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• Genomic and transcriptomic determinants of therapy resistance and immune landscape evolution during anti-EGFR treatment in colorectal cancer

  Despite biomarker stratification, the anti-EGFR antibody cetuximab is only effective against a subgroup of colorectal cancers (CRC). This genomic and transcriptomic analysis of the cetuximab resistance landscape in 35 RAS wild-type CRCs identified associations of NF-1 and non-canonical RAS/RAF-aberrations with primary resistance and validated transcriptomic CRC-subtypes as non-genetic predictors of benefit. 64% of biopsies with acquired resistance harbored no genetic resistance drivers. Most of these had switched from a cetuximab-sensitive transcriptomic subtype pre-treatment to a fibroblast- and growth factor-rich subtype at progression. Fibroblast-supernatant conferred cetuximab resistance in vitro, confirming a major role for non-genetic resistance through stromal remodeling. Cetuximab treatment increased cytotoxic immune infiltrates and PDL1 and LAG3 immune-checkpoint expression, potentially providing opportunities to treat cetuximab-resistant CRCs with immunotherapy.

  Study EGAS00001003367

• CD36 defines CML cells less sensitive to imatinib

  Tyrosine kinase inhibitors (TKIs) are highly effective for treatment of chronic myeloid leukemia (CML), but very few patients are cured. Major drawbacks with TKIs are their low efficacy in eradicating the leukemic stem cells responsible for disease maintenance and relapse upon TKI cessation. Here, we performed RNA-sequencing of flow-sorted primitive (CD34+CD38low) and progenitor (CD34+CD38+) chronic phase CML cells and identified transcriptional upregulation of 32 cell surface molecules relative to corresponding normal bone marrow cells. Focusing on novel markers with increased expression on primitive CML cells, we confirmed upregulation of the scavenger receptor CD36 and the leptin receptor (LEPR) by flow cytometry. We also delineate a subpopulation of primitive CML cells expressing CD36 that is less sensitive to imatinib treatment. Using CD36 targeting antibodies, we show that the CD36 positive cells can be targeted and killed by antibody dependent cellular cytotoxicity (ADCC). In summary, CD36 defines a subpopulation of primitive CML cells with decreased imatinib sensitivity that can be effectively targeted by ADCC using an anti-CD36 antibody.

  Study EGAS00001002421

• Development of New Diagnostics, Therapeutics, and Prevention Methods for Personalized Medicine Based on Comprehensive Cancer-Related Gene Exome Analysis and Information Analysis Using Cancer Specimens Stored in TMDU Biobank.

  Biobanked tumor samples are a valuable resource in real-world solid tumor research. Panel-based genomic profiling enables the identification of clinically significant alterations that inform personalized diagnostic and treatment decisions. This study aimed to characterize the genomic landscape of solid tumors collected through the TMDU Biobank by summarizing mutational, copy number, and gene fusion alterations in a large and diverse patient cohort. This dataset contains summary-level genomic information from 1,996 tumor samples analyzed by ACT Genomics and ACT med using the ACTOnco Comprehensive 440-Gene Cancer Panel. Data provided includes (1) gene-level mutation counts, (2) a summary of copy number alterations, and (3) a summary of detected fusion events. Clinical attributes such as ICD-10 codes, age group, sex, tumor mutational burden (TMB), and microsatellite instability (MSI) status were included at the aggregate level. Summary statistics were generated from three source tables (gene, sample, and copy number data) using standardized processing rules. Due to contractual and ethical considerations, individual-level mutation locations and raw sequence data are not included; only summary-level information is provided. This dataset will support future research in tumor-type-specific genomic patterns, molecular characterization of solid malignancies, and precision oncology.

  Study JGAS000863

• Indonesian Microbiome Ecology and Evolution v1 - Data Access Policy

  This Data Access Policy sets forth the terms, conditions, and limitations governing access to and use of the raw sequencing data of samples in the Indonesian Microbiome Ecology and Evolution (IndoMEE) v1 dataset by individuals who are not part of the Data Producer. The IndoMEE v1 dataset comprises 126 human faecal samples collected across Indonesia between 2015 and 2021, that was collected to study patterns of human microbiome variation across Indonesia’s diverse geography and lifestyles.

  Dac EGAC50000000587

• Multi-Region WES of Metastatic Colorectal Cancer

  In order to reconstruct the evolutionary history of metastatic colorectal cancer, we performed whole-exome sequencing of 12 metastatic colorectal cancer patients for whom the primary tumor and matched distant metastases to the brain (n=10) and liver (n=2). For 8 of the 12 patients, multiple regions (n=3-7) of the primary tumor and distant metastases were sequenced.

  Dataset EGAD00001004896

• MSK SPECTRUM - SPatiotemporal Evolution of Cancer Traced Using Multimodalities

  MSK SPECTRUM is a multi-modal, interdisciplinary prospective study of spatiotemporal determinants of high-grade serous ovarian cancer (HGSOC) evolution, treatment and response. Accounting for ~80% of ovarian cancers, HGSOC is the most lethal gynecological malignancy and is a cancer of major unmet clinical need. Challenges in disease management relate to several unresolved questions about disease biology and diagnostic modalities. Prospective longitudinal collection of tissues and blood from laparoscopic biopsies and debulking surgeries enable multi-modal molecular measurements. The program brings together formidable expertise at Memorial Sloan Kettering Cancer Center (MSKCC) across the disciplines of high-resolution genomics and computer science, radiology and radiomics, surgery, tissue banking and sample preparation, medical oncology, immuno-oncology and high-resolution tissue profiling to generate a comprehensive and integrative dataset that will allow us to address the following major aims: i) characterize malignant and immune diversity at diagnosis, ii) survey the co-evolution of malignant cells and the immune response, and iii) stratify patients on standard-of-care and investigational compounds based on their genomic and transcriptomic signatures and changes to relevant genes (TP53, CCNE1, BRCA1/2, CDK12). The goal is to create a framework to utilize integrated multi-modal data as a route to advanced diagnostics and to ultimately establish a proof-of-concept for integrated diagnostics.

  Study phs002857

• Somatic mutation and clonal evolution in premalignant lung disease

  In this study we aim to characterise the landscape of mutation and clonal selection in normal lung and premalignant lung disease. The study combines targeted sequencing and whole-genome sequencing of microbiopsies of lung and bronchial epithelium. The range of patients studied will include healthy individuals, both smokers and non-smokers, and patients with premalignant lung disease. . This dataset contains all the data available for this study on 2023-03-09.

  Dataset EGAD00001010122

• Impact of mutational profiles on response of primary oestrogen receptor-positive breast cancers to oestrogen deprivation

  Presurgical studies allow study of the relationship between mutations and response of estrogen receptor positive (ER+) breast cancer to aromatase inhibitors (AIs) but have been limited to small biopsies. Here in Phase I of this study, we perform exome sequencing on baseline, surgical core-cuts and blood from 60 patients (40 AI treated, 20 Controls). In poor responders (based on Ki67 change) we find significantly more somatic mutations than good responders. Subclones exclusive to baseline or surgical cores   occur in approximately 30% of tumours. In Phase II we combine targeted sequencing on another 28 treated patients with Phase I. We find six genes frequently mutated: PIK3CA, TP53, CDH1, MLL3, ABCA13 and FLG with 71% concordance between paired cores. TP53 mutations are associated with poor response. We conclude that multiple biopsies are essential for confident mutational profiling of ER+ breast cancer and TP53 mutations are associated with resistance to oestrogen deprivation therapy.

  Dataset EGAD00001002651

• Single cell RNA sequencing of synovial B cells in early Rheumatoid Arthritis

  Rheumatoid Arthritis (RA) is a prevalent autoimmune disease characterized by inflammation of the peripheral joints and occurence of autoantibodies, i.e. Rheumatoid Factor (RF) and anti-citrullinated protein antibodies (ACPA), in circulation. Previous studies have shown that there are memory B cells and autoantibody producing plasma cells present in the joint tissue of patients with long-standing RA. However, it has remained unclear, whether these B cell populations are already present in the joint tissue of patients at the disease onset and whether these are autoreactive. Here, we used a single cell RNA sequencing approach to dissect the B cell repertoire at this early timepoint. We found evidence for B and T cell interaction and presence of memory and plasma cell pools in ACPA- and ACPA+ RA. Our results demonstrated clonal relationships between the memory and plasma cell compartments and autoreactivity within the plasma cell pool. These findings challenge our understanding of the local adaptive immune response in the joints of ACPA- and ACPA+ RA patients with direct implications for B and T cell targeting therapy in both patient subgroups.

  Study EGAS00001005144

• NIDDK International IBD Genetics Consortium Repository Global Screening Array

  The purpose of this GWAS meta-analysis is to assess IBD risk alleles using data collected by members of the International IBD Genetics Consortium and their collaborators around the world. Data from over 30 cohorts have been identified and are being combined for analysis. Genotyping has been conducted using a variety of chips with most samples genotyped using GSAMD-24v1-0 or GSA-CHO-Custom. Individual level genotype data will be made available whenever possible (some groups are only able to provide summary statistics due to institutional and/or governmental restrictions on data sharing), together with information on sex, self-reported ancestry, IBD affection status and diagnosis. This first batch includes data from North American sites who are members of the NIDDK-funded IBD Genetics Consortium. Additional data will be provided in an update as soon as they have gone through the QC process.

  Study phs002336

• H3K27ac ChIP-seq in a selected group of AML patients

  ChIP-seq data were generated for a number of selected patients to investigate changes in enhancer and promoter regions. ChIP was performed as described previously with slight modifications27. Briefly, cells were crosslinked with 1% formaldehyde for 10 minutes at room temperature and the reaction was quenched with glycine at a final concentration of 0.125 M. Chromatin was sheared using the Covaris S220 focused-ultrasonicator to an average size of 250–350 bp. A total of 2.5 µg of antibody against H3K27ac (Abcam, ab4729) was added to sonicated chromatin of 2 × 106 cells and incubated overnight at 4 °C. Protein A sepharose beads (GE healthcare) were added to the ChIP reactions and incubated for 2 h at 4 °C. Beads were washed and chromatin was eluted. After crosslink reversal, RNase A and proteinase K treatment, DNA was extracted with the Monarch PCR & DNA Cleanup kit (NEB). Sequencing libraries were prepared with the NEBNext Ultra II DNA Library Prep Kit for Illumina (NEB) according to the manufacturer’s instructions. The quality of dsDNA libraries was analyzed using the High Sensitivity D1000 ScreenTape Kit (Agilent) and concentrations were assessed with the Qubit dsDNA HS Kit (Thermo Fisher Scientific). Libraries were single-end sequenced on a HiSeq 4000 (Illumina). ChIP-seq reads were aligned to the human reference genome build hg19 with bowtie

  Dataset EGAD00001007582

• Fecal microbiome of T2D patients undergoing semaglutide or empagliflozin treatment

  The gut microbiome has been shown to be affected by the use of many human-targeted medications, and the interaction can be bidirectional. This has been clearly demonstrated for type 2 diabetes medications that have been in clinical use for several decades. However, the bidirectional effects of novel type 2 diabetes drugs semaglutide, empagliflozin, and the gut microbiome have yet to be clearly described. We investigated the effect of semaglutide and empagliflozin initiation on the gut microbiome of type 2 diabetes patients. In addition, we analyzed whether the pre-treatment gut microbiome can predict the treatment efficacy. Twenty subjects (10 women and 10 men) were enrolled in the study between November 2019 and January 2023 from the University of Tartu Hospital, Tartu, Estonia. All participants had been diagnosed with type 2 diabetes. The study group taking semaglutide included 6 women and 4 men, and the group prescribed empagliflozin included 4 women and 6 men. Gut microbiome fecal samples donated at four timepoints (Baseline, Month 1, Month 3; Month 12) were studied using 16S ribosomal RNA gene sequencing and analysis.

  Dataset EGAD50000000756

• RNA sequencing of periprostatic fat after a 6 month deep androgen deprivation therapy

  Androgen deprivation therapy treated patients (n=11) were recruited from an open label neoadjuvant phase II study in which patients with high-risk disease received a ‘supercastration’ regimen consisting of degarelix 240/80 mg subcutaneously every four weeks; abiraterone acetate 500 mg orally daily titrating upwards every two weeks by 250 mg to a final dose of 1000 mg daily; bicalutamide 50 mg orally daily; and prednisolone 5 mg orally twice daily for a total of 6 months (Australian New Zealand Clinical Trials Registry 12612000772842). Untreated patients with similar pre-treatment characteristics were obtained from a prospective prostatectomy biorepository22,23. Prior to ligation of the dorsal venous complex and prostate pedicles, the anterior prostate was defatted and the specimen was removed immediately, placed in a sterile container and transferred on ice for long-term storage in the vapour phase of liquid nitrogen. A total of 50–100 µg of adipose tissue was separated from fresh frozen samples stored at −160°C. RNA was isolated using the Qiagen RNeasy Lipid Tissue Mini Kit and eluted in 35 µL nuclease-free water. 0.5–1 µg of total RNA was used as the input for cDNA library synthesis using TruSeq RNA Sample Prep Kit v2 (Illumina), and libraries were constructed according to manufacturer’s instructions. Samples were sequenced on a HiSeq 2500 (Illumina) using 101 base paired-end chemistry, aiming for 50 million mapped paired-end reads per sample.

  Dataset EGAD00001004971

• The Dutch Microbiome Project: Defining the (un)healthy gut microbiome

  The Dutch Microbiome Project (DMP) data includes raw data generated by shotgun metagenomic sequencing of faecal samples of 8,208 Dutch individuals, processed microbiome data analysed using Biobakery2 tools (including taxonomy, pathway, virulence factors and antibiotic resistance gene profiles), and basic phenotypes (age and sex, BMI). Data is made available in two randomly assigned batches to facilitate the data access and maintenance. Access to this dataset requires a minimal access procedure (data access form at https://forms.gle/eHeBdXJMXbVvCJRc8 or email request to the data access committee (DAC) of this study, listed at DAC EGAC00001001996, https://ega-archive.org/dacs/EGAC00001001996). This access procedure is to ensure that the data is being requested for research/scientific purposes only and thus complies with the informed consent signed by Lifelines participants, which specifies that the collected data will not be used for commercial purposes. Submitted data access forms will be evaluated by the DAC and Lifelines, and a response to requests will be given within two weeks. For requests from verified academic parties, access will be given without further delay. For requests from commercial parties, Lifelines will perform a pre-DPIA (Data Privacy Impact Assessment) to assess the risks of the proposed processing of personal data (e.g. purpose, storage, access, archiving, etc.) with respect to the GDPR (EU privacy laws) subject rights. Based on the outcome of the pre-DPIA, Lifelines will decide whether sharing data with the commercial entity is allowed and/or whether additional measures have to be taken.

  Study EGAS00001005027

• TMD-AMKL targeted follow-up part 2

  Genomic libraries will be generated from total genomic DNA derived from 200+ patients with childhood Transient Myeloproliferative Disorder (TMD) and or Acute Megakaryocytic Leukemia (AMKL) as well some matched constitutional samples (n < 50). Libraries will be enriched for a selected panel of genes using a bespoke pulldown protocol. 96 Samples will be individually barcoded and subjected to up to two lanes of Illumina HiSeq. Paired reads will be mapped to build 37 of the human reference genome to facilitate the characterisation of known gene mutations in cancer as well as the validation of potentially novel variants identified by prior exome sequencing.

  Dataset EGAD00001000879

• Colorectal cancer study

  Matrix metalloproteinase-11 (MMP11) is an enzyme with proteolytic activity against matrix and non-matrix proteins. Although most MMPs are secreted as inactive proenzymes and they are later activated extracellularly, MMP11 is activated intracellularly by furin within the constitutive secretory pathway. It is a key factor in physiological tissue remodeling and its alteration may play an important role in the progression of epithelial malignancies and other diseases. TCGA colon and colorectal adenocarcinoma data showed that upregulation of MMP11 expression correlates with tumorigenesis and malignancy. Here, we provide evidence that a germline variant in the MMP11 gene (NM_005940: c.232C>T; p.(Pro78Ser)), identified by whole exome sequencing, can increase the tumorigenic properties of colorectal cancer (CRC) cells. P78S is located in the prodomain region, which is responsible for blocking MMP11’s protease activity. This variant was detected in the proband and all the cancer-affected family members analyzed, while it was not detected in healthy relatives. In silico analyses predict that P78S could have an impact on the activation of the enzyme. Furthermore, our in vitro analyses show that the expression of P78S in HCT116 cells increases tumor cell invasion and proliferation. In summary, our results show that this variant could modify the structure of the MMP11 prodomain, producing a premature or uncontrolled activation of the enzyme that may contribute to an early CRC onset in these patients. The study of this gene in other CRC cases will provide further information about its role in CRC development, which might improve patient treatment in the future.

  Study EGAS00001006489

• Profiling of gene expression and epigenomics in the fetal brain

  scRNA-seq and Cut&Tag from a sample of the human fetal brain. To compare neurogenesis in the primary human brain with that in organoids, we profiled transcriptome and chromatin accessibility (10X multiome) as well as bulk Cut&Tag of histone modifications H3K27me3, H3K27ac and H3K4me3. We used a human brain sample from GW 19 for all experiments.

  Dataset EGAD50000000225

• Exome reads

  This dataset contains WES data (.bam files) and associated phenotype information from 10 patients included in our microbiome study who went on to anti PD-1 immunotherapy for the treatment of metastatic melanoma at the University of Texas MD Anderson Cancer Center. Both tumor and matching germ line normal were sequenced on each patient using Illumina HiSeq 2500. The average coverage was 283X in tumors and 135X in germline (tumor+germline overall:209, Range: 0-1552).

  Dataset EGAD00001003797

• Detecting PKD1 variants in Polycystic Kidney Disease patients by single-molecule long-read sequencing

  Cohort of 19 ADPKD patients characterized using long-read sequencing. The variant identification provided high sensitivity in identifying PKD1 pathogenic variants, with a diagnostic yield of 94.7%. This dataset includes all sequencing data (BAM files) of the 19 patients, in addition to their raw variants (unfiltered) obtained from the long-read sequencing as well as Sanger sequencing (VCF file).

  Dataset EGAD00001003103

• Leiden_melanomafamilies

  Around 10% of patients who present in melanoma clinics have a first degree relative with a previous diagnosis of melanoma. While around 3% have three or more relatives who have been diagnosed with the disease. In this project we will whole genome sequence patients from large Dutch familial melanoma pedigrees to identify mutations in genes that drive melanomagenesis. The identification of these genes will facilitate the management of familial melanoma patients and their families.

  Dataset EGAD00001002186

• Amplicon sequencing libraries from the study "Histological Transformation and Progression in Follicular Lymphoma: a Clonal Evolution Study".

  Amplicon sequencing libraries from the study "Histological Transformation and Progression in Follicular Lymphoma: a Clonal Evolution Study". These are Illumina amplicon deep sequencing libraries (n = 118) to validate somatic predictions made in the whole genome sequencing libraries. Specifically, there are 72 tumor libraries and 46 normal libraries. Some patients may have multiple amplicon libraries sequenced.

  Dataset EGAD00001002896

• Targeting EGFR in NF1 Mutant Melanoma

  Our study focused on melanoma patients with driver mutations in the neurofibromin 1 (NF1) tumor suppressor gene, a subset of melanoma patients that have not benefitted from recent treatment advances. We have leveraged patient-derived short-term cultures (STCs) and multiomics approaches to identify molecular features that could be developed into therapies for NF1 mutant melanoma patients. Our studies revealed that the epidermal growth factor receptor (EGFR) is highly expressed and active in NF1 mutant melanoma cells, and that genetic or pharmacological EGFR inhibition impaired tumor cell proliferation, survival, and cell growth in patient-derived NF1 mutant but not NF1 wild-type melanoma models.

  Study phs003906

• RNA sequencing and Illumina 2.5M SNP array data collected from 675 commonly used human cancer cell lines.

  Tumor-derived cell lines have served as vital models to advance our understanding of oncogene function and therapeutic response1. Although substantial effort has been directed to defining the genomic constitution of cancer cell line panels2–4, the transcriptome – which represents the active program of a cell – remains understudied. Here, we describe RNA sequencing and SNP array analysis of 675 commonly used human cancer cell lines. We explore numerous transcriptome features including coding and non-coding gene expression, transcribed mutations, gene fusion and expression of non-human sequences. Aside from many known aberrations we find new surprising characteristics, including more than 2200 unique fusion gene pairs representing a vast, testable repertoire of oncogenic fusions, many of which have analogs found in primary human tumors. We show that a combination of multiple genome and transcriptome features in a novel pathway-based approach enhances prediction of response to various targeted therapeutics. Our results provide valuable new insights into these critical pre-clinical models and provide added context for interpreting the numerous studies that employ these widely used cell lines.

  Study EGAS00001000610

• Comprehensive molecular profiling identifies novel genetic drivers and subtypes underlying medulloblastoma

  Current therapies for medulloblastoma (MB), a highly malignant childhood brain tumor, impose debilitating effects on the developing child, warranting the development of molecularly targeted treatments with reduced toxicities. Prior studies have failed to disclose the full spectrum of driver genes and molecular processes operative in MB or adequately explain heterogeneity among molecular subgroups. Herein, we detail the somatic landscape across 491 sequenced MBs and molecular heterogeneity amongst 1,256 epigenetically analyzed cases, identifying subgroup-specific mutational signatures, driver genes, and pathway alterations including previously unappreciated actionable therapeutic targets. Integrative approaches for assigning driver genes to subgroups explained >65-70% of Group 3 and Group 4, doubling previous knowledge. Novel subtypes underlying Group 3 and Group 4 were differentially enriched for specific driver events, including hotspot in-frame indels targeting KBTBD4 and ‘enhancer hijacking’ driving activation of PRDM6. Thus, application of integrative genomics to an unprecedented cohort of clinical samples derived from a single childhood cancer entity has disclosed a series of new cancer genes and biologically relevant subtype diversity that represent attractive therapeutic targets for treating MB.

  Study EGAS00001001953

• TRACERx Renal 100

  Evolutionary dynamics of clear cell renal cell carcinoma (ccRCC) have not been studied prospectively or across all disease stages. Through the multi-centre prospective cohort study, Renal TRACERx Renal, we analysed 1209 primary tumour regions from 101 patients with ccRCC. We detect up to 30 driver events in a single tumour, and show that subclonal diversification is associated with known clinical parameters. Defining driver event co-occurrence, mutual exclusivity and timing at clone level, we reveal deterministic patterns of clonal evolution and disease progression. We find that ccRCC can be grouped into seven distinct evolutionary subtypes, ranging from tumours characterised by early fixation of multiple mutational and copy number driver events that can disseminate widely and rapidly; to highly branched tumours with >10 subclonal drivers and extensive parallel evolution presenting with oligometastatic disease. We identify either heterogeneity or chromosome instability, or both, as determinants of patient outcome. Our insights reconcile the variable clinical behaviour of ccRCC and the benefit of surgical intervention in early and late-stage disease; and offer potential biomarker opportunities to maximise the benefit of both surgery and active surveillance.

  Study EGAS00001002793

• The Human Phenotype Project (HPP) is a large-scale deep-phenotype prospective longitudinal and ethnically diverse cohort

  The Human Phenotype Project (HPP) is a large-scale deep-phenotype prospective longitudinal and ethnically diverse cohort and biobank that we established. To date, approximately 28,000 participants have enrolled in the study, with over 13,000 having completed their initial visit. The project is aimed at identifying novel molecular signatures with diagnostic, prognostic and therapeutic value, and at developing AI-based predictive models for disease onset and progression. A unique feature of the HPP is its deep and longitudinal profiling that includes medical history, lifestyle and nutritional habits, vital signs, anthropometrics, blood tests, continuous glucose and sleep monitoring, imaging modalities and molecular profiling of the transcriptome, genetics, gut, vaginal and oral microbiome, metabolome and immune system. For several of these modalities, the HPP is the first or largest cohort of its kind. Our analyses of this data provide novel insights into the variation of phenotypes with age and ethnicity, highlighting the importance of having ethnically diverse cohorts and the need for establishing age-dependent norms. We demonstrate how the HPP can be used to unravel personalized molecular signatures of disease by comparison to patient-specific and disease-specific matched healthy controls. Leveraging the extensive dietary and lifestyle HPP data, we systematically identify associations between lifestyle factors and health outcomes. Finally, we present a multi-modal foundation AI model that is trained using self-supervised learning on diet and CGM data and outperforms existing methods in predicting future onset of disease. We extend this AI framework to integrate all data modalities of each subject as a continuous sequence of diverse medical events, creating a digital twin that can simulate interventions and predict health trajectories and outcomes.

  Study EGAS00001008040

• Whole_genome_sequencing_in_a_multiplex_Crohn_s_disease_family

  In 2009 we identified a four-generation family with over 700 members and 41 affected with Crohn's disease (CD). At the time we sequenced the exome of 6 affected individuals but did not identify any coding variants which appear to explain the high prevalence of disease. Since then we have collected DNA from a large number of additional family members, genotyped linkage arrays on the entire family to refine genomic regions shared by identity by descent and genotyped affected and unaffected members at known CD risk loci identified by Genome Wide Association Studies (GWAS). These analyses have confirmed that a significant unexplained excess of disease remains after accounting for all known genetic factors, and that several regions of the genome are shared by a large fraction of affected individuals. We therefore perform whole genomes sequencing from 8 individuals which will allow us to impute the complete sequence of nearly all the members of the two largest and most severely affected branches of the family.

  Study EGAS00001000060

• 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

• Copy number profiling using PlasmaSeq

  In order to establish copy number profiles from the various samples we prepared libraries and subjected them to whole-genome sequencing at a shallow sequencing depth (0.1x)

  Dataset EGAD00001000761

• Whole_exome_sequencing_for_HELIC

  The HELIC study has been whole genome sequencing individuals from 2 Greek isolatedpopulations at 1x depth. The genotype calling process crucially involves a VQSR stepfollowed by imputation-based refinement. We have been investigating optimal ways toincrease calling accuracy. To aid us in setting appropriate parameters for VQSR and otherQC steps, we have carried out whole exome sequencing of a small number ofHELIC samples.

  Study EGAS00001000602

• Histone acetylome-wide association study on tuberculosis infection

  Epigenetic mechanisms are thought to play an important role in the pathogenesis of infectious diseases. Here, we describe the first histone acetylome-wide association study (HAWAS) of an infectious disease, based on genome-wide H3K27 acetylation profiling of peripheral granulocytes and monocytes from subjects with active Mycobacterium tuberculosis (Mtb) infection and healthy controls (135 ChIP-seq datasets).

  Study EGAS00001003118

• IL_10_signalling_and_macrophage_gene_expression

  Study to stimulate WT and IL-10RB mutant macrophages with LPS in presence or absence of recombinant IL-10 and compare their gene expression profiles by RNASeqThese data are 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/

  Study EGAS00001001283

• Chronic myelomonocytic leukemia

  Chronic myelomonocytic leukemia is an aggressive hematological malignancy with dismal outcomes, with the pCMML subtype in particular having median OS of <2 years and high rates of AML transformation (Patnaik et al., 2014). Given limited therapeutic options for affected patients, we carried out this study to define the genetic and epigenetic landscape of pCMML and identify therapies that could modify disease biology.

  Study EGAS00001005107

• Exome Sequencing of Spanish Patients with rare genetic diseases.

  Whole exome sequencing of Spanish patients suffering from a rare genetic disease. The study was carried out in 2013 as a part of a public call from CNAG (Centro Nacional de Análisis Genómico), where data of eight spanish families were sent to analyse. The study concluded with three solved cases: two of aniridia and one syndromic RP.

  Study EGAS00001004028

• UKF_Paediatric_Tumours_Behjati_WellcomeCore_RNA_Managed_Access

  Children born with DS have a substantially higher risk of developing childhood leukaemia. Approximately 10% are diagnosed with a preleukemic condition at birth; transient abnormal myelopoiesis (TAM). Of these, 20% - 30% of cases may progress to myeloid leukaemia associated with DS (MLDS) by the age of five. We are interested in directly characterizing the transcriptional changes underlying this stepwise development of TAM and MLDS.

  Study EGAS00001007524

• Single-cell RNA sequencing of breast cancer lung metastasis and adjacent normal tissue

  This dataset contains single-cell RNA sequencing data from two samples: L1 (breast cancer metastasis to lung) and N3 (adjacent normal lung tissue) from a female patient. The samples were processed using 10X Chromium 3' technology and sequenced on Illumina NextSeq 500. This data supports the study "Endocrine therapy reprogramming of breast cancer facilitates metastatic escape via upregulation of P-Rex1/Rac1 signalling" which investigates how endocrine therapy reprograms breast cancer cells, leading to upregulation of P-Rex1/Rac1 signalling pathways that facilitate metastatic escape. The single-cell analysis reveals cellular reprogramming mechanisms in endocrine therapy-resistant breast cancer cells that form metastases in the lung.

  Dataset EGAD00001015769

• L1-Architect Project DAC

  This Data Access Committee and policies are for controlling the correct use of the omics datasets generated within the L1-Architect Project, to investigate the impact of L1 transposable elements in tumours with high and ultrahigh rates of somatic retrotransposition

  Dac EGAC50000000289

• Gastric_Mutational_Signatures__GMS_

  This study aims to characterise the mutation burdens and signatures of adult stem cells derived from different regions of the stomach in order to gain insight into the causes and preclinical evolution of the diverse cancer subtypes. Clonal populations of cells from different anatomical locations of the stomach will be derived through organoid culture and/or laser microdissection and interrogated by whole genome sequencing and/or targeted pulldown. A total of circa 300 samples from 20 – 30 donors (cancer and non-cancer patients undergoing total/partial gastrectomy) will be analysed for mutational burden and signatures and genomic findings correlated with topology, age, risk factors and different stages of pre-neoplastic or neoplastic progression.

  Study EGAS00001002938

• Gastric_Mutational_Signatures__GMS_

  This study aims to characterise the mutation burdens and signatures of adult stem cells derived from different regions of the stomach in order to gain insight into the causes and preclinical evolution of the diverse cancer subtypes. Clonal populations of cells from different anatomical locations of the stomach will be derived through organoid culture and/or laser microdissection and interrogated by whole genome sequencing and/or targeted pulldown. A total of circa 300 samples from 20 – 30 donors (cancer and non-cancer patients undergoing total/partial gastrectomy) will be analysed for mutational burden and signatures and genomic findings correlated with topology, age, risk factors and different stages of pre-neoplastic or neoplastic progression.

  Study EGAS00001002939

• Whole genome sequencing of 25 South African individuals with myasthenia gravis

  This study investigated the genetic basis of an ophthalmoplegic subphenotype of MG (OP-MG) which occurs in a proportion of myasthenics with juvenile symptom onset and African genetic ancestry. This OP-MG subphenotype is characterised by treatment resistant weakness of the extraocular muscles (EOMs) and the pathogenetic mechanism(s) underlying its development is unknown. The aim of this study was to use a hypothesis-generating genome-wide case-control analysis to identify candidate OP-MG susceptibility genes and pathways. Whole genome sequencing (WGS) was performed on 25 AChR-antibody positive myasthenic individuals of African genetic ancestry sampled from the phenotypic extremes: 15 with OP-MG (cases) and 10 individuals with control MG (EOM treatment-responsive).

  Study EGAS00001003462

• Genentech whole genome and transcriptome sequencing of four hepatocellular carcinoma patients

  Hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC). In this study we sequenced the whole genome (~80X) and transcriptome of tumor and non-tumor samples from four HCC patients and identified over two hundred HBV integration sites. We found significant clonal expansion of HBV-integrated hepatocytes specifically in the tumor samples. We observed a diverse collection of genomic perturbations near viral integration sites, including gene disruption, viral promoter-driven human transcription, viral-human transcript fusion and DNA copy number alteration. We also sequenced one patient at ultra-high coverage (~240X) to build the most comprehensive HBV-integration landscape yet attempted. Our data suggest that the viral integration significantly expands carcinogenic opportunities in HBV-infected individuals.

  Study phs000384

• The Simons Genome Diversity Project: 300 genomes from 142 diverse populations

  Here we report the Simons Genome Diversity Project data set: high quality genomes from 300 individuals from 142 diverse populations. These genomes include at least 5.8 million base pairs that are not present in the human reference genome. Our analysis reveals key features of the landscape of human genome variation, including that the rate of accumulation of mutations has accelerated by about 5% in non-Africans compared to Africans since divergence. We show that the ancestors of some pairs of present-day human populations were substantially separated by 100,000 years ago, well before the archaeologically attested onset of behavioural modernity. We also demonstrate that indigenous Australians, New Guineans and Andamanese do not derive substantial ancestry from an early dispersal of modern humans; instead, their modern human ancestry is consistent with coming from the same source as that in other non- Africans.

  Study EGAS00001001959

• Multi-omic single-cell profiling of peripheral blood immune cells from COVID-19 patients and controls.

  The COVID-19 pandemic, caused by SARS coronavirus 2 (SARS-CoV-2), has resulted in excess morbidity and mortality as well as economic decline. To characterise the systemic host immune response to SARS-CoV-2, we performed single-cell RNA-sequencing coupled with analysis of cell surface proteins, providing molecular profiling of over 800,000 peripheral blood mononuclear cells from a cohort of 130 patients with COVID-19. Our cohort, from three UK centres, spans the spectrum of clinical presentations and disease severities ranging from asymptomatic to critical. Three control groups were included: healthy volunteers, patients suffering from a non-COVID-19 severe respiratory illness and healthy individuals administered with intravenous lipopolysaccharide to model an acute inflammatory response. Full single cell transcriptomes are coupled with quantification of 188 cell surface proteins, and T and B lymphocyte antigen receptor repertoires.

  Study EGAS00001005465

• Replication data for RNA-SEQUENCING: A RELIABLE TOOL TO UNVEIL TRANSCRIPTIONAL LANDSCAPE OF PAEDIATRIC B-OTHER ACUTE LYMPHOBLASTIC LEUKAEMIA

  This dataset contains the raw data of the RNA-seq experiments described in the paper "RNA-Sequencing: a reliable tool to unveil transcriptional landscape of pediatric B-other acute lymphoblastic leukemia" It contains the raw data from 60 pediatric patients diagnosed with B cell progenitor acute lymphoblastic leukemia lacking the main genetic alterations. RNA material was extracted from bone marrow or periphereal blood and RNA libraries were prepared using Illumina® TruSeq™ stranded mRNA kit following manufacturer's instructions and were sequenced in a NextSeq 550 using a v2 HighOutput 150 cycle kit 2x75bp. Funding: Instituto de Salud Carlos III (ISCIII), PI21/00213 

  Dataset EGAD50000000981

• Risk and modifying factors in Frontotemporal Dementia

  Understanding the molecular mechanisms underlying frontotemporal dementia (FTD) is essential for the development of successful therapies. Here, we present Phase 1 of a multi-omics, multi-model data resource for FTD research which will allows in-depth molecular research into these mechanisms. We have integrated and analysed data from the frontal lobe of FTD patients with mutations in MAPT, GRN and C9orf72 and detected common and distinct dysregulated cellular pathways. Our results highlight that excitatory neurons are the most vulnerable neuronal cell type and that vascular aberrations are a common hallmark in FTD. Via integration of multi-omics data, we detected several transcription factors and pathways which regulate the strong neuroinflammation observed in FTD-GRN. Finally, using small RNA-seq data and verification experiments in cellular models, we identified several up-regulated miRNAs that inhibit cellular trafficking pathways in FTD and lead to microglial activation. In this work we shed light on novel mechanistic and pathophysiological hallmarks of FTD. In addition, we believe that this comprehensive, multi-omics data resource will further mechanistic FTD research by the community.

  Study EGAS00001004895

• Tamoxifen Response at Single Cell Resolution in Estrogen Receptor Positive Primary Human Breast Tumors

  Primary breast tissue, normal and cancerous, was collected immediately after resection. The tissue was dissociated and treated with 10uM tamoxifen or control media for 12 hours in suspension. Single cell libraries were then created using a 10x Genomics gel bead droplet-based kit and sequenced via Illumina sequencing platforms. Differences in cell response to tamoxifen was observed between cell types and distinct responsive and unresponsive cell populations were determined.

  Study phs003186

• Reconstitution of Human Brain Cell Diversity in Organoids via Four Protocols [scRNAseq]

  Single-cell RNA-sequencing of brain organoids at day 120 grown in four distinct growth protocols designed to generate dorsal (D) and ventral (V) forebrain, midbrain (M) and striatum (S) tissue using eight different pluripotent stem cell lines. Per per cell line-protocol combination two organoids (biological replicates) were grown. For cell line 176 the experiment was conducted in two independent biological replicates (repititions E1 and E2).

  Study EGAS50000000662

• Profiling of 27 type 2 diabetes GWAS loci using next-generation (NG) capture C in a human beta-cell model

  Most type 2 diabetes association signals are due to variants that impact gene regulation but identifying the genes they impact is challenging. We generated interaction profiles at 27 T2D GWAS loci using next-generation (NG) capture C in a human beta-cell model ( EndoC-betaH1) and contrasted our maps with public Hi-C/promoter capture Hi-C maps in EndoC-betaH1 cells or human islets.

  Study EGAS00001006105

• RNA sequencing of NK cells in human lung

  Human lung tissue-resident NK cells (trNK cells) are likely to play important roles in viral infections, inflammation and cancer. However, knowledge about lung trNK cells is lacking but is fundamental for exploiting these cells in therapeutic approaches. Here we analysed the transcriptome of CD69+CD49a+CD103+CD16-CD56bright, CD69+CD49a+CD103-CD16-CD56bright, CD69+CD49a-CD103-CD16-CD56bright, CD69-CD49a-CD103-CD16-CD56bright, and CD56dimCD16+NKG2A+CD57- NK cells isolated from human lung.

  Study EGAS00001003544

• Genetic scoring guide for personalized risk assessment in pediatric B-cell precursor Acute Lymphoblastic Leukemia

  In this study a next-generation sequencing based method was applied to comprehensively screen for recurrent, disease-relevant copy number aberrations in a cohort of Hungarian patients. Diagnostic bone marrow samples from 260 children with B-cell acute lymphoblastic leukemia and were investigated by digital multiplex ligation-dependent probe amplification using the disease-specific D007 probemix. Whole chromosome gains and losses, as well as subchromosomal copy number aberrations were simultaneously profiled.

  Study EGAS00001007239