Search Results - EGA European Genome-Phenome Archive

Subclonal diversification of primary breast cancer

Cancers are ecosystems of genetically related clones, competing across space and time for limited resources. To understand the clonal structure of primary breast cancer, we applied genome and targeted sequencing to 295 samples from 49 patients’ tumors. The extent of subclonal diversification varied considerably among patients and encompassed many spatial patterns, including local growth, intraductal dissemination and clonal intermixture. Landmarks of disease progression, such as acquiring invasive or metastatic potential, arose within detectable subclones of antecedent lesions, suggesting that subclonal mutations could be relevant if actionable. No defined temporal order of mutation was evident, with the commonest genes, including PIK3CA, TP53, BRCA2, PTEN and MYC, mutated early in some, late in others, often exhibiting parallel evolution across subclones. Signatures of homologous recombination deficiency correlated with response to neoadjuvant chemotherapy. Thus, the interplay of mutation, growth and competition drives clonal structures of breast cancer that are complex, variable across patients and clinically relevant.

Dataset EGAD00001000898

Synthetic - FEGA Sweden Heilsa synthetic dataset December 2023

Synthetic - This submission contains a subset of a synthetic dataset derived from the project Heilsa Tryggvedottir - a Nordic collaboration on sharing sensitive human data. Heilsa Tryggvedottir is funded by the Nordic e-Infrastructure Collaboration (NeIC), the ELIXIR nodes of Finland, Norway, and Sweden, Computerome in Denmark, and the Estonian Scientific Computing Infrastructure (ETAIS). In the synthetic data creation process, it was attempted to strike a fine balance between the usability of the datasets (e.g. technical FEGA development, testing, user training, and basic bioinformatics) and compliance with GDPR. File names and file content (e.g. headers in fastq) are anonymized. Moreover, the X, Y, and mitochondrial sequences have been discarded from the original data since these data can be used for maternal, paternal, or ethnic origin tracing. The dataset does not follow natural haplotype distribution (inherent to imputation panels). The only inputs derived from real sequence data are variant distribution density per chromosome and learning sequencing error models. The synthetic dataset consists of two fastq files, a cram file, a vcf file, and two index files.

Dataset EGAD50000000119

DAC Admixture histories of São Tomé e Príncipe

Contacts: Paul Verdu +33144057317 paul.verdu@mnhn.fr CNRS-MNHN-Université de Paris UMR7206 Eco-anthropology Jorge M. Rocha jrocha@cibio.up.pt CIBIO Short description The Data Access Committee for acess to genotype and sample information used in the article "Nested admixture during and after the Trans-Atlantic Slave Trade in the island of Sao Tome" by Ciccarella M et al.2025 ensures that data-access requests comply with the Informed Consent provided by donors, and with ethical and deontological guidelines with respect to privacy. Research sampling protocols followed the Declaration of Helsinki guidelines and written informed consent was obtained from all volunteer participants involved in the sampling in São Tomé e Príncipe. The study of the São Tomé e Príncipe sample was undertaken with the support and permission of the Provincial Government of the Ministry of Health of the Democratic Republic of São Tomé e Príncipe, and the Provincial Government of Príncipe. Research sampling protocols also followed the French laws of scientific research deontology (Loi n° 2016-483 du 20 avril 2016) and were approved by the French ethics committees and CNIL (Declaration n°1972648).

Dac EGAC50000000437

Analysis of TKI resistant mechanism for gastrointstinal stromal tumor

Gastrointestinal stromal tumors are the most common mesenchymal tumor of the digestive tract and the proliferation is driven by gain-of-function mutations in KIT. Despite its proven benefits, half of the patients treated with imatinib develop disease progression within 2 years due to secondary resistance mutations in the KIT kinase domains. To characterize the changes associated with imatinib resistance, we performed genomic and transcriptomic analyses of four resistant cell lines and one cell line briefly exposed to imatinib. We also performed exome sequencing of drug-resistant clinical samples.

Study JGAS000039

Whole-genome sequencing analysis for understanding of the stepwise progression of lung adenocarcinoma

In this study, we performed long and short read whole-genome sequencing analysis of lung adenocarcinoma from early to advanced stages to identify molecular events associated with the stepwise progression of lung adenocarcinoma. We particularly focused on very early stage of lung adenocarcinoma, such as adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA). In addition to the whole-genome sequencing analysis, we conducted transcriptome and epigenome analysis, multiplex fluorescence immunostaining. This study would enable us to understand important molecular events of pathogenesis in detail during lung adenocarcinoma progression.

Study JGAS000570

Searching for rare/low frequency variants in rheumatoid arthritis by exome sequencing

Rheumatoid arthritis (RA) is a multifactorial and systemic autoimmune disease and characterized by synovial inflammation and hyperplasia, autoantibody production, cartilage and bone destruction and systemic features including cardiovascular, pulmonary, psychological and skeletal disorders. Although the causality of RA is not completely understood, genetic factors contribute to the onset. About 60% of the RA risk is genetic. To identify causative- or susceptible- rare/low-frequency variants in RA, exome sequencing of 39 patients with RA was conducted. We also conducted genotyping of pooled healthy men and women exome-sequencing data.

Study JGAS000035

Establishment of an integrated database for clinical and genomic data in cancer

In this study, to clarify the genomic varieties of MM in Asian population, we planned to investigate the genomic features in Japanese population, represented as an Asian cohort, and preformed the comprehensive genomic analysis of MM cells with newly diagnosed multiple myeloma (NDMM) by means of targeted capture sequencing (TCS) method. In our TCS assay, MM cells are subjected to the detection of following genomic abnormalities; IG rearrangements, IG associated translocations, CNAs, and somatic mutations from 340 genes related to the pathogenesis and therapeutic agent of MM.

Study JGAS000206

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

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

Dataset EGAD50000002306

The DIRECT study: A roadmap for ctDNA-based risk prediction, molecular profiling and MRD detection in Diffuse Large B Cell Lymphoma

DIRECT was a prospective, multisite study assessing the feasibility and utility of circulating tumor DNA (ctDNA) in 188 patients with aggressive B-cell non-Hodgkin lymphoma using capture panel sequencing and an open-source computational pipeline. The aims of the study were 1)baseline risk stratification, 2)genetic profiling and 3)ultrasensitive minimal residual disease (MRD) assessment. This study highlighted the considerable potential, but also the caveats and limitations, of ctDNA technology when applied to aggressive B-cell lymphoma.

Study EGAS50000000968

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/

Dataset EGAD00001005741

10x dataset of an obese human subject

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

Dataset EGAD00001005101

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

MARS-seq dataset of five obese human subjects and a lean human subject

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

Dataset EGAD00001005100

Human liver mtDNA sequencing

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

Dataset EGAD00001007991

The mutational landscape of normal human endometrial epithelium

All normal somatic cells are thought to acquire mutations. However, characterisation of the patterns and consequences of somatic mutation in normal tissues is limited. Uterine endometrium is a dynamic tissue undergoing cyclical shedding and reconstitution lined by a gland-forming epithelium. Whole genome sequencing of normal endometrial glands showed that most are clonal cell populations derived from a recent common ancestor, with mutation burdens differing from other normal cell types and many fold lower than endometrial cancers. Mutational signatures found ubiquitously account for most mutations. Many, in some women all, endometrial glands are colonised by cell clones carrying driver mutations in cancer genes, often with multiple drivers. Total and driver mutation burdens increase with age, but are also influenced by other factors, including body mass index and parity, and clones with drivers often originate during early decades of life. The somatic mutational landscapes of normal cells differ between cell types and are revealing the procession of neoplastic change leading to cancer.

Dataset EGAD00001004547

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

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

Dataset EGAD00001003705

Genome-wide search for higher order epistasis as modifiers of treatment effects on bone mineral density in childhood cancer survivors

Survivors of pediatric acute lymphoblastic leukemia (ALL) exposed to curative treatments that adversely affect BMD (age- and sex-adjusted BMD Z-scores, measured via QCT). Specifically, after SNP QC and annotation, we considered 75523 autosomal SNPs mapped to putative promoter or enhancer regions to restrict our search to 3-way SNP interactions that potentially reflect gene regulation events that influence BMD. We replicated 3-SNP interactions as modifiers of treatment effects in a cohort of adult survivors of non-ALL pediatric cancers (N=1428).

Study EGAS00001002645

DERMATLAS: Hidradenoma papilliferum_RNAseq

Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible.For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previously, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles.

Dataset EGAD00001015480

Extensive three-dimensional intratumor proteomic heterogeneity revealed by multiregion sampling in high-grade serous ovarian tumor specimens

Enriched tumor epithelium, tumor-associated stroma, and whole tissue were collected by laser microdissection from thin sections across spatially separated levels of ten high-grade serous ovarian carcinomas (HGSOCs) and analyzed by mass spectrometry, reverse phase protein arrays, and RNA sequencing. Unsupervised analyses of protein abundance data revealed independent clustering of an enriched stroma and enriched tumor epithelium, with whole tumor tissue clustering driven by overall tumor “purity.” Comparing these data to previously defined prognostic HGSOC molecular subtypes revealed protein and transcript expression from tumor epithelium correlated with the differentiated subtype, whereas stromal proteins (and transcripts) correlated with the mesenchymal subtype. Protein and transcript abundance in the tumor epithelium and stroma exhibited decreased correlation in samples collected just hundreds of microns apart. These data reveal substantial tumor microenvironment protein heterogeneity that directly bears on prognostic signatures, biomarker discovery, and cancer pathophysiology and underscore the need to enrich cellular subpopulations for expression profiling.

Dataset EGAD00001008344

Precise reconstruction of the tumor microenvironment using bulk RNA-seq and a unique machine learning-based algorithm trained on artificial transcriptomes

Cellular deconvolution algorithms virtually reconstruct tissue composition by analyzing the gene expression of complex tissues. Here, we present the decision tree machine learning algorithm, Kassandra, trained on a broad collection of > 9,400 tissue and blood sorted cell RNA profiles to accurately reconstruct the tumor microenvironment (TME). Bioinformatic correction for technical and biological variability, aberrant cancer cell expression inclusion, and the accurate quantification and normalization of transcript expression increased the stability and robustness of Kassandra. Performance was validated on over 4,000 H&E tissue slides and more than 1,000 normal and tumor tissues by comparison with cytometric, immunohistochemical or single-cell RNA-seq measurements. Kassandra accurately deconvolved stromal and immune elements of blood and tumors, revealing the role of the TME in tumor pathogenesis. Digital TME reconstruction revealed that the presence of PD1-positive CD8+ T cells strongly correlated with immunotherapy response and increased the predictive potential of established biomarkers, indicating that Kassandra could potentially be utilized in future clinical applications.

Dataset EGAD00001008776

Dataset for urologic_cancer-RNA

Rare cancer sequencing data of 75 runs in tumor/control pairs, which were uploaded to umbrella studies. The sequencing was always paired

Dataset EGAD00001008851

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

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

Dataset EGAD00001008601

RNA sequencing on colonic biopsies from inflammatory bowel disease patients treated with vehicle control, MEK inhibitor, or infliximab

This dataset consists of RNA sequencing data (FASTQs) from intestinal mucosal biopsies from 9 IBD patients. All patients endoscopically active disease and were not receiving immunosuppressive or biologic therapies. All biopsies (6 per donor) were collected from a single inflamed site. Biopsies were cultured for 18 hours at an air-liquid interface in media containing either DMSO (vehicle control), PD-0325901 (0.5uM) or infliximab (10ug/ml; MSD) - two biopsies per condition. Sequencing was performed on a NovaSeq 6000 (100bp, PE reads). After 18 hours, biopsies were harvested and snap frozen. After lysis, RNA was extracted using an AllPrep DNA/RNA Mini Kit (Qiagen). Sequencing libraries were prepared from 10ng RNA using the SMARTer Stranded Total RNA-Seq Kit v2 - Pico Input Mammalian (Takara) following the manufacturer’s instructions. The quality and molarity of all libraries was assessed using a BioAnalyzer 2100 and the libraries were sequenced on a NovaSeq 6000 (100bp, PE reads).

Dataset EGAD00001011333

20210708_EGA_Melanoma_mk2 WGS 570 donors

Illumina platform whole genome sequencing data for matched tumour-normal DNA samples from 570 melanoma patients

Dataset EGAD00001008798

Dataset for soft_tissue_tumor-EXON

Rare cancer sequencing data of 246 runs in tumor/control pairs, which were uploaded to umbrella studies. The sequencing was always paired

Dataset EGAD00001008897

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

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

Dataset EGAD00001008538

A developmental cell atlas of the human thyroid gland - WGS

The thyroid gland produces hormones essential for health from embryogenesis to adulthood. Thyroid disorders, including congenital hypothyroidism and thyroid carcinoma, are prevalent and pose significant health challenges. Congenital hypothyroidism often results from thyroid dysgenesis or impaired hormone synthesis, is particularly prevalent in trisomy 21 (T21), while thyroid carcinoma is the most frequent endocrine malignancy, affecting both paediatric and adult populations. Understanding the molecular basis of these conditions requires deeper insights into fetal thyroid development. We generated a spatiotemporal atlas of the human thyroid during early pregnancy, revealing key cell types, including hormone-producing thyrocytes. Thyroid follicular cells are heterogeneous, with two functional cell states (fTFC1, fTFC2) that persist into adulthood, with fTFC2 characterised by elevated PAX8 expression. We demonstrated that T21 thyroids displayed dysgenesis with disrupted follicular morphology, and altered extracellular matrix interactions, and that the fTFC2 signature was enriched in paediatric papillary thyroid cancer compared to adults. These findings uncover thyrocyte heterogeneity across the lifespan, advancing understanding of thyroid development and disease.

Dataset EGAD00001015447

A developmental cell atlas of the human thyroid gland - RNA

The thyroid gland produces hormones essential for health from embryogenesis to adulthood. Thyroid disorders, including congenital hypothyroidism and thyroid carcinoma, are prevalent and pose significant health challenges. Congenital hypothyroidism often results from thyroid dysgenesis or impaired hormone synthesis, is particularly prevalent in trisomy 21 (T21), while thyroid carcinoma is the most frequent endocrine malignancy, affecting both paediatric and adult populations. Understanding the molecular basis of these conditions requires deeper insights into fetal thyroid development. We generated a spatiotemporal atlas of the human thyroid during early pregnancy, revealing key cell types, including hormone-producing thyrocytes. Thyroid follicular cells are heterogeneous, with two functional cell states (fTFC1, fTFC2) that persist into adulthood, with fTFC2 characterised by elevated PAX8 expression. We demonstrated that T21 thyroids displayed dysgenesis with disrupted follicular morphology, and altered extracellular matrix interactions, and that the fTFC2 signature was enriched in paediatric papillary thyroid cancer compared to adults. These findings uncover thyrocyte heterogeneity across the lifespan, advancing understanding of thyroid development and disease.

Dataset EGAD00001015448

Transcriptional consequences of SETBP1 variants in developmental disorders and malignancies

The SETBP1 gene encodes a DNA-binding nuclear protein that regulates gene expression across multiple tissues. Precise control of SETBP1 dosage is essential for normal cellular function, as both loss- and gain-of-function variants of SETBP1 can lead to severe phenotypic consequences. De novo germline gain-of-function point mutations that prolong SETBP1 half-life result in Schinzel-Giedion syndrome (SGS), an ultra-rare and severe congenital disorder associated with extensive developmental abnormalities and health complications. These SGS-associated variants cluster within a hotspot in the SKI-homology domain of SETBP1, overlapping with somatic mutations recurrently observed in myeloid leukaemia with poor prognosis. Thus far, the precise mechanisms by which these SETBP1 mutations drive disease remain largely unclear. Here, through single-cell and single-nucleus mRNA sequencing of a rare collection of primary patient samples with SGS and myeloid leukaemia, we examined the transcriptional consequences of SETBP1 gain-of-function variants in haematopoietic cells, comparing their impacts when acquired in the germline and somatically in malignancies.

Dataset EGAD00001015482

Genomic Advances in Sepsis (GAinS) genotyping

This cohort comprises a subset of patients enrolled in the Genomic Advances in Sepsis (GAinS) study, an established biobank of adult sepsis patients. Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Patients with sepsis due to community acquired pneumonia or faecal peritonitis were recruited from 35 hospitals across the UK from 2005-2018, with samples for functional genomics and detailed clinical information collected over the first five days of ICU admission to investigate how host genetics affects the individual repsonse to sepsis. DNA was extracted from buffy coat or whole blood samples using the Qiagen DNA extraction protocol, the automated Maxwell Blood purification kit (Promega), or the QIAamp Blood Midi kit protocol (Qiagen). Genotyping data were generated using the Illumina HumanOmniExpress BeadChip (295 patients), the Infinium CoreExome BeadChip (655 patients), and the Infinium Global Screening Array BeadChip (307 patients). Genotyping QC and imputation into the Haplotype Reference Consortium was perfomed within each batch. The datasets were combined and following post-imputation filtering data were available on 1168 samples.

Dataset EGAD00001015369

Genomics of acral lentiginous melanoma

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

Dataset EGAD00001010126

RNA sequencing in primary inflammatory (TPP) macrophages following deletion of a disease-associated gene desert at chr21q22, disruption of ETS2, or treatment of ETS2-edited macrophages with a HIF1α stabiliser.

This dataset comprises raw RNA sequencing data (FASTQs) from primary inflammatory (TPP) macrophages that were unedited (non-targeting control, NTC), edited to delete the disease-associated chr21q22 enhancer region (n=5), or edited to disrupt ETS2 with 1 of 2 independent gRNAs (n=9). We also performed RNA-sequencing in NTC or ETS2-edited TPP macrophages that were treated for 12 hours with vehicle (DMSO) or roxadustat (30 uM, n=3). Macrophages were detached using Accutase and lysed. RNA was extracted from cell lysates using an AllPrep DNA/RNA Mini Kit (Qiagen). Sequencing libraries were prepared from 10ng RNA using the SMARTer Stranded Total RNA-Seq Kit v2 - Pico Input Mammalian (Takara) following the manufacturer’s instructions. The quality and molarity of all libraries was assessed using a BioAnalyzer 2100 and the libraries were sequenced on a NextSeq500. Raw data are provided as 50 bp paired-end Illumina reads.

Dataset EGAD00001011338

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

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

Dataset EGAD00001012101

Haplotype-specific assembly of shattered chromosomes in oesophageal adenocarciomas

Genomic and epigenomic sequencing of 5 oesphageal adenocarciomas with evidence of chromothripsis. Genomic sequencing includes: Pacbio circular consensus sequencing, Pacbio continuous long read sequencing, 10X linked read and Illumia HiSeq X Ten sequencing. Epigenomic sequencing includes: Hi-C chromosome capture, ATAC-seq, ChIP seq (for H3K27ac, H3K4me3, H3K27me3 and CTCF) and long read RNA sequencing. All data types have the bam files which have not undergone haplotype resolution (demarcated as unresolved) and some data types also have haplotype resolved reads (demarcated as resolved).

Dataset EGAD00001010871

DERMATLAS: Hidradenoma papilliferum_WES

Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible.For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previously, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles.

Dataset EGAD00001015481

A non-canonical lymphoblast in refractory childhood T-cell leukaemia

Refractory cancers may arise either through the acquisition of resistance mechanisms or represent distinct disease states. The origin of childhood T-cell acute lymphoblastic leukaemia (T-ALL) that does not respond to initial treatment, i.e. refractory disease, is unknown. Refractory T-ALL carries a poor prognosis and cannot be predicted at diagnosis. Here, we perform single cell mRNA sequencing of T-ALL from 58 children (84 samples) who did, or did not respond to initial treatment. We identify a transcriptionally distinctive blast population, exhibiting features of innate-like lymphocytes, as the major source of refractory disease. Evidence of such blasts at diagnosis heralds refractory disease across independent datasets and is associated with survival in a large, contemporary trial cohort. Our findings portray refractory T-ALL as a distinct disease with the potential for immediate clinical utility. This dataset contains 56 single-cell RNA sequencing data files with corresponding single-cell T cell receptor sequencing data files. The data here form the validation cohort in our paper.

Dataset EGAD00001015673

Melanoma PEACE Dataset

Dataset for the initial melanoma PEACE paper in Cancer Discovery, March 2023.

Dataset EGAD00001010877

Gene expression QTL mapping in stimulated iPSC-derived macrophages

Immune cells sense and respond to external stimuli, initiating an inflammatory response, with genetic variants potentially altering these responses. Traditional QTL mapping often uses naïve cells, missing condition-specific variants detectable post-stimulation. Our study uses a high-throughput platform to map eQTLs across 24 conditions using iPSC-derived macrophages, identifying that 76% of eQTLs in stimulated conditions were also present in naïve cells. We found response eQTLs (reQTLs) vary widely across conditions, with rare single-condition reQTLs being overrepresented among disease-colocalizing eQTLs. This study nominates 21.7% more disease effector genes at GWAS loci through reQTL colocalization, with 38.6% not found in the GTEx catalogue, highlighting the importance of condition-specific regulatory variation in understanding disease risk alleles. Our findings underscore the value of condition-specific studies in elucidating the genetic mechanisms underlying complex diseases. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

Dataset EGAD00001015380

Multi-omic and functional analysis for classification and treatment of sarcomas with FUS-TFCP2 or EWSR1-TFCP2 fusions(H021/INF)

Many rare cancers are not well understood, and pathogenesis-directed therapies are often lacking, resulting in poor patient outcomes. Leveraging two (inter)national precision oncology trials that enroll large numbers of rare cancers, we investigated the clinical, histopathologic, molecular, and functional characteristics of rhabdomyosarcoma (RMS) with fusions of FUS or EWSR1 to the TFCP2 transcription factor, a recently discovered ultra-rare entity whose classification, pathogenesis, and optimal treatment are unclear. Unusually for fusion-driven sarcomas, most cases had highly rearranged genomes, including chromothripsis, and signs of defective homologous recombination DNA repair. All tumors showed extreme expression of a truncated TERT variant and the ALK receptor tyrosine kinase, which was additionally affected by intragenic deletions and aberrant splicing, resulting in the expression of shortened variants in 58% of cases. Three ALK variants were oncogenic in immortalized cells, and patient-derived tumor cells expressing two variants responded to certain ALK inhibitors. Other recurrent alterations included CDKN2A/MTAP co-deletions and mutations in PAPPA2, encoding an IGFBP5-specific proteinase, in 67% and 25% of cases, respectively. DNA methylation analysis, along with 19 other soft-tissue sarcoma classes, revealed a close relationship with undifferentiated sarcoma but not other RMS subtypes, suggesting that TFCP2-rearranged RMS is a separate entity, possibly arising from a distinct cell of origin. Expression of TFCP2 fusions in immortalized human cells blocked late myogenic differentiation and significantly induced genes that were also highly expressed in patient tumors, including ALK, TERT, and two known regulators of skeletal muscle cells, IGFBP5 and PTH1R. Genome-wide chromatin profiling demonstrated direct binding of FUS-TFCP2 to the ALK and TERT loci outside their regular promoters, which correlated with the expression of alternative transcript variants. Finally, FUS-TFCP2 inhibited the repair of DNA double-strand breaks in immortalized cells, rendering them sensitive to treatment with cisplatin. This study provides insight into the pathogenesis and therapeutic vulnerabilities of a new RMS subtype and illustrates the value of linking comprehensive molecular diagnostics and functional annotation within multicenter consortia to improve the understanding and clinical management of rare cancers.

Study EGAS00001006939

University of Pennsylvania CAR T Cell Responding and Non-responding Patients

The adoptive transfer of autologous T cells genetically modified to express a CD19-specific, 4-1BB/CD3zeta-signaling chimeric antigen receptor (CAR; CTL019) has shown remarkable activity in patients with B acute lymphoblastic leukemia. Similar therapy can induce long-term remissions for relapsed/refractory chronic lymphocytic leukemia (CLL) patients, but in only a small subset of subjects. The determinants of response and resistance to CTL019 therapy of CLL are not fully understood. We employed next generation sequencing of RNA (RNA-seq) to identify predictive indicators of response to CTL019 treatment. We performed RNA-seq on leukapheresis and manufactured infusion product T cells from patients with heavily pre-treated and high-risk disease. To characterize potency, we also performed RNA-seq on the cellular infusion product after CAR-specific stimulation. Our findings indicate that durable remission in CLL is associated with gene expression signatures of early memory T cell differentiation (e.g., STAT3), while T cells from poorly- or non-responding patients exhibited elevated expression of key regulators of late memory as well as effector T cell differentiation, apoptosis, aerobic glycolysis, hypoxia and exhaustion. These gene expression signatures, along with additional immunological biomarkers, may be used to identify which patients are most likely to respond to cellular therapies and suggest manufacturing modifications that might potentiate the generation of maximally efficacious infusion products. In a follow-up study, we report multiplex CRISPR-Cas9 gene editing on T cells in humans to test the hypothesis that disrupting genes encoding the endogenous T cell receptor (TCR), TCRα (TRAC) and TCRβ (TRBC), as well as PD-1 (PDCD1) would enhance the efficacy of autologous T cells engineered to express a transgenic NY-ESO TCR. We used single cell RNA-seq to comprehensively characterize the transcriptomic phenotype of this T cell product and its evolution over time in a patient with sarcoma. Notably, this patient's transferred T cells that persisted in vivo demonstrated increases in expression of genes associated with a central memory state (IL7R, TCF7). These findings may guide future trials involving administration of genetically redirected, genome -edited T cells.In this follow-up study, we investigated whether CRISPR-Cas9-mediated disruption of PDCD1 and/or CTLA-4 could restore CART dysfunction in healthy donors and/or CLL patients. We show that depletion of CTLA-4 rescues the function of T cells from leukemia patients that previously failed CART cell treatment. We performed single-cell RNA sequencing and characterized the transcriptomic landscape of CTLA-4 KO CART19 cells that showed higher proliferation and anti-tumor efficacy by permitting unopposed CD28 signaling and maintenance of CAR expression on the T cell surface under stress-test conditions of chronic antigen exposure. Our findings reveal that selective disruption of CTLA-4 invigorates dysfunctional patient T cells, providing a strategy for increasing patient responses to CART cell therapy.

Study phs001707

Defining T cell States Associated with Response to Checkpoint Immunotherapy in Melanoma

Checkpoint blockade therapy using antibodies targeting CTLA4, PD1 or PDL1 have changed the way cancer patients with advanced disease are being treated, as evident by their FDA approval in a wide variety of malignancies, and their ability to induce high response rates when compared to conventional therapies (e.g. chemotherapy). However, even in melanoma, despite the high response rate, most patients are refractory to therapy or acquire resistance in 10-12 months. To identify key immunological elements coupled with response or resistance to checkpoint immunotherapy, we performed an unbiased analysis on 16,291 CD45+ immune cells from 32 patients (48 samples) treated with checkpoint therapy (anti-PD1=37; anti-PD1/CTLA4=11), using single cell transcriptomics. Initial unsupervised clustering of all CD45+ cells identified 11 clusters. When examining the association of these clusters with clinical outcome, we found that two clusters (B-cells, p=0.005; memory T-cells, p=0.03) were significantly enriched in responder lesions while 4 clusters (monocytes/macrophages, p=0.003; dendritic cells, p=0.015; exhausted CD8+ T-cells, p=0.005; and exhausted/cell-cycle lymphocytes, 1.3x10-5) are enriched in non-responder lesions. Next, by leveraging our unbiased single cell approach, we identified not only clusters but also specific markers associated with either responder lesions (PLAC8, LTB, LY9, SELL, TCF7, IGKC and CCR7) or non-responder ones (CCL3, CD38, HAVCR2, ENTPD1 and WARS), many of which were not previously reported to be associated with clinical outcome to checkpoint therapy. Due to the importance of CD8+ T-cells in controlling tumors, the significant association of T-cell states with clinical outcome, and their high abundance in melanoma tumors, we next focused our analysis on CD8+ T-cells and identified 2 main clusters CD8_G (with increased expression of genes linked to memory) and CD8_B (enriched for genes linked to cell dysfunction), that were significantly enriched in responder (CD8_G, p=1.4x10-6) and non-responder (CD8_B, p=0.005) lesions, respectively. Since cells with both states coexist in each of the responder and non-responder lesions, we decided to calculate the ratio between the number of cells in these 2 clusters and observed a significant separation between responders (CD8_G/CD8_B>1) and non-responders (CD8_G/CD8_B<1) when looking at all samples, baseline or post samples separately. Similar results were detected when looking at the expression of a single transcription factor, TCF7, in CD8 T-cells in an independent cohort (n=43) using a simple immunofluorescence assay. Additionally, we validated the identity and function of some of the newly identified cell states as well as their epigenetic landscape, and found that cells expressing the inhibitory molecules CD39 and TIM3, on top of being enriched in non-responder lesions, are likely to play a crucial role in T-cell exhaustion in melanoma. Collectively, our study provides extensive unbiased data in human tumors for discovery of predictors and therapeutic targets to checkpoint immunotherapy.

Study phs001680

Blood Somatic Mutations in TCGA Donors Suffering from Solid Tumors

Blood somatic mutations identified across 8,530 solid tumor patients in TCGA cohort. We reasoned that low-coverage whole-genome sequencing of blood samples routinely carried out in cancer genomics projects may be repurposed to detect clonal hematopoiesis (CH). Thus, inspired by a previous approach to identify early mutations in the development of the hematopoietic system, we implemented a pipeline to systematically carry out this "reverse" somatic mutation calling on the paired blood/tumor samples. Blood somatic mutations were called using a 'reverse' approach, in which the tumor sample taken from each patient was used as control of their germline genome. Blood somatic mutations are thus detected as variants in the blood (with respect to the human reference genome) that are absent in the tumor sample. The variant calling was carried out in our in house cluster on downloaded blood/tumor BAM files. The matched blood and tumoral BAM files -- masked and deduplicated using GATK -- of 8,530 whole-exome patients were obtained as described above. The variant calling was carried out using Strelka2 (employing default parameters) with the blood sample as the tumoral input and the tumor sample as control (reverse calling). All variants with two or more supporting reads matching the caller PASS filter and with VAF<0.5 were kept. Mutations in lowly mappable regions as defined by the DUST algorithm (k=30) and UMAP68 (36-kmers) were excluded. Contiguous variants were merged into double-base substitutions. Variants with greater frequency across the cohorts than the DNMT3A R882H or JAK2 V617F hotspot in a cohort-specific Panel of Normals and in gnomAD v2.1 were removed. This was equivalent to discarding variants present in these datasets with an allele frequency greater than 0.008 in PoN TCGA and 0.0003 in gnomAD v2.1. Additionally, common SNPs as defined by the dbSNP 151 Common UCSC track and dbSNP were excluded. Mutations within segmental duplications, simple repeats and masked regions as defined in UCSC tracks were also removed. Finally, samples with the mutation count above the 97.5 percentile of the mutation burden across the cohort were deemed unreliable and excluded for further analyses. We call the set of variants obtained after the application of these filters the full set. A more conservative subset of somatic mutations was generated from the full set of blood somatic mutations. To this end, we applied MosaicForecast, a software designed to phase mutations to polymorphisms with the aim of identifying somatic mutations in a small number of cells and also predict mosaicism for the unphased ones with a random forest classifier. As a result, we obtained a subset of mosaic-phased mutations, and a subset of mutations likely to be somatic (mosaic set).In order to obtain access to this study, please first obtain access to TCGA study (phs000178).

Study phs002867

NHLBI GO-ESP: Heart Cohorts Exome Sequencing Project (Siblings with Ischemic Stroke Study, SWISS)

The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied. These data may help researchers understand the causes of disease, contributing to better ways to prevent, diagnose, and treat diseases, as well as determine whether to tailor prevention and treatments to specific populations. This could lead to more effective treatments and reduce the likelihood of side effects. GO-ESP is comprised of five collaborative components: 3 cohort consortia - HeartGO, LungGO, and WHISP - and 2 sequencing centers - BroadGO and SeattleGO. The Siblings with Ischemic Stroke Study (SWISS) is an affected sibpair (ASP) study of patients and their brothers/sisters who have had similar strokes. The study was conducted to determine the genes that contribute to an individual's risk of developing an ischemic stroke (a stroke due to sudden interruption of blood flow to a part of the brain). Over 600 people have participated in SWISS, with the coordination of the recruitment and flow of the samples occurring at the Mayo Clinic, Jacksonville, FL, under the direction of James F. Meschia, MD. The University of Virginia (Stephen S. Rich, PhD) served as the analytic site for the genetic data. Participants were excluded from SWISS if they had stroke following an invasive cerebrovascular or cardiovascular procedure, if their stroke occurred shortly following an aneurismal subarachnoid hemorrhage, if the stroke occurred in the setting of a mechanical aortic or mitral valve, if the patient had definite CNS vasculitis or if the patient had a Mendelian mitochondrial stroke disorder, including CADASIL, MELAS, Fabry disease, sickle cell anemia or homocysteinemia. For the NHLBI ESP, the youngest 51 ASPs (102 individuals) from SWISS were selected to undergo exome sequencing. These ASPs were selected from among all SWISS participants, excluding those pedigrees with individuals who had TOAST subtypes of stroke of other etiology or of stroke with undetermined etiology. In addition, the affected siblings were required to have the same TOAST subtype (both small vessel (lacunar) or both large vessel (atherosclerotic)). Of those selected, 98 samples passed initial quality control metrics, and 94 completed exome sequencing and were deposited in dbGaP. An additional set of 590 samples from the SWISS collection has been genotyped on the ExomeChip that contained a subset of rare/infrequent variants identified by exome sequencing. These samples include 495 affected individuals (from multiple affected family members) as well as 95 unaffected family members. These genetic and phenotypic data also will reside in dbGaP.

Study phs000327

NHLBI and NIA The New England Centenarian Study (NECS)

Supercentenarians (age 110+ years old) generally delay or escape age-related diseases and disability well beyond the age one hundred and this exceptional survival is likely to be influenced by a genetic predisposition that includes both common and rare genetic variants. In this report, we describe the complete genomic sequences of male and female supercentenarians, both age >114 years old. We show that: (1) the sequence variant spectrum of these two individuals' DNA sequences is largely comparable to existing non-supercentenarian genomes; (2) the two individuals do not appear to carry most of the well-established human longevity enabling variants already reported in the literature; (3) they have a comparable number of known disease-associated variants relative to most human genomes sequenced to date; (4) approximately 1% of the variants these individuals possess are novel and may point to new genes involved in exceptional longevity; and (5) both individuals are enriched for longevity-associated variants that we discovered through a large genome-wide association study. These analyses suggest that there are both common and rare longevity associated variants that may counter the effects of disease predisposing variants and extend lifespan. The continued analysis of the genomes of these rare individuals who have survived to extremely old ages should provide insight into the processes that contribute to the maintenance of health during extreme ageing.

Study phs000451

North Carolina Clinical Genomic Evaluation by NextGen Exome Sequencing (NCGENES)

North Carolina Clinical Genomic Evaluation by Next-generation Exome Sequencing This study is part of a larger consortium project investigating the validity and best use of next-generation sequencing (in particular, whole exome sequencing, or WES) in clinical care. Participants are patients who were either seen in the UNC Cancer and Adult Genetics Clinic or referred to the study by their physician. They will be approached by their physician or a genetic counselor for recruitment. Once enrolled, a clinical geneticist or genetic counselor will obtain consent and collect blood samples to be analyzed using WES. Results may include information related to a diagnosis and incidental information. Medically actionable incidental findings will be CLIA-certified and returned to participants in a routine genetic counseling session, along with diagnostic findings. Eligible adult participants will be randomized to have the opportunity to choose to get certain types of non-medically actionable incidental findings, as well. Their decisions will be investigated, as will psychosocial and behavioral responses to sequencing and receiving sequencing information. This is a longitudinal, mixed methods study (i.e., multiple assessments pre- and post-return of results, with both quantitative and qualitative methods used to gather data). Because only the quantitative component of the study uses randomization, only measures and procedures associated with that component are included here. The third study release includes data of additional n=189 subjects.

Study phs000827

BRAIN Cell EncyclOpeDia of Transcribed Elements (BRAINcode)

BRAINCODE: How Does the Human Genome Function in Specific Brain Neurons? The human brain comprises about 86 billion neurons whose function is central to human biology. How does the human genome program high performing neurons and neural networks in response to experience? What subprograms does the genome express in physiologically and morphologically distinct brain cells? The goal of the BRAIN Cell encyclOpeDia of transcribed Elements Consortium (BRAINcode) is to provide a map of gene expression - both protein-coding and non-coding - in specific cell types, not in culture, but in situ in brains of people. Going beyond traditional mRNA sequencing, polyadenylated and non-polyadenylated transcripts were ultra deeply sequenced using ribo-depleted RNA from neurons laser-captured from human post-mortem brains. Three prototypical neuron types, dopamine neurons, pyramidal neurons, and Betz cells, were prioritized because of their key biologic roles and differential vulnerability to important neurodegenerative diseases such as Parkinson's or Alzheimer's disease. Genetic variation between individuals was examined for correlation with differences in transcribed sequences to identify regions of the genome that influence whether, how, and how much a transcript is expressed in specific cell types in human brains. Our results indicate a vast universe of annotated and novel non-coding RNAs expressed in brain cells and suggest a more diverse and much more complex transcriptional architecture than previously imagined.

Study phs001556

OMRF SLEGEN GWAS Data from European-American Women with Lupus

"Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease with complex etiology but strong clustering in families (lambda(S) = approximately 30). We performed a genome-wide association scan using 317,501 SNPs in 720 women of European ancestry with SLE and in 2,337 controls, and we genotyped consistently associated SNPs in two additional independent sample sets totaling 1,846 affected women and 1,825 controls. Aside from the expected strong association between SLE and the HLA region on chromosome 6p21 and the previously confirmed non-HLA locus IRF5 on chromosome 7q32, we found evidence of association with replication (1.1 x 10-7 < P(overall) < 1.6 x 10-23; odds ratio = 0.82-1.62) in four regions: 16p11.2 (ITGAM), 11p15.5 (KIAA1542), 3p14.3 (PXK) and 1q25.1 (rs10798269). We also found evidence for association (P < 1 x 10-5) at FCGR2A, PTPN22 and STAT4, regions previously associated with SLE and other autoimmune diseases, as well as at > or =9 other loci (P < 2 x 10-7). Our results show that numerous genes, some with known immune-related functions, predispose to SLE." Reprinted from Nature Genetics, 2008 Feb; 40(2):204-10, PMID:18204446, with permission from Nature Publishing Group. Data submitted to dbGaP includes 297 samples from Oklahoma. (Please see also Study Accession: phs000216.v1.p1)

Study phs000202

GWAS in African Americans, Latinos and Japanese

The Multiethnic Cohort Study is a population-based prospective cohort study (n=215,251) that was initiated between 1993 and 1996 and includes subjects from various ethnic groups - African Americans and Latinos primarily from Californian (great Los Angeles area) and Native Hawaiians, Japanese-Americans, and European Americans primarily from Hawaii. State drivers' license files were the primary sources used to identify study subjects in Hawaii and California. Additionally, in Hawaii, state voter's registration files were used, and, in California, Health Care Financing Administration (HCFA) files were used to identify additional African American study subjects. In the cohort, incident cancer cases are identified annually through cohort linkage to population-based cancer Surveillance, Epidemiology, and End Results (SEER) registries in Hawaii and Los Angeles County as well as to the California State cancer registry. Information on estrogen receptor status is also obtained through these registries. Blood sample collection in the MEC began in 1994 and targeted incident breast cancer cases and a random sample of study participants to serve as controls for genetic analyses. Subjects are frequency matched on age at blood draw and ethnicity. The following number of breast cancer cases and controls were genome-wide scanned as part of this study: African Americans, 473 cases and 464 controls; Japanese: 885 cases and 822 controls; Latinos, 520 cases and 544 controls.

Study phs000517

Genomic Analysis of Extra-Nodal Natural Killer/T-Cell Lymphoma (ENKTCL)

In this study, we performed extensive genetic profiling on 209 extra-nodal natural killer/T-cell lymphoma (ENKTCL) nasal-type cases, including 174 Chinese from four hospitals in China, and 31 Hispanic and 4 Caucasian patients from City of Hope and Eberhard Karls University of Tübingen. All of the cases were reviewed by experienced hematopathologists to confirm diagnosis. Written informed consents from patients were reviewed and approved by the institutional review board of each institution. We deposited targeted exon sequencing data of a selected 333-gene panel on the ENKTCL cases in dbGaP. DNA was extracted from formalin-fixed paraffin-embedded (FFPE) tissues with an AllPrep DNA/RNA FFPE Kit. A custom platform (Agilent SureSelect) was used to capture target exons from genomic DNA of ENKTCL tumors. DNA was fragmented to 200bp using a Covaris S220 Focused-ultrasonicator and was end-repaired and ligated to Illumina adaptors with a KAPA Hyper Prep Kit. Ligated products were purified and amplified with a 7-cycle PCR. Exome capture from the PCR products was performed using a SureSelect Target Enrichment Kit. The captured exomes were further amplified with an 8-cycle PCR and purified for cluster generation using the cBot cluster generation system with a HiSeq PE Cluster Kit V4. 100bp paired-end reads were generated from an Illumina HiSeq 2500 system with a HiSeq SBS Kit V4.

Study phs002925

The Human Gut Microbiome and Recurrent Abdominal Pain in Children

This project explores the nature of the human intestinal microbiome in healthy children and children with recurrent abdominal pain. The overall goal is to obtain a robust knowledge-base of the intestinal microbiome in children without evidence of pain or gastrointestinal disease, children with functional abdominal pain, and children with abdominal pain and changes in bowel habits (irritable bowel syndrome). Multiple strategies have been deployed to navigate and understand the nature of the intestinal microbiome in childhood. These strategies include 454 pyrosequencing-based strategies to sequence 16S rRNA genes and understand the detailed composition of microbes in healthy and disease groups. Microarray-based hybridization with the PhyloChip and quantitative real-time PCR (qPCR) probes are being applied as complementary strategies to gain an understanding of the intestinal microbiome from various perspectives. Data collected and analyzed during the HMP UH2 and UH3 Demo project, from a set of healthy and IBS children may enable the identification of core microbiomes in children in addition to variable components that may distinguish healthy from diseased pediatric states. We are currently analyzing the dataset for the presence of disease-specific signatures in the human microbiome, and correlating these microbial signatures with pediatric health or IBS disease status. This study explores the nature of core and variable human microbiomes in pre-adolescent healthy children and children with recurrent abdominal pain.

Study phs000265

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