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• Aberrant Activation of Wound Healing Programs within the Metastatic Niche Facilitates Lung Colonization by Osteosarcoma Cells

  Lung metastasis is responsible for nearly all deaths caused by osteosarcoma, the most common pediatric bone tumor. How malignant bone cells coerce the lung microenvironment to support metastatic growth is unclear. This study delineates how osteosarcoma cells educate the lung microenvironment during metastatic progression.Using single-cell transcriptomics (scRNA-seq), we characterized genome– and tissue-wide molecular changes induced within lung tissues by disseminated osteosarcoma cells in both immunocompetent murine models of metastasis and patient samples. We confirmed transcriptomic findings at the protein level and determined spatial relationships with multi-parameter immunofluorescence. We evaluated the ability of nintedanib to impair metastatic colonization and prevent osteosarcoma-induced education of the lung microenvironment in both immunocompetent murine osteosarcoma and immunodeficient human xenograft models.Osteosarcoma cells induced acute alveolar epithelial injury upon lung dissemination. scRNA-seq demonstrated that the surrounding lung stroma adopts a chronic, non-resolving wound-healing phenotype similar to that seen in other models of lung injury. Accordingly, metastasis-associated lung demonstrated marked fibrosis, likely due to the accumulation of pathogenic, pro-fibrotic, partially-differentiated epithelial intermediates. Inhibition of fibrotic pathways with nintedanib prevented metastatic progression in multiple murine and human xenograft models. Our work demonstrates that osteosarcoma cells co-opt fibrosis to promote metastatic outgrowth. When harmonized with data from adult epithelial cancers, our results support a generalized model wherein aberrant mesenchymal-epithelial interactions are critical for promoting lung metastasis. Adult epithelial carcinomas induce fibrotic pathways in normal lung fibroblasts, whereas osteosarcoma, a pediatric mesenchymal tumor, exhibits fibrotic reprogramming in response to the aberrant wound-healing behaviors of an otherwise normal lung epithelium, which are induced by tumor cell interactions.

  Study phs003569

• UCSF Pediatric Bithalamic Glioma Genome Project

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

  Dataset EGAD00001005499

• Transcriptome study of differential expression in schizophrenia

  Schizophrenia is a common and severe psychotic disorder. While some common SNPs and rare copy number variants have been identified as being significantly associated with disease risk, the biological mechanisms remain undefined. To identify gene expression abnormalities in schizophrenia, we generated whole-genome gene expression profiles using microarrays on lymphoblastoid cell lines from a total of 413 cases and 446 controls. Regression analysis identified 95 transcripts differentially expressed by affection status at a genome-wide false discovery rate of 0.05, while simultaneously controlling for confounding effects. These transcripts represented 89 genes with functions such as neurotransmission, gene regulation, cell cycle progression, differentiation, apoptosis, and immunity. The observed differential expression of extended major histocompatibility complex region genes converges with the genetic evidence from schizophrenia genome-wide association studies, which find the same region to be the most significant schizophrenia susceptibility locus. Our analysis also provides novel candidate genes for further study to assess their potential contribution to schizophrenia.

  Study phs000775

• Colorectal cancer samples WES

  The whole exome was sequenced in two cancer-affected members (II:1 and III:1) of the family. The family subject of this study showed an autosomal dominant mode of CRC inheritance, fulfilling the Amsterdam I clinical criteria with three CRCs in two consecutive generations. The exome capture was performed using SureSelectXT Human All Exon V3 (51Mb, Agilent Technologies), and the library was sequenced on an Illumina HiSeq 2000 platform with paired-end reads of 101bp and a 50x average coverage depth.

  Dataset EGAD00001009170

• Blood plasma and paired genomic DNA from neuroblastoma patients

  The dataset is comprised of 3 blood plasma samples (Patient 1-3_plasma_cfDNA) paired with genomic DNA (Patient 1-3_tumor gDNA) from the corresponding primary neuroblastoma from three patients. For all these samples whole-exome sequencing (WES) data have been generated.

  Dataset EGAD00001006012

• NHLBI TOPMed: Genomic Activities such as Whole Genome Sequencing and Related Phenotypes in the Framingham Heart Study

  The Framingham Heart Study (FHS) is a prospective cohort study of 3 generations of subjects who have been followed up to 65 years to evaluate risk factors for cardiovascular disease. Its large sample of ~15,000 men and women who have been extensively phenotyped with repeated examinations make it ideal for the study of genetic associations with cardiovascular disease risk factors and outcomes. DNA samples have been collected and immortalized since the mid-1990s and are available on ~8000 study participants in 1037 families. These samples have been used for collection of GWAS array data and exome chip data in nearly all with DNA samples, and for targeted sequencing, deep exome sequencing and light coverage whole genome sequencing in limited numbers. Additionally, mRNA and miRNA expression data, DNA methylation data, metabolomics and other 'omics data are available on a sizable portion of study participants. This project will focus on deep whole genome sequencing (mean 30X coverage) in ~4100 participants and imputed to all with GWAS array data to more fully understand the genetic contributions to cardiovascular, lung, blood and sleep disorders. Also available are aptamer proteomic profiling, RNAseq and 850K array DNA methylation data that predominantly overlap with participants with WGS data. Comprehensive phenotypic and pedigree data for study participants are available through dbGaP phs000007.

  Study phs000974

• Rearrangements of the MAST Kinase and Notch Gene Families in Breast Cancer

  Paired-end transcriptome sequencing was performed on a panel of breast cancer cell lines and tissues and a set of benign cell line and tissue controls. Analyses of the paired end sequences were performed and chimeric transcripts derived from gene rearrangement events were identified. Sequencing was performed on Illumina GAII and HiSeq 2000 platforms with read lengths from 40 to 100 bases.

  Study phs000513

• A Genome-Wide Association Study for Post-bronchodilator Lung Function in Children with Asthma

  In this study, we conducted a genome-wide association study (GWAS) of post-bronchodilator (BD) FEV1 (forced expiratory volume in 1 second) and FEV1/FVC (forced vital capacity) in Puerto Rican children with asthma. From September 2003 to June 2010, we recruited 618 Puerto Rican children with asthma, which was defined as physician diagnosed asthma and at least one episode of wheezing in the previous year. The recruited children include 267 from public schools in Hartford, Connecticut and 351 from randomly selected households in San Juan, Puerto Rico.

  Study phs001216

• NHLBI TOPMed: Stanford Cardiovascular Institute iPSC Biobank Study (SCVI)

  The proposed Stanford Cardiovascular Institute (SCVI) Biorepository will curate and manage an expanded collection of human induced pluripotent stem cell (iPSC) lines and provide investigators with iPSC materials generated using standardized protocols, with the overall objective of promoting the continued adoption and development of iPSC technology in cardiovascular research. Human iPSCs have revolutionized disease modeling, drug screening, and therapeutic research. However, it is also recognized that the need for specialized technical expertise and the associated cost have largely prevented individual research laboratories from adopting iPSC models in their inquiries, particularly in studies requiring multiple cell lines. To address this bottleneck, the proposed Biorepository will maintain our existing collection of iPSC lines and further expand the collection of iPSCs by recruiting 1,000 healthy, hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) donors of both sexes and diverse racial/ethnic backgrounds (African Americans, Asians, Hispanics, and Whites).

  Study phs002338

• Genomic study of an AT-AML

  Ataxia Telangiectasia (A-T) is caused by biallelic mutations in ATM and confers predisposition to cancer, with acute myeloid leukaemia (AML) being rarely observed. We investigated an AML arising in an A-T patient for secondary genetic events by performing whole exome sequencing of serial samples over the disease course. AML samples were compared to a reference "germline" sample from a much earlier time point. Goldgraben et al 2020, Pediatric Blood & Cancer

  Study EGAS00001004392

• Y_phylogeny_haplogroupDE

  High-coverage whole genome sequences using Hiseq X for 4 individuals to investigate their Y chrosmosmes' relationship to the known phylogeny. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001002674

• 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

• Sézary Syndrome Originates from Heavily Mutated Hematopoietic Progenitors

  The pathogenesis of cutaneous T cell lymphoma (CTCL) remains unclear. To study the malignant transformation of CTCL, we collected matched hematopoietic stem cell (HSC) extracts from bone marrow, CD4+CD26- malignant T cells, CD4+CD26+ normal T cells, and CD34+ HSCs from apheresis performed on 4 patients. To establish the baseline for calling true mutations without using hematopoietic cells, we also cultured bone marrow fibroblasts from each patient to use as normal controls. Whole exome sequencing (WES) was performed on all samples for somatic mutation calling. We identified >200 mutations in CD34+ HSCs derived from either bone marrow or apheresis. Previously reported key oncodrivers in Sezary Syndrome were identified in autologous HSCs and malignant peripheral cells, but not in progenitor (bone marrow HSCs) cells. Also, we identified specific mutations shared by autologous HSCs and malignant peripheral cells in every patient. WES data of bone marrow HSCs, apheresis HSCs, CD4+CD26- T cells, CD4+CD26+ T cells, and fibroblasts will be available through dbGaP.

  Study phs003158

• RNA-seq data of bone marrow CD34-positive cells from 57 patients with myelodysplastic syndromes (MDS) and 5 healthy individuals (62 participants in total)

  Genetic mutations in hematopoietic neoplasms, seen in disease-specific and non-specific ways, are key drivers in pathogenesis. Typically, these mutations alone don't cause neoplasms; rather, multiple mutations or breakdowns in regulatory mechanisms occur, progressing the disease through stages. Genetic mutation patterns vary even within subtypes, suggesting shared gene expression abnormalities from different mutations may drive neoplasm development. Identifying these "common factors" is vital for effective molecular-targeted therapy development. Our study aims to elucidate neoplasm pathogenesis by analyzing patient genetic abnormalities, pinpointing "common factors" in each subtype for novel targeted therapy development.

  Study JGAS000724

• Targeted therapy of advanced parathyroid carcinoma guided by genomic and transcriptomic profiling (hipo_021)

  Parathyroid carcinoma (PC) is an orphan malignancy with a high risk of recurrence after surgery. Tumor-directed systemic treatments for PC are not established. We used whole-genome and RNA sequencing in four patients with advanced PC to identify molecular alterations that could guide clinical management. In two cases, the genomic and transcriptomic profiles provided targets for experimental therapies that resulted in biochemical response and prolonged disease stabilization: (i) immune checkpoint inhibition with pembrolizumab based on high tumor mutational burden and a single-base substitution signature associated with APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) overactivation; (ii) multi-receptor tyrosine kinase inhibition with lenvatinib due to overexpression of FGFR1 and RET and, later in the course of disease, PARP inhibition with olaparib prompted by signs of defective homologous recombination DNA repair. In addition, our data provided new insights into the molecular landscape of PC with respect to the genome-wide footprints of specific mutational processes and pathogenic germline alterations. These data underscore the potential of comprehensive molecular analyses to improve care for patients with ultra-rare cancers based on insight into disease biology.

  Study EGAS00001006747

• To determine the mutational impact of the in vitro culture, clonal human adult and pluripotent stem cell lines were subjected to a second clonal step after 3 months of culture. These subclones were whole genome sequenced to identify all the mutations that accumulated during the 3 month culture period.

  Genetic changes acquired during culture pose a potential risk for the successful application of stem cells. To assess the risk of in vitro expansion on mutation accumulation we have performed whole genome sequencing of clonally expanded human induced pluripotent stem cells (iPS cells) and adult stem cells (ASCs) to identify all mutations that accumulated over a fixed culture period. We find that ASCs acquire more single nucleotide variants (SNVs) and indels per population doubling than the iPS cells. When compared with ASCs, iPS cells are more vulnerable to mutations in genes and promoters. Mutational analysis revealed a clear in vitro induced mutational signature that is irrespective of stem cell type. This in vitro signature is characterized by C to G transversions that are probably caused by oxidative stress. Additionally, we observed stem cell specific mutational signatures and differences in transcriptional strand bias, indicating differential activity of DNA repair mechanisms between stem cell types in culture. In conclusion, in vitro culture induces mutation accumulation in iPS cells and ASCs. Culture under low-oxygen tension may help to reduce the number of culture-induced mutations.

  Study EGAS00001002955

• CIRCLE-seq of PDAC PDO

  CIRCLE-seq was performed on a PDAC PDO to validate the presence and the structure of ecDNAs

  Study EGAS50000000194

• Admixture Mapping of Staphylococcus aureus Bacteremia

  In this study, we used admixture mapping to test the hypothesis that genomic variations with different frequencies in European and African ancestral genomes influence susceptibility to Staphylococcus aureus bacteremia (SAB) in a sample of African Americans. A total of 565 adult African Americans were genotyped for admixture mapping. Cases were unique African American adult inpatients with monomicrobial SAB (N=390) and controls are age-matched adult African American inpatients with no current or past S. aureus infection (N=175). After empirical multiplicity adjustment, one region on chromosome 6 (52 SNPs, P = 4.56e-05) in the HLA class II region was found to exhibit a genome-wide statistically significant increase in European ancestry. This region encodes genes involved in HLA-mediated immune response and these results provide additional evidence for genetic variation influencing HLA-mediated immunity, modulating susceptibility to SAB.

  Study phs001441

• DAC for "Longitudinal copy number variation analysis from plasma DNA of head and neck cancer patients under re-radiotherapy"

  This is the DAC for "Longitudinal copy number variation analysis from plasma DNA of head and neck cancer patients under re-radiotherapy" with Florian Janke f.janke@dkfz-heidelberg.de German Cancer Research Center, Division of Cancer Genome Research Holger Sültmann h.sueltmann@dkfz-heidelberg.de German Cancer Research Center, Division of Cancer Genome Research Magdalena Görtz magdalena.goertz@dkfz-heidelberg.de German Cancer Research Center, Multiparametric Methods for Early Detection of Prostate Cancer

  Dac EGAC50000000114

• Human Hi-C

  This dataset contains 2 human tumor-derived cell lines and 1 human tumor Hi-C samples. The raw fastq files and the processed .hic file is provided for each sample.

  Dataset EGAD00001009050

• An essential role for MYB in driving oncogenic EVI1 expression in enhancer-rearranged leukemias

  In acute myeloid leukemia (AML) with inv(3)(q21;q26) or t(3;3)(q21;q26), a translocated GATA2 enhancer drives oncogenic expression of EVI1. We generated an EVI1-GFP AML model and applied an unbiased CRISPR/Cas9 enhancer scan to uncover sequence motifs essential for EVI1 transcription. Using this approach, we pinpoint a single regulatory element in the translocated GATA2 enhancer that is critically required for aberrant EVI1 expression while being dispensable for GATA2 expression from its endogenous locus. This element contains a DNA binding motif for the transcription factor MYB that heavily occupies this site specifically at the translocated allele. MYB knockout as well as peptidomimetic blockade of p300-dependent MYB function resulted in downregulation of EVI1 but not of GATA2. Targeting MYB or mutating its DNA-binding motif within the GATA2 enhancer resulted in myeloid differentiation and cell death, suggesting that interference with MYB-driven EVI1 transcription provides a potential entry point for therapy of inv(3)/t(3;3) AMLs.

  Study EGAS00001004839

• RNAseq of 704 patients with soft tissue tumors

  The dataset contains transcriptome sequencing (RNA-seq) data of 704 soft tissue tumors (STT) from 704 patients. The sequencing data comes in FASTQ format and contains 1408 files. A total of 56 different STT types were included in the present study and each tumor type was represented by >2 samples. The vast majority of the patients had been diagnosed and treated at the sarcoma centers in Lund (Sweden) or Stockholm (Sweden) during the period 1988-2020, but also a few samples from other centers, obtained through previous collaborative projects, were included. RNA was extracted from fresh frozen tumor material and samples were primary lesions unless otherwise indicated. The sequencing was performed using 2x150 bp paired-end chemistry on a series of Illumina instruments at various facilities during the period 2013-2023.Samples were obtained after informed consent from the patients and the study was approved by the regional ethics committee (Etikprövningsmyndigheten, Uppsala, dnr 2023-01550-01, dnr 2025-02997-02).

  Dataset EGAD50000002120

• Single_Cell_RNAseq_at_various_stages_of_HiPSCs_differentiating_toward_definitive_endoderm_and_endoderm_derived_lineages

  When comparing the differentiation capacities of pluripotent stem cell lines that have different genetic backgrounds, batch to batch experimental variablility poses a significant challenge, especially when trying to identify smaller effects. One way to address this issue is to differentiate several different lines in the same culture dish, thereby elimating experimental variation. In addition, it allows researchers to analyze many more lines with less experiments. Parallel single cell RNA-Seq exploits that individual cells are tagged and hence each cell can be reliably assigned to the donor of origin based on the genetic variants it contains. In addition, analyzing the genetic signature of single cells within a differentiating population can reveal differentation stages that are not easily detected in bulk RNAseq data. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001002278

• CRUK Accelerator: oesophageal adenocarcinoma whole exome and RNA-seq raw sequencing data

  Whole exome and RNASeq raw sequencing data for a cohort of 7 male patients with oesophageal adenocarcinoma. Median age at diagnosis was 68. Tumour tissue and PBMCs were used for whole exome sequencing and RNA sequencing. This data was generated as part of a study funded by a Cancer Research UK Centres Network Accelerator Award Grant (A21998).

  Dataset EGAD00001008489

• Deep multi-region whole-genome sequencing reveals heterogeneity and gene-by-environment interactions in treatment-naive, metastatic lung cancer

  Our understanding of genomic heterogeneity in lung cancer is largely based on the analysis of early-stage surgical specimens. Here we used endoscopic sampling of paired primary and intrathoracic metastatic tumors from 11 lung cancer patients to map genomic heterogeneity inoperable lung cancer with deep whole-genome sequencing. Intra-patient heterogeneity in driver or targetable mutations was predominantly in the form of copy number gain. Private mutation signatures, including patterns consistent with defects in homologous recombination, were highly variable both within and between patients. Irrespective of histotype, we observed a smaller than expected number of private mutations, suggesting that ancestral clones accumulated large mutation burdens immediately prior to metastasis. Single-region whole-genome sequencing of from 20 patients showed that tumors in ever-smokers with the strongest tobacco signatures were associated with germline variants in genes implicated in the repair of cigarette-induced DNA damage. Our results suggest that lung cancer precursors in ever-smokers accumulate large numbers of mutations prior to the formation of frank malignancy followed by rapid metastatic spread. In advanced lung cancer, germline variants in DNA repair genes may interact with the airway environment to influence the pattern of founder mutations, whereas similar interactions with the tumor microenvironment may play a role in the acquisition of mutations following metastasis.

  Study EGAS00001003830

• Emory University African American Vaginal, Oral, and Gut Microbiome in Pregnancy Cohort Study

  The Emory University African American Microbiome in Pregnancy Cohort Study prospectively enrolls African American women between 18-40 years of age without chronic medical conditions into a longitudinal follow-up study that involves completing microbiome sampling and data collection at two time points in pregnancy (8-14 weeks gestation and 24-30 weeks gestation). The study is investigating the role of the oral, vaginal, and gut microbiome on preterm birth and other pregnancy outcomes as well as biobehavioral factors that shape the microbiome among this socio-demographically diverse group of women. Microbiome sampling involves the oral, vaginal, and gut sites. Biobehavioral factors that are being explored for their association with microbiome composition at the three body sites include measures of sociodemographic status as well as diet and nutrition, infectious and stress exposures.

  Study phs001865

• National Institute on Alcohol Abuse and Alcoholism (NIAAA) Postmortem Prefrontal Cortex eQTL and mQTL Study

  Mapping expression and methylation quantitative trait loci (eQTLs and mQTLs) using genome-wide genotype, transcriptome, and DNA methylome data can provide an unbiased approach to identify novel functional variants. One critical issue of the eQTL/mQTL analysis is that the role of genetic variants in regulating gene expression (or DNA methylation) can be tissue- or cell-specific. To unravel causal variants from disease-associated loci, it would be necessary to map eQTLs and mQTLs in both patients and controls. Those eQTLs and mQTLs in patients are more likely to be causal variants for the disease. Identification of disease- and tissue-specific eQTLs and mQTLs will help disentangle the role of the specific tissue in disease development as well. In the present study, we mapped eQTLs and mQTLs in postmortem prefrontal cortex of patients with alcoholism or alcohol use disorder (AUD) and matched control subjects by integrative analyses of genome-wide SNP genotype, mRNA transcriptome, and DNA methylome data. As AUD is comorbid with schizophrenia (SCZ), bipolar disorder (BIP), major depressive disorder (MDD), and attention deficit/hyperactivity disorder (ADHD), we further examined the co-localization of PFC eQTLs/mQTLs and GWAS-identified SNPs (mainly noncoding SNPs) that were associated with AUD as well as comorbid SCZ, BIP, MDD, and ADHD. Our study demonstrated the enrichment of PFC eQTLs/mQTLs in the above psychiatric disorder-associated genetic variants identified by genome-wide association studies (GWAS).

  Study phs001981

• Whole genome sequencing for novel neuromuscular disease gene discovery

  This peripheral neuropathy patient underwent whole genome sequencing to find the cause of their disease. They were undiagnosed by current standard-of-care practice, which is neurogenetic panel screening. This is a paediatric case.

  Study EGAS00001004535

• Genomics of Acute Myeloid Leukemia

  Sequence data from the Genomics of AML PPG program at Washington University since 2009 is made available. This repository contains data from tumors (bone marrow or peripheral blood) from Acute Myeloid Leukemia (AML) and several other related disorders - myelodysplastic syndromes (MDS), secondary AML (sAML) and therapy-related AML (tAML). It also contains matched normal data (skin or buccal swab) and healthy donors for comparison. A variety of DNA sequencing assays were used, including whole genome sequencing (WGS), exome sequencing, targeted panels of AML genes, or targeted panels for validation. Other modalities, including RNA-seq, small RNA-seq, whole genome bisulfite sequencing, CHIP-seq, ATAC-seq, and single-cell RNAseq are also represented.

  Study phs000159

• Multi-layered molecular characterization defines prognostic subtypes of lung adenocarcinoma in Asian never-smokers

  Multi-layered genomic studies such as the TCGA project have greatly advanced our understanding on molecular pathogenesis of lung cancer. For Asian nonsmoker patients, however, majority of studies have been limited to mutational analyses, emphasizing ethnic differences in driver mutations (e.g. more frequent EGFR mutations and ALK fusions). In essence, a comprehensive multi-layered characterization that could lead to molecular etiology and patient stratification scheme to be translated into clinical applications for this patient group is still missing. Here we report molecular profiling of tumor and matched normal tissues from 114 non-small-cell lung adenocarcinoma patients using whole exome sequencing, transcriptome sequencing, and array comparative genomic hybridization (CGH).

  Study EGAS00001003705

• RNAseq profiling of pediatric osteosarcoma

  Primary pediatric osteosarcoma samples were collected and profiled using RNAseq. When possible, germline and tumor samples were collected. For some patients, multiple tumor tissues were collected and sequenced. Some of the samples were used to derive PDTX models, which were also profiled with RNAseq. Paired end sequencing was performed on Illumina HiSeq instruments and FASTQ files reported.

  Dataset EGAD00001004538

• Dataset of methylation data from whole blood DNA

  This dataset includes raw data (.idat) for the Illumina Human450k beadchip and methylation levels (.txt files). Methylation level were treated for normalization and background substraction. We removed probes with at least one of the following characteristics: (1) weak signal (p > 0.01) (2128 CpG sites), (2) SNP-enriched sites (4100 sites), (3) out of a CpG context (not on a CG) (3149 sites), or (4) located on sex chromosomes (11,129 sites). A total of 465,071 CpG sites were analyzed initially. Signal was then normalized, first by scaling to the internal controls using the methylumi R package, then by applying the method of subset-quantile within array normalization (SWAN) implemented in the minfi R package.

  Dataset EGAD00010001593

• Whole genome sequencing of colon organoid cultures with artificially induced oncogenic mutations

  Using the CRISPR-Cas9 genome editing system, various oncogenic mutations were introduced in the genome of normal adult stem cells derived from the colon. The resulting clonal cultures were subjected to whole genome sequencing. In addition, the cultures were transplanted in a mouse and the resulting primary and metastatic tumors were also subjected to whole genome sequencing. The initial bulk culture, which was used to generate the mutations, was also whole genome sequenced and served as a reference sample to filter germline variants.

  Study EGAS00001001969

• Transcriptome profiling of prostate tissue samples from early onset prostate cancer patients and normal controls by RNA-seq

  The dataset contains RNA-seq data of 96 EOPC patients and 9 controls. For some patients multiple tissue samples were sequenced ("multi-area" samples). The RNA extraction and sequencing protocol was earlier described in Weischenfeldt et al, Cancer Cell, 2013.

  Dataset EGAD00001004791

• Exome sequencing of a cohort of Rett syndromelike patients (2017-08-16)

  The aim of the project is the definition of the molecular defect in a cohort of Rett-like patients negative for mutations in known disease genes. To this aim, a number of unrelated trios (patients plus parents) will be analysed by exome sequencing. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/ This dataset contains all the data available for this study on 2017-08-16.

  Dataset EGAD00001003564

• Ensilication as a Cold‑Chain–Free Solution for High‑Fidelity DNA Preservation in tumor samples

  Nucleic acid preservation requires continuous refrigeration at -20 °C to -80 °C, creating infrastructure barriers limiting genomic medicine access globally. While ambient-temperature preservation methods exist, their effects on DNA integrity and sequence fidelity remain incompletely characterized. The project aims to evaluate ensilication as a method for preserving DNA at ambient temperatures and to determine whether it can match or exceed the fidelity of conventional ultra‑low‑temperature storage. It seeks to assess the technology’s ability to maintain diagnostic accuracy, including detection of clinically actionable variants in tumor samples. Another goal is to compare sequencing‑related artifact rates between ensilicated and cryogenically stored DNA to quantify improvements in data quality. Ultimately, the project aims to establish ensilication as a cold‑chain‑independent solution that enables more accessible global genomic testing and biobanking.

  Study EGAS50000001698

• Investigate the evolutionary trajectories during invasiveness acquisition in early lung adenocarcinoma

  The evolutionary trajectories of early lung adenocarcinoma (LUAD) have not been fully elucidated. We hypothesize that genomic analysis between pre-invasive and invasive components will facilitate the description of LUAD evolutionary patterns. We micro-dissect malignant pulmonary nodules (MPNs) into paired pre-invasive and invasive components for panel-genomic sequencing and recognize three evolutionary trajectories. Evolutionary mode 1 (EM1) demonstrates none of the common driver events between paired components, but another two modes, EM2A and EM2B, exhibit critical private alterations restricted to pre-invasive and invasive components, respectively. When ancestral clones harbor EGFR mutations, truncal mutation abundance significantly decrease after the acquisition of invasiveness, which may be associated with the intratumoral accumulation of infiltrated B cells. Harboring EGFR mutations is critical to the selective pressure and further impacts the prognosis. Our findings extend the understanding of evolutionary trajectories during invasiveness acquisition in early LUAD.

  Study EGAS00001004754

• Mutation tracking in single cell RNA-Seq reveals consequences of subclonal evolution in acute myeloid leukemia

  Total bone marrow from AML patients was FACS index sorted with staining for Lineage markers (Lin), CD33, CD34, CD38, CD45RA, CD90, CD99, Tim3 and GPR56, and enrichment for Lin- and Lin-CD34+ cells. Single cells were subjected to a modified smart-seq2 protocol with targeting of mutant sites of interest ("MutaSeq”).

  Study EGAS00001003414

• Whole Exome Sequencing Study of TGFΒ Pathway Genes in HCV Liver Fibrosis

  Despite the astonishing progress in treating chronic hepatitis C virus (HCV) infection with direct-acting antiviral agents, liver fibrosis remains a major health concern in HCV infected patients, in particular due to the treatment cost and insufficient HCV screening in many countries. Only a fraction of patients with chronic HCV infection develop liver fibrosis. While there is evidence that host genetic factors are involved in the development of liver fibrosis, the common variants identified so far, in particular by genome-wide association studies, were found to have limited effects. Here, we conducted an exome association study in 88 highly selected HCV-infected patients with and without fibrosis. A strategy focusing on TGF-β pathway genes revealed an enrichment in rare variants of the endoglin gene (ENG) in fibrosis patients. Replication studies in additional cohorts (617 patients) identified one specific ENG variant, Thr5Met, with an overall odds ratio for fibrosis development in carriers of 3.04 (1.39-6.69). Our results suggest that endoglin, a key player in TGF-β signaling, is involved in HCV-related liver fibrogenesis.

  Study phs001902

• MASQ targeted amplicon sequencing data of AML samples at presentation, remission, and relapse, and MASQ data demonstrating performance ranges of the method.

  MASQ targeted amplicon sequencing of AML blood or bone marrow at presentation, and relapse, when available, for 5 patients. Remission samples of both blood and bone marrow are included for 5 patients. Multiple batches (b1,b2) are used for 2 patients. There are 25 assays of AML data. MASQ data demonstrating sensitivity, input range, and batch size are also included, as 12 assays. All data is provided in paired FASTQ files.

  Dataset EGAD00001005121

• Genomics Define Malignant Transformation in Myeloma Precursor Conditions

  Multiple myeloma (MM) is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). While these precursor conditions are asymptomatic, they are not entirely benign and carry a lifelong risk of progression to MM. Unlike other cancers defined by pathology, malignant transformation from MGUS or SMM to MM has so far relied on demonstration of clinical end-organ damage as morphology and cytogenetics cannot reliably distinguish them. In this study, using genomic data from 374 patients with MGUS or SMM (277 training, 97 validation), to our knowledge, we demonstrate for the first time the ability to identify malignant transformation in MGUS and SMM. We introduce the concept of genomic MM and genomic MGUS to differentiate the subsets of MGUS and SMM that are biologically malignant with genomic features indistinguishable from MM from the subset that is premalignant and unlikely to progress to malignancy. Importantly, we find that most SMM has biological features of malignant transformation indistinguishable from MM. As expected, this subset that we consider having genomic MM is associated with a high risk of progression to MM although some patients remained progression-free beyond 5 years. Conversely, 60% of MGUS and 10% of SMM have no evidence of malignant transformation (genomic MGUS), with no progression during follow-up. Integration of genomic features with the 2/20/20 International Myeloma Working Group model significantly improved the prediction of progression among genomic MM. These findings support the use of genomic criteria to refine the classification and the risk stratification in myeloma precursor conditions.

  Dataset EGAD00001015768

• Genetics_of_gene_expression_in_human_macrophage_response_to_Salmonella

  This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001002236

• 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

• Studies in the Pathogenesis of Systemic Capillary Leak Syndrome (SCLS, Clarkson Disease)

  Systemic capillary leak syndrome (Clarkson disease) is an ultra-rare disease of unknown etiology. Patients experienced transient and recurrent episodes of hypotensive shock and massive peripheral edema due to plasma extravasation, often precipitated by minor viral infections. Disease onset occurs most frequently in middle age, and there is no family history. More than 90% of patients with the disease have monoclonal gammopathy of unknown significance (MGUS). The goal of the study is to determine pathogenic mechanisms and identify genetic underpinnings of the disease. Toward this end, we performed whole genome sequencing (WGS).

  Study phs003261

• Integrative Somatic and Germline Computational Biology to Redefine Clinical Actionability in Solid Tumors

  Neuroendocrine tumors (NETs) are rare cancers that arise in the gastrointestinal tract and pancreas. The fundamental mechanisms driving gastroenteropancreatic NETs (GEP-NETs) growth remain incompletely elucidated; however, the heterogeneous clinical behavior of GEP-NETs suggests that both cellular lineage dynamics and tumor microenvironment influence tumor pathophysiology. Here, we performed single-cell RNA-sequencing (scRNA-seq) of fresh resections of GEP-NETs, including four pancreatic NETs, three small intestinal NETs, and one perigastric NET. We used single-cell sequencing to investigate the tumor and immune cellular landscapes of GEP-NET patients. Malignant GEP-NET gene and regulon expression was compared with normal, gastrointestinal endocrine cell differentiation and fate determination stages. We further characterized immune-immune and immune-tumor interaction networks within GEP-NETs, identifying novel therapeutic opportunities in the myeloid compartment of the microenvironment. Our findings highlight the transcriptomic heterogeneity that distinguishes the cellular landscapes of GEP-NET anatomic subtypes and reveal potential avenues for future precision medicine therapeutics.

  Study phs003141

• Pervasive H3K27 acetylation and ERV expression in H3.3K27M gliomas present a therapeutic vulnerability

  High-grade gliomas (HGG) defined by histone 3 K27M driver mutations exhibit global loss of H3K27 trimethylation and reciprocal gain of H3K27 acetylation, respectively shaping repressive and active chromatin landscapes. We generated tumor-derived isogenic models bearing this mutation and show that it leads to pervasive H3K27ac deposition across the genome. In turn, active enhancers and promoters are not created de novo and instead reflect the epigenomic landscape of the cell of origin. H3K27ac is enriched at repeat elements, resulting in their increased expression, which in turn can be further amplified by DNA demethylation and histone deacetylase inhibitors providing an exquisite therapeutic vulnerability. These agents may therefore modulate anti-tumor immune responses as a therapeutic modality for this untreatable disease.

  Study EGAS00001003572

• Deciphering the genomic, epigenomic and transcriptomic landscapes of pre-invasive lung cancer lesions to determine prognosis

  Background: Lung carcinoma-in-situ (CIS) lesions are the pre-invasive precursor to lung squamous cell carcinoma. However, only half progress to invasive cancer in three years, while a third spontaneously regress. Whether modern molecular profiling techniques can identify those pre-invasive lesions that will subsequently progress and distinguish them from those that will regress is unknown. Methods: Progressive and regressive CIS lesions were laser-captured and their genome, epigenome and transcriptome interrogated. We analysed 83 progressive lesions, 41 regressive and 33 normal epithelial control samples. DNA methylation and gene expression profiles were further validated using publicly available lung cancer data. Results: Somatic mutation burden was higher in progressive lesions than regressive CIS lesions, across base substitutions, rearrangements, and copy number changes. Driver mutations were present in both progressive and regressive CIS lesions, but were more numerous in progressive cases. Progressive and regressive CIS lesions had distinct epigenomic and transcriptional profiles, with a strong chromosomal instability signature. Gene expression, methylation and copy number profiles can all predict accurately which CIS lesions will progress to lung cancer. Conclusion: Pre-invasive CIS lesions that will subsequently progress to invasive lung cancer can be distinguished from those that will regress using molecular profiling. Progression is associated with a strong chromosomal instability signature. These findings inform the development of novel therapeutic targets.

  Dataset EGAD00001003883

• Sequencing to Guide Cancer Care (CanSeq)

  The overall goal of the CanSeq U01 project is to study the impact of whole-exome sequencing (WES) on the clinical care of cancer patients and oncology provider practices. The aims of Project 1 are to implement and establish the feasibility of germline and somatic WES in patients with advanced solid tumors (lung and colon); to develop a framework for interpreting and reporting for exome sequencing data; to determine the proportion of patients with "actionable items" compared to existing technologies; and to report on the percentage of patients in whom unique WES findings led to a clinical action. The aims of Project 2 are to implement a production-scale platform for WES from archival (FFPE) material; to identify biologically relevant somatic and germline alterations existing in tumor/normal DNA from individual patients; to produce an evidence-based list of clinically "actionable" genetic alterations; and to develop inferential models that predict the utility of tumor genomic data within the larger clinical context. The goals of Project 3 are to describe the impact of information derived through WES on cancer patients; to test the hypothesis that patients will want to receive information about all potentially informative somatic and germline variants; to study patients' understanding of disclosed genomic information; and to describe the experiences of oncology providers as they implement WES into cancer care delivery.

  Study phs001075

• The HLA-DQβ1 insertion is a strong achalasia risk factor and displays a geospatial north-south gradient among Europeans

  Idiopathic achalasia is a severe motility disorder of the esophagus and is characterized by a failure of the lower esophageal sphincter to relax due to a loss of neurons in the myenteric plexus. Most recently, we identified an 8 amino acid insertion in the cytoplasmic tail of HLA-DQβ1 as strong achalasia risk factor in a sample set from Central Europe, Italy, and Spain. Here, we tested whether the HLA-DQβ1 insertion also confers achalasia risk in the Polish and Swedish population. We could replicate the initial findings and the insertion shows strong achalasia association in both samples (Poland P = 1.84×10-04, Sweden P = 7.44×10-05). Combining all five European data sets – Central Europe, Italy, Spain, Poland, and Sweden – the insertion is achalasia associated with Pcombined = 1.67×10-35. In addition, we observe that the frequency of the insertion shows a geospatial north-south gradient. The insertion is less common in northern (around 6-7% in patients and 2% in controls from Sweden and Poland) compared to southern Europeans (around 16% in patients and 8% in controls from Italy) and shows a stronger attributable risk (AR) in the southern European population. Our study provides evidence that the prevalence of achalasia may differ between populations.

  Study EGAS00001001515

• RRBS sequencing of 7 tumour regions and a normal sample from a single TRACERx patient.

  Background: Epigenetic heterogeneity within a tumour can play an important role in tumour evolution and the emergence of resistance to treatment. It is increasingly recognised that the study of DNA methylation (DNAm) patterns along the genome - so-called `epialleles' - offers greater insight into epigenetic dynamics than conventional analyses which examine DNAm marks individually. Results: We have developed a Bayesian model to infer which epialleles are present in multiple regions of the same tumour. We apply our method to reduced representation bisulfite sequencing (RRBS) data from multiple regions of one lung cancer tumour and a matched normal sample. The model borrows information from all tumour regions to leverage greater statistical power. The total number of epialleles, the epiallele DNAm patterns, and a noise hyperparameter are all automatically inferred from the data. Uncertainty as to which epiallele an observed sequencing read originated from is explicitly incorporated by marginalising over the appropriate posterior densities. The degree to which tumour samples are contaminated with normal tissue can be estimated and corrected for. By tracing the distribution of epialleles throughout the tumour we can infer the phylogenetic history of the tumour, identify epialleles that differ between normal and cancer tissue, and define a measure of global epigenetic disorder. Conclusions: Detection and comparison of epialleles within multiple tumour regions enables phylogenetic analyses, identification of differentially expressed epialleles, and provides a measure of epigenetic heterogeneity.

  Study EGAS00001002484