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• Bulk WES Fastq Files for 103 Samples of Cornell-NCI DLBCL Genomic Project

  Paired-read fastq files were derived from standard Illumina WES NGS sequencing for 103 DLBCL biopsy samples. This is one of three datasets associated with the multi-platform NGS sequencing efforts of the Cornell-NCI DLBCL genomic study.

  Dataset EGAD50000001747

• BAM files from whole-exome sequencing of 5 agressive B-cell lymphoma tumour samples

  This dataset contains BAM files from whole-exome sequencing (WES) of 5 agressive B-cell lymphoma tumour samples for cases 2, 3, 4 and 5. For case 2, non-tumor whole-exome sequencing is also available.

  Dataset EGAD50000000803

• Oslo University Hospital Data Access Committee for Celiac Disease datasets submitted to FEGA Norway

  This is the Data Access Committee appointed by Oslo University Hospital for governing access to Celiac Disease datasets submitted to FEGA Norway, under the Regional Ethical Committee approval 6544, with main contact Ludvig M. Sollid.

  Dac EGAC50000001032

• Whole Exome Sequencing of High grade T1 non-muscle invasive bladder cancer

  The dataset consists of a multisample VCF (version 4.1) and the corresponding annotated MAF file, containing the somatic point mutations found from exome sequencing across the high-grade T1 bladder cancer cohort (HGT1, n=61 samples). The VCF file is in accordance with the HTS format specifications (https://samtools.github.io/hts-specs/). The dataset comprises also a CSV file with clinical data.

  Dataset EGAD00001006346

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

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

  Study EGAS50000000334

• Combination of CDK4/6 with BET-bromodomain and PI3K/mTOR inhibitors in medulloblastoma in vitro and in vivo

  Despite improvement in the treatment of medulloblastoma (MB) over the last years, numerous patients with MYC- and MYCN-driven tumors still fail the current therapeutic regimen. The retinoblastoma (RB) pathway is often compromised in MB with RB remaining intact suggesting that CDK4/6 inhibition might represent a therapeutic strategy for which drug combination remains understudied. Using tumor lines grown in stem cell conditions referred as tumorspheres as well as tumor cells freshly dissociated from the brain of mice harboring intracranial patient-derived xenografts (PDX) of Group3 (G3) and Sonic Hedgehog (SHH) MB, we conducted high throughput drug combination screens using the CDK4/6 inhibitor (CDK4/6i) ribociclib as an anchor and 87 oncology drugs approved by FDA or currently in clinical trials. Bromodomain and extra terminal (BET) and PI3K/mTOR inhibitors potentiated ribociclib’s inhibition of proliferation in G3 and SHH MB. A reverse combination screen using BET inhibitor JQ1 as the anchor, revealed the three FDA approved CDK4/6i as the most potentiating drugs. Those synergistic combinations were tested in vivo in mice intracranially implanted with G3 and SHH MB tumor cells. Ribociclib showed single agent activity in several in vivo MB models. However, despite in vitro synergy, combinations of ribociclib with JQ1 and ribociclib with the PI3K/mTOR inhibitor paxalisib failed to improve the survival of MB bearing mice compared to ribociclib alone. Our data illustrates the difficulty in translating in vitro findings to in vivo for brain tumors partly due to insufficient free brain concentration and altered signaling pathways activation in vitro compared to in vivo.

  Study EGAS00001006286

• Oncogenome of Kaposi Sarcoma

  Kaposi Sarcoma (KS) is an aggressive cancer caused by the Kaposi Sarcoma Herpesvirus (KSHV/HHV-8). Individuals with immunodeficiencies, exemplified by HIV, have an elevated risk of developing KS. However, understanding of the genetic factors contributing to KS progression is still limited. To explore potential genetic alterations in KS that could offer biological or therapeutic insights, whole exome sequencing was performed on 78 KS tumors and matching normal skin samples from 59 adults with KS (46 with HIV-associated KS and 13 with HIV-negative KS) receiving treatment at the Uganda Cancer Institute in Kampala, Uganda. Results showed a very low mutational burden in all samples except one (median = 11 mutations), which is the smallest number of mutations found across all 33 cancer types in The Cancer Genome Atlas (TCGA). No recurrent mutations were identified. Mutational signatures included impaired DNA mismatch repair and smoking. There was no evidence suggesting that multiple tumors from the same patient originated from a single clone. The number of genome copy alterations per genome was higher in tumors from individuals without HIV and those with advanced-stage disease. This suggests that lesions that take longer to develop may accumulate more alterations, although the overall number of alterations remains low compared to other cancers. These findings suggest that KS pathogenesis differs from other cancers, with KSHV viral infection and the expression of viral oncogenes being the primary drivers of carcinogenesis, rather than clonal oncogenic transformation arising from genetic alterations of cancer-related cellular genes.

  Study phs003897

• Emirati T2T Assembly

  This study generates a telomere-to-telomere (T2T) trio-based genome assembly for a female Emirati individual, creating a high-quality reference representative of an understudied population. We produced multi-platform sequencing for a single family trio: PacBio HiFi (>60× per parent, >120× offspring), ONT ultra-long reads (>110× offspring), and Illumina short-read WGS (>100× for all three). The offspring genome was assembled in a trio framework to leverage parental information for accurate phasing and error resolution. Scaffolding and finishing utilized NTLink for initial scaffolding, RagTag for reference-guided refinement, and Quartett for gap filling, resulting in a contiguous, population-relevant assembly suitable for downstream variant discovery and pangenome integration.

  Study EGAS50000001235

• scRNA-seq data of Anti-Her2-CAR T cells treated with immunomodulatory metabolites

  Anti-Her2-CAR T cells produced from T cells derived from healthy human donors were treated with DMSO (control) or either of the immunomodulatory metabolites indole‐3‐carboxaldehyde (ICA), valeric acid (VA) and isovaleric acid (IVA) to assess effects on CAR T cell function. scRNA-seq libraries were generated on a 10X Chromium controller with On-Chip-Multiplexing. The individual samples in a library are distinguished during analysis on the single-cell level via the cell barcode class.

  Dataset EGAD50000002012

• Arkansas Children’s Research Institute (ACRI) Data Access Committee – Kelly Research Group

  The Arkansas Children’s Research Institute (ACRI) Data Access Committee – Kelly Research Group oversees requests for access to controlled human genomic and transcriptomic data generated by the Kelly Research Group. The committee ensures that all data access requests are consistent with participants’ informed consent, institutional review board (IRB) approvals, and applicable regulatory requirements. All approved users must agree to use the data solely for biomedical research purposes, maintain data confidentiality, and acknowledge the data source in resulting publications.

  Dac EGAC50000000819

• Dataset of 10 WES from bladders tumors and PBMC of 4 non-muscle invasive bladder cancer patients

  WES (FASTQ files) of paired tumor and PBMC samples of non-muscle-invasive bladder cancer patients. All CTRL samples originate from PBMC. For patient UC2, DNA from 3 different synchronous tumors were extracted. DNA from tumors was extracted from fresh frozen tumors,except for patient UC4 (FFPE). NB : patients aliases are the following :ROXY : UC1, OMAD : UC2, MAKI : UC3, HAPE : UC4

  Dataset EGAD50000002008

• miRNAseq of paired FL and tFL samples

  This dataset contains miRNA-seq of paired FL and tFL samples (n=10 pairs) sequenced by Illumina NextSeq500. Libraries used in this miRNA-seq dataset were prepared with NEBNext Multiplex Small RNA Library Prep Set for Illumina (NEB,Catalog number: E7560S). RNAs used for library preparation were isolated from FFPE tissues using High Pure miRNA Isolation Kit (Roche,Catalog number: 05080576001). Data are uploaded as FASTQ format.

  Dataset EGAD50000001385

• Whole genome sequencing of Xeroderma Pigmentosum leukemias samples

  In the current study we report for the first time the unique collection of 6 leukemias and two sarcomas from XP-C. Comprehensive WGS-based mutational analysis provides genetic explanation for the increased incidence of leukemia in XP-C and describes an unique mutational process in internal tumors associated with NER deficiency. Raw data are provided in FASTQ format and variant analysis as VCF files.

  Dataset EGAD00001006322

• Structural Alterations Driving Castration-Resistant Prostate Cancer Revealed by Linked-Read Genome Sequencing

  Adapted from manuscript in review: Nearly all prostate cancer deaths are from metastatic castration-resistant prostate cancer (mCRPC) but there have been few whole genome sequencing (WGS) studies of this disease state. We performed linked-read WGS on 23 mCRPC biopsy specimens and analyzed cell-free DNA sequencing data from 86 patients with mCRPC. In addition to frequent rearrangements affecting known prostate cancer genes, we observed complex rearrangements of the AR locus in most cases. These include highly recurrent tandem duplications involving an upstream enhancer of AR. A subset of cases also displayed a genome-wide tandem duplicator phenotype associated with CDK12 inactivation. Our findings highlight the complex genomic structure of mCRPC nominate new alterations that may inform prostate cancer treatment, and suggest that additional recurrent events in the noncoding mCRPC genome remain to be discovered.

  Study phs001577

• Single-cell analysis reveals fibroblast clusters linked to immunotherapy resistance in cancer

  A subset of Cancer-Associated Fibroblasts (CAF-S1) mediates immunosuppression in breast cancers (BC), but its heterogeneity and its impact on immunotherapy response remain unknown. Here, we identify 8 CAF-S1 clusters by analyzing more than 18000 single CAF-S1 fibroblasts from BC. We validate the 5 most abundant clusters by flow cytometry and in silico analyses in other cancer types, highlighting their relevance. Myofibroblasts from clusters 0 and 3, characterized by extra-cellular matrix proteins and TGF signaling respectively, are indicative of primary resistance to immunotherapies. Cluster 0 up-regulates PD-1 and CTLA-4 protein levels in regulatory T lymphocytes (Tregs), which in turn increases CAF-S1 cluster 3 cellular content. Thus, our study highlights a positive feedback loop between specific CAF-S1 clusters and Tregs and uncovers their role in immunotherapy resistance.

  Study EGAS00001004030

• 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

• Panel-based NGS data for ADME genes in human liver samples

  Panel-based next-generation sequencing data of 150 human surgical liver samples from Caucasian donors. The panel was designed for 340 ADME (absorption, distribution, metabolism and excretion) and ADME-related genes. NGS was carried out on the Illumina HiSeq2500 system (Illumina Inc., San Diego, CA, United States) at high depth with 2 × 100 bps paired-end reads. Variants were called using samtools and varscan (2.3.5). Data on n=15,727 filtered variants for the 150 patients are comprised in one vcf file.

  Dataset EGAD00001005116

• ESR1 mutations in tamoxifen-associated endometrial cancer versus spontaneous arisen endometrial tumors

  An increased incidence of endometrial cancer has been described for patients that have received tamoxifen to treat breast cancer. Using samples from endometrial tumors, isolated from surgivcal specimens of patients who previously received tamoxifen treatment for breast cancer, we aimed to identify whether there are specific somatic mutations enriched in this population, relative to endometrial tumors from the general population. For this, WES was performed on matched endometrial tumors and healthy tissue (n=21).

  Dataset EGAD00001009088

• Single-cell RNA sequencing of pediatric Hodgkin Lymphoma to study the inhibition of T cell subtypes

  Here, we applied single-cell RNA-sequencing (scRNA-seq) on isolated HRS cells and the immune cells from the same cHL tumors. This allowed us to identify genes of cell surface proteins that are consistently overexpressed in HRS cells and can potentially be used as targets for antibody-drug conjugates or CAR T cells. Finally, we identify potential interactions by which HRS cells inhibit T cells, among which the Galectin-1/CD69 and HLA-DRA/LAG3 interactions. However, high levels of inter-patient heterogeneity of the interaction strength were observed. In conclusion, this study identifies new potential therapeutic targets for cHL and highlights the importance of studying heterogeneity when identifying therapy targets.

  Study EGAS50000000432

• Mid-frequency hearing loss is a characteristic clinical feature of OTOA-associated hearing loss

  In this study, we performed NGS analysis of a large Japanese hearing loss cohort, and identified 7 patients with OTOA-associated hearing loss. As novel clinical features identified in this study, the audiometric configurations of OTOA-associated hearing loss patients was found to be mid-frequency.

  Study JGAS000200

• microRNA-seq of human serum from a longitudinal study of 66 women with no history of cancer

  This dataset includes microRNA sequencing data from 198 human serum samples, representing a subset of 66 women with no history of cancer who participated in the UKCTOCS study and with serum samples collected at three timepoints over a period of up to 5 years. Small RNA libraries prepared from the serum samples were sequenced with 50-bp single end reads on an Illumina HiSeq 2000 instrument. Data is provided as FASTQ files.

  Dataset EGAD00001004348

• Ultra-deep sequencing of cell-free DNA derived from reference materials and a patient with asymmetric overgrowth

  This dataset contains: Ultra-deep sequencing data using the Duplex sequencing technology of: 1.) SeraSeq cfDNA reference materials with spike-in variants with allele frequencies from 0% to 5% 2.) One cfDNA sample from a CRC patient 3.) One cfDNA sample from a patient with asymmetric overgrowth Paired-end sequencing was performed with 2x151 bp reads on the NextSeq 500 system. Data is provided as mapped .bam files (aligned to GRCh38/hg38).

  Dataset EGAD00001009784

• Transcriptional profiling of ovarian tumours and cell lines

  Purpose: Endogenous retroviruses (ERVs) play a role in a variety of biological processes, including embryogenesis and cancer. DNA methyltransferase inhibitors (DNMTi)-induced ERV expression triggers interferon responses in ovarian cancer cells via the viral sensing machinery. Baseline expression of ERVs also occurs in cancer cells, though this process is poorly understood and previously unexplored in epithelial ovarian cancer (EOC). Here, the prognostic and immunomodulatory consequences of baseline ERV expression was assessed in EOC. Experimental Design: ERV expression was assessed using EOC transcriptional data from TCGA and from an independent cohort (HH), as well as from untreated or DNMTi-treated EOC cell lines. LASSO logistic regression defined an ERV expression score to predict patient prognosis. Immunohistochemistry (IHC) was conducted on the HH cohort. Combination of DNMTi treatment with γδ T cells was tested in vitro, using EOC cell lines and patient-derived tumor cells. Results: ERV expression was found to define clinically relevant subsets of EOC patients. An ERV prognostic score was successfully generated in TCGA and validated in the independent cohort. In EOC patients from this cohort, a high ERV score was associated with better survival (log-rank p=0.0009) and correlated with infiltration of CD8+PD1+ T cells (r=0.46, p=0.0001). In vitro, baseline ERV expression dictates the level of ERV induction in response to DNMTi. Manipulation of ERV expression by DNMTi resulted in improved EOC cell killing by cytotoxic immune cells. Conclusions: These findings uncover the potential for baseline ERV expression to robustly inform EOC patient prognosis, influence tumor immune infiltration and affect anti-tumor immunity.

  Study EGAS00001004814

• Evolution of Resistance in ER+ Breast Cancer

  While the combination of endocrine therapy and CDK4/CDK6 inhibitors has been shown to be effective in the metastatic ER+ breast cancer setting, to test whether it is effective in an earlier stage neoadjuvant setting, the FELINE trial (NCT02712723) was established to test the efficacy of letrozole and ribociclib in a ER-positive, HER2-negative patients in a randomized, placebo-controlled, multicenter trial. Patients were randomized to one of three arms: those in Arm A received letrozole and placebo, Arm B letrozole and intermittent ribociclib, and Arm C letrozole and continuous ribociclib. Samples were collected at screening (Day 0), Cycle 1 (Day 14), and end of trial (Day 180). Samples from 24 patients, where cancer cells were present at Day 0 and one additional time point, were subjected to whole-exome sequencing profiling.

  Study phs002287

• Integrated Transcriptomic and Regulatory RNA Profiling Reflects Complex Pathophysiology and Uncovers a Conserved Gene Signature in End Stage Heart Failure RNA-Seq data

  Heart failure (HF) is a complex syndrome. Despite availability of multiple treatment options, the mortality remains high and the quality of life poor. Better understanding of the underlying pathophysiological processes can lead to development of novel therapies. Multiple comparative transcriptomics studies, which revealed gene level changes in the key pathophysiological pathways in failing hearts, point towards heterogeneity from interplay of disease stage, etiologies and ethnicity. Transcriptomic characterization of HF in patients from different ethnicities can potentially help in understanding the heterogeneity imparted by various factors and the core elements in heart failure.

  Study EGAS50000000810

• TSCA-LI amplicon sequencing of called variants in WXS data of DSALL.

  Targeted resequencing of samples was done with TruSeq custom amplicon low input kit (TSCA-LI, Illumina). The oligo capture probes were designed to include a prefix of 8 random nucleotides at the 5 end of each probe. The assay is designed such that each targeted locus is annealed with two probes, resulting in amplicons tagged with unique molecular identifiers (UMI) (22) of 16 bases. Raw FASTQ sequencing files were processed as following: (a) The first 8 bases were trimmed from each read and recorded with the corresponding base quality scores (BQ) in the attribute field. (b) Reads were aligned with BWA. (c) First round of PCR duplicate cleaning was performed with picard tools markDuplicates using the parameters BARCODE_TAG=BC TAGGING_POLICY=All REMOVE_DUPLICATES=true (d) Since in the previous step only duplicate reads with identical UMIs were removed, a second pass of filtering was done. Reads with identical mapping were considered unique only if their corresponding UMIs were different in at least 3 positions (i.e., UMI edit distance > 2). (e) Paired-end read pairs overlapping genomic positions were clipped to avoid overestimation of the sequencing coverage using bamUtils clipOverlap.

  Dataset EGAD00001003275

• Single-cell multi-omics and mtDNA genotyping of human peripheral blood cells

  This dataset comprises two mtscATAC-seq libraries (customized 10X ATAC-seq) generated from donor M80 and donor H05, and one DOGMA-seq library (customized 10X multiome) generated from donor H05, all derived from primary human peripheral blood mononuclear cells. Patient M80 is an 80-year-old male with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), while donor H05 is a healthy 5-year-old pediatric donor. The raw FASTQ files have been provided.

  Dataset EGAD50000001489

• Whole genome sequencing of Osteosarcoma clonal evolution

  Multiple large-scale genomic profiling efforts have been undertaken in osteosarcoma to define the genomic drivers of tumorigenesis, therapeutic response, and disease recurrence. The spatial and temporal intratumor heterogeneity could also play a role in promoting tumor growth and treatment resistance. Here, we conducted longitudinal whole-genome sequencing of 37 tumor samples from eight patients with osteosarcoma that relapsed or became refractory to initial therapy. We found that the chemoresistant population in recurrent osteosarcoma is subclonal at diagnosis, emerges at the time of primary resection due to selective pressure from neoadjuvant chemotherapy, and is characterized by unique oncogenic amplifications.

  Dataset EGAD00001011285

• A rare CTSC mutation in Papillon-Lefèvre Syndrome

  Papillon-Lefèvre Syndrome (PLS) is an autosomal recessive monogenic disease caused by loss-of-function mutations in the CTSC gene. In this study we performed whole genome sequencing on two siblings, with the PLS-typical symptoms. After sequencing the CTSC gene was analyzed to confirm the PLS diagnosis genetically.

  Study EGAS00001005040

• Single-Cell DNA and RNA Sequencing over A 29-Year Period of A CLL Patient Demonstrating Evolution of Multiple Cell Clones

  Chronic lymphocytic leukemia (CLL) is a frequent B-cell malignancy characterized by recurrent somatic chromosome alterations and a low level of point mutations. Here we present single nucleotide polymorphism (SNP) microarray analyses of a single CLL patient over 29-years of observation and treatment, and transcriptome and whole genome sequencing at selected timepoints. We identified chromosome alterations of 13q14-, 6q- and 12q+ in early cell clones, elimination of clonal populations following therapy, and subsequent appearance of a clone containing trisomy 12 and a chromosome 10 copy neutral loss of heterogeneity (LOH) that marks a major population dominant at death. Serial single cell RNA sequencing revealed elevated mRNA expression of the FOS, JUN and KLF4 genes just before the appearance of acute disease requiring therapy. This gene expression pattern became undetectable following therapy, but reoccurred following relapse. Transcriptome evolution indicates that complex expression changes occur over time. In conclusion, CLL can evolve gradually during indolent phases, and undergo rapid changes following therapy.

  Study phs001181

• Mutational signature in colorectal cancer induced by genotoxic pks+ E. coli

  Various species of the intestinal microbiota have been associated with the development of colorectal cancer (CRC), yet a direct role of bacteria in the occurrence of oncogenic mutations has not been established. Escherichia coli can carry the pathogenicity island pks, which encodes a set of enzymes that synthesize colibactin. This compound alkylates DNA on adenine residues and induces double strand breaks in cultured cells. Here, we exposed human intestinal organoids to genotoxic pks+ Escherichia coli by repeated luminal injection over a period of 5 months. Whole genome sequencing (WGS) of clonal organoids before and after this exposure reveals a distinct mutational signature, absent from organoids injected with isogenic pks-mutant bacteria. The same mutational signature is detected in a subset of 3668 human metastatic cancer genomes, predominantly in a subset of CRC cases. Our study describes a distinct mutational signature in CRC and implies that the underlying mutational process directly results from past exposure to bacteria carrying the colibactin-producing pks pathogenicity island.

  Study EGAS00001003934

• NHLBI TOPMed: GOLDN Epigenetic Determinants of Lipid Response to Dietary Fat and Fenofibrate

  The GOLDN study was initiated to assess how genetic factors interact with environmental (diet and drug) interventions to influence blood levels of triglycerides and other atherogenic lipid species and inflammation markers (registered at clinicaltrials.gov, number NCT00083369). The study recruited Caucasian participants primarily from three-generational pedigrees from two NHLBI Family Heart Study (FHS) field centers (Minneapolis, MN and Salt Lake City, UT). Only families with at least two siblings were recruited and only participants who did not take lipid-lowering agents (pharmaceuticals or nutraceuticals) for at least 4 weeks prior to the initial visit were included. The diet intervention followed the protocol of Patsch et al. (1992). The whipping cream (83% fat) meal had 700 Calories/m2 body surface area (2.93 mJ/m2 body surface area): 3% of calories were derived from protein (instant nonfat dry milk) and 14% from carbohydrate (sugar). The ratio of polyunsaturated to saturated fat was 0.06 and the cholesterol content of the average meal was 240 mg. The mixture was blended with ice and flavorings. Blood samples were drawn immediately before (fasting) and at 3.5 and 6 hours after consuming the high-fat meal. The diet intervention was administered at baseline as well as after a 3-week treatment with 160 mg micronized fenofibrate. Participants were given the option to complete one or both (diet and drug) interventions. Of all participants, 1079 had phenotypic data and provided appropriate consent, and underwent whole genome sequencing through the Trans-Omics for Precision Medicine (TOPMed) program. Comprehensive phenotypic and pedigree data for GOLDN study participants are available through dbGaP phs000741.

  Study phs001359

• An integrative model of pathway convergence in genetically heterogeneous blast crisis chronic myeloid leukemia (CML)

  Targeted therapies against the BCR-ABL1 kinase have revolutionized treatment of chronic phase (CP) chronic myeloid leukemia (CML). In contrast, management of blast crisis (BC) CML remains challenging because BC cells acquire complex molecular alterations that confer stemness features to progenitor populations and resistance to BCR-ABL1 tyrosine kinase inhibitors. Comprehensive models of BC transformation have proved elusive because of the rarity and genetic heterogeneity of BC, but are important for developing biomarkers predicting BC progression and effective therapies. To better understand BC, we performed an integrated multiomics analysis of 74 CP and BC samples using whole-genome and exome sequencing, transcriptome and methylome profiling, and chromatin immunoprecipitation followed by high-throughput sequencing. Employing pathway-based analysis, we found the BC genome was significantly enriched for mutations affecting components of the polycomb repressive complex (PRC) pathway. While transcriptomically, BC progenitors were enriched and depleted for PRC1- and PRC2-related gene sets respectively. By integrating our data sets, we determined that BC progenitors undergo PRC-driven epigenetic reprogramming toward a convergent transcriptomic state. Specifically, PRC2 directs BC DNA hypermethylation, which in turn silences key genes involved in myeloid differentiation and tumor suppressor function via so-called epigenetic switching, whereas PRC1 represses an overlapping and distinct set of genes, including novel BC tumor suppressors. On the basis of these observations, we developed an integrated model of BC that facilitated the identification of combinatorial therapies capable of reversing BC reprogramming (decitabine+PRC1 inhibitors), novel PRC-silenced tumor suppressor genes (NR4A2), and gene expression signatures predictive of disease progression and drug resistance in CP.

  Study EGAS00001001751

• MP2PRT: Identification of Genetic Changes Associated with Relapse and/or Adaptive Resistance in Patients Registered as Favorable Histology Wilms Tumor on AREN03B2

  The Molecular Profiling to Predict Response to Treatment (MP2PRT) program is part of the NCI's Cancer Moonshot Initiative. The aim of this program is the retrospective characterization and analysis of biospecimens collected from completed NCI-sponsored trials of the National Clinical Trials Network and the NCI Community Oncology Research Program. This study, titled "Identification of Genetic Changes Associated with Relapse and/or Adaptive Resistance in Patients Registered as Favorable Histology Wilms Tumor on AREN03B2", performs genomic characterization (WGS 30X, Total RNAseq, miRNAseq) on a discovery set of 70 trio cases (normal tissue, tumor tissue at time of diagnosis, tumor tissue at time of relapse) from patients who relapsed with Favorable Histology Wilms Tumor. Prioritized findings from the discovery set will be validated using Targeted Sequencing in an independent validation set of 47 relapse samples.

  Study phs001965

• SCANDARE MACARON

  Among gynecological cancers, high-grade serous ovarian cancer has the highest prevalence and more than 75% of patients have advanced stage at diagnosis with a 5-year survival of 40%. When the initial complete surgical removal is not possible (60% of patients), an interval surgery can be considered after three to four cycles of neoadjuvant chemotherapy to reduce the tumor mass. However, in approximately 50% of cases the tumor has little or no response to neoadjuvant chemotherapy. Therefore, identification of potential drug targets, biomarkers and/or pathways whose modulation can help in the prevention, interception, or curing of the disease is essential to address the unmet need. Therefore, MACARON project aims to address these issues through the identification of shared neoantigens arising out of somatic alterations and aberrant transcriptional programs in ovarian cancer DNA/RNA datasets.

  Study EGAS50000000145

• Vento_Placental_Cell_Atlas

  The Human Cell Atlas initiative is an ambitious global research effort which aims to describe every cell in the human body across all developmental stages to generate a reference map to accelerate progress in science and medicine particularly relating to human development and disease. The initiative is led by investigators based at the Wellcome Sanger Institute and the Broad Institute of MIT and Harvard and funding support from the Wellcome and NIH. This specific project will assess human development. We aim to interrogate the cellular composition and molecular regulators underpinning development and maturation through single cell RNA-sequencing/spatial transcriptomics and computational algorithms to predict cellular developmental trajectories and cell-cell interactions. We will subsequent validate these findings in situ using allied imaging technologies e.g. immunohistochemistry and RNAscope and in vitro culture of human intestinal organoids (HIOs).

  Study EGAS00001004187

• Comprehensive cancer predisposition gene testing in an adult multiple primary tumor series shows a broad range of deleterious variants and atypical tumor phenotypes

  Multiple primary tumors (MPT) affect a substantial proportion of cancer survivors and may result from various causes including inherited predisposition. Currently, germline genetic testing of MPT cases for cancer predisposition gene (CPG) variants is mostly targeted by tumor type. We ascertained pre-assessed MPT cases from genetics centers (defined as ≥2 primaries by age 60 years or ≥3 by 70) and performed whole genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment/molecular investigations, pathogenic variants in moderate and high-risk CPGs were detected in 67/440 (15.2%) of probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies including structural variants at low frequency (6/440 (1.4%) of probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant) the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice site CPG variants and at least one discordant tumor type was significantly higher than a control population (χ2=43.642 P=<0.0001). 2/67 (3%) of probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Summing together variant detection rates from a similarly ascertained previous MPT case series, the present results suggest that first-line comprehensive CPG analysis in a clinical genetics referral-based MPT cohort would detect a deleterious variant in about a third of cases.

  Dataset EGAD00001004088

• HiDEF-seq single-molecule sequencing of single-strand mismatches and damage

  Our study sought to resolve, with single-molecule fidelity, the mismatches and damage events that precede DNA mutations. Using a novel single-molecule, long-read sequencing method (HiDEF-seq) we detect base substitutions when present in either one or both DNA strands. We also detect cytosine deamination, a common type of DNA damage, with single-molecule fidelity. This study profiled 134 samples from diverse tissues, including from individuals with cancer predisposition syndromes. These samples revealed single-strand mismatch and damage signatures. Since double-strand DNA mutations are only the endpoint of the mutation process, our approach enables new studies of how mutations arise in a variety of contexts, especially in cancer and aging.

  Dataset EGAD50000000460

• IKZF5 RNAseq samples for platelets, neutrophils, monocytes and CD4+ T-cells.

  To identify novel causes of hereditary thrombocytopenia, we performed a genetic association analysis of whole-genome sequencing (WGS) data from 13,037 individuals enrolled in the NIHR BioResource, including 233 cases with isolated thrombocytopenia. We found an association between rare variants in the transcription factor (TF)-encoding gene IKZF5 and thrombocytopenia. We report five causal missense variants in or near IKZF5 zinc fingers (Znfs), of which two occurred de novo and three co-segregated in three pedigrees. A canonical DNA-Znf binding model predicts that three of the variants alter DNA recognition. Expression studies showed that chromatin binding was disrupted in mutant compared to wild-type (WT) IKZF5 and electron microscopy (EM) revealed a reduced quantity of alpha granules in normally sized platelets. Proplatelet formation (PPF) was reduced in megakaryocytes (MKs) from seven cases relative to six controls. Comparison of RNA-seq data from platelets, monocytes, neutrophils and CD4+ T-cells from three cases and 14 healthy controls showed 1,194 differentially expressed genes (DEGs) in platelets but only four DEGs in each of the other blood cell types. In conclusion, IKZF5 is a novel transcriptional regulator of megakaryopoiesis and the eighth transcription factor associated with dominant thrombocytopenia in humans.

  Dataset EGAD00001005107

• The CCA Genome Core is responsible for archiving the sequencing data generated by the Cancer Centre Amsterdam (CCA).

  Dac EGAC00001000181

• Psoriasis PBMCs

  This DAC is for the purpose of controlling access to Psoriasis PBMC scRNA-seq data of the study Spermidine/spermine N1-acetyltransferase controls tissue-specific regulatory T cell function in chronic inflammation

  Dac EGAC50000000470

• COMET TCRseq raw data

  This is the raw TCRseq data for the manuscript T cell receptor repertoire sequencing reveals chemotherapy-driven clonal expansion in colorectal liver metastases.

  Dataset EGAD00001010269

• Characterization of the oral and gut microbiome of melanoma patients before initiation of ant-PD-1 therapy, and confirmation of the phenotype in germ-free mice

  The oral and gut microbiomes of melanoma patients were characterized before the initiation of ant-PD1 immunotherapy, and compared to treatment response. Validation studies were performed in germ-free mice using stool from patients who responded/did not respond to ant-PD1 immunotherapy. All baseline oral(n=86) and gut (n=43) microbiome samples were subject to 16S sequencing - V4 region ( merged fastq files have been made available through this portal). Whole genome shotgun sequencing (WGS) was performed on a subset of fecal samples (n=25)- these files are also available( paired end reads). Also available are 16S sequencing results of stool samples from donors (n=2) used in fecal microbiota transplant and murine samples (n=12) from germ-free mice transplanted with stool from responder/non-responder patients. The fastq files associated with this dataset are stored at ENA under the following links: Fecal 16S – PRJEB22894 https://www.ebi.ac.uk/ena/browser/view/PRJEB22894 Oral 16S – PRJEB22874 https://www.ebi.ac.uk/ena/browser/view/PRJEB22874 Murine 16S – PRJEB22895 https://www.ebi.ac.uk/ena/browser/view/PRJEB22895 Fecal WGS – PRJEB22893 https://www.ebi.ac.uk/ena/browser/view/PRJEB22893

  Dataset EGAD00001003943

• Tobacco exposure and somatic mutations in normal human bronchial epithelium

  That tobacco smoking causes lung cancer is well-established, but we lack quantitative understanding of its effects on genomes of normal bronchial epithelium. We sequenced whole genomes of 632 colonies derived from single bronchial epithelial cells across 16 subjects. Tobacco smoking is the major influence on mutation burden, adding 1000-10,000+ mutations/cell, massively increasing both between-subject and within-subject variance, and generating several distinct signatures of substitutions and indels. A population of cells in subjects with smoking history had mutation burdens equivalent to that expected for never-smokers: these cells lacked tobacco-specific mutational signatures, were four-fold more frequent in ex-smokers than current smokers, and had significantly longer telomeres than their more mutated counterparts. Driver mutations increased in frequency with age, affecting 4-14% of cells in middle-aged never-smokers. In current smokers, ≥25% of cells carried driver mutations and 0-6% cells had 2 or even 3 drivers. Thus, tobacco smoking increases mutation burden, cell-to-cell heterogeneity and driver mutations, but quitting promotes replenishment of bronchial epithelium from mitotically quiescent cells that have avoided tobacco mutagenesis.

  Dataset EGAD00001005193

• Molecular and clinical diversity in primary central nervous system lymphoma: a LOC Network study

  Primary central nervous system lymphoma (PCNSL) is a distinct extranodal lymphoma presenting with limited stage disease but variable response rates to treatment despite homogenous pathological presentation. The likely underlying molecular heterogeneity and its clinical impact is poorly understood. We performed a comprehensive genome-wide analysis of 147 PCNSL from fresh-frozen tumor tissue from immunocompetent, treatment naïve PCNSL patients, employing whole-exome sequencing, assessment of somatic copy number alterations and DNA methylation, and RNA expression. These data were integrated and correlated with the clinico-radiological characteristics and outcomes of the patients. We validated our results in an independent series of 93 PCNSL formalin-fixed, paraffin-embedded (FFPE) samples. Consensus clustering of multi-omics data identified four robust, non-overlapping, prognostically significant clusters (CS) within PCNSL. The CS1 group, characterized by high proliferation and Polycomb Repressive Complex 2 (PRC2) complex activity had an intermediate outcome between CS2/CS3 and CS4. Patients who had PCNSL with an “immune-hot” (CS4) profile had the most favorable clinical outcome. In contrast, patients with the immune-cold hypermethylated CS2 and the heterogenous-immune CS3 groups had a poor prognosis. Nearly all PCNSL patients with meningeal infiltration harbored HIST1H1E mutations, enriched in the CS3 group. The integrated analysis suggests that the CS4 group may be more susceptible to immunotherapy. The integration of genome-wide data from multi-omics data revealed four molecular patterns in PCNSL with a distinctive prognostic impact that significantly improved the current clinical stratification. This molecular classification using FFPE samples facilitates routine use in clinical practice and provides potential precision-medicine strategies in PCNSL.

  Study EGAS00001006191

• Genomic evolution and natural history of myeloproliferative neoplasms on therapy - triple-negative-ET

  Philadelphia-negative myeloproliferative neoplasms are chronic blood neoplasms. Treatments control blood counts but disease can progress to myelofibrosis or acute myeloid leukaemia. We performed longitudinal whole-genome and targeted sequencing in 30 patients, integrating clonal dynamics with 7,986 blood counts and clinical histories. Distinct evolutionary patterns distinguished stable from progressive disease, with leukaemic transformation arising via TP53 loss, stepwise driver mutation acquisition within complex clones, or emergence of independent leukaemic clones. In contrast, stable disease showed long-term clonal equilibrium without new drivers. Phylogenetic analysis using 203 whole-genomes of haematopoietic colonies revealed age-appropriate polyclonal haematopoiesis in triple-negative essential thrombocythaemia and germline predisposition to thrombocytosis, supporting non-neoplastic origins. Therapy-associated mutagenesis was observed, including C>G mutations following azacitidine and characteristic T>A/T>G after hydroxycarbamide exposure in blood cells, although not in skin where UV damage predominated. These findings demonstrate progression is genomically encoded years in advance and support serial monitoring and further study of treatment-related mutagenesis.

  Dataset EGAD00001016066

• Genomic evolution and natural history of myeloproliferative neoplasms on therapy - MPN_bulk

  Philadelphia-negative myeloproliferative neoplasms are chronic blood neoplasms. Treatments control blood counts but disease can progress to myelofibrosis or acute myeloid leukaemia. We performed longitudinal whole-genome and targeted sequencing in 30 patients, integrating clonal dynamics with 7,986 blood counts and clinical histories. Distinct evolutionary patterns distinguished stable from progressive disease, with leukaemic transformation arising via TP53 loss, stepwise driver mutation acquisition within complex clones, or emergence of independent leukaemic clones. In contrast, stable disease showed long-term clonal equilibrium without new drivers. Phylogenetic analysis using 203 whole-genomes of haematopoietic colonies revealed age-appropriate polyclonal haematopoiesis in triple-negative essential thrombocythaemia and germline predisposition to thrombocytosis, supporting non-neoplastic origins. Therapy-associated mutagenesis was observed, including C>G mutations following azacitidine and characteristic T>A/T>G after hydroxycarbamide exposure in blood cells, although not in skin where UV damage predominated. These findings demonstrate progression is genomically encoded years in advance and support serial monitoring and further study of treatment-related mutagenesis.

  Dataset EGAD00001016067

• Genomic evolution and natural history of myeloproliferative neoplasms on therapy - SCC_CALRmutated ET

  Philadelphia-negative myeloproliferative neoplasms are chronic blood neoplasms. Treatments control blood counts but disease can progress to myelofibrosis or acute myeloid leukaemia. We performed longitudinal whole-genome and targeted sequencing in 30 patients, integrating clonal dynamics with 7,986 blood counts and clinical histories. Distinct evolutionary patterns distinguished stable from progressive disease, with leukaemic transformation arising via TP53 loss, stepwise driver mutation acquisition within complex clones, or emergence of independent leukaemic clones. In contrast, stable disease showed long-term clonal equilibrium without new drivers. Phylogenetic analysis using 203 whole-genomes of haematopoietic colonies revealed age-appropriate polyclonal haematopoiesis in triple-negative essential thrombocythaemia and germline predisposition to thrombocytosis, supporting non-neoplastic origins. Therapy-associated mutagenesis was observed, including C>G mutations following azacitidine and characteristic T>A/T>G after hydroxycarbamide exposure in blood cells, although not in skin where UV damage predominated. These findings demonstrate progression is genomically encoded years in advance and support serial monitoring and further study of treatment-related mutagenesis.

  Dataset EGAD00001016068

• The transition from quiescent to activated states in human hematopoietic stem cells is governed by dynamic 3D genome reorganization

  To elucidate the epigenetic changes which occur when human long-term hematopoietic stem cells (LT-HSC) become activated we performed Bulk ATAC-Seq on 13 sorted bulk hematopoietic populations from cord bloodas well as single-cell ATAC-Seq upon CD34+CD38-CD45RA- cells enriched for HSC as well as CD34+/CD38+ progenitor cells both from cord blood. These studies revealed gains of chromatin accessibility around CTCF binding sites during HSPC activation, as such we additionally performed Low-C to directly profile the 3D conformation of human cord-blood derived LT-HSC and Short-term hematopoietic stem cells (ST-HSC), as well as Hi-C , ATAC-Seq and CTCF ChIP-Seq upon the OCIAML-2 cell line in which CTCF sites gained during LT-HSC activation are enriched. Finally we transduced human cord-blood LT-HSC with an shCTCF vector; in-vitro cultured LT-HSC cells harbouring shCTCF were used to perform RNA-Seq, and scATAC-Seq was performed on CD34+/CD38- human CB cells transduced with shCTCF, four weeks post xeno-transplantation into mice. Collectively these studies have helped us demonstrate the role of 3D chromatin conformation changes during human LT-HSC activation.

  Dataset EGAD00001006447

• Moroccan Genome Project: Sequencing Data from 109 Whole Genomes of Moroccan Individuals

  This study is the first phase of the Moroccan Genome Project, which included the complete sequencing of 109 genomes from the Kingdom of Morocco. The sequencing was performing using the Illumina NovaSeq6000 platform, with a mean coverage of 30X.

  Dac EGAC50000000353