chemical exposures and biomarkers. Two epigenetic markers will be available through dbGaP: miRNA expression in pregnancy (measured via Nanostring human assay, v3) and DNA methylation from pregnancy and children's cord blood (measured via EPIC array). Principal findings of this research described differences in miRNA expression profiles between early and late pregnancy, as well as miRNA expression affected by psychosocial stress.

  Study phs003194

• Data Access Committee for the Centre National de Recherche en Génomique Humaine (CNRGH)

  Dac EGAC00001000723

• Targeted de novo phasing and long-range assembly by template mutagenesis

  Study EGAS00001005899

• HTAN Pilot Project: Single-Cell Transcriptomics Toolbox for Fresh and Frozen Human Tumors (Lung, Breast, Ovarian, Melanoma, Neuroblastoma, Sarcoma, Glioblastoma, Glioma, and Leukemia)

  Single cell transcriptomics is a powerful tool to map the complex tumor microenvironment, providing unprecedented resolution into cell types, cell states, cell interactions, and tumor heterogeneity. Depending on their tissue site and whether processing begins from a fresh or frozen sample, different tumors require different optimizations in order to obtain high quality single cell transcriptomic data. In this study, we profiled a range of tumor types, varying in cell-of-origin, solid and non-solid forms, patient ages, and transitions. The tumors also further varied in their tissue site and in their sample collection method. To enable profiling of such diverse samples, we developed a systematic toolbox for single cell RNA-Seq and single nucleus RNA-Seq of fresh and frozen clinical tumor samples. We validated this toolbox for 216,490 cells and nuclei extracted from 39 samples across 23 tumors (some tumors were split into multiple samples). The 23 tumors represented eight unique tumor types. This toolbox comprises both experimental and computational protocols as well as guidelines for comparing and selecting protocols for the biological problem of interest.

  Study phs001983

• Somatic Mutations in Individual Skin Cells

  Ultraviolet (UV) radiation is the primary cause of melanoma through the acquisition of driver mutations in melanocytes. It also plays a significant role in oncogenesis in other skin cells, such as keratinocytes. However, the mutational profiles vary widely among different skin cancers, and the early mutational processes in different cell types from the same skin, is not well understood. Additionally, our preliminary studies also suggest that the mutation burden in different skin cells vary significantly based on risk factors such as the anatomical site and the use of tanning beds. To explore this, we employed innovative Next Generation Sequencing (NGS) tools to perform a site-matched comparison of the genomic landscapes of melanocytes, keratinocytes, and fibroblasts. From 20 biopsies of physiologically normal skin, collected from various anatomical sites across 16 donors, we have performed DNA-sequencing on 106 melanocytes, 78 keratinocytes and 13 fibroblasts. Of these samples, we have also simultaneously performed RNA-sequencing on 78 melanocytes, 46 keratinocytes and 9 fibroblasts. For normal bulk DNA, we also performed targeted (UCSF500; n=9) or exome sequencing (n=8) of skin or saliva samples from the donors.

  Study phs003683

• The Scientific ethical comittee capital region of Denmark (De videnskabs etiske komiteer region hovedstaden)

  Dac EGAC00001001063

• Expanding the neurodevelopmental phenotypes of individuals with de novo KMT2A variants Data Access Committee

  Dac EGAC00001001147

• Magdalena_de_Cao_Peru

  Samples from Magdalena de Cao, Peru

  Dataset EGAD00010001934

• Columbia-Yale-Bilkent Study: Genetics Study of Essential Tremor

  This is a research development/planning grant application to initiate collaborative studies with investigators at Bilkent University in Turkey to study the genetics of Essential Tremor (ET). ET is one of the most common neurological diseases, with an estimated 7 million affected individuals in the United States. The most characteristic clinical feature of ET is a kinetic tremor in the hands or arms, which is mild early in the disease process. As the disease progresses, tremor becomes more severe and more anatomically widespread (e.g., head, trunk). Aside from tremor, patients with ET may also present with other motor features including gait ataxia. Non-motor features can include psychiatric manifestations, cognitive decline and dementia. Despite its extraordinarily high prevalence, the genetic causes of ET are largely unknown. We propose to develop a genetic study of ET focusing on consanguineous families in Turkey. Turkey with a population of about 70 million has a high rate of consanguineous marriages. The rate of consanguinity is estimated to be as much as 20-25% with approximately 70% of all consanguineous marriages involving first cousins. Studying the genetics of ET in the Turkish population, particularly in large consanguineous families, may identify novel genetic causes of ET that are also relevant to ET populations in the United States and worldwide. The proposed research has a high probability of success with our collaborators Drs Ozcelik and Tekinay's expertise in human genetics and functional studies together with an established resource of large consanguineous ET families. The specific aims of this planning grant are to: (1) further develop and solidify collaborations with the team in Bilkent and define the scope of the research that will be the focus of an R01 application, (2) assess the Bilkent team's resources and needs in order to successfully conduct the research, (3) implement cross-training between the United States and Turkish groups in the areas of human genetics, genetic epidemiology and risk factor assessment, genomics, clinical diagnosis, functional studies and personalized genomic medicine, and (4) conduct pilot studies to generate preliminary data necessary for an R01 application.

  Study phs001507

• Autism Sequencing Consortium (ASC)

  The ARRA Autism Sequencing Collaboration was created in 2010 bringing together expert large-scale sequencing center (at the Baylor College of Medicine, PI Richard Gibbs and the Board Institute of MIT and Harvard, PI Mark J. Daly) and a collaborative network of research labs focused on the genetics of autism (brought together by the Autism Genome Project and the Autism Consortium). These groups worked together to utilize dramatic new advances in DNA sequencing technology to reveal the genetic architecture of autism through comprehensive examination of the exotic sequence of all genes. The Autism Sequencing Consortium (ASC) was founded by Joseph D. Buxbaum and colleagues as an international group of scientists who share autism spectrum disorder (ASD) samples and genetic data. The PIs are Drs. Joseph D. Buxbaum (Icahn School of Medicine at Mount Sinai), Mark J. Daly (Broad Institute of MIT and Harvard), Bernie Devlin (University of Pittsburgh School of Medicine), Kathryn Roeder (Carnegie Mellon University, Matthew State and Stephan Sanders (University of California, San Francisco). The rationale for the ASC is described in Buxbaum et al. 2012, and this paper should be cited when referencing the data set. All shared data and analysis is hosted at a single site, which enables joint analysis of large-scale data from many groups. The ASC was first supported by a cooperative agreement grant to four lead sites funded by the National Institute of Mental Health (U01MH100233, U01MH100209, U01MH100229, U01MH100239), with additional support from the National Human Genome Research Institute. The NIMH recently renewed their support with a second grant (U01MH111661, U01MH111660, U01MH111658 and U01MH111662) to expand the project from 29,000 genomes to more than 50,000 exomes over the next 5 years. NHGRI provides ongoing sequencing support for the ASD through the Broad Center for Common Disease Genomics (UM1HG008895, Mark Daly, PI).

  Study phs000298

• Synthetic genotypes and phenotypes of 500.000 individuals

  The goal of our study is to establish a pipeline for creating synthetic genotype and phenotype data on a Biobank scale. Such data can be used for developing new methodologies of analysis of common and rare diseases without risking de-identifying the underlying samples.

  Study EGAS00001006552

• DAC for study: "Circulating tumour DNA abundance and potential utility in de novo metastatic prostate cancer"

  Dac EGAC00001001099

• Prostate Cancer and Normal Adjacent Prostate RNA-seq samples, NGS-ProToCol

  The dataset "Prostate Cancer and Normal Adjacent Prostate RNA-seq samples, NGS-ProToCol" includes 41 Normal Adjacent Prostate and 51 ribo-depleted Prostate Cancer RNA-seq samples. ---- Detection of fusion transcripts and their genomic breakpoints from RNA sequencing data Youri Hoogstrate, Malgorzata A. Komor, René Böttcher, Job van Riet, Harmen J. G. van de Werken, Stef van Lieshout, Ralf Hoffmann, Evert van den Broek, Anne S. Bolijn, Natasja Dits, Daoud Sie, David van der Meer, Floor Pepers, Chris H. Bangma, Geert J. L. H. van Leenders, Marcel Smid, Pim French, John W.M. Martens, Wilbert van Workum, Peter J. van der Spek, Bart Janssen, Eric Caldenhoven, Christian Rausch, Mark de Jong, Andrew P. Stubbs, Gerrit A. Meijer, Remond J.A. Fijneman, Guido Jenster

  Study EGAS00001002816

• PCa-LINES

  PCa-LINES: Ribo-minus RNA-seq of 4 patient samples and 2 PCa cell lines ---- Detection of fusion transcripts and their genomic breakpoints from RNA sequencing data Youri Hoogstrate, Malgorzata A. Komor, René Böttcher, Job van Riet, Harmen J. G. van de Werken, Stef van Lieshout, Ralf Hoffmann, Evert van den Broek, Anne S. Bolijn, Natasja Dits, Daoud Sie, David van der Meer, Floor Pepers, Chris H. Bangma, Geert J. L. H. van Leenders, Marcel Smid, Pim French, John W.M. Martens, Wilbert van Workum, Peter J. van der Spek, Bart Janssen, Eric Caldenhoven, Christian Rausch, Mark de Jong, Andrew P. Stubbs, Gerrit A. Meijer, Remond J.A. Fijneman, Guido Jenster bioRxiv 2021.05.17.441778; doi: https://doi.org/10.1101/2021.05.17.441778 https://www.biorxiv.org/content/10.1101/2021.05.17.441778v1

  Study EGAS00001004613

• Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA

  These data relate to Abbosh et al 2023 'Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA'. Some patients were included in this work that were excluded from the other TRACERx 421 papers (Frankell et al and Al-bakir et al) often due to exclusion criteria in the TRACERx clinical trial. Reasons include partial contamination with C&gt;A artefact mutational signature (CRUK0480 ,0490) which were included for ctDNA detection analyses using high confidence clonal mutations but not clonality analyses, incomplete resection at primary surgery (CRUK0291, 0234, 0230, 0387, 0622) and a concurrent oesophageal second primary cancer (CRUK0498). The primary tissue exome sequencing for these patients that were used in this study are included in this repository. Deep targeted sequencing of (median 200) tumour specific mutations in plasma for 1069 samples from 198 TRACERx patients are also included. Additional details related to these patients and samples can be found in the supplementary or data repositories from Frankell et al and Abbosh et al.

  Study EGAS00001006923

• McGill EMC Community projects Release 7 for cell line "hTERT RPE1"

  Complete reference epigenome (as defined by IHEC) of normal hTERT RPE1 cell line as well as hTERT RPE1 cell lines engineered to express EPC1-PHF1 and JAZF1-SUZ12 fusion proteins, found in Endometrial Stromal Sarcoma.

  Dataset EGAD00001007680

• WES+WGS OSCCs Boot et al. 2018

  WES of 18 OSCCs with paired normal (blood)WGS of TC1 and 62074759 (exomes previously published in Vettore et al. genome medicine 2015)

  Study EGAS00001003131

• MYCN Amplification and ATRX Mutations are Incompatible in Neuroblastoma

  Age and stage of disease at diagnosis is associated with outcome in neuroblastoma. A previous study identified ATRX point mutations and in-frame deletions in older patients with stage 4 disease. To validate the frequency of ATRX mutations and assess the relation of mutations and known prognostic variables, we collaborated with the Children’s Oncology Group and sequenced the entire ATRX genomic locus in 475 neuroblastoma tumor samples to validate the frequency of ATRX mutations and assess the relation of mutations and known prognostic variables. Older age at diagnosis, stage 4 disease, and unfavorable histology were significantly associated with mutations in the ATRX gene; MYCN amplification was mutually exclusive from ATRX mutations. To directly test if ATRX mutations and MYCN amplification are incompatible in neuroblastoma, we mutated the ATRX gene in MYCN amplified neuroblastoma cell lines and ectopically expressed MYCN in ATRX mutant neuroblastoma cell lines. Both approaches showed that ATRX and MYCN amplification are incompatible in neuroblastoma in culture and in vivo. To gain a better understanding of the underlying molecular and cellular mechanisms of this incompatibility, we performed a series of experiments including telomere analysis, epigenetic profiling, electron microscopic analysis and metabolic profiling. We discovered that induction of MYCN expression in ATRX mutant neuroblastomas cells leads to metabolic reprogramming, mitochondrial dysfunction, increased reactive oxygen species and replicative stress. We propose that this leads to synthetic lethality in ATRX mutant neuroblastomas because of the underlying replicative stress in those cells as a result of dysfunction of this essential histone chaperone.

  Study EGAS00001003257

• Whole exome sequencing of SU- DIPG-XIII from different sites

  Whole exome sequencing of diffuse intrinsic pontine glioma (DIPG) cells isolated from the pons and from a sub-ventricular zone site of spread within the frontal lobe from the same individual (SU- DIPG-XIII)

  Dataset EGAD00001003563

• Single-cell RNA sequencing of human skin tumors (BCC, SCC and Melanoma)

  Cancer-associated fibroblasts (CAFs) play a key role in cancer progression and treatment outcome. Here, we elucidate the yet unresolved intra-tumoral CAF variety in three skin cancer types at molecular and spatial single-cell resolution in a large cohort. We show that two out of three CAF subtypes contribute to tumor immune surveillance with distinct mechanisms. Matrix CAFs (mCAFs) ensheath tumor nests and synthesize extracellular-matrix to prevent T cell invasion. Immunomodulatory CAFs (iCAFs), which express proinflammatory and immunomodulatory factors, are only detected in high abundance in aggressive tumors. Strikingly, iCAFs but not tumor cells are (apart from immune cells) the exclusive cell type producing chemokines and, thus, play a key role in immune cell recruitment and activation. Mechanistically, we show that cancer cells transform adjacent healthy fibroblasts into cytokine-expressing iCAFs, which subsequently recruit immune cells and modulate the immune response. In conclusion, targeting CAF variants holds promise for improved efficacy of immunotherapy.

  Study EGAS50000000365

• Single-cell RNA-seq of immune cells sorted from human melanoma tumors

  Tumor immune cell compositions play a major role in response to immunotherapy but the heterogeneity and dynamics of immune infiltrates in human cancer lesions remain poorly characterized. Here we identify conserved intratumoral CD4 and CD8 T cell behaviors in scRNA-seq data from 25 melanoma patients. We discover a large population of CD8 T cells showing continuous progression from an early effector "transitional" into a dysfunctional T cell state. CD8 T cells that express a complete cytotoxic gene set are rare, and TCR sharing data suggest their independence from the transitional and dysfunctional cell states. Notably, we demonstrate that dysfunctional T cells are the major intratumoral proliferating immune cell compartment and that the intensity of the dysfunctional signature is associated with tumor-reactivity. Our data demonstrate that CD8 T cells previously defined as exhausted, are in fact a highly proliferating, clonal and dynamically differentiating cell population within the human tumor microenvironment.

  Study EGAS00001003363

• Analysis of Somatic Mutations in Pediatric AML FAB-M7 Subtype by Whole Transcriptome Sequencing

  High resolution analysis of DNA copy number abnormalities and loss-of-heterozygosity on acute myeloblastic leukemia samples utilizing SNP arrays has demonstrated that in contrast to pediatric ALL, de novo AML is characterized by a very low burden of genomic alterations (Radtke, et al., PNAS, 2009). Samples for this study represented a cross-section of the different subtypes of pediatric AML. The only AML subtype that was an outlier from the above observations was acute megakaryocytic leukemia (AML FAB-M7), with the majority of these cases being characterized by complex chromosomal rearrangements and a high number of copy number alterations. To more fully define the genomic landscape of this subtype, we performed transcriptome sequence analysis on 14 pediatric FAB-M7 cases and mutation recurrence screening in a panel of 62 adult and pediatric AML FAB-M7 samples using the Illumina platform. Our results identified chromosomal rearrangements resulting in the expression of novel fusion transcripts in 11/14 cases. Remarkably, in 7/14 cases we detected an inversion on chromosome 16 that results in the juxtaposition of the CBFA2T3 gene next to the GLIS2 gene resulting in a CBFA2T3-GLIS2 chimeric gene that encoded an in frame fusion protein. This fusion led to the acquisition or preservation of self-renewal in colony forming assays, providing functional evidence for a role in leukemogenesis. In addition to novel chimeric transcripts, we found mutations in genes previously identified to play a role in megakaryoblastic leukemia that carry a proliferative advantage to the cell, such as JAK2 and MPL. These data demonstrate that AML FAB-M7 is characterized by cooperating Class I and Class II mutations leading to leukemogenesis.

  Study phs000413

• Institute of Pathology at the University Hospital of Lausanne CHUV

  Prof Laurence de Leval

  Dac EGAC50000000314

• Genetics of Cerebral Hemorrhage with Anticoagulation (GOCHA)

  This is a prospective, longitudinal cohort study of spontaneous ICH. Subjects were recruited from among consecutive patients &#8805; 55 years old who presented with primary hemorrhage to the Massachusetts General Hospital or one of our off-site collaborators from 1999 to 2010. Potential subjects were identified by screening lists of all admissions to the neurology and neurosurgery inpatient services. All patients underwent routine clinical evaluation, including history taking and physical examination, laboratory testing, and computed tomography of the brain.

  Study phs000416

• Childhood Cancer Data Initiative (CCDI): Pediatric In Vivo Testing Program – Sarcomas and other Solid Tumors

  The primary goal of this project involves the comprehensive molecular profiling of patient-derived xenograft (PDX) mouse tumor models. Molecular profiling of each PDX model will include whole exome sequencing (WES), RNAseq, MethylEPIC arrays, CytoSNP array, and DNA fingerprint for quality control. Limited clinical demographic data (e.g. diagnosis, disease site, disease status) will be obtained. This data can be utilized to validate PDX models with matched patient tumors and can be used to guide model selection for downstream preclinical drug testing.

  Study phs003161

• scRNAseq of human primary nasal epithelium differentiated at air-liquid interface exposed to SARS-CoV2

  The nasal epithelium is a plausible entry point for SARS-CoV-2, a site of pathogenesis and transmission, and may initiate the host response to SARS-CoV-2. Antiviral interferon responses are critical to outcome of SARS-CoV-2. Yet little is known about the interaction between SARS-CoV-2 and innate immunity in this tissue. Here we applied single-cell RNA sequencing and proteomics to a primary cell model of human primary nasal epithelium differentiated at air-liquid interface.

  Study EGAS00001005633

• TRanscriptomic ANalySis of left ventriCulaR gene Expression (TRANSCRibE)

  Myocardial ischemia occurs when there is a mismatch between coronary oxygen delivery and metabolic requirements of the myocardium, which may be clinically manifested during angina, coronary angioplasty or cardiopulmonary bypass (CPB). Myocardial ischemia may lead to a spectrum of myocardial stunning, hibernating myocardium, and ultimately cell death if the ischemic insult is severe. In the human heart, irreversible damage begins after approximately 20 to 40 minutes of oxygen deprivation. Observed molecular and cellular changes of myocardial ischemia are characteristic of an inflammatory response, but the exact mechanisms that underlie this pathological process are unclear and may not be full emulated by animal models of ischemia or infarction. Thus, we felt it valuable to investigate a human ischemia model. During cardiac surgery, CPB with aortic cross-clamping (AoXC) and cardioplegic arrest is associated with excellent clinical outcomes and suitable operative conditions. However, despite the use of cardioprotective strategies, AoXc during CPB is accompanied by a variable, yet obligate ischemic period lasting 1 to 3 hours, resulting in hypoxia, metabolic substrate depletion, reperfusion injury, apoptosis, and necrosis. Cardiac specific biomarkers of ischemia and infarction, including troponin, are elevated even after routine coronary artery bypass graft surgery and correlate with the duration of ischemia from AoXc.This process of CPB provides us with the ability to examine the transcriptional profile before and after an expected, consistent, and reproducible human ischemic event, albeit induced by cold cardioplegic arrest and not coronary occlusion. In addition, the absence of reperfusion in this time period allows us to examine the transcriptomic response to intermittent ischemia, without having to account for the perturbations of reperfusion injury. Although various animal models have been used to examine the effects of ischemia on cardiac function, no human data exist which examine the early transcriptomic response to a left ventricular (LV) ischemic insult. We therefore characterized the effect of cold cardioplegia induced acute ischemia on the transcriptional profile of the LV by performing whole transcriptome next-generation RNA-sequencing (RNA-seq) in patients undergoing cardiac surgery by sampling human LV tissue prior to, and after, the obligate ischemia during AoXC. We hypothesized that the cold cardioplegia induced ischemic injury will dramatically alter transcription in the human myocardium, and that we would identify genes and pathways, which will identify interventional targets for pharmacological therapy. Methods:We have collected left ventricle tissue samples and blood sample from patients undergoing heart surgery. We obtained punch biopsies (~3-5&#956;g total RNA content) from the site of a routinely placed surgical vent in the anterolateral apical left ventricular wall of patients undergoing elective aortic valve replacement surgery with cardiopulmonary bypass. After an average of 79 minutes of aortic cross-clamping with intermittent cold blood cardioplegia for myocardial protection every 20 minutes, a second biopsy was obtained in the same manner. Tissue samples were immediately placed in RNAlater&#174; (Ambion, ThermoFisher Scientific, Waltham, MA), and after 48 hours at +4&#176;C were stored at -80&#176;C until RNA extraction. Total RNA was isolated with Trizol and RNA quality was assessed using the Agilent Bioanalyzer 2100 (Agilent, Santa Clara, CA). Libraries were prepared by poly(A) mRNA isolation and reverse transcription Polymerase Chain Reaction (RT-PCR), then sequenced on the Illumina HiSeq2000 or HiSeq2500 (Illumina, San Diego, CA). As samples were analyzed at different times, different read lengths were employed, initially using single-end reads (n=20) and then transitioning to paired end reads (n=216), ranging from 36 - 100 base pairs. Raw sequencing files were processed using Sickle, Skewer, and STAR software, and aligned to GrCh37 or UCSC Hg19. DNA was isolated from whole blood using standard methods. SNP genotyping was performed using the Illumina Omni2.5Exome-8 BeadChip array with additional exome content (Illumina, San Diego, CA) chip, version 1.1. We first phased and imputed 93 subjects using a phasing tool called SHAPEIT and an imputation tool called MINIMAC, with 1000 Genomes phase 1 version 3 for the reference panel. We then phased and imputed 26 more subjects using SHAPEIT, an imputation tool called IMPUTE2, and 1000 Genomes phase 3 version 5.

  Study phs001679

• Multi-focal genomic dissection of synchronous primary and metastatic tissue from de novo metastatic prostate cancer - Data Access Committee

  Dac EGAC00001002905

• DAC for the BCTL

  DAC for submissions from the BCTL (Hopital Jules Bordet, Université LIbre de Bruxelles)

  Dac EGAC50000000323

• Grady Trauma Project (GTP)

  Not everyone exposed to traumatic experience develops Posttraumatic Stress Disorder (PTSD). Genetic background is one of the predisposing risk factors causing differential outcomes of trauma exposure. A primary goal of the Grady Trauma Project (GTP) is to pinpoint and understand genetic polymorphisms that contribute to development of PTSD. Both PTSD diagnosis binary labels and PTSD severity scores are studied as target phenotypes. Also, both candidate gene studies and genome-wide association studies are performed. Besides genetic variants, other measurements that are studied as risk factors for PTSD include lifetime history of trauma and peri-traumatic response. Study participants are primarily African American, trauma-exposed populations of low socioeconomic status recruited from Grady Memorial Hospital in Atlanta.

  Study phs002046

• Identification and functional characterisation of a rare MTTP variant underlying familial non-alcoholic fatty liver disease

  We identified a rare causal variant in MTTP, c.1691T&gt;C p.I564T (rs745447480) encoding microsomal triglyceride transfer protein (MTP) causing progressive non-alcoholic fatty liver disease with cirrhosis and hepatocellular carcinoma unrelated to metabolic syndrome, without manifestations of abetalipoproteinemia, in a four generation family with South Asian ancestry. Variant-expressing hepatocyte-like-cells (HLCs) derived from human induced pluripotent stem cells generated from homozygous donor skin fibroblasts had lower lipoprotein ApoB secretion, compared to wild type cells. Cytoplasmic triglyceride accumulation in HLCs triggered endoplasmic reticulum stress, secretion of pro-inflammatory mediators, production of reactive oxygen species, delineating the progression of disease associated with homozygosity for MTTP p.I564T

  Study EGAS00001005254

• Somatic Mutational Analysis by Exome Sequencing Endometrial Carcinosarcomas

  The purpose of this study was to identify somatic (tumor-specific) mutations in endometrial carcinosarcoma tumor exomes. The dataset was generated at the NIH Intramural Sequencing Center (NISC) and NHGRI by next generation sequencing the exomes of 14 de-identified primary tumor DNAs and matched non-tumor DNAs.

  Study phs001152

• Data Access Committee for the DNA sequencing data included in the study "Multifocal cohort analysis unveils cell types associated with regional lymph node seeding in prostate cancer".

  A data transfer agreement (DTA), based on the example DTA provided by UZ Gent, is to be filled out by the requester and Multifocal RNA-seq and tNGS data from primary and metastatic tissues of locally advanced and de novo metastatic cohorts - Data Access Committee. https://www.uzgent.be/nl/over-uz-gent/organisatie/data-access-comite/wat-zijn-de-opdrachten-van-het-data-access-comite Coordinator: Muriel Fouquet E-mail: dataaccesscommittee@uzgent.be

  Dac EGAC50000000930

• Non-coding mutations drive persistence of a founder pre-leukemic clone which initiates late relapse in T-ALL

  T-ALL relapse usually occurs early but can occur much later, which has been suggested to represent a de novo leukemia. However, we conclusively demonstrate late relapse can evolve from a pre-leukemic subclone harbouring a non-coding mutation that evades initial chemotherapy.

  Study EGAS50000000129

• Single cell Transcriptomic Analysis of Cellular Heterogeneity in Human Colorectal Tumors

  1,591 single cells from 11 colorectal cancer patients were profiled using Fluidigm based single cell RNA-seq protocol to characterized cellular heterogeneity of colorectal cancer. 630 single cells from 7 cell lines were profiled similarly to benchmark de novo cell type identification algorithms.

  Study EGAS00001001945