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• Catalogue Statistics

  EGA Statistics Bibliography Growth Community Archive Distribution Catalogue What is in the EGA? The European Genome-phenome Archive (EGA) overview The EGA archives and distributes the results of several types of studies. Such studies include genome-wide association studies (GWAS), different purpose sequencing and molecular diagnosis assays among others. Moreover, these studies target many different kind of diseases from cancer to neurodegenerative alterations. We summarised all this data in the charts below. The statistics are computed daily based on an updated list of studies. Each pie chart depicts a different aspect of the studies: which disease type was studied, which type of sampling method was used and what was the scope of the genomic analysis. Number of studies per disease type Studies in the EGA by disease barHorizontalChart('disease-graph', 'https://stats.ega-archive.org/catalog/by_disease') Number of studies per technology type Studies in the EGA by technology barHorizontalChart('technology-graph', '/stats/studies/technology', 'Include dbGaP') Number of studies per sample type Studies in the EGA by samples barChart('samples-graph', '/stats/studies/sample-types', 'Include dbGaP')

  Documentation about/statistics/catalogue

• A GWAS for cutaneous leishmaniasis in Brazil

  Our goal was to identify genetic risk factors for cutaneous leishmaniasis (CL) caused by Leishmania braziliensis. Genotyping 2066 CL cases and 2046 controls using Illumina HumanCoreExomeBeadChips provided data for 4,498,586 imputed single nucleotide variants (SNVs). Genome-wide association testing using linear mixed models took account of genetic diversity/ethnicity/admixture. Post-GWAS positional, expression quantitative trait locus (eQTL), and chromatin interaction mapping was performed in FUMA. Transcriptional data were compared between lesions and normal skin, and cytokines measured using flow cytometry and Bioplex assay.

  Study EGAS00001004596

• Massive parallel RNA sequencing of highly purified mesenchymal cells derived from bone marrow specimens of 45 low-risk myelodysplastic syndrome cases

  Highly purified mesenchymal cells (CD45-/7AAD-/CD235a-/CD31-/CD271+/CD105+) were prospectively FACS-isolated from bone marrow specimens of 45 low-risk myelodysplastic syndrome (LRMDS) cases. Gene expression profiles (GEPs) of the 45 LRMDS have been compared to GEPs derived from likewise highly purified mesenchymal cells obtained from bone marrow specimens of healthy donors for the identification of inflammatory signatures. Additionally, an overlap in inflammatory signatures has been determined by comparing the GEPs of these 45 LRMDS cases to the GEPs of 4 Shwachman-Diamond syndrome and 3 Diamond-Blackfan anemia cases, both representing different subclasses of congenital pre-leukemia syndromes with a tendency of leukemic progression and perturbed niche compartment. Finally, the GEPs and gene expression signatures have been utilized for prognostication and the prediction of leukemic progression.

  Dataset EGAD00001002658

• Lung cancer organoids addition

  Organoids are self-organizing 3D structures grown from stem cells that recapitulate essential aspects of organ structure and function. Here we describe a method to establish long-term culture conditions of human airway epithelial organoids that contain all major cell populations and allow personalized human disease modelling. We collected macroscopically inconspicuous lung tissue from non-small-cell lung cancer (NSCLC) patients undergoing medically indicated surgery and isolated epithelial cells to engineer 3D organoids. We exploit the potential to derive sub-clones from AOs to demonstrate the feasibility of CRISPR gene editing. Finally, we show that AOs readily allow modelling of viral infections such as RSV and for the first time demonstrate the possibility to study neutrophil-epithelium interaction in an organoid model. Taken together, we anticipate that human AOs will find broad applications in the study of adult human airway epithelium in health and disease.

  Dataset EGAD00001004943

• single cell RNA-seq of peripheral blood from analysis in infants with MLL-rearranged Acute Lymphoblastic Leukemia

  This dataset contains two experiments. 1) Single cell RNA-seq of peripheral blood diagnostic samples from patients with MLL-rearranged infant ALL that underwent relapse or not (samples ending in R relapsed, samples ending in N did not), sequenced with SORT-seq (see cell systems, 2016, doi:10.1016/j.cels.2016.09.002). For some of the patients, multiple indipendent plates were produced (each plate is a sample). Barcode-well correspondence can be found here: https://bitbucket.org/princessmaximacenter/sharq/src/master/data/celseq2_bc384-v4.csv . 2) Single cell RNA-seq of peripheral blood diagnostic samples from patients with MLL-rearranged infant ALL that underwent relapse or not (samples ending in R relapsed, samples ending in N did not), sequenced with10x Genomics Version 2.

  Dataset EGAD00001007752

• Bulk-tissue paired-end RNA-sequencing of anterior cingulate cortex samples derived from Lewy body disease patients

  Profiling of 24 human anterior cingulate cortex samples by bulk-tissue RNA-sequencing. Samples were derived from 5 non-neurological control individuals and 19 individuals with Lewy body disease (Parkinson’s disease = 7 individuals; Parkinson’s disease with dementia = 6 individuals; dementia with Lewy bodies = 6 individuals). Paired-end FASTQ files for each of the human samples are provided and are denoted by the suffixes R1 (read 1) and R3 (read 2). Fastp (v 0.20.0), a fast all-in-one FASTQ pre-processor, was used for adapter trimming, read filtering and base correction. Fastp default settings were used for quality filtering and base correction. Further details on parameters used are available here: https://github.com/RHReynolds/RNAseqProcessing/blob/master/QC/prealignmentQC_fastp_PEadapters.R.

  Dataset EGAD00001007698

• Prediction of HLA genotypes using NGS data

  High-precision human leukocyte antigen (HLA) genotyping is crucial for anti-cancer immunotherapy, but existing tools predicting HLA genotypes using next-generation sequencing (NGS) data are insufficiently accurate. We compared the availability and accuracy of eight HLA genotyping tools (OptiType, HLA-HD, PHLAT, seq2HLA, arcasHLA, HLAscan, HLA*LA, and Kourami) using 1,275 cases from the 1000 Genomes Project data and created a new HLA-genotyping algorithm combining tools. Then, we assessed the new algorithm’s performance in 39 in-house samples with normal whole-exome sequencing (WES) data and polymerase chain reaction–sequencing-based typing (PCR-SBT) results.

  Dataset EGAD00001007733

• Plasma cfDNA dsDNA and ssDNA shallow whole genome and exome sequencing data

  This dataset includes fastq files from sWGS and exome sequencing data derived from dsDNA and ssDNA libraries of plasma cfDNA samples extracted by a column- or bead-based DNA extraction method

  Dataset EGAD00001007019

• COVID-19 Severity First Wave of Infection for Severe Patients in Madrid

  We recruited 98 hospitalised patients displaying severe COVID-19 symptoms from the first wave of infection. A stringent exclusion criteria based on non-genetic factors such as age, blood oxygen, radiologic findings and other typical COVID-19 signs was performed. Gingival or peripheral blood samples were taken for 98 individuals and whole exome sequencing performed using ExomeCapture-Seq capture KAPA HyperExome on Illumina machines.

  Dataset EGAD00001008464

• RNA-seq of high-grade serous ovarian cancer in long-term survivors (MOCOG study)

  RNA-seq dataset of high-grade serous ovarian cancer (HGSC) tumours from long-term survivors performed as part of the Multidisciplinary Ovarian Cancer Outcomes Group (MOCOG) study. The dataset includes fastq files from 56 HGSC tumours (53 primary tumours and 3 recurrent tumours) from 53 long-term survivor patients. Libraries were generated using the Illumina Stranded mRNA Prep and 150 bp paired-end sequencing was performed to a minimum of 100 million reads on Illumina NovaSeq 6000 instruments.

  Dataset EGAD00001008537

• Germline RUNX1 Variation and Predisposition to Childhood Acute Lymphoblastic

  Somatic mutations of RUNX1, which encodes the myeloid and lymphoid transcriptional factor RUNX1, are common in both B- and T- acute lymphoid leukemia (ALL) and are associated with poor prognosis of T-ALL. However, there has been no comprehensive investigation of the pattern or prevalence of RUNX1 germline mutation in both B- and T-ALL. Here we report germline RUNX1 variants in 1.23% of B-ALL and 2.11% of T-ALL, identifying 31 unique variants in 62 B-ALL and 18 unique variants in 26 T-ALL children. The majority of frameshift and nonsense variants affected RUNX1 function in transcriptional regulation, hematopoiesis, and cellular proliferation. We identified JAK3 as the most frequent somatic mutation in T-ALL with RUNX1 variants. These results not only identify RUNX1 as a leukemia predisposition gene but also further underline the importance of germline genetic variants to the development of ALL

  Dataset EGAD00001007793

• Garvan/St Vincent’s Prostate Cancer Tissue and Data

  The cohort (n=53) consists of prostate cancer patients from Australia. For each patient, a pair of blood and tumour samples were collected. The sequencing data was mapped to hg38 reference. Blood BAMs are named with “-B” as suffix and tumour BAMs are named with “-T” as suffix.

  Dataset EGAD00001009066

• RNA sequencing of end-stage kidney disease patients with COVID-19

  This dataset contains paired RNA sequencing data for end-stage kidney disease (ESKD) patients on dialysis. There are two cohorts. The first includes 179 samples from 51 COVID-19 patients recruited during the initial phase of the COVID-19 pandemic (April-May 2020) and 55 non-infected ESKD patients as controls. 17 patients initially recruited as controls as part of the Wave 1 cohort were later infected with COVID-19 in January-March 2021. We acquired a total of 90 samples during the acute infection and convalescent samples for 12 of the 17 patients following the acute COVID-19 episode. RNA-seq counts and full clinical metadata for these cohorts are available without restriction from Zenodo (https://doi.org/10.5281/zenodo.6497251).

  Dataset EGAD00001009752

• Leiomyosarcoma Whole Genome Sequencing

  DNA was extracted from fresh frozen LMS material for 29 untreated tumors (24 primary tumors, 5 metastatic 13 relapses) and 13 tumors treated with radiation (7 primaries, 6 metastatic relapses). DNA from matched blood was used as a normal reference. Whole-genome sequencing was performed using established protocols on Illumina instruments.

  Dataset EGAD00001007722

• Rare Disease Synthetic Dataset

  The purpose of this project is to provide public human datasets for the study of rare diseases. The use of public human genomic background combined with the in-silico insertion of real disease-causing variants enable to have a representative dataset for testing purposes without facing ethical and legal issues associated with the use of human sensitive data. This project aims to help development of technical implementations for rare disease data integration, analysis, discovery, and federated access.

  Dataset EGAD00001008392

• Atypical teratoid/rhabdoid tumors (ATRT) are comprised of three epigenetic subgroups with distinct enhancer landscapes

  Atypical teratoid/rhabdoid tumor (ATRT) is one of the most common brain tumors in infants and young children. Although the prognosis of ATRT patients is poor, some patients respond very well to current treatments, suggesting inter-tumor molecular heterogeneity. To investigate this further, we genetically and epigenetically analyzed a large cohort of ATRTs (n = 170). Three distinct molecular subgroups of ATRTs, associated with differences in demographics, tumor location and type of SMARCB1 alterations, were identified using DNA-methylation or gene expression analyses. Whole genome DNA- and RNA-sequencing found no other recurrent mutations explaining the differences between subgroups. However, whole genome bisulfite-sequencing and H3K27Ac ChIP-sequencing of primary tumors revealed clear differences in methylation patterns and enhancer landscapes, leading to the identification of subgroup-specific regulatory networks.

  Dataset EGAD00001001444

• Targeted Sequencing of 173 genes

  Targeted sequencing of 173 genes in 2433 primary breast tumours. Data includes 2433 tumour samples, 523 adjacent normal (breast) samples and 127 blood samples. Libraries were prepared with Illumina's Nextera custom enrichment kit targetting all the exons of the most frequently mutated breast cancer genes. Libraries were multiplexed (48 libraries per lane) and sequenced on Illumina HiSeq 2000 (100bp paired-end reads). Somatic mutations were calling with a custom pipeline. We identified 40 mutation-driver (Mut-driver) genes, and determined associations between mutations, driver CNA profiles, clinical-pathological parameters and survival. We assessed the clonal states of Mut-driver mutations, and estimated levels of intra-tumour heterogeneity using mutant-allele fractions. The results emphasize the importance of genome-based stratification of breast cancer, and have important implications for designing therapeutic strategies. Referece: Pereira et al. (2016) The somatic mutation profiles of 2,433 breast cancers refines their genomic and transcriptomic landscapes. Nature Communications

  Dataset EGAD00001002115

• Comparison of transcriptional response of induced pluripotent stem (iPS) cell-derived and monocyte-derived macrophages to bacterial lipopolysaccharide stimulation

  In the first part of this project, we will differentiate IPS cells from 5 human donors into macrophages, and extract RNA from unstimulated and LPS stimulated macrophages to perform RNA sequencing. We will also extract RNA before and after stimulation in blood- derived macrophages from 5 additional, unrelated healthy samples. In the second part of the project, RNA-seq data will be analysed to compare LPS response of these two macrophage populations. In summary, we will perform 75bp PE RNA-seq on 20 samples (10 pre and post stimulus), on the HiSeq 2500 platform. Samples will be multiplexed at 5 samples / lane, so we will require 4 flow cells in total.This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Dataset EGAD00001001106

• Somatic L1 retrotransposition in normal colorectal epthelium

  Throughout an individual’s lifetime, genomic alterations accumulate in somatic cells. However, the mutational landscape induced by retrotransposition of long interspersed nuclear element-1 (L1), a widespread mobile element in the human genome, is poorly understood in normal cells. Here, we explored the whole-genome sequences of 406 normal colorectal clones, 12 MUTYH-associated adenomatous clones, and 19 matched colorectal cancer tissues. In addition, we analyzed promoter DNA methylation status of retrotransposition-competent L1 (in 139 clones) and read-through RNA expression profiles (in 116 clones) to investigate the epigenetic regulation of L1 activity.

  Dataset EGAD00001010183

• Ither2 WXS dataset - Implementation of pediatric precision oncology into clinical practice: The individualized Therapies for Children with cancer program “iTHER”

  iTHER is a prospective national precision oncology program aiming to define tumor molecular profiles in children and adolescents with primary very high-risk, relapsed, or refractory pediatric tumors in order to identify relevant aberrations to inform treatment.

  Dataset EGAD00001010178

• Ither2 RNA-Seq dataset - Implementation of pediatric precision oncology into clinical practice: The individualized Therapies for Children with cancer program “iTHER”

  iTHER is a prospective national precision oncology program aiming to define tumor molecular profiles in children and adolescents with primary very high-risk, relapsed, or refractory pediatric tumors in order to identify relevant aberrations to inform treatment.

  Dataset EGAD00001010179

• INSPIRE multi-timepoint cfMeDIP dataset

  This dataset contains raw sequencing data from multi-timepoint cell-free methylated DNA immunoprecipitation and sequencing (cfMeDIP-seq) of plasma samples from the INSPIRE study (NCT02644369). Details about the study, including inclusion/exclusion criteria and interventions are available at https://clinicaltrials.gov/study/NCT02644369. Briefly, five cohorts were included, INS-A (head & neck squamous cell carcinoma), INS-B (triple-negative breast cancer), INS-C (high-grade serous ovarian cancer), INS-D (melanoma), and INS-E (mixed solid tumors). All patients in the study were diagnosed with advanced cancer and received treatment with pembrolizumab. Plasma samples were collected at baseline and every 3 cycles until disease progression, death, loss of follow-up, or completion of the study. Plasma samples were first processed for cell-free DNA mutations and remaining samples were then processed by cfMeDIP-seq, prioritizing baseline and post-cycle 3 samples. In total, data from 204 timepoints from 87 distinct patients are deposited.

  Dataset EGAD00001011312

• Genetic Basis of Early Onset Bicuspid Aortic Valve Disease

  The study protocol was approved by the Committee for the Protection of Human Subjects at the University of Texas Health Science Center at Houston (HSC-MS-11-0185). Study recruitment began on July 1, 2017, and concluded on March 30, 2022. After written informed consent, we enrolled probands with early onset BAV disease (EBAV), which we defined as individuals with BAV who were under the age of 30 at the time of first clinical event. Clinical events were defined as aortic replacement, aortic valve surgery, aortic dissection, moderate or severe aortic stenosis or aortic regurgitation, large aneurysm (Z > 4.5), or intervention for BAV-related conditions. Those with hypoplastic left heart, known genetic mutations, genetic syndromes, or complex congenital heart disease were excluded. Samples were collected and genotyped as previously reported. For comparison, we analyzed a cohort of older individuals of European ancestry with sporadic BAV disease selected from the International BAV Consortium (BAVGWAS). Phenotypes were derived from record review with confirmation of image data whenever possible [25-26]. The computational pipeline for CNV analysis of Illumina single nucleotide polymorphism (SNP) array data included three independent CNV detection algorithms.GenomeStudio was used to exclude samples with indeterminate sex or more than 5% missing genotypes, and single nucleotide polymorphisms (SNPs) with GenTrain = 0. Principal component analysis was used to remove outliers that did not cluster with European ancestry. Prior to CNV analysis, each dataset was trimmed by selecting a common set of 650,000 SNPs that were genotyped on each of the microarrays used in this study.Three independent algorithms (PennCNV, cnvPartition, and QuantiSNP) were used to generate CNV calls and sample-level quality statistics from SNP intensity data. PennCNV and QuantiSNP were run on Unix clusters and cnvPartition data were exported from GenomeStudio. The analysis was run using default configurations. PennCNV was used to generate QC data and remove CNV calls that intersect with polymorphic genomic regions. Samples that met any of the following criteria were excluded, standard deviation of the LogR ratio (obtained from PennCNV) > 0.35 or number of CNVs > 2 standard deviations above the mean for each data set. CNV calls less than 20 Kilobases in length and/or spanned by fewer than 6 probes were excluded. The overlap function for rare CNVs in PLINK was used to construct CNV regions (CNVRs) after adjacent regions were merged using PennCNV. LogR ratio (LRR) and B allele frequency (BAF) data at CNVRs and calls of interest were visualized in GenomeStudio for validation. For segregation analysis, GenomeStudio was used to determine the presence of CNVs in relatives.A total of 22,014 unselected control Illumina Genotypes obtained from the Database of Genotypes and Phenotypes were analyzed using identical methods (S1 Table). The Wisconsin Longitudinal Study (WLS) includes data on a cohort of 10,300 individuals who graduated from Wisconsin high schools in 1957. The Health and Retirement Study (HRS) includes data on 37,000 individuals aged 50 above from 23,000 households across the United States. Principal component analysis was used to select European ancestry genotypes from these datasets for analysis. Datasets were paired for case-control analysis based on the concordance of log-transformed sample-level quality control statistics (number of CNV calls and standard deviation of logR ratios). Chi-squared or Fisher exact tests were used to compare CNV frequencies in cases and controls.Rare CNV functions in PLINK (v1.7) were used to perform permutation-based burden tests or gene set-based enrichment tests. Case control burden tests were restricted to CNVs that were longer than 110 Kb and less than 0.1% in frequency. CNV overlap functions in PLINK were used to identify rare CNVs that intersect between datasets or involve specific BAV or CHD genes . The list of candidate genes included 190 CHD genes that have strong cumulative evidence to cause BAV or related congenital malformations from human or animal model data. Genome Reference Consortium Human Build 37 was used for CNV annotation [34].

  Study phs003705

• Cellular Diversity of the Developing Human Cerebral Cortex

  We sought to characterize cellular heterogeneity in the human cerebral cortex at a molecular level during cortical neurogenesis. We captured single cells and generated sequencing libraries using the C1TM Single-Cell Auto Prep System (Fluidigm), the SMARTer Ultra Low RNA Kit (Clontech), and the Nextera XT DNA Sample Preparation Kit (Illumina). We performed unbiased clustering of the single cells and further examined transcriptional variation among cell groups interpreted as radial glia. Within this population, the major sources of variation related to cell cycle progression and the stem cell niche from which radial glia were captured. We found that outer subventricular zone radial glia (oRG cells) preferentially express genes related to extracellular matrix formation, migration, and stemness, including TNC, PTPRZ1, FAM107A, HOPX, and LIFR and related this transcriptional state to the position, morphology, and cell behaviors previously used to classify the cell type. Our results suggest that oRG cells maintain the subventricular niche through local production of growth factors, potentiation of growth factor signals by extracellular matrix proteins, and activation of self-renewal pathways, thereby contributing to the developmental and evolutionary expansion of the human neocortex. For study version 2, we have updated this data set to include additional primary cells that we infer to represent microglia, endothelial cells, and immature astrocytes, as well as additional cells from the developing neural retina, and from iPS-cell derived cerebral organoids. The genes distinguishing these cell populations may reveal biological processes supporting the diverse functions of these cell types as well as vulnerabilities of specific cell types in human genetic diseases and in viral infections. For study version 3, we have updated the data set to include additional primary cells, including those published in Nowakowski et al., 2017 (PMID:29217575). For study version 4, we have additionally performed parallel analyses of transcriptomes and physiological responses of 476 single cells isolated from developing human cortex. As a result, we were able to identify physiological response profiles of specific progenitor and neuronal cell types during human cortical development.For study version 5, we have additionally performed bulk RNA sequencing of organotypic primary cultures from the developing human cortex with or without exposure to SARS-CoV-2 to understand the infectability and transcriptomic effects of SARS-CoV-2 on the developing human cortex.For study version 6, we investigated the impact of LIFR signaling on neural proliferation and differentiation of human oRG cells. Specifically, we isolated oRG cells from the primary developing neocortex and cultured them for four weeks with and without LIF treatment. We then performed single-cell RNA sequencing using the Chromium Single Cell 3’ Reagent Kits (v3.1, Dual index) from 10x Genomics to understand the molecular and cellular changes of oRG differentiation upon LIF treatment.

  Study phs000989

• Privacy Notice for Helpdesk service

  Privacy Notice for EGA Helpdesk service This Privacy Notice explains what personal data is collected by the specific service you are requesting, for what purposes, how it is processed, and how we keep it secure. Note that this service collects personal data directly provided by the user, and also collects personal data from users that is provided by other organisations. 1. Who controls your personal data and how to contact us? European Genome- Phenome Archive - EGA offers a service for permanent archiving and sharing of all types of personally identifiable genetic and phenotypic data resulting from biomedical research projects, jointly managed by European Molecular Biology Laboratory – European Bioinformatics Institute (EMBL-EBI) and Fundació Centre de Regulació Genòmica - Centre for Genomic Regulation (CRG). EMBL-EBI and CRG represent joint Data Controllers’ of processing of your personal data. They and their Data protection officers may be contacted for data protection queries and for exercising your rights under Section 8. You may contact EMBL-EBI, represented by dr. Thomas Keane, by: email at: tk2@ebi.ac.uk or post at EMBL-EBI, Wellcome Genome Campus, CB10 1SD Hinxton, Cambridgeshire, UK. EMBL’s Data Protection Officer may be contacted by: telephone at +49 6221 387-8590, email at dpo@embl.org , or post at EMBL Heidelberg, Data protection officer, Meyerhofstraße 1, 69117 Heidelberg, Germany. You may contact CRG, whose EGA team is represented by dr. Jordi Rambla de Argila, by: email at jordi.rambla@crg.eu, or post at Fundació Centre de Regulació Genòmica - Centre for Genomic Regulation (CRG), Dr.Aiguader 88, PRBB Building, 08003 Barcelona, Spain. CRG Data protection officer may be contacted by: email at dpo@crg.eu post at Fundació Centre de Regulació Genòmica - Centre for Genomic Regulation (CRG), C/ Dr. Aiguader, 88, PRBB Building, 08003 Barcelona, Spain. 2. Which is the lawful basis for processing personal data? We process your personal data on the grounds of important public interest. For monitoring your activities on the website, we process your personal data on the grounds of important public interest. Such legal basis is found in Article 5(1)(a) of EMBL Internal Policy No 68 on General Data Protection (hereinafter IP 68), which is equivalent to Article 6 (1)(e) of the EU General Data Protection Regulation (hereinafter GDPR) and upon which personal data are processed for the achievement of the aims laid down in 1973 agreement establishing EMBL, such as the promotion of the cooperation in the fundamental research, in the development of advanced instrumentation and in advanced teaching in molecular biology and dissemination of information. 3. What personal data is collected from users of the service? How do we use this personal data? We collect the following personal data from users of the service: Name Email address Job title Date and time when the support request was sent We will use your personal data for the following purposes: To provide uninterrupted user access to the service To better understand the needs of the users and guide future improvements of the service To create anonymous usage statistics 4. Who will have access to your personal data? The personal data will be disclosed to: Authorised staff in the data controller’s institutions acting on data controller`s behalf and instructions. 5. Will your personal data be transferred to third countries (i.e. countries not part of EU/EEA) and/or international organisations? There are no personal data transfers to third countries or international organizations. 6. How long do we keep your personal data? Any personal data directly obtained from you will be retained as long as the service is live. Such duration serves the purpose of enabling scientific research and ensures legal compliance and facilitates internal and external audits if they arise. By contrast, the log files for the data categories related to anonymous usage statistics (raw web service logs) are processed only for 30 days and thereafter erased. 7. The joint Data Controllers provide these rights regarding your personal data You have the right to: Not be subject to decisions based solely on an automated processing of data (i.e. without human intervention) without you having your views taken into consideration. Request at reasonable intervals and without excessive delay or expense, information about the personal data processed about you. Under your request we will inform you in writing about, for example, the origin of the personal data or the preservation period. Request information to understand data processing activities when the results of these activities are applied to you. It must be clarified that rights under points 4 and 5 are only available whenever you need support whilst using our website. For other processing based on the grounds of important public interest you cannot exercise your rights to object, rectify or erase your personal data according to the Article 13(2)(a)(b) of IP 68 (equivalent to Article 17(3)(b)(d) and Article 21(6) of the GDPR). 8. Supervisory authority If you wish to complain against the processing of your personal data, you may do so by post at: EMBL Heidelberg, Data Protection Committee, Meyerhofstraße 1, 69117 Heidelberg, Germany, or Autoritat Catalana de Protecció de Dades (Catalan Data Protection Authority), C/Rosselló 214, Esc A, 1r 1a, Barcelona 08008, Spain. Published at: February 6, 2019

  Documentation data-protection/privacy-notice/ega-helpdesk

• Molecularly matched targeted therapies plus radiotherapy in patients with newly diagnosed glioblastoma without MGMT promoter hypermethylation (N2M2/NOA-20 phase I/IIa umbrella trial)

  Background: Patients with glioblastoma without MGMT promoter hypermethylation are unlikely to benefit from temozolomide (TMZ). Trials aiming at replacing TMZ with targeted agents in not molecularly selected patient populations have failed. Methods: This phase I/IIa umbrella trial aimed at showing safety, feasibility, and preliminary efficacy of targeted compounds in addition to standard radiotherapy initiated within 42 days postoperatively. Molecular diagnostics and bioinformatic evaluation are performed within 28 days after surgery. Stratification for treatment takes place in five subtrials, including alectinib, idasanutlin, palbociclib, vismogedib and temsirolimus, according to the best matching molecular alteration. Patients without matching alterations are randomized between subtrials without strong biomarkers using atezolizumab and asunercept and TMZ as standard of care. Primary objective of the phase I parts of the trial was dose finding or dose validation. In the phase IIa trials, centrally determined progression-free survival at six months (PFS-6) is used as endpoint for efficacy with interim analyses for futility (H0: p=0.231). Results: From May 2018 through July 2022, 301 patients were enrolled and 228 treated in 13 German NOA sites. The alectinib and vismodegib subtrials were closed since no molecularly matching patients were accrued; the idasanutlin subtrial was closed prior to the optimal dose at nine patients at discretion of the company providing the drug. The TMZ subtrial showed a PFS-6 of 18.52% (10/54 patients) (p=0.831) and a median overall survival (OS) of 12.1 months. Asunercept: PFS-6 of 15.4% (4/26) (p=0.8825) and OS of 12.8 months. Atezolizumab: PFS-6 of 21.4% (9/42) (p=0.660) and OS of 11.7 months. Palbociclib with patients demonstrating CDK4 amplification or CDKN2A/B codeletion: PFS-6 of 24.4% (10/41) (p=0.4823) and OS of 12.6 months. Temsirolimus with patients demonstrating mTOR activation: PFS-6 of 39.1% (18/46) (p=0.0109) and OS of 15.4 months. The regimen-limiting toxicity (RLT)-rate is 34.8%, which is insignificantly above the predefined unacceptable rate for RLTs of 30%. Most RLTs had severity grade 3, one RLT had severity grade 4. No RLTs resulted in death. Conclusions: N2M2 allows for elaborate molecular testing being integrated into the treatment decision and efficient determination of treatment activity for patients with newly diagnosed glioblastoma. There is clinical activity of temsirolimus in patients with tumors harboring an activated mTOR pathway although this is not positively prognostic without mTOR inhibition; there is no clinical activity for asunercept and atezolizumab in not molecularly selected patients and also palbociclib in molecularly selected patients.

  Study EGAS00001008033

• Analysis of the Whole Transcriptomes of Human Testis with Complete Spermatogenesis and of Human Testes with Sertoli Cell-Only Syndrome

  Sertoli cell-only syndrome is severe form of human male infertility in which most seminiferous tubules appear to lack all spermatogenic cells, including spermatogonial stem cells (SSCs). However, a few small tubule segments of some patients have active spermatogenesis and, thus, functional stem cell niches and SSCs. Normally SSCs replicate, migrate and refill adjacent empty niches, but this does not appear to occur in SCO syndrome. We hypothesized that this failure occurs because most niches are dysfunctional. As Sertoli cells are essential to formation of these niches, we used RNAseq to compare the transcriptomes of human testes with qualitatively normal (complete) spermatogenesis (n=4) with the transcriptomes of human testes with SCO syndrome (n=7). We then focused our analysis on the expression of transcripts that bioinformatic analyses identified as Sertoli cell signature transcripts. Results show that Sertoli cells in SCO testes express abnormally low levels of GDNF, FGF8 and BMP4, all of which are important regulators of mouse SSCs and/or progenitor spermatogonia. Sertoli cells in SCO testes express significantly reduced levels of transcripts for proteins that polarize the Sertoli cell plasma membrane and regulate the trafficking of cell adhesion and gap junction proteins in and out of that plasma membrane.

  Study phs001777

• Whole Transcriptome Sequencing of Human Tumor Cells and Hematopoietic Stem and Progenitor Cells During Aging and Bone Marrow Disorders

  Whole transcriptome sequencing analyses were performed on human hematopoietic stem and progenitor cells during aging and bone marrow disorders. For this purpose, normal and diseased bone marrow or peripheral blood-derived mononuclear cells were FACS-purified into hematopoietic stem (CD34+CD38-Lin-) or hematopoietic progenitor (CD34+CD38+Lin-) populations. Primary human samples from healthy individuals were used along with comparative analyses in some pre-malignant and malignant conditions, including myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and plasma cell dyscrasias (e.g., multiple myeloma). Studies were also performed on total mononuclear cell fractions from patients with newly-diagnosed or relapsed multiple myeloma, or plasma cell leukemia. Briefly, RNA was extracted from all samples and quality was assessed using a Bioanalyzer instrument. Only samples with RNA integrity (RIN) values >7 were subjected to library preparation for RNA-sequencing. The SMARTer v4 cDNA amplification kit was used along with library construction by the NEB Ultra DNA kit for Illumina. Paired-end sequencing was performed on Illumina NextSeq instruments (Scripps Next Generation Sequencing Core), with all samples run over two separate flow-cells (to generate additional sequencing reads); >95M reads were generated in total for each sample. The RNA-sequencing data are available as FASTQ files.

  Study phs002291

• Genetic Epidemiology of Lung Cancer Consortium GWAS of Familial Lung Cancer

  Familial lung cancer cases were collected by the Genetic Epidemiology of Lung Cancer Consortium (GELCC) recruitment sites: University of Cincinnati, Karmanos Cancer Institute at Wayne State University, Louisiana State University Health Sciences Center-New Orleans, Mayo Clinic, and Medical College of Ohio. Familial cases for this study came from three sources: 1) one case each from families (at least 3 affected lung cancer cases in the family) included in the linkage analysis; 2) one case from linkage-eligible families (at least 3 affected lung cancer cases in the family) but where there were insufficient biospecimens available to make them informative for linkage analysis; and 3) one case from families not eligible for the linkage study with a family history of at least one first or second degree relative affected with lung cancer. Unrelated controls were selected from 1) among the spouses of family members, thus matching on socio-economic status (SES) and ethnicity (typically) of the cases or 2) from case-control studies of lung cancer conducted in the same location in which the linkage families were collected and matched on age, sex, and race. All cases and controls self-reported as European American. Biospecimens used for normal DNA extraction included blood, saliva or mouthwash. Some samples underwent whole genome amplication.

  Study phs000629

• Genomic Sequencing of Cervical Cancers

  Cervical cancer is responsible for 10-15% of cancer related deaths in women worldwide. The etiological role of infection with high-risk human papilloma viruses (HPV) in carcinomas of the cervix is well established. In general, the development of cervical carcinomas follows a progression from persistent HPV infection through precancerous lesions to invasive cancer. Previous studies have implicated somatic mutations in PIK3CA, PTEN, TP53, STK11 and KRAS as well as chromosome-arm level copy number alterations in the pathogenesis of cervical carcinomas. Here, we report whole exome sequencing analysis of 118 cervical carcinoma-normal paired samples from patients in Norway and Mexico, as well as transcriptome sequencing of 80 cases and whole genome sequencing of 13 tumor-normal pairs. Novel somatic mutations include recurrent E322K substitutions in the MAPK1 gene encoding the ERK2 kinase and inactivating mutations in the HLA-B gene. In addition, recurrent somatic mutations in FBXW7, EP300, and NFE2L2 are novel in the context of primary cervical carcinomas. Analysis of HPV integration sites revealed recurrent integration into the RAD51B locus as well as co-occurrence of HPV genome integration and copy number gains within several genomic loci. These findings shed new light on the pathogenesis of cervical carcinomas and suggest potential novel therapeutic targets.

  Study phs000600

• International Multi-Center ADHD Genetics Project

  The goal of the project is to complete a 600,000 tag SNP genome-wide association scan of 958 parent-child trios from the International Multisite ADHD Genetics (IMAGE) project, in order to assess the association of SNP markers with ADHD, analyze quantitative ADHD phenotypes, complete copy number analyses, assess parent of origin effects and season of birth effects, and test for epistasis among apparently uncorrelated genes. Acquiring DNA Samples All consent forms stipulate that the samples can only be used by researchers who have been approved by the National Institute of Mental Health (NIMH), National Institutes of Health. All consent forms, except those used at the Zürich site (N=141 subjects), explicitly indicate that the samples may be used by researchers from commercial enterprises seeking to benefit financially from the analysis of the samples. The Zürich consent does not prohibit such use. The Zürich consent form also included an "opt out" that allowed the subjects to indicate that they did not want their samples stored at the NIMH repository or used by researchers external to the project. No subjects enrolled in the project opted out. Consent groups and participant set ADHD (ADHD): 2758 (924 trios)

  Study phs000016

• Genomic Studies of Gilles de la Tourette Syndrome

  This study consists of three components. The first component includes genome-wide association study (GWAS) data on 695 TS cases and 198 ancestry matched controls from the first TS GWAS of 1285 TS cases and 4964 ancestry matched controls. The second component includes genome-wide association study (GWAS) data on 2106 TS cases from the second TS GWAS of 2716 TS cases and 3762 ancestry matched controls. The third component consists of 438 individuals representing 146 probands with DSM-IV-TR diagnosed Tourette Syndrome and their parents (146 complete parent-offspring trios). These individuals are part of the whole exome sequencing study, aiming to use whole exome sequencing of TS parent-offspring to identify de novo protein-truncating variants (PTVs) that are present in the child with TS but not in either parent. All subjects were collected by the Tourette Association of America International Consortium for Genetics (TAAICG) at seven sites in the United States and Canada. Both affected individuals and unaffected relatives were assessed for the presence of Tourette Syndrome and Chronic (Persistent) Tic Disorder (CTD) using a standardized, semi-structured interview, which has high clinical validity and reliability for the diagnoses of TS and CTD (TSAICG, Am J Hum Genet, 2007 (PMID: 17304708)); Darrow et al., Psychiatric Research, 2015 (PMID: 26054936)).

  Study phs001380

• Integrated Genomic Analysis of Periampullary Tumors at The Human Genome Sequencing Center, Baylor College of Medicine (HGSC-BCM)

  Adenocarcinomas arising in the complex environment of the ampulla of Vater constitute a histopathological heterogenous group, presumably originating from the different epithelial cellular constituents present at the site: pancreas, bile duct, and intestinal duodenum. These tumors have been described in many different ways: intra-ampullary, periampullary, intra-ampullary papillary-tubular neoplasm, ampullary-ductal, periampullary-duodenal, and ampullary-not otherwise specified. These varied classifications reflect the difficulty in classifying these tumors into specific groups. Only the tumors clearly localized in the bile duct or duodenum are identified as distal cholangiocarcinomas (CAC) or duodenal adenocarcinomas (DUOAC). The current classification is based on macroscopic features that may distinguish the epithelium of origin, microscopic features, clinicopathological criteria, histopathology and expression of differential markers. This classification is subjective and prone to inter-observer variability and significantly impacts on treatment selection and therapeutic development. In order to define subtypes of periampullary cancer with clinical relevance, we performed whole exome sequencing and copy number analysis of 160 cancers arising in the periampullary region, 62 of these clearly arising from either the bile duct (n = 44), or the duodenum (n = 18) and 98 periampullary cancers (AMPAC) where the epithelium of origin could not be clearly defined.

  Study phs000895

• Trisomy21: Risk Factors for Chromosome Nondisjunction (T21NDJ)

  The overall goal of the project is to identify genetic risk factors associated with chromosome 21 nondisjunction in the oocyte. The dataset derives from multi-site collection of live birth probands with Down syndrome due to standard trisomy 21 (T21) and their biological parents. The type of nondisjunction error (NDJ)(maternal or paternal) in all cases has been determined to be maternal in origin based on the chromosome 21 variants contributed from parent to proband. The Center of Inherited Disease with support from NICHD has conducted genome-wide genotyping using the Illuminia Human OmniExpress Plus Exome array on approximately 800 women who have been identified through their offspring with DS and have been characterized as having a maternal meiois I (MI) or meiosis II (MII) nondisjunction error. Genotypes from biological fathers of the offspring with DS can be used with the data on mothers to better define the type of nondisjunction error (MI or MII) and to refine the chromosome 21 recombination profile. We provide the type of nondisjunction error, knowing that this will be updated based on the new panel. We do not provide the recombination profile, as this can be best defined using the new comprehensive set of SNPs in the OmniExpress panel.

  Study phs000718

• NIDDK IBD Genetics Consortium Repository Immunochip

  The Immunochip is a custom Illumina Infinium chip comprising 196,524 SNPs and small indels selected primarily based on GWAS analysis of 12 autoimmune and inflammatory diseases. The chip has two purposes: fine mapping of 289 established associations corresponding to 187 distinct loci, and deep replication of suggestive, but not yet proven, associations. Fine-mapping regions were defined as 0.2cM centered on GWAS hit SNPs, and all SNPs and short indels in these regions from the 1000 Genomes Project low coverage pilot CEU samples, as well as variants discovered in resequencing experiments conducted by groups collaborating in the chip design were selected for inclusion. Replication of autoimmune and inflammatory GWAS (including Crohn's disease and ulcerative colitis) contributed the bulk of the remaining SNP lists. Approximately 25,000 SNPs were included as replication of unrelated diseases as part of the WTCCC2 project, which serve as useful null SNPs for these analyses. In total, approximately 240,000 SNPs were selected for inclusion, with an assay design success rate of ~80%. Reprinted from Jostins et al. (2012), with permission from Springer Nature (see https://www.nature.com/reprints/permission-requests.html). Jostins, L., et al. (2012) Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature, 491, 119-24. PMID: 23128233.

  Study phs001721

• Tandem DNA Repeats Activate hTERT Gene Transcription

  Multiple independent sequence variants of the hTERT locus have been associated with telomere length and cancer risks in genome-wide association studies. Here, we identified an intronic variable number tandem repeat, VNTR2-1, as an enhancer-like element, which activated hTERT transcription in a cell and chromatin-dependent manner. VNTR2-1, consisting of 42-bp repeats with an array of E-boxes, cooperated with the proximal promoter in hTERT regulation by bHLH transcription factors and maintained hTERT expression during embryonic stem cell differentiation. Genomic deletion of VNTR2-1 in MelJuSo melanoma cells markedly reduced hTERT transcription, leading to telomere shortening, cellular senescence, and impairment of xenograft tumor growth. Interestingly, VNTR2-1 lengths varied widely in human populations.  To assess the genetic polymorphism of VNTR2-1 in human populations, we analyzed genomic DNA samples of Caucasian Americans and African Americans enrolled in the Georgia Centenarian Study.  VNTR2-1 in these genomic DNA samples were PCR amplified and subjected to sequencing analysis usinb the PacBio® SMRT method. The result showed that all VNTR2-1 alleles in Caucasian Americans contained 76 or more 42-bp repeats, whereas 32% of VNTR2-1 alleles in African Americans had fewer than 76 repeats.  

  Study phs002428

• PIEZO1 Loss of Function Compound Heterozygous Mutation in the Rare Congenital Human Disorder Prune Belly Syndrome

  Prune Belly Syndrome (PBS) is a rare congenital myopathy that is incompletely understood genetically. In this IRB approved study, one white Non-Hispanic 35 year-old male PBS proband was prospectively enrolled and phenotyped. Blood lymphocyte DNA from the proband underwent paired-end Whole Exome Sequencing using the Illumina SureSelect kit and HiSeq2500 sequencer with data pipeline analysis. We aligned the subject's sequence against the GRCh38/hg19 assembly and variant calling was performed using data training sets from the 1000 Genomes Project, Omni 2.5 M SNP microarray, and HapMap phase 3.3. These variants were filtered for rare minor allele frequency ( 0.9, CADD score > 20, GERP > 4, MutationTaster = “DC”, Mutation Assessor = “M” or “NE”, and Vest > 3.00. Rare and novel candidate functional variants were screened in the ClinVar database for prior association with smooth muscle myopathy (SMM). Only variants that met these criteria were included for further analysis. Confirmed variants had inheritance analysis performed on available samples. Our WES analysis identified novel compound heterozygous variants in the PIEZO1 gene. We conducted an extensive functional analysis of the PIEZO1 PBS variants that revealed loss-of-function characteristics. Thus, PIEZO1 mutations may be causal for PBS. Our WES data will be available through dbGaP.

  Study phs003475

• DEMENTIA-SEQ: WGS in Lewy Body Dementia and Frontotemporal Dementia

  Lewy body dementia, amyotrophic lateral sclerosis/frontotemporal dementia, and multiple system atrophy are age-related, neurodegenerative syndromes that are poorly understood. Delineating the genetic risk that is driving the pathophysiology of these neurological diseases is fundamental for understanding disease mechanisms and for developing disease-modifying treatments. In version 1 of the study/dbGaP deposition, we performed a whole-genome sequencing study consisting of 7,403 total samples, including 2,633 genomes from patients with Lewy body dementia, 2,641 frontotemporal dementia patients, and 1,980 neurologically healthy controls. Of these, 6,907 were uploaded to dbGaP as the basis of the DementiaSeq, phs001963 dataset. The data relating to these samples are available on dbGaP. In version 2 of this study/dbGaP deposition, we made much of these data available on Anvil. More specifically, data for 6,254 of these samples were also uploaded to the ALS Compute platform on AnVIL. The data for the remaining 653 samples are only available on dbGaP. The dbGaP/AnVIL Table lists the availability of dbGaP and AnVIL for each individual sample: phd008475.In version 3 of the study/dbGaP deposition, we added whole-genome sequence data generated using DNA samples obtained from 683 patients diagnosed with multiple system atrophy.

  Study phs001963

• Joint-Specific TF Regulation in RA

  The mechanisms responsible for the distribution and severity of joint involvement in rheumatoid arthritis (RA) are not known. To explore whether site-specific fibroblast-like synoviocyte (FLS) biology might be associated with location-specific synovitis and explain the predilection for hand (wrist/metacarpal phalangeal joints) involvement in RA, we generated bulk, whole-genome transcriptomic and chromatin accessibility data from FLS. Samples were matched in age, sex, and were homogeneous in that all had significant joint damage with longstanding disease requiring surgical intervention. Analysis revealed joint-specific patterns of FLS phenotypes, with proliferative, migratory, proinflammatory, and matrix-degrading characteristics observed in resting FLS derived from the hand joints compared with hip or knee. TNF-stimulation amplified these differences, with greater enrichment of proinflammatory and proliferative genes in hand FLS compared with hip and knee FLS. Hand FLS also had the greatest expression of markers associated with an ‘activated' state relative to the ‘resting' state, with the greatest cytokine and MMP expression in TNF-stimulated hand FLS. Predicted differences in proliferation and migration were biologically validated with hand FLS exhibiting greater migration and cell growth than hip or knee FLS. Distinctive joint-specific FLS biology associated with a more aggressive inflammatory response might contribute to the distribution and severity of joint involvement in RA.

  Study phs003633

• Pre-Existing Skin-Resident CD8 and γδ T Cell Circuits Mediate Immune Response in Merkel Cell Carcinoma and Predict Immunotherapy Efficacy

  Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with a ~50% response rate to immunotherapy. Here, we attempted to identify novel predictive biomarkers of response through extensive and deep multi-omics interrogation of 186 samples from 116 patients. We collectively integrated bulk RNAseq, single-cell RNAseq, multiplex immunofluorescence, and spatial transcriptomics. Importantly, we were also able to study 14 matched pairs of tissue samples from pre- and post-immunotherapy. In non-responders, tumors show evidence of increased tumor cell cycling, expression of neuronal stem cell markers, and IL-1α/β. Responders have evidence of increased type I/II interferon signatures and evidence of pre-existing tissue resident (Trm) CD8 or Vδ1 γδ T cells that functionally converge with overlapping antigen-specific transcriptional programs and clonal expansion of multiple T cell receptors. Spatial transcriptomics demonstrated higher co-localization of T cells with B and dendritic cells in responders, with evidence of expression of chemokines important for co-stimulation. Finally, immunotherapy increased clonal expansion or recruitment of Trm and Vδ1 cells in tumors in responders, further underscoring their therapeutic importance. These data identify potential novel actionable biomarkers and therapeutic targets for MCC.

  Study phs003629

• Chronic Renal Insufficiency Cohort (CRIC) - GWAS

  The Chronic Renal Insufficiency Cohort (CRIC study) was established in 2001 by the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK) to improve the understanding of the relationship between chronic kidney disease and cardiovascular disease. The goals of the CRIC Study are to examine risk factors for progression of chronic kidney disease and cardiovascular disease among patients with chronic kidney disease and to develop predictive models to identify high-risk subgroups, informing future treatment trials and increasing application of available preventive therapies. Data available at dbGaP include genotype data for 3527 participants released in version 1. Plasma metabolomics and plasma proteomics data will be available at dbGaP in "Chronic Renal Insufficiency Cohort (CRIC) Study Metabolomics and Proteomics". Additional phenotypic, clinical, and outcomes data are available at the NIDDK Central Repository and can be linked to data available at dbGaP. More than 330 manuscripts have been published, reporting on the effects of a broad range of risk factors (from molecular biomarkers of disease pathways to clinical, demographic, and behavioral characteristics) on the progression of CKD and other health consequences. The full CRIC bibliography can be found at http://cristudy.org/Chronic-Kidney-Disease/Chronic-Renal-Insufficiency-Cohort-Study/bibliography-2024-2023.

  Study phs000524

• Hematopoietic Tet2 inactivation enhances the response to checkpoint blockade immunotherapy

  Somatic mutations inactivating TET2 are among the most common drivers of clonal hematopoiesis (CH). While TET2 inactivation is associated with monocyte-derived inflammation and improved chimeric antigen-receptor-T cell function, its impact on immunotherapy response is unknown. In murine models, hematopoietic Tet2 mutation enhanced the immune checkpoint blockade (ICB) response via the combined presence of phagocytes, CD4 and CD8 T cells. This effect was lost with myeloid- or T-cell restricted Tet2 inactivation, or in mice with 20% Tet2-mutant hematopoiesis. Mechanistically, in Tet2-mutant tumor-infiltrating leukocytes (TILs), ICB preferentially restricted cell states linked to tumor progression while inducing anti-tumor states. Tet2-mutant monocytes activated costimulatory programs, while Tet2-mutant T cells showed enhanced T cell memory signatures, alongside decreased exhaustion and regulatory phenotypes. This murine data was clinically relevant, since tumors from colorectal cancer and melanoma patients with TET2 driver mutation-CH (TET2-CH) showed enhanced immune infiltration, inflammation, and T cell activation. In melanoma patients treated with ICB, TET2-CH was associated with 6-fold greater odds of clinical benefit. Collectively, we demonstrate that hematopoietic Tet2 inactivation primes leukocytes for anti-tumor states associated with immunotherapy response and provides a potential biomarker for personalized therapy.

  Study EGAS50000001191

• Rapid detection of expanded short tandem repeats in personal genomics using hybrid sequencing.

  Long expansions of short tandem repeats (STRs); i.e., DNA repeats of 2-6 nucleotides, are associated with some genetic diseases. Cost-efficient high throughput sequencing can quickly produce billions of short reads that would be useful for uncovering disease-associated STRs. However, enumerating STRs in short reads remains largely unexplored because of the difficulty in elucidating STRs much longer than 100 bp, the typical length of short reads. We propose ab initio procedures for sensing and locating long STRs promptly by utilizing the frequency distribution of all STRs and paired-end read information. We validated the reproducibility of this method using biological replicates and used it to locate an STR associated with a brain disease (SCA31). Subsequently, we sequenced this STR site in eleven SCA31 samples using SMRT? sequencing (Pacific Biosciences), determined 2.3-3.1 kb sequences at nucleotide resolution, and revealed that (TGGAA)- and (TAAAATAGAA)-repeat expansions determined the instability of the repeat expansions associated with SCA31. Our method could also identify common STRs, (AAAG)- and (AAAAG)-repeat expansions, which are remarkably expanded at four positions in an SCA31 sample. This is the first proposed method for rapidly finding disease-associated long STRs in personal genomes using hybrid sequencing of short and long reads.

  Study JGAS000002

• Genomic and Genetic Analysis of Brain Tumors and Analysis of Their Clinicopathological Significance

  The treatment outcome of glioma patients remains disappointing, and more studies are needed to improve therapeutic strategies. In particular, it is crucial to understand the mechanisms underlying resistance to treatment and malignant transformation, as well as the intratumoral heterogeneity and interaction of tumor cells and host immunity. Recent advances in omics analysis techniques, such as next-generation sequencing (NGS), have enabled us to obtain omics data more easily and accelerated our ability to integrate this information and precisely characterize cases. In our project, we have already collected more than 100 pairs of human glioma/normal tissue samples, of which some are multiple specimens collected from initial and recurrent tumors, and some include multiple specimens collected from different regions within a single tumor. We used our in-house algorithms, composed of alignment and variant calling programs, to analyze omics data from multiple platforms, such as whole-exome sequencing (WES), RNA sequencing (RNA-seq), and methylation array, with our original cohort of glioma patients. Using several informatics tools, the information about genetic and epigenetic status and expression signatures were analyzed. Those data are expected to provide key information for investigating the mechanisms discussed above. Through this project, we hope to improve strategies for personalized therapy based on comprehensive omics data.

  Study JGAS000004

• Emergence of oncofetal plasticity is ubiquitous in early colorectal cancers

  Metastasis formation is classically considered a late-stage event in colorectal cancer (CRC) evolution. Yet, the time and patterning by which metastatic competence is acquired remain poorly understood. Here, we show that metastasis-associated oncofetal cell states already emerge at the earliest stages of CRC, concurrent with invasive front formation. However, while necessary for metastasis, we detect them ubiquitously among early non-metastatic cancers, highlighting additional bottlenecks like immune evasion. To understand how oncofetal cells first emerge, we generated multiregional organoid models that reflect successive tumor progression stages within individual early-stage CRCs. Whole-genome sequencing and growth factor-dependency assays exclude tumor cell-intrinsic acquired traits. In contrast, single-cell spatial atlases of the tumor-microenvironment before and after malignant transformation revealed stereotypic patterning of fibroblast subtypes resembling normal tissue architecture, resulting in distinct regional microenvironments. At the onset of malignant growth into the submucosa, the first cancer-associated fibroblasts (CAFs) to appear strongly resemble submucosal trophocytes and colocalize with oncofetal cell states at invasive fronts. Functionally, fibroblast-organoid co-cultures confirm that these trophocyte-like CAFs induce plastic transitioning to oncofetal states. Thus, interactions between tumor and submucosal fibroblasts directly following malignant transformation dictate the timing and location at which oncofetal plasticity first occurs during CRC progression.

  Study EGAS50000001532

• Myeloid cell networks govern re-establishment of original immune landscapes in recurrent ovarian cancer

  Immunotherapy has produced disappointing results in recurrent ovarian cancer (OC). However, the prognostic value of tumour-infiltrating lymphocytes (TILs) is largely based on the analysis of treatment-naive tumours. To understand the immunobiology of recurrent cancers, and their evolution, we profiled a total of 697 OC tumour samples (566 primary and 131 recurrent including 69 patient-matched samples) from 595 patients of five independent multi-institutional cohorts. By capturing heterogeneous TIL distributions, we identified four immune phenotypes associated with differential prognosis, TILs states and TILs:myeloid networks, which dictate malignant progression after chemotherapy and recurrence. Notably, recurrent tumours recapitulate the immunogenic landscapes of original cancers. Mirroring inflamed human OC, preclinical recurrent Brca1mut tumours maintained activated TILs:dendritic cells (DCs) niches but evaded immune control through COX/PGE2 signaling upregulation. Conversely, recurrent Brca1wt tumours displayed loss of TILs:DCs niches and accumulated immunosuppressive myeloid networks featuring Trem2/ApoEhigh TAMs and Nduf4l2high/Galectin3high malignant states. Our study highlights that persistent immunogenicity in recurrent OC is governed by the BRCA-dependent crosstalk between dissimilar myeloid cells and TILs. We propose new targets to modulate the malignant and TAM compartments which improve efficacy of standard of care chemotherapy in mouse OC models with HR deficiency.

  Study EGAS50000001069

• Characterizing microbiome-directed fibre snacks in gnotobiotic mice and humans

  Knowledge of the interrelationships between what we eat and the configurations of our gut microbial communities is providing important insights into how food components that are not directly metabolized by human enzymes are linked to our physiology and health status. Changing food preferences brought about by Westernization that have deleterious health effects1,2, plus rapid population expansion, ongoing challenges to sustainable agriculture, and other forces contributing to increased food insecurity, are catalyzing efforts to identify more nutritious and affordable foods3. The gut microbial community is complex, dynamic, and exhibits considerable intra- and interpersonal variation in its composition and functions. The massive number of potential interactions between its components makes it challenging to define the mechanisms by which food ingredients affect community properties. There is also a paucity of information about the ‘bioactive’ ingredients of foods that influence the fitness and expressed functions of community members. Here, plant fibres, from different sustainable sources and targeting distinct features of obese human gut microbiomes in gnotobiotic mice, were formulated into snack prototypes and used to supplement controlled diets consumed by overweight and obese adults; the results revealed fibre-specific changes in their microbiomes that were linked to changes in their plasma proteomes indicative of altered physiologic state.

  Study EGAS00001005268

• MutWP1__CRUK_Grand_Challenge_Mutographs_of_Cancer__Colorectal

  he Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Different patterns of somatic mutation are generated by the different environmental, lifestyle and genetic factors that cause cancer, many of them are still unknown. Within Mutographs, the International Agency for Research on Cancer is coordinating the recruitment of 5000 individuals with cancer (colorectal, renal, pancreatic, oesophageal adenocarcinoma or oesophageal squamous cancers) across 5 continents to explore whether different mutational signatures explain marked variation in incidence. In brief, through an international network of collaborators around the world, biological materials are collected, along with demographic, histological, clinical and questionnaire data. Whole genome sequences of tumour-germline DNA pairs are generated at the Wellcome Trust Sanger Institute. Somatic mutational signatures are subsequently extracted by non-negative matrix factorisation methods and correlated with risk factors data. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development.

  Study EGAS00001003774

• Botswana 15 autosomal unlinked microsatellites

  Population structure was investigated in 990 Botswana individuals according to ethno-linguistics, Bantu and Khoisan, and geography (the nine administrative districts) using the AmpFLSTR Identifiler autosomal microsatellite markers. Genetic diversity and forensic parameters were calculated for the overall population, and according to ethno-linguistics and geography. The overall combined power of exclusion (CPE) was 0.9999965412 and the combined match probability 6,28 x 10-19. CPE was highest for the Khoisan Tuu ethnolinguistic group and the Northeast District at 0.9999582029 and 0.9999922652 respectively. CMP ranged from 6.28 x 10-19 (Khoisan Tuu) to 1,02 x 10-18 (Northwest district). Using pairwise genetic distances (FST), analysis of molecular variance (AMOVA), factorial correspondence analysis (FCA), and the unsupervised Bayesian clustering method found in STRUCTURE and landscape genetics software TESS, ethno-linguistics were found to have a greater influence on population structure than geography. FCA showed clustering between Bantu and Khoisan, and within the Bantu. This Bantu sub-structuring was not seen with STRUCTURE and TESS, which detected clustering only between Bantu and Khoisan. The patterns of population structure revealed highlight the need for regional reference databases that include ethno-linguistic and geographic location information. These markers have important potential for bio-anthropological studies as well as for forensic applications.

  Study EGAS00001002380

• WGS of 32 paired SRCC samples

  Signet-ring cell carcinoma (SRCC) has specific epidemiology and oncogenesis in gastric cancer, however with no systematical investigation for prognostic genomic features. We systematically investigated the clinical characteristics of 1,868 Chinese gastric cancer patients, and found that signet-ring cell content was significantly related to multiple clinical characteristics and treatment outcomes. Next, we performed whole genome sequencing for 32 SRCC patients with > 80% signet-ring cells in tumor, and identified frequent5 CLDN18-ARHGAP26/6 fusion (25%). With additional 797 patients for validation, we notice that prevalence of CLDN18-ARHGAP26/6 fusion is positively associated with signet-ring cell content (P = 4.1 x 10 -9 ), younger age at diagnosis (P = 4.2 x 10 -10 ), female/male ratio (P = 1.7 x 10 -9 ), and advanced TNM stage (P = 1.7 x 10 -5 ). Importantly, patients with CLDN18-ARHGAP26/6 fusion had a worse survival outcomes (P = 0.03), and got no benefit0 from platinum/fluoropyrimidines based chemotherapy (P = 0.92) compared to fusion-free patients (P = 0.001), which is consistent with the fact of oxaliplatin/fluoropyrimidine resistance acquired in CLDN18-ARHGAP26 introduced gastric cancer cell lines. Overall, this study provides new insights into the clinical and genomic features of SRCC, and highlights the importance of frequent CLDN18-ARHGAP26/6 fusions in chemotherapy response for SRCC.

  Study EGAS00001002668

• Summary statistics from genome-wide association study in glioma of 12,488 cases and 18,169 controls.

  Genome-wide association studies (GWAS) have transformed our understanding of glioma susceptibility, but individual studies have had limited power to identify risk loci. We performed a meta-analysis of existing GWAS and two new GWAS, which totaled 12,488 cases and 18,169 controls. We identified five new loci for glioblastoma (GBM) at 1p31.3 (rs12752552; P = 2.04 × 10-9, odds ratio (OR) = 1.22), 11q14.1 (rs11233250; P = 9.95 × 10-10, OR = 1.24), 16p13.3 (rs2562152; P = 1.93 × 10-8, OR = 1.21), 16q12.1 (rs10852606; P = 1.29 × 10-11, OR = 1.18) and 22q13.1 (rs2235573; P = 1.76 × 10-10, OR = 1.15), as well as eight loci for non-GBM tumors at 1q32.1 (rs4252707; P = 3.34 × 10-9, OR = 1.19), 1q44 (rs12076373; P = 2.63 × 10-10, OR = 1.23), 2q33.3 (rs7572263; P = 2.18 × 10-10, OR = 1.20), 3p14.1 (rs11706832; P = 7.66 × 10-9, OR = 1.15), 10q24.33 (rs11598018; P = 3.39 × 10-8, OR = 1.14), 11q21 (rs7107785; P = 3.87 × 10-10, OR = 1.16), 14q12 (rs10131032; P = 5.07 × 10-11, OR = 1.33) and 16p13.3 (rs3751667; P = 2.61 × 10-9, OR = 1.18). These data substantiate that genetic susceptibility to GBM and non-GBM tumors are highly distinct, which likely reflects different etiology.

  Study EGAS00001003372

• MutWP1__CRUK_Grand_Challenge_Mutographs_of_Cancer__Colorectal_LCM

  The Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Different patterns of somatic mutation are generated by the different environmental, lifestyle and genetic factors that cause cancer, many of them are still unknown. Within Mutographs, the International Agency for Research on Cancer is coordinating the recruitment of 5000 individuals with cancer (colorectal, renal, pancreatic, oesophageal adenocarcinoma or oesophageal squamous cancers) across 5 continents to explore whether different mutational signatures explain marked variation in incidence. In brief, through an international network of collaborators around the world, biological materials are collected, along with demographic, histological, clinical and questionnaire data. Whole genome sequences of tumour-germline DNA pairs are generated at the Wellcome Trust Sanger Institute. Somatic mutational signatures are subsequently extracted by non-negative matrix factorisation methods and correlated with risk factors data. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development.

  Study EGAS00001003455

• Large-scale viral genome analysis identifies novel clinical associations between hepatitis B virus and chronically infected patients

  Despite the high global prevalence of chronic hepatitis B (CHB) infection, datasets covering the whole hepatitis B viral genome from large patient cohorts are lacking, greatly limiting our understanding of the viral genetic factors involved in this deadly disease. We performed deep sequencing of viral samples from patients chronically infected with HBV to investigate the association between viral genome variation and patients’ clinical characteristics. We discovered novel viral variants strongly associated with viral load and HBeAg status. Patients with viral variants C1817T and A1838G had viral loads nearly three orders of magnitude lower than patients without those variants. These patients consequently experienced earlier viral suppression while on treatment. Furthermore, we identified novel variants that either independently or in combination with precore mutation G1896A were associated with the transition from HBeAg positive to negative phase of infection. These observations are consistent with the hypothesis that mutation of the HBeAg open reading frame is an important factor driving CHB patient’s HBeAg status. This analysis provides a detailed picture of HBV genetic variation in the largest patient cohort to date and highlights the diversity of plausible molecular mechanisms through which viral variation affects clinical phenotype.

  Study EGAS00001003689

• The Molecular Landscape of Asian Breast Cancers Reveals Clinically Relevant Population-Specific Differences

  Molecular profiles of breast cancer have contributed to an improved understanding of the disease, enabled development of molecular prognostic signatures to guide treatment decisions and unveiled new or more accurate therapeutic options for breast cancer patients. However, the extent to which differences in genetic, environmental and lifestyle factors influence molecular profiles in different populations remains poorly characterised, as relatively few large-scale molecular studies of breast tumours in non-Caucasian populations have hitherto been reported. Here, we present the molecular profiles of 560 Asian breast tumours and a comparative analysis of breast cancers arising in Asian and Caucasian women. Compared to the breast tumours in predominantly Caucasian women reported in TCGA and METABRIC, we show an increased prevalence of Her2-enriched molecular subtypes and higher prevalence of TP53 somatic mutations in ER+ Asian breast tumours. Using gene expression and immunohistochemistry, we observed elevated immune scores in Asian breast tumours, suggesting potential clinical response to immune checkpoint inhibitors. Whilst Her2-subtype and enriched immune score are associated with improved survival, presence of TP53 somatic mutations is associated with poorer survival in ER+ tumours. Taken together, these population differences unveil new opportunities to improve the understanding of this disease and lay the foundation for precision medicine in different populations.

  Study EGAS00001004518

• Nanopore_and_Illumina_sequencing_of_human_glioblastomas

  Liquid biopsy analysis refers to methods designed to detect tumour-specific material (e.g., circulating tumour cells or tumour DNA) in body fluids, such as urine or blood samples. A widely-used liquid biopsy approach consists of genotyping the circulating tumour DNA (ctDNA) through sequencing of plasma/serum DNA. Although useful in the context of metastatic disease (where the concentration of ctDNA is high), current liquid biopsy technologies show limited sensitivity of detection for the early detection of cancer, and low specificity, as cancer-related mutations accumulate in healthy tissues as part of the ageing process, thus making it difficult to distinguish these from tumour mutations, and because sequencing errors and true mutations show overlapping profiles. Therefore, developing liquid biopsy protocols with increased sensitivity and specificity represents an urgent clinical need. Here we harness extrachromosomal circular DNA (eccDNA) elements, which are circular DNA structures physically separated from the chromosomes of up to several Mbp long pervasive in human cancers, for liquid biopsy analysis. In this pilot study we will focus on the analysis of glioblastomas, because there is strong evidence for the presence of eccDNA in these tumour types, and because developing liquid biopsy approaches for brain tumours to reduce the invasiveness of brain tumour biopsies remains an unmet clinical need.

  Study EGAS00001005812

• RNA-seq study of human long-term and short-term hematopoietic stem cells from umblical cord blood with lentiviral overexpression of S1PR3

  To investigate the molecular and biological pathways altered by S1PR3OE in human hematopoietic stem cells (HSC), we performed RNA-sequencing (RNA-seq) of LT- and ST-HSC 3 days after transduction with control or S1PR3 overexpression (OE) lentiviral vectors. LT-HSC and ST-HSC from 3 pool of CB lin- were FACS-purified, cells were prestimulated for 4 hours and transduced with lentiviral vectors. At day 3, 2000-5300 BFP+ cells were FACS-purified for RNA isolation with a PicoPure kit. We were able to isolate only 1600-1800 BFP+ cells from LT-HSC control samples as opposed to 4000-5400 BFP+ cells from S1PR3OE samples. Thus, we pooled all control BFP+ LT-HSC cells into one sample for RNA-seq analysis. BFP- LT-HSC from control vector transduction were purified from CB1 as an additional LT-HSC control. Nextera libraries generated from 10 ng RNA from 5 LT-HSC samples (2 controls, 3 S1PR3OE) and 6 ST-HSC samples (3 controls, 3 S1PR3OE) were subjected to 125 bp, paired-end RNA-sequencing on the Illumina HiSeq 2500 with an average of 50 million reads/sample at the Center for Applied Genomics, Sick Kids Hospital.

  Study EGAS00001004798

• Proteogenomics of chronic lymphocytic leukemia

  Cancer heterogeneity at the proteome level may explain differences in therapy response and prognosis beyond the currently established genomic and transcriptomic based diagnostics. The relevance of proteomics for disease classifications remains to be established in clinically heterogeneous cancer entities such as chronic lymphocytic leukemia (CLL). Here, we characterized the proteome and transcriptome in-depth alongside genetic and ex-vivo drug response profiling in a clinically well annotated CLL discovery cohort (n= 68). Unsupervised clustering of the proteome data revealed six subgroups. Five of these proteomic groups were associated with genetic features, while one group was only detectable at the proteome level. This new group was characterized by accelerated disease progression, high spliceosomal protein abundances associated with aberrant splicing, and low B cell receptor signaling protein abundances (ASB-CLL). We developed classifiers to identify ASB-CLL based on its characteristic proteome or splicing signature in two independent cohorts (n= 165, n= 169) and confirmed that ASB-CLL comprises about 20 % of CLL patients. The inferior overall survival observed in ASB-CLL was independent of both TP53- and IGHV mutation status. Our multi-omics analysis refines the classification of CLL and highlights the potential of proteomics to improve cancer patient stratification beyond genetic and transcriptomic profiling. This is the transcriptomics data of the discovery cohort.

  Study EGAS00001005746

• MutWP1__CRUK_Grand_Challenge_Mutographs_of_Cancer__clear_cell_renal_cell_carcinoma___2

  The Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Different patterns of somatic mutation are generated by the different environmental, lifestyle and genetic factors that cause cancer, many of them are still unknown. Within Mutographs, the International Agency for Research on Cancer is coordinating the recruitment of 5000 individuals with cancer (colorectal, renal, pancreatic, oesophageal adenocarcinoma or oesophageal squamous cancers) across 5 continents to explore whether different mutational signatures explain marked variation in incidence. In brief, through an international network of collaborators around the world, biological materials are collected, along with demographic, histological, clinical and questionnaire data. Whole genome sequences of tumour-germline DNA pairs are generated at the Wellcome Trust Sanger Institute. Somatic mutational signatures are subsequently extracted by non-negative matrix factorisation methods and correlated with risk factors data. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development.

  Study EGAS00001003542

• Human leukocyte antigen alleles associate with COVID-19 vaccine immunogenicity and risk of breakthrough infection

  SARS-CoV-2 vaccine immunogenicity varies between individuals, and immune responses correlate with vaccine efficacy. Using data from 1,076 participants enrolled in ChAdOx1 nCov-19 vaccine efficacy trials in the United Kingdom, we find that inter-individual variation in normalised antibody responses against SARS-CoV-2 spike (S) and its receptor binding domain (RBD) at 28 days following first vaccination shows genome-wide significant association with major histocompatibility complex (MHC) class II alleles. The most statistically significant association with higher levels of anti-RBD antibody was HLA-DQB1*06 (P=3.2 x 10-9), which we replicate in 1,677 additional vaccinees. Individuals carrying HLA-DQB1*06 alleles were less likely to experience PCR-confirmed breakthrough infection during the Wuhan and Alpha-variant waves compared to non-carriers (HR 0.63, 0.42-0.93, P=0.02). We identify a distinct S-derived peptide that is predicted to bind effectively to HLA-DQB1*06 compared to other equivalent alleles, and find evidence of increased spike-specific memory B-cell responses in HLA-DQB1*06 carriers at 84 days post first vaccination. Our results demonstrate association of HLA type with COVID-19 vaccine antibody response and risk of breakthrough infection, with implications for future vaccine design and implementation.

  Study EGAS00001006909

• Single cell transcriptomic landscape of pediatric B-cell acute lymphoblastic leukemia: dissection of transcriptional heterogeneity and B-cell developmental state

  Introduction: Genomic analyses of bulk ALL samples have improved our understanding of the genetic basis and risk stratification of B-ALL, but do not directly examine intratumor heterogeneity or enable inference of leukemia developmental state and cell of origin. Methods: We profiled 89 B-ALL samples by single-cell RNA-seq (scRNA-seq) (10X Genomics 5’v2) and compared them to a scRNA-seq reference map of normal human B-cell development. Results: Analysis of heterogeneity of inferred DNA copy number alterations at single cell level showed that aneuploid ALL with near haploidy and hyperdiploid harbor chromosomal losses or gains in all blasts, consistent with early, synchronous origin rather than sequential accumulation. Intra-sample heterogeneity was driven by five gene expression signatures: cell cycle, metabolism, differentiation, inflammation, refining leukemic subtyping. An atlas of B cell development was established to map B-ALL samples to specific developmental states. Hyperdiploid samples resembled pro-B cells, while MEF2D-r and TCF3::PBX1 showed high pre-B abundance. Patients with high early lymphoid abundance had poorer outcomes. Conclusions: Understanding variation in transcriptional programs and developmental states of B-ALL blasts by sc transcriptome refines existing clinical and genomic classifications and provides novel prognostic markers.

  Study EGAS00001007512

• Pooled scRNA-seq of iPSC-derived neural stem cells from ADHD and control individuals

  This dataset comprises paired-end FASTQ files from single-cell RNA sequencing (scRNA-seq) of neural stem cells (NSCs) derived from induced pluripotent stem cells (iPSCs). The iPSCs were reprogrammed from somatic cells (keratinocytes, PBMCs, or lymphoblastoid cell lines) collected from individuals diagnosed with attention-deficit hyperactivity disorder (ADHD) and age-matched healthy controls (ages 6–18 years). Reprogramming was carried out using the non-integrative Sendai virus system (CytoTune-iPS 2.0, Thermo Fisher Scientific), introducing OCT3/4, SOX2, KLF4, and cMYC. iPSCs were cultured in Essential 8 medium on vitronectin and underwent rigorous quality control including immunocytochemistry, qRT-PCR, mycoplasma testing, and SNP genotyping (Illumina Global Screening Array). NSCs were generated using a standardized neural induction protocol and validated via qRT-PCR and immunostaining for markers including PAX6, SOX2, NESTIN, TUJ1, and FOXG1. Two independent scRNA-seq multiplexed experiments were performed: Experiment 1 (ADHD: n = 7; Control: n = 6) and Experiment 2 (ADHD: n = 9; Control: n = 7). Samples were pooled and demultiplexed using the Ensemblex algorithm, incorporating prior genotype data. After quality control filtering (>500 unique RNA molecules per cell), 30,433 single-cell transcriptomes were retained. Differential gene expression analysis was conducted to identify transcriptional signatures associated with ADHD compared to controls.

  Study EGAS00001008169

• Patient-derived pediatric brain tumor organoids faithfully recapitulate primary tumors

  Extensive molecular analysis by many groups has revealed a heterogeneous landscape of embryonal brain tumors, including medulloblastoma (MB) and atypical teratoid/rhabdoid tumor (ATRT). MB, the most common malignant pediatric brain tumor, is comprised of four molecularly distinct subgroups: Wingless (WNT), Sonic Hedgehog (SHH), Group 3 (G3), and Group 4 (G4). Among these, MB-SHH harboring MYCN amplification and TP53 mutation and MB-G3 with MYC overexpression or amplification constitute the most aggressive tumors, have the poorest clinical outcomes, and lack effective therapeutic options for recurrent disease. Here we describe the establishment of tumor organoid (TO) models from patient-derived orthotopic xenografts (PDOX) of MYCN-amplified and TP53-mutant MB-SHH, MYC-amplified MB-G3 and two ATRT which all grew in mice when reimplanted into the cortices of naïve recipient animals (TOX). Methylation, bulk and single-cell RNA sequencing, and whole genome sequencing demonstrated that TOs and TOXs faithfully recapitulated the molecular landscape and heterogeneity of PDOXs and primary patient tumors compared to established cell lines. The development of TOs will facilitate in vitro high-throughput drug or CRISPR screens without the need for use tumor-bearing mice. This will also accelerate the identification and validation of new vulnerabilities and in vivo preclinical testing toward clinical trials.

  Study EGAS00001008305

• Swarm Learning to identify COVID-19, tuberculosis and leukemia patients based on blood transcriptomes

  Identification of patients with life-threatening diseases including leukemias or infections such as tuberculosis or COVID-19 is an important goal of modern precision medicine. However, there is an increasing divide between what is technically possible and what is allowed because of privacy legislation. We have recently illustrated that classical machine learning can identify leukemia patients based on their blood transcriptomes. To facilitate integration of any omics data from any data owner world-wide without violating privacy laws, we here introduce Swarm Learning (SL), a decentralized machine learning approach uniting edge computing, artificial intelligence (AI), blockchain and privacy protection without the need for a central coordinator thereby going beyond federated learning. To illustrate its feasibility, using more than 12,000 transcriptomes from peripheral blood mononuclear cells and more than 2,000 peripheral blood transcriptomes we demonstrate that SL of omics data distributed across different individual sites leads to disease classifiers that outperform those developed at individual sites. Yet, SL completely protects local privacy regulations by design. We propose this approach to noticeably accelerate the introduction of precision medicine.

  Dataset EGAD00001006231

• NIPT samples for systematic evaluation of NIPT aneuploidy detection software tools

  This dataset contains two sets of samples. The reference sample set consists of a total of 669 samples that had been reported previously to be euploid by the NIPTIFY screening test. The validation sample set is based on a previously published validation study by Zilina et al. (1), consisting of 423 samples, of which 259 were high-risk pregnancies that had undergone diagnostic invasive prenatal analysis (1). All samples were sequenced with Illumina NextSeq 500 platform, producing 85 bp single-end reads with an average per-sample coverage of 0.32× at the University of Tartu, Institute of Genomics Core Facility, according to the manufacturer’s standard protocols, as described previously (1). This study was performed with the approval of the Research Ethics Committee of the University of Tartu (#315/T-13). 1. Zilina O, Rekker K, Kaplinski L, Sauk M, Paluoja P, Teder H, et al. Creating basis for introducing non‐invasive prenatal testing in the Estonian public health setting. Prenat Diagn [Internet]. 2019 Dec 6;39(13):1262-8. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1002/pd.5578

  Dataset EGAD00001007712

• Genetic drivers of epigenetic and transcriptional variation of human immune responses to infection (RNA-seq, ATAC-seq and ChIPmentation)

  RNA-seq, ATAC-seq and ChIPmentation data from monocyte-derived macrophages that were infected with Influenza A virus strain PR8WT, or a matching non-infected control.

  Dataset EGAD00001008422

• MutWP1__CRUK_Grand_Challenge_Mutographs_of_Cancer__clear_cell_renal_cell_carcinoma

  The Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Different patterns of somatic mutation are generated by the different environmental, lifestyle and genetic factors that cause cancer, many of them are still unknown. Within Mutographs, the International Agency for Research on Cancer is coordinating the recruitment of 5000 individuals with cancer (colorectal, renal, pancreatic, oesophageal adenocarcinoma or oesophageal squamous cancers) across 5 continents to explore whether different mutational signatures explain marked variation in incidence. In brief, through an international network of collaborators around the world, biological materials are collected, along with demographic, histological, clinical and questionnaire data. Whole genome sequences of tumour-germline DNA pairs are generated at the Wellcome Trust Sanger Institute. Somatic mutational signatures are subsequently extracted by non-negative matrix factorisation methods and correlated with risk factors data. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development.

  Study EGAS00001002608

• 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

• scRNA-seq of human follicular lymphoma and lymph node

  Cryopreserved cells from human nodal follicular lymphoma and lymph node samples were thawed and processed for scRNA-seq analysis. CD3+ CD19− 7-AAD− live T cells (six FL samples from the Original cohort) or 7-AAD− whole live hematopoietic cells (five lymph node and nine FL samples from Validation cohort 1) were sorted using a FACS Aria II or III instrument (BD Biosciences). To generate single-cell emulsions, 6,000–10,000 live cells were loaded into the 10X Genomics Chromium Controller for single-cell partitioning, along with the reverse transcriptase reagent mixture and 3' or 5' gel beads. Sorted T or whole hematopoietic cells were converted to barcoded scRNA-seq libraries using 10X Genomics Chromium single cell 3' reagent kits (v3) for the Validation cohort 1, 5' reagent kits (v1) for the Original cohort, according to the manufacturer’s instructions. The libraries were sequenced on an Illumina HiSeq X Ten or NovaSeq X Plus system, mapped to the human genome (build GRCh38), and demultiplexed using CellRanger pipelines (v3.1.0, 10x Genomics).

  Dataset EGAD50000001143

• SUM-seq data for spontaneously differentiated iPSCs to EBs

  Clonal CRISPRi/a hiPS cell lines were plated to induce spontaneous differentiation in KSR medium (KSR medium: knockout DMEM/F12 (Gibco, 12660012), 2 mM GlutaMAX, 1× NEAAs, 20% knockout serum replacement (Gibco, 10828010) and 0.1 mM β-mercaptoethanol (Merck-Millipore)). non-TC plates and dishes were used. At the day of plating, KSR medium was supplemented with Y-27632 (10 µM). The next day, medium was replaced with fresh KSR medium. Medium changes were performed every other day. EBs were transferred to 15 ml conical tubes and allowed to sediment at room temperature for 5 min. The supernatant was replaced with fresh KSR medium and cells were transferred onto non-TC treated plates and maintained at 37 °C, 5% CO2. On day 12 of differentiation, the KSR medium was replaced with Essential 6 medium (Gibco, A1516401). EBs were collected and subjected to SUM-seq library preparation as described in Lobato-Moreno et al. 2025 Nature Methods.

  Dataset EGAD50000001589

• Characterization of a New Case of XMLV (Bxv1) Contamination in the Human Cell Line Hep2 (Clone 2B) Using High-Throughput DNA- and RNA-Seq

  We have sequenced DNA and RNA from the Hep2 (clone 2B) cell line (Sigma-Aldrich catalog number: 85011412-1VL) using short read Illumina sequencing. We show that this cell line is indistinguishable from the HeLa cell line (as mentioned on the Sigma-Aldrich website) by mapping integrations of the human papillomavirus 18. We also show that the cell line is contaminated by the Bxv1 xenotropic murine leukemia virus. This contamination has to be taken into account when using the cell line in future experiments.

  Study phs001944

• 16S rRNA gene V4 region sequencing data, ASV profiles, and sample metadata of human faecal samples predominantly from the Estonian population

  This dataset comprises 16S rRNA gene V4 region amplicon sequencing data generated from 1,826 human faecal samples, predominantly from the Estonian population. The dataset includes raw sequencing reads and processed amplicon sequence variant (ASV) outputs, consisting of ASV abundance tables, representative ASV sequences, and taxonomic assignments. In addition, a sample metadata table is provided, containing sample and host information, including sample identifier, sequencing run identifier, date of sampling, sex, age, height, weight, nationality, disease status, and Bristol stool type. Sequencing was performed using the Illumina MiSeq and iSeq 100 platforms. The cohort includes individuals with no reported disease (n = 889), gastrointestinal diseases (n = 217), allergies and asthma (n = 194), thyroid gland disorders (n = 117), cardiovascular diseases (n = 103), various general health conditions (n = 139), cancer (n = 28), diabetes (n = 20), gynaecological issues (n = 7). Disease status was unavailable for 112 samples.

  Dataset EGAD50000002306

• Impact of Mutated CTCF DNA binding sites of Topologically associating domains on nearby Cancer Gene Regulation: A Multi-Omics Analysis

  Cutaneous squamous cell carcinoma (cSCC) is the most common lethal malignancy world-wide. Due in most part to the extremely high mutational burden (TMB) in cSCC, making sense of it’s non-coding and regulatory regional genomic variation has lagged that of other far less common cancers. This study presents the first investigation of mutations at CCCTC-binding factor binding sites (CTCFbs) of Topologically associating domains (TAD) across defined cSCC progression stages—primary non-metastatic (PNM), primary metastat-ic (PM), and lymph node metastasis (LNM).

  Study EGAS50000001686

• Identification of fusion transcripts by RNA-sequencing and Whole genome sequencing of a METABRIC patient sample

  Fusion transcripts and their exact breakpoints were identified in RNA-seq data (30X) of an ER-,HER2+ breast cancer. DNA-level breakpoints associated with the fusion events were determined by analyzing whole genome sequencing (WGS) data (30X) from the same donor. The RNA-seq and WGS data for this case were generated on the Illumina platform using standard protocols. The patient (MB-0152) derives from the METABRIC cohort for which array based copy number and gene expression data were previously described (EGAS00000000083).

  Study EGAS00001002475

• RUNX1 mutated families show phenotype heterogeneity and a somatic mutation profile unique to germline predisposed AML

  We present the clinical phenotypes and genetic mutations detected in 10 novel RUNX1 mutated FPD-MM families. Genomic analyses on these families detected two partial gene deletions, three novel mutations and five recurrent mutations as the germline RUNX1 alterations leading to FPD-MM. On 15 individuals, across the 10 families, we performed additional whole exome or myeloid panel sequencing on blood or bone marrow to determine somatic mutations that co-exist with the germline RUNX1 mutation in tumour and pre-leukaemic states.

  Study EGAS00001004273

• 10x dataset of an obese human subject

  Biopsies from visceral adipose tissue from the omental depot (OAT) were obtained from an obese individual with participant informed consent obtained after the nature and possible consequences of the studies were explained under protocols approved by the Institutional Review Boards of the Perelman School of Medicine at the University of Pennsylvania, the Children’s Hospital of Philadelphia, or the Tel Aviv Sourasky Medical Center. The obese donor underwent bariatric surgery, the lean donor underwent cholecystectomy. OAT samples were placed in 1 mL of DMEM, and finely minced under sterile conditions before digestion in 50 mL of DMEM with 3 mg/1 mL collagenase IV (Gibco). Samples were incubated at 37°C in a rotating oven for 20-60 min. Adipocyte and stromal vascular fractions (SVF) were separated by centrifugation, and red blood cells (RBCs) were removed from the SVF by histopaque gradient (Sigma). Single-cell RNA-sequencing libraries were prepared using the Chromium platform (10x genomics), and sequenced on the MiSeq 500 or HiSeq 2500 Sequencing System (Illumina).

  Dataset EGAD00001005101

• Lenalidomide Resistance in del(5q) Myelodysplastic Syndrome Follows Loss of RUNX1/TP53-mediated Megakaryocytic Differentiation

  Interstitial deletion of the long arm of chromosome 5 (del(5q)) is the commonest structural genomic variant in myelodysplastic syndromes (MDS). Lenalidomide (LEN) is the treatment of choice for patients with del(5q) MDS, but half of the responding patients become resistant within two years. TP53 mutations are detected in ~20% of patients who become resistant to LEN. Our data show that patients who become resistant to LEN harbor either TP53 or RUNX1 mutations or loss of RUNX1 expression. Here we show that LEN-induced degradation of IKZF1 permits a RUNX1/GATA2 complex to drive megakaryocytic differentiation and consequent del(5q) MDS progenitor cell death via CRBN-mediated CSNK1A1 degradation. Overexpression of GATA2 is able to restore LEN sensitivity in the context of RUNX1 or TP53 mutations by enhancing LEN-induced megakaryocytic differentiation. Screening for TP53 and RUNX1 mutations or downregulation should identify patients resistant to LEN, and strategies to activate GATA2 may resensitize del(5q) MDS cells to LEN.

  Dataset EGAD00001005769

• FASTQ files of the polyA+ (oligo-dT) RNA-Seq dataset from the POPS SGA (Small for Gestational Age) samples and their matched controls.

  FASTQ files of the polyA+ (oligo-dT) RNA-Seq dataset from the POPS SGA (Small for Gestational Age) samples and their matched controls. The POP study placental biopsies were collected within 30 minutes of birth and flash frozen in RNAlater (ThermoFisher). For each biopsy, total placental RNA was extracted from approximately 5 mg of tissue using the “mirVana miRNA Isolation Kit” (Ambion) followed by DNase treatment (“DNA-free DNA Removal Kit”, Ambion). RNA quality was assessed with the Agilent Bioanalyzer and all the samples with RIN values ≥ 7.0 were used in the downstream experiments. RNA-libraries were prepared from 1g of total placental RNA with the TruSeq Stranded mRNA Library Prep Kit (Illumina) which captures polyA-tailed transcripts by oligo-dT beads, then pooled and sequenced (single-end, 50bp) using a Single End V4 cluster kit and Illumina HiSeq2500

  Dataset EGAD00001006304

• WES data

  WES FASTq files of 76 bulk pre-treatment tumors and 76 matched peripheral blood mononuclear cells from GO30140 group A

  Dataset EGAD00001008129

• The polarity and specificity of antiviral T lymphocyte responses determine susceptibility to SARS-CoV-2 infection in cancer patients and healthy individuals

  We monitored patient's anti SARS-CoV-2 immune responses using an in vitro cross presentation assay. The goal of this study was to identify immune correlates of clinical protection against SARS-CoV-2 infection. Briefly, peripheral blood mononuclear cells of patient were divided into a monocyte and lymphocyte. Monocyte were differentiated into monocyte derived dendritic (mo-DC)cells using GM-CSF and Interferon alpha. Mo-DC were then loaded with SARS-CoV-2 culture lysates , or VeroE86 lysates. SARS-CoV-2 loaded mo-DC were then used to stimulates their autologous lymphocytes and T cell cytokine secretion was monitored in the supernatant. We discriminated patients producing IL-2 and patients producing IL-5. RNA sequencing was performed for 18 patients, to identify gene profile associated with IL-2 or IL-5 production.

  Dataset EGAD00001008538

• Whole exome sequencing of non-small cell lung cancer patient-derived xenografts

  Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths worldwide. Only a fraction of NSCLC harbour actionable driver mutations and there is an urgent need for patient-derived model systems that will enable the development of new targeted therapies. We generated NSCLC patient-derived xenografts (PDXs) that recapitulate the histology and molecular features of primary NSCLC. Here, we completed whole exome sequencing on 122 NSCLC PDXs.

  Dataset EGAD00001008601

• Human liver mtDNA sequencing

  BAM files containing paired-end mtDNA sequencing data from morphologically normal human liver. Clonal CCO-deficient patches of hepatocytes were identified in human liver samples, and samples were taken along a line spanning approximately from the portal triad to the central hepatic vein. Individual BAM files are named according to their patch, line and cut, where cut 1 is nearest to the portal triad, and cuts 2, 3 etc. lying further from the portal triad. Other file types include "Bulk" samples, contain sequencing data of the remaining CCO-deficient cells that were not sampled as part of the line of cuts, and "Stroma" control samples (used for identifying germ-line variants). Sequenced on NextSeq 500 platform.

  Dataset EGAD00001007991

• Mechanisms of patient response to Dabrafenib in Melanoma

  Samples will be from the BRF113683 (BREAK-3) study which is a Phase III Randomized, Open-label Study Comparing GSK2118436 to Dacarbazine (DTIC) in Previously Untreated Subjects With BRAF Mutation Positive Advanced (Stage III) or Metastatic (Stage IV) Melanoma (n=250 enrolled)*NGS [Agilent capture (Sanger V2 panel): 360 genes and 20 gene fusions; Illumina HiSEQ Sequencing]*CNV: [via NGS or Affy SNP 6.0 or Illumina Omni (TBD)]Bioinformatics: Analysis will be performed using core Sanger informatics pipelines similar to those previously described (Papaemmanuil E et al. (2013) Blood. 22:3616 -3627). Briefly, copy number analysis will be performed using the ASCAT algorithm, and base substitutions, small insertions and deletions using the CAVEMAN and Pindel algorithms, respectively. Statistical approaches including generalized linear models will be used to predict clinical variables such as maximum clinical response and duration of response using genetic data. Sanger and EBI to conduct analysis; Raw data and correlation with clinical endpoints to be analyzed by both EBI/Sanger and GSK (unique pipeline analyses to increase call confidence)

  Dataset EGAD00001001375

• Integrative single-cell and cell-free plasma RNA transcriptomics elucidates placental cellular dynamics

  10 single-cell placental RNA libraries were generated using the Chromium Single Cell 3′ Reagent Kit (10X Genomics). All single-cell libraries were sequenced with a customized paired end with dual indexing (98/14/8/10-bp) format according to the recommendation by 10X Genomics. The data were aligned using the Cell Ranger Single-Cell Software Suite (version 1.0). Moreover, plasma RNA from 22 samples were extracted using the RNeasy Mini Kit (Qiagen). cDNA reverse transcription, second-strand synthesis, and RNA-sequencing (RNA-seq) library construction were performed using the Ovation RNA-seq System V2 (NuGEN) kit according to the manufacturer’s protocol. For alignment of the plasma RNA library, adaptor sequences and low-quality bases on the fragment ends (i.e., quality score < 5) were trimmed, and reads were aligned to the human reference genome (hg19) using the TopHat (v2.0.4) software. All aligned reads were deposited in bam file format.

  Dataset EGAD00001003705

• Somatic mutations and clonal dynamics in healthy and cirrhotic human liver

  Chronic liver injury predisposes to cirrhosis and hepatocellular carcinoma, but how somatic mutations accumulate in liver disease is unexplored. We sequenced whole genomes of 400 microdissections of 100-500 hepatocytes from 5 normal and 6 cirrhotic livers. Compared to normal liver, cirrhotic liver had higher mutation burden, especially structural variants, including chromothripsis. Cirrhotic nodules were oligoclonal; sometimes entirely derived from a single, recent common ancestor. Clonal expansions millimeters in diameter occurred in cirrhosis in the absence of known driver mutations. Endogenous mutational processes predominated, although signatures of polycyclic aromatic hydrocarbon and aristolochic acid exposure occurred in some samples. Up to 10-fold within-patient variation in activity of exogenous signatures existed between adjacent cirrhotic nodules, with both clone-specific and microenvironmental forces shaping this heterogeneity. Synchronous hepatocellular carcinomas drew from the same repertoire of mutational signatures as background cirrhotic liver, but with higher burden. Somatic mutations chronicle the exposures, toxicity, regeneration and clonal structure of liver tissue as it progresses from health to disease.

  Dataset EGAD00001004578

• Tagged-amplicon deep sequencing

  This dataset contains a collection of tumour samples from high grade serous ovarian carcinoma patients with recurrent disease collected near the point of diagnosis as well as tumour samples collected after patient relapse upon or some time after study entry. Whole blood samples were also collected from patients at study entry for the purpose of germline variant detection. The majority of diagnosis samples were preserved in neutral buffered formalin whereas the majority of post-relapse samples were preserved in universal molecular fixative (UMFIX, Sakura Finetek USA, Inc). DNA was extracted and the tagged-amplicon deep sequencing assay was applied (TAm-Seq, Forshew et al. 2002, Sci Transl Med) with the aid of fluidigm access array technology. Targeted loci were sequenced at very high depths (typically >100X) for the detection of both somatic and germline variants. Sequenced reads were aligned to the GRCh37 reference genome (release hs37d5).

  Dataset EGAD00001011058

• Genomics of acral lentiginous melanoma

  Melanoma is the most aggressive type of skin cancer, causing about 75% of dermatological cancer deaths. Acral lentiginous melanoma (ALM) is the most common subtype of melanoma in admixed Latin American populations, but very few tumour genomes and exomes, all from European-descent individuals, have been analysed across several studies. Because of this, the genomic landscape of ALM is mostly unknown. Our aim in this project is to define this landscape and identify driver somatic alterations by whole-exome sequencing a collection of ALM germline/tumour paired FFPE samples from the National Cancer Institute of Mexico. . This dataset contains all the data available for this study on 2023-03-09.

  Dataset EGAD00001010126

• The ALT pathway generates telomere fusions that can be detected in the blood of cancer patients

  Telomere fusions (TFs) can trigger the accumulation of oncogenic alterations leading to malignant transformation and drug resistance. Despite their relevance in tumour evolution, our understanding of the patterns and consequences of TFs in human cancers remains limited. Here, we characterize the rates and spectrum of somatic TFs across >30 cancer types using whole-genome sequencing data. TFs are pervasive in human tumours with rates varying markedly across and within cancer types. In addition to end-to-end fusions, we find novel patterns of TFs that we mechanistically link to the activity of the alternative lengthening of telomeres (ALT) pathway. We show that TFs can be detected in the blood of cancer patients, which enables cancer detection with high specificity and sensitivity even for early-stage tumours and cancers of high unmet clinical need. Overall, we report a novel genomic footprint that enables characterization of the telomere maintenance mechanism of tumours and liquid biopsy analysis.

  Dataset EGAD00001012101

• Selection of somatic escape variants in SERPINA1 in liver tissue of patients with alpha-1 anti-trypsin deficiency - WGS

  Somatic variants accumulate in non-malignant tissues with age. Functional variants leading to clonal advantage of hepatocytes accumulate in the liver from patients with acquired chronic liver disease (CLD). Whether somatic variants are common to CLD from differing aetiologies is unknown. We analysed liver somatic variants in patients with genetic CLD from alpha-1 anti-trypsin (A1AT) deficiency or haemochromatosis. We show that somatic variants in SERPINA1, the gene encoding A1AT, are strongly selected for in A1AT deficiency, with evidence of convergent evolution. Acquired SERPINA1 variants are clustered leading to truncation or coding change at the C-terminus of A1AT. In vitro and in vivo, C-terminal truncation variants reduce disease-associated Z-A1AT polymer accumulation and disruption of the endoplasmic reticulum, supporting the C-terminal domain swap mechanism. Therefore, somatic escape variants from a deleterious germline variant are selected for in A1AT deficiency, suggesting functional somatic variants are disease-specific in CLD and point to disease-associated mechanisms.

  Dataset EGAD00001015430

• The scRNA dataset for TIGIT in MCL with CART

  We collected longitudinal samples from 15 patients with MCL at various clinical time points before and after CAT-T therapy brexucabtagene autoleucel (BA) infusion. The patients were grouped into three categories based on their clinical responses after BA treatment: 1) responsive (n = 9), 2) relapsed (n = 5), and 3) refractory (n = 1). All patients in category #1 and #2 had initially attained a complete response (CR) after BA therapy. The responsive group maintained CR with no relapse at the time of last follow up, while the relapsed group achieved initial CR but eventually relapsed. The 10x Chromium™ Single-Cell 5′ Reagent Kit v2 (PN-1000190, 10x GENOMICS) and Chromium Single-Cell Human TCR amplification Kit (PN-1000252, 10x GENOMICS) were used to perform single-cell separation, cDNA amplification, and library construction for gene expression and TCR repertoire following the manufacturer’s guidelines. Thirty-nine samples passed quality control and underwent single-cell transcriptome profiling with simultaneous single-cell T-cell receptor (TCR) repertoire analysis.

  Dataset EGAD00001010180

• Somatic mutation in edited cholangiocyte organoids

  Primary human cells cultured in organoid format have great promise as potential regenerative cellular therapies. However, their immunogenicity and mutagenic profile remain unresolved, impeding effective long-term translation to the clinic. In this study we report, for the first time, the generation of human leukocyte antigen (HLA)-I and HLA-II knock-out human expandable primary cholangiocyte organoids (PCOs) using CRISPR-Cas9 as a potential ‘universal’ low-immunogenic therapy for bile duct disorders. HLA-edited PCOs (ePCOs) displayed the same phenotypic and functional characteristics as parental unedited PCOs. Despite minimal off-target edits, duplex sequencing approaches demonstrated that ePCOs and PCOs acquire mutations in culture at similar rates, but without evident selection for cancer-driver mutations. ePCOs induced reduced T cell-mediated immunity and donor-dependent NK cell cytotoxicity in vitro and evaded cytotoxic responses with increased graft survival in humanized mice in vivo. Our findings have important implications for assessment of safety and immunogenicity of primary cell-derived organoid cellular therapies.

  Dataset EGAD00001015455

• WGS dataset of Characterization of UV DNA damage in B-cell precursor acute lymphoblastic leukemia

  We characterized B-cell precursor acute lymphoblastic leukemia (BCP-ALL) patients that present with the mutational signature SBS7a. We found clear subtype specificity, but presence of SBS7a did not seem linked to heterogeneity within subtypes. To further distinguish the incidence of SBS7a in pediatric cancer we analyzed a pan-cancer WGS cohort and identified frequent SBS7a in anaplastic large cell lymphomas. As SBS7a is commonly found in skin cancers and has been linked to UV-light induced DNA damage, we compared the features of UV-light induced DNA damage in skin cancer and SBS7a in ALL, and found high similarity. We found no defects in UV damage response pathways in SBS7a-positive samples, indicating no additional UV vulnerability. Additionally, transcriptomic data showed no differences between samples with and without SBS7a. Finally we looked into the moment of exposure to the source of SBS7a by deep sequencing of diagnosis-relapse pairs and single cell whole genome sequencing of diagnosis samples with high SBS7a.

  Dataset EGAD00001015600

• Somatic mutation in edited cholangiocyte organoids

  Primary human cells cultured in organoid format have great promise as potential regenerative cellular therapies. However, their immunogenicity and mutagenic profile remain unresolved, impeding effective long-term translation to the clinic. In this study we report, for the first time, the generation of human leukocyte antigen (HLA)-I and HLA-II knock-out human expandable primary cholangiocyte organoids (PCOs) using CRISPR-Cas9 as a potential ‘universal’ low-immunogenic therapy for bile duct disorders. HLA-edited PCOs (ePCOs) displayed the same phenotypic and functional characteristics as parental unedited PCOs. Despite minimal off-target edits, duplex sequencing approaches demonstrated that ePCOs and PCOs acquire mutations in culture at similar rates, but without evident selection for cancer-driver mutations. ePCOs induced reduced T cell-mediated immunity and donor-dependent NK cell cytotoxicity in vitro and evaded cytotoxic responses with increased graft survival in humanized mice in vivo. Our findings have important implications for assessment of safety and immunogenicity of primary cell-derived organoid cellular therapies.

  Dataset EGAD00001015457

• Selection of somatic escape variants in SERPINA1 in liver tissue of patients with alpha-1 anti-trypsin deficiency - Exome

  Somatic variants accumulate in non-malignant tissues with age. Functional variants leading to clonal advantage of hepatocytes accumulate in the liver from patients with acquired chronic liver disease (CLD). Whether somatic variants are common to CLD from differing aetiologies is unknown. We analysed liver somatic variants in patients with genetic CLD from alpha-1 anti-trypsin (A1AT) deficiency or haemochromatosis. We show that somatic variants in SERPINA1, the gene encoding A1AT, are strongly selected for in A1AT deficiency, with evidence of convergent evolution. Acquired SERPINA1 variants are clustered leading to truncation or coding change at the C-terminus of A1AT. In vitro and in vivo, C-terminal truncation variants reduce disease-associated Z-A1AT polymer accumulation and disruption of the endoplasmic reticulum, supporting the C-terminal domain swap mechanism. Therefore, somatic escape variants from a deleterious germline variant are selected for in A1AT deficiency, suggesting functional somatic variants are disease-specific in CLD and point to disease-associated mechanisms.

  Dataset EGAD00001015431

• Somatic mutation in edited cholangiocyte organoids

  Primary human cells cultured in organoid format have great promise as potential regenerative cellular therapies. However, their immunogenicity and mutagenic profile remain unresolved, impeding effective long-term translation to the clinic. In this study we report, for the first time, the generation of human leukocyte antigen (HLA)-I and HLA-II knock-out human expandable primary cholangiocyte organoids (PCOs) using CRISPR-Cas9 as a potential ‘universal’ low-immunogenic therapy for bile duct disorders. HLA-edited PCOs (ePCOs) displayed the same phenotypic and functional characteristics as parental unedited PCOs. Despite minimal off-target edits, duplex sequencing approaches demonstrated that ePCOs and PCOs acquire mutations in culture at similar rates, but without evident selection for cancer-driver mutations. ePCOs induced reduced T cell-mediated immunity and donor-dependent NK cell cytotoxicity in vitro and evaded cytotoxic responses with increased graft survival in humanized mice in vivo. Our findings have important implications for assessment of safety and immunogenicity of primary cell-derived organoid cellular therapies.

  Dataset EGAD00001015456

• NHLBI TOPMed: Pediatric Cardiac Genomics Consortium (PCGC)'s Congenital Heart Disease Biobank

  The Pediatric Cardiovascular Genetics Consortium (PCGC) proposes to define genetic causes for congenital heart defects (CHD) as part of the TOPMed Program are the most common form of heart disease in childhood and are also the most prevalent form of birth defects, occurring in 2-3% of live births. The PCGC has recruited and clinically characterized = 10,000 CHD probands and parents (CHD trios). From whole exome sequencing (WES) of >2800 CHD trios, we identified a substantial enrichment of damaging de novo mutations in genes important for cardiogenesis, particularly implicating histone modifier enzyme gene defects. Analysis of whole genome sequencing (WGS) of 350 probands with CHD unexplained by WES and their parents preliminarily implicated de novo mutations in enhancers of genes previously shown to cause CHD in mouse knock out models. Sequencing of RNA (RNAseq) from discarded cardiac tissues from CHD probands has revealed likely causal allele-specific expression (ASE) as well as biallelic loss of expression (LOE). We have also discovered de novo epimutations, differentially methylated regions (DMRs), some with underlying de novo DNA variation, that are detectable in peripheral blood leukocytes and appear to underlie 10% of CHD. Of note, these assorted 'omic' approaches have enabled one another, both for attributing causality and assessing functional impact. Based on these extensive preliminary data, we hypothesize that PCGC probands with uninformative exomic analyses (WES-negative) harbor de novo genetic and/or epigenetic mutations in critical regulatory elements that participate in developmental expression of cardiac genes. To identify these etiologies, we propose analyses of WGS in 1000 WES-negative CHD trios, prioritizing those with probands with banked CHD tissues (n=78), one damaging variant in a recessive CHD gene, and older fathers (age>45). We also request WGS for 230 probands, for whom we have cardiac tissues but not parental DNAs. We request RNAseq for 308 cardiac tissues. For DNA methylation, which TOPMed will offer through the Illumina 850k array platform, we are requesting analysis of DNAs from peripheral blood leukocytes for all probands for whom WGS will be performed (1000 from trios, 230 singletons) as well as DNAs from cardiac tissues (n=308) to pair with the WGS, RNAseq and blood DNA methylation data. We will use existing resources and capabilities of the PCGC to confirm relevant mutations and those of its companion consortium in the Bench to Bassinet Program, the Cardiovascular Development Consortium, to inform analyses of non-coding mutations as well as to perform confirmatory functional genomics studies using cell and animal models. We expect that the studies resulting from data generated through TOPMed will provide novel insights into the molecular basis for CHD and fundamental knowledge about genes and pathways involved in cardiac development. Aside from being relevant to CHD, we anticipate that our findings will inform the understanding of later-onset cardiovascular diseases, including some arising in adulthood.

  Study phs001735

• Viral Respiratory Pathogens Genetics

  The overall purpose of this study is to investigate the host genetic factors in response to influenza virus infection, with the focus on influenza vaccination in the first substudy "Adult Influenza Vaccine Genetics" and with the focus on influenza natural infection and other acute respiratory infections (ARIs) in the second substudy "Acute Viral Respiratory Infection Genetics". In the first substudy, healthy adults were enrolled in 2008 (male cohort) and 2010 (female cohort) and immunized with seasonal influenza vaccine. In the second substudy, healthy adults were invited to enroll to be followed for acute respiratory illness through two consecutive influenza seasons 2009-2010 and 2010-2011. Peripheral blood genomic DNA samples were collected from all the subjects, and time-series RNA and serum samples were obtained pre- and post- immunization/infection. Genotyping was carried out on peripheral blood genomic DNA samples using Illumina HumanOmniExpress-12 v1 arrays. Peripheral blood RNA samples obtained at each visit were analyzed using Illumina Human HT-12 (for all the samples) and HiSeq 2000 (for 130 samples in the "Acute Viral Respiratory Infection Genetics" study). Serum specimens were tested using hemagglutination-inhibition (HAI) antibody assay for Influenza H1N1, H3N2, and Influenza B strains. A detailed description of each substudy is provided under their own pages below and via the grouping tool in the right-hand box: phs000635 Adult Influenza Vaccine Genetics phs001031 Acute Viral Respiratory Infection Genetics

  Study phs001030

• Identification of Rare Germline Variants in Familial Patients with Non-medullary Thyroid Cancer

  As the most common malignancy of the endocrine system, thyroid cancer is classified into two major categories, non-medullary thyroid cancer (NMTC) and medullary thyroid cancer (MTC) according to the origins and clinical features. NMTC includes papillary thyroid cancer (PTC), follicular thyroid cancer (FTC), and anaplastic thyroid cancer (ATC). Sporadic non-medullary thyroid cancer (SNMTC) accounts for ~90% of all thyroid cancers. Compared to SNMTC, familial non-medullary thyroid cancer (FNMTC) is rare, constituting only 3 - 9%. FNMTC is a complex genetic disease that often shows an autosomal dominant mode of inheritance. Characterization of the germline variants causing the disease is still challenging given the heterogeneity of affected families. In recent years, some mutations in known cancer susceptive coding genes have been reported using targeted DNA sequencing method in FNMTC cases. Still, little is known for the novel mutations in other thyroid cancer predisposition genes. With the decreasing cost and rapid development of next generation sequencing technology, more rare germline mutations underlying different types of cancer susceptibility in families had been discovered by whole genome sequencing (WGS). In this study, we performed WGS in familial NMTC patients in the U.S. Our aim is to identify rare germline variants with high penetrance that may contribute to thyroid cancer predisposition in NMTC families.

  Study phs001758

• Whole Exome Sequencing and RNA-Seq to Characterize the Somatic Breast Cancer Landscape Among Latinas in California

  Somatic mutational profiles are increasingly being used to guide treatment. However, there is a dearth of data from non-European populations. To address this gap, we conducted paired tumor/normal whole exome paired-end sequencing and tumor RNA-Seq on 146 breast tumors from 140 Hispanic/Latina (H/L) women with breast cancer. We characterized somatic mutations, copy number alterations, tumor subtypes [Prediction Analysis of Microarray 50 (PAM50)], Catalogue Of Somatic Mutations In Cancer (COSMIC) mutation signatures and expression profiles, and compared them to breast tumors from non-Hispanic White (White) women in The Cancer Genome Atlas (TCGA). Using MutSigCV, we found that the most commonly mutated genes, including TP53, RUNX1, PTEN, PIK3CA, MAP3K1, GATA3, CDH1 and CBFB, were similar to those in breast tumors from non-Hispanic white women. Novel findings were that outliers of BLTP2 (aka KIAA0100) over-expression and COSMIC mutational signature 16 were more common in tumors from H/L women than White women. We also identified that the known germline APOBEC3A/B deletion variant was significantly more common in H/L women and was associated with indigenous American ancestry. Data available through dbGaP will be whole-exome sequencing (WES) and RNA sequencing (RNA-Seq) data, as well as phenotypic data, including estrogen receptor, progesterone receptor, and HER2 receptor status, tumor histology, stage, and grade, and age at diagnosis.

  Study phs003218

• Genetic Determinants of Viral Clearance in HCV-Infected Populations

  The World Health Organization estimates there are 170 million persons with HCV infection worldwide, and an estimated 4 million persons are infected in the United States. Persistent HCV infection can cause cirrhosis and hepatocellular cancer. Long term disease consequences do not occur in persons who spontaneously recover. It is not known why 10-40% recover from hepatitis C (and are not at increased risk of cirrhosis and cancer), but that knowledge would contribute to efforts to treat and/or prevent HCV infection. The overall purpose of this study is to investigate the host genetic basis for recovery from hepatitis C virus (HCV) infection. There is strong evidence that host genetic differences determine HCV recovery. After accidental exposure to the same HCV inoculum, some persons recover while others develop persistent infection. Recovery from HCV infection is an outstanding phenotype for genetic studies since both viral exposure and viral recovery can be ascertained with high sensitivity and specificity and since there are no known viral or environmental determinants. The study group is comprised of an ethnically and geographically diverse international population. All cohorts comprising this study group of 3350 individuals are well characterized. This case-control study is comprised of approximately 40% clearance individuals who are matched by age and HIV status within their respective cohorts at a ratio of 1:1 or 1:2 with HCV chronically infected individuals.

  Study phs000248

• Gabriella Miller Kids First Pediatric Research Program: An Integrated Clinical and Genomic Analysis of Treatment Failure in Pediatric Osteosarcoma

  The Gabriella Miller Kids First Pediatric Research Program (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in childhood cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource). Both childhood cancers and structural birth defects are critical and costly conditions associated with substantial morbidity and mortality. Elucidating the underlying genetic etiology of these diseases has the potential to profoundly improve preventative measures, diagnostics, and therapeutic interventions. All of the WGS and phenotypic data from this study are accessible through dbGaP and kidsfirstdrc.org, where other Kids First datasets can also be accessed. Although the survival of children with relapsed osteosarcoma is very poor, little is known about the etiology of treatment failure in this disease. The purpose of this project is to perform whole genome sequencing on serial samples from patients with osteosarcoma obtained before treatment, after treatment, and at relapse/metastasis in order to identify the mutations and pathways that are drivers of drug resistance. If successful, our results may help identify patients at high risk for treatment failure and may yield new treatments for children who cannot currently be cured.

  Study phs001714