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• Harnessing the Electronic Health Record to Predict Risk of Cardiovascular Disease: Sangre Por Salud (SPS) Biobank GWAS Data

  These data are from subjects in the Sangre Por Salud (SPS) Biobank, a Latino population from the Southwest United States. Subjects were genotyped in 2 batches on the Illumina Multi-ethnic Global Array. Data from this study were used for testing a new cardiovascular risk score and evaluating polygenic risk scores. SPS biobank GWAS data is available on 3699 subjects.

  Study phs003553

• Tumor-resident T-cell regulate responses to checkpoint blockade immunotherapies

  In cancer models, CD103+CD8 TRM cells are implicated in the response to anti-PD-1 immunotherapy, and a subset of CD4 TRM cells expressing the integrin CD49a is required for response to anti-CTLA-4 immunotherapy. We performed single-cell RNA sequencing on tumour-infiltrating T lymphocytes (TILs) isolated from colon carcinoma et unsupervised analyses reveal several TRM populations.

  Study EGAS50000000826

• Collagen Proteostasis in Health and Disease

  This study uses human iPSC-derived cartilage to investigate the effects of the p.Arg719Cys mutation in the COL2A1 gene, which is linked to precocious osteoarthritis. Using a CRISPR-edited isogenic cell line pair, we compared wild-type and mutant cartilage for matrix defects and cellular stress responses. We performed RNA-sequencing and quantitative proteomics to characterize changes in gene expression, protein interactions, and collagen folding.

  Study phs004112

• Analysis of Loose Ends in Cancer Genome Structure

  Short-read sequencing (SRS) forms the basis of our understanding of cancer genome evolution, yet it is widely thought to be inadequate for detecting structural variants (SVs). To understand the nature of cancer SVs missed by SRS, we introduce the concept of "loose ends" - sites of missing rearrangements revealed by balancing copy number (CN) across the genomic intervals and adjacencies of a genome graph.

  Study EGAS00001007324

• Transcriptomes_of_human_lymphocytes

  In this study we will compare the single cell transcriptomes of immune cells from asthmatics responding to steroids, those refractory to steroids, and a control population.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 EGAS00001001755

• Whole transcriptome and exome sequencing of childhood ALL

  Gene fusion is a major class of genomic abnormalities in childhood acute lymphoblastic leukemia (ALL) and sentinel chromosomal rearrangements involving EP300 and CREBBP may cause global epigenetic deregulation during leukemogenesis with potentials for therapeutic targeting. This dataset includes whole transcriptome sequencing of 231 children with acute lymphoblastic leukemia from a Singapore-Malaysia frontline clinical treatment protocol.

  Study EGAS00001001858

• Whole-genome bisulfite sequencing analysis of low-grade astrocytomas in the ICGC PedBrain Tumor Project

  Pilocytic Astrocytoma (PA) is the most common pediatric brain tumor. While genome and transcriptome landscapes are well-studied, data of the complete methylome, tumor cell composition and immune infiltration are scarce. We generated whole genome bisulfite sequence data (WGBS) of nine PAs to find evidence for a link of focal methylation differences and differential gene expression to immune infiltration.

  Study EGAS00001004019

• Brain transcriptome of hereditary cerebral haemorrhage with amyloidosis–Dutch type (HCHWA-D)

  HCHWA-D is an early onset hereditary form of Cerebral Amyloid Angiopathy (CAA) caused by a point mutation resulting in an amino acid change (NP_000475.1:p.Glu693Gln) in the Amyloid Precursor Protein (APP). Post-mortem brain tissue (9 patients and 9 age-related controls; frontal and occipital cortex) was used for next generation sequencing of RNA (RNA-Seq with ribosomal RNA depletion).

  Study EGAS00001002730

• University of Washington Cerebrospinal Fluid Biomarker Study for Parkinson disease

  There is a clear need to develop biomarkers for Parkinson disease (PD) diagnosis and monitoring disease progression. In this study we evaluated cerebrospinal fluid (CSF) proteins, which are known to be critically involved in PD or identified in our preliminary profiling studies, aptamers, and RNAs as potential PD biomarkers. Access to subjects for this study was via the Pacific Northwest Udall Center (PANUC) and the Alzheimer's Disease Research Center (ADRC) at the University of Washington and Oregon Health and Sciences University (OHSU). Using CSF samples from 30 well-characterized patients with PD and 30 age-, sex-matched healthy controls, we prepared RNA seq libraries and performed deep sequencing of all RNA species, including small and long RNA, mRNAs, noncoding RNAs and differentially spliced transcripts. We then tried several methods for RNAseq data analysis to optimize our analysis pipeline. We identified a total of 3381 transcripts corresponding to 182 long intergenic RNAs (LincRNAs), 11 microRNAs (miRNAs), 2861 protein-coding transcripts, 200 pseudogenes and 127 antisense RNAs; some of them were differentially expressed between PD and control groups. Selected differentially expressed RNAs have been validated in the same set of CSF samples using real-time PCR (RT-PCR). Further validations in independent, larger cohorts of samples are still ongoing. Our results obtained so far suggested that CSF proteins and RNAs could be used as good indexes for PD diagnosis and disease severity/progression. This study is a part of the NIDDS-funded Parkinson's Disease Biomarkers Program (PDBP).

  Study phs000901

• JAK Inhibitor Withdrawal Causes a Transient Proinflammatory Cascade: A Potential Mechanism for Major Adverse Cardiac Events

  This is a study of mesenchymal stromal cells (MSCs) from salivary glands. The salivary glands were derived from participants who had dry eye or dry mouth symptoms but did not have evidence of systemic autoimmune disease (sicca controls). The aim of the study was to determine the effects of Type I and Type II Janus kinase (JAK) inhibitors (JAKinibs) withdrawal on these cells in vitro. The MSCs were treated in vitro with a) IFN-gamma (10 ng/mL) for the entire duration, b) IFN-gamma (10 ng/mL) and withdrawal of ruxolitinib (1 µM), c) IFN-gamma (10 ng/mL) and withdrawal CHZ-868 (1 µM), and d) IFN-gamma (10 ng/mL) and ruxolitinib (1 µM) for the entire duration. For the drug (CHZ-868 and ruxolitinib) conditions, after IFN-gamma treatment for 48 hours, we washed the cells with PBS and treated them with standard growth media with 0.01% DMSO, 10 ng/mL IFN-gamma + 0.01% DMSO, or 10 ng/mL IFN-gamma + JAKinib for 48 hours. For withdrawal conditions, we washed the cells twice and then treated them with standard growth media with either 0.01% DMSO or with 10 ng/mL IFN-gamma + 0.01% DMSO for 24 hours before harvest.

  Study phs003915

• UniKilinikum Wuerzburg MSNZ AGRasche/AG Riedel EMD DAC

  This is a Data access committee for the Data presented in the paper tilted "Spatially resolved transcriptomics reveals profound subclonal heterogeneity and T cell dysfunction in extramedullary myeloma"

  Dac EGAC50000000173

• Liver Tumours WGS (2020-02-20)

  The aim of this study is to define the mutational landscape of human liver tumours. . This dataset contains all the data available for this study on 2020-02-20.

  Dataset EGAD00001005993

• Res1_HT29_exp1_MC_02.03.22

  1 sample is pure plasmid DNA and 10 samples are cell pellets for genomic DNA extraction. CRISPR PCR1 and PCR2 indexing - Please use standard Kozuke primers.

  Dataset EGAD00001012230

• Res1_H23_exp1_MC_04.03.22

  1 sample is pure plasmid DNA and 8 samples are cell pellets for genomic DNA extraction. CRISPR PCR1 and PCR2 indexing - Please use standard Kozuke primers.

  Dataset EGAD00001012229

• Res1_HT29_exp2_MC_03.03.22

  1 sample is pure plasmid DNA and 10 samples are cell pellets for genomic DNA extraction. CRISPR PCR1 and PCR2 indexing - Please use standard Kozuke primers.

  Dataset EGAD00001012231

• Early detection of ovarian cancer using cell-free DNA fragmentomes and protein biomarkers

  Ovarian cancer is the leading cause of death from gynecological cancers worldwide. No effective screening methods exist, and tumors are commonly detected at advanced stages where treatment is much less effective. In this study, we used whole-genome cell-free DNA (cfDNA) fragmentome and protein biomarker (CA-125 and HE4) analyses to evaluate 591 women from the European Union or the United States with ovarian cancer, benign adnexal masses, or without ovarian lesions. Using a machine learning model that incorporated multi-analyte fragmentome data and protein measurements, we detected ovarian cancer with high specificity >99% and sensitivity of 72%, 69%, 87%, and 100% for stages I–IV, respectively (AUC=0.96, 95% CI: 0.94-0.99), including 90% of high grade serous ovarian cancers. At the same specificity, CA-125 alone detected 34%, 62%, 63%, and 100% of ovarian cancers for stages I–IV (p=0.001, two-sided test of equal proportions). Additionally, our approach distinguished benign masses from ovarian cancers with high accuracy (AUC of 0.88, 95% CI=0.83-0.92). These results were validated in an independent population. These findings show that integrated cfDNA fragmentome and protein analyses detect ovarian cancers with high performance, enabling a new accessible approach for noninvasive ovarian cancer screening and diagnostic evaluation.

  Study EGAS50000000484

• 3D tissue engineered human skeletal muscle modelling Facioscapulohumeral Muscular Dystrophy

  acioscapulohumeral muscular dystrophy (FSHD) is caused by sporadic misexpression of the transcription factor double homeobox 4 (DUX4) in skeletal muscles. So far, monolayer cultures and animal models have been used to study the FSHD disease mechanism and for FSHD therapy development, but these models do not fully recapitulate the disease and there is a lack of knowledge on how DUX4 misexpression leads to skeletal muscle dysfunction. To overcome these barriers, we have developed a 3D tissue engineered skeletal muscle (3D-TESM) model by generating genetically matched myogenic progenitors (MPs) from human induced pluripotent stem cells of three mosaic FSHD patients. 3D-TESMs derived from genetically affected MPs recapitulate pathological features including DUX4 and DUX4 target gene expression, smaller myofiber diameters, and reduced absolute forces upon electrical stimulation. RNA sequencing data illustrates increased expression of DUX4 target genes in 3D-TESMs compared to 2D myotubes, and cellular differentiation was improved by 3D culture conditions. Treatment of 3D-TESMs with small molecules identified in drug development screens in 2D muscle culture showed no improvements in contractile force and sarcomere organization, highlighting the potential benefit of 3D-TESMs for preclinical drug potency screening by eliminating false-positive compounds for FSHD research and drug development.

  Study EGAS50000000502

• Microbiomic and immunogenic biomarkers of adjuvant chemotherapy efficacy in stage III colorectal cancer

  The standard treatment for stage III colorectal cancer (CRC) is surgery, followed by adjuvant chemotherapy (AC). However, the efficacy of AC is limited, and approximately 30% of patients experience recurrence. Therefore, easily assessable molecular biomarkers that can predict response to AC are needed. Here, we aimed to identify predictive biomarkers of response to AC using tumor transcriptomic data. Tumor specimens from 253 patients who underwent surgery for stage III CRC between 1997 and 2019 were analyzed using RNA sequencing. Transcriptional subtyping and analyses of gut microbiome, immune cell fractions, and T-cell receptor (TCR) were performed to identify factors associated with recurrence-free survival (RFS) in patients treated with or without AC. Of 253 patients, 118 (46.6%) received AC. Twenty phyla and 799 species of the microbiomes were identified, among which Fusobacteria were identified in 247 patients (97.6%). Multivariable Cox proportional hazards regression analysis of patients who received AC showed that intratumoral Fusobacterium and M1 macrophage abundance and diversity of TCR alpha and delta (TRAD) were independently associated with RFS. Fusobacterium and M1 macrophage abundance, and TRAD diversity were associated with the response to AC, suggesting that these factors could serve as biomarkers for personalized treatment in stage III CRC.

  Study JGAS000875

• Developmental_Dysplasia_of_the_Hip__DDH_

  The National Joint Registry for England and Wales (NJR) has become established as one of the largest repositories of clinical information about patients undergoing hip and knee replacement. The primary aim of this proposal is to examine the feasibility of adding value to that clinical information by partnering it with a DNA dataset to allow its use to be extended to the study of the underlying pathogenesis of diseases of the hip and knee, and the complications of their treatment. We will do this 1) by establishing a mechanism for accessing and linking pseudo-anonymised demographic and phenotype data between the NJR database and the proposed DNA Biobank; 2) by validating the collection of postal DNA samples from consenting NJR patients; and 3) by genotyping genome-wide 900 patients with the condition developmental dysplasia of the hip (DDH) to find variants that play a role in this heritable condition. The successful demonstration that the NJR can be used to establish a DNA Biobank will provide a powerful platform to examine the genetic basis for a wide range of joint diseases, and the complications of their treatment. This proposal is to carry out the genotyping portion of this project on the current CoreExome array

  Study EGAS00001000916

• Natural genetic variation of the cardiac transcriptome in non-diseased donors and patients with dilated cardiomyopathy

  Background: Genetic variation is an important determinant of RNA transcription and splicing, which in turn contributes to variation in human traits including cardiovascular diseases.Results: Here we report the first in-depth survey of heart transcriptome variation using RNA-sequencing in 149 (97)* patients with dilated cardiomyopathy and 113 (108)* non-diseased controls. We reveal extensive differences of gene expression and splicing between dilated cardiomyopathy patients and controls, affecting known as well as novel dilated cardiomyopathy genes. Moreover, we show a widespread effect of genetic variation on the regulation of transcription, isoform usage and allele specific expression. Systematic annotation of genome wide association SNPs identifies 60 functional candidate genes for heart phenotypes, representing 20% of all published heart genome wide association loci. Focusing on the dilated cardiomyopathy phenotype we found that eQTL variants are also enriched for dilated cardiomyopathy genome wide association signals in two independent cohorts.Conclusions: RNA transcription, splicing and allele specific expression are each important determinants of the DCM phenotype and are controlled by genetic factors. Our results represent a powerful resource for the field of cardiovascular genetics. (*) numbers in parentheses represent samples that the publication is based on.

  Study EGAS00001002454

• The Prediction and Prevention of Preeclampsia

  The Prediction and Prevention of Preeclampsia (PREDO) is a prospective birth cohort study of Finnish women who were pregnant between 2005 and 2010 and their children. The PREDO study cohort was set up to identify novel risk factors and biomarkers in pregnant women associated with the development of preeclampsia and intrauterine growth restriction (IUGR). Two groups of pregnant women were enrolled during the first trimester of their pregnancy: first, pregnant women with a known clinical risk factor status for preeclampsia and IUGR (N=1079; 969 of these women had at least one and 110 had none of the known risk factors for preeclampsia and IUGR), and second, pregnant women who volunteered to participate regardless of their risk factor status for preeclampsia and IUGR (N=3698). Both samples were monitored during pregnancy with four clinical visits and bi-weekly self-reports. The post-delivery follow-up has taken place at approximately 2 weeks, 6 months, and 3.5 years after the delivery. The most recent follow-up started in 2016 and is ongoing. In the high-risk sample, cord blood samples were collected and genome-wide genotyping has been conducted with Illumina OmniExpressExome 1.2 and genome-wide methylation status has been analysed with Illumina 450k HM array.

  Study EGAS00001001898

• High-throughput telomere length measurement at nucleotide resolution using the PacBio high fidelity sequencing platform

  Telomeres are specialized nucleoprotein structures at the ends of linear chromosomes that are essential for the stability as well as the complete replication of the human genome. The progressive shortening of steady-state telomere length in normal human somatic cells is a promising biomarker for age-associated diseases. However, there remain substantial challenges in quantifying telomere length in clinics and research laboratories due to the lack of accurate and high-throughput telomere length measurement method. Here, we describe a novel workflow to capture and analyze telomeres accurately at the single-nucleotide resolution. By using newly designed telobaits that are complementary to the single-stranded G-rich 3’ telomeric overhangs, we can specifically and efficiently capture full-length telomeres and subject them to single-molecule real-time (SMRT) sequencing. We show that the telomere length can be measured at nucleotide resolution using the PacBio high fidelity (HiFi) sequencing platform, which provides the necessary accuracy and throughput to uncover the steady-state telomere length distribution in human culture cell lines as well as clinical patient samples. This new method is a valuable tool not only in population-wide epidemiology studies but also for the longitudinal assessment of telomere attrition in individuals. Our results also reveal the extreme heterogeneity of telomeric variant sequences (TVSs) that is dispersed throughout the telomere repeat region. Importantly, the unique distribution pattern and sequence of TVSs in individuals may be used as a fingerprint for sample identification. In addition, the presence of TVSs disrupts the continuity of the canonical (5’-TTAGGG-3’)n telomere repeats, which could affect the binding of shelterin complexes at the chromosomal ends. Therefore, TVSs may act as a form of genetic polymorphisms that impairs telomere protection. Together with the absolute telomere length in each individual, TVSs may have profound implications in human aging and diseases.

  Study EGAS00001006103

• High-throughput telomere length measurement at nucleotide resolution using the PacBio high fidelity sequencing platform, P49-P104 and run1 replicates

  Telomeres are specialized nucleoprotein structures at the ends of linear chromosomes that are essential for the stability as well as the complete replication of the human genome. The progressive shortening of steady-state telomere length in normal human somatic cells is a promising biomarker for age-associated diseases. However, there remain substantial challenges in quantifying telomere length in clinics and research laboratories due to the lack of accurate and high-throughput telomere length measurement method. Here, we describe a novel workflow to capture and analyze telomeres accurately at the single-nucleotide resolution. By using newly designed telobaits that are complementary to the single-stranded G-rich 3’ telomeric overhangs, we can specifically and efficiently capture full-length telomeres and subject them to single-molecule real-time (SMRT) sequencing. We show that the telomere length can be measured at nucleotide resolution using the PacBio high fidelity (HiFi) sequencing platform, which provides the necessary accuracy and throughput to uncover the steady-state telomere length distribution in human culture cell lines as well as clinical patient samples. This new method is a valuable tool not only in population-wide epidemiology studies but also for the longitudinal assessment of telomere attrition in individuals. Our results also reveal the extreme heterogeneity of telomeric variant sequences (TVSs) that is dispersed throughout the telomere repeat region. Importantly, the unique distribution pattern and sequence of TVSs in individuals may be used as a fingerprint for sample identification. In addition, the presence of TVSs disrupts the continuity of the canonical (5’-TTAGGG-3’)n telomere repeats, which could affect the binding of shelterin complexes at the chromosomal ends. Therefore, TVSs may act as a form of genetic polymorphisms that impairs telomere protection. Together with the absolute telomere length in each individual, TVSs may have profound implications in human aging and diseases.

  Study EGAS00001006595

• DNA methylation atlas of normal human cell types

  DNA methylation is a fundamental epigenetic mark that governs chromatin organization, cell identity, and gene expression. Here we describe a human methylome atlas, based on deep whole-genome bisulfite sequencing allowing fragment-level analysis across thousands of unique markers for 39 cell types sorted from 205 healthy tissue samples. Replicates of the same cell-type are >99.5% identical, demonstrating robustness of cell identity programs to genetic variation and environmental perturbation. Unsupervised clustering of the atlas recapitulates key elements of tissue ontogeny, and identifies methylation patterns retained since gastrulation. Loci uniquely unmethylated in an individual cell type often reside in transcriptional enhancers and contain DNA binding sites for tissue-specific transcriptional regulators. Uniquely hyper-methylated loci are rare and are enriched for CpG islands, polycomb targets, and CTCF binding sites, suggesting a novel role in shaping cell type-specific chromatin looping. The atlas provides an essential resource for interpretation of disease-associated genetic variants, and a wealth of potential tissue-specific biomarkers for use in liquid biopsies.

  Study EGAS00001006791

• Epigenome and transcriptome profiling of chronic lymphocytic leukemia patients

  Chronic lymphocytic leukemia (CLL) is characterized by substantial clinical heterogeneity, despite relatively few genetic alterations. To provide a basis for studying epigenome deregulation in CLL, we established genome-wide chromatin accessibility maps for 88 CLL samples from 55 patients using the ATAC-seq assay, and we also performed ChIPmentation and RNA-seq profiling for ten representative samples. Based on the resulting dataset, we devised and applied a bioinformatic method that links chromatin profiles to clinical annotations. Our analysis identified sample-specific variation on top of a shared core of CLL regulatory regions. IGHV mutation status – which distinguishes the two major subtypes of CLL – was accurately predicted by the chromatin profiles, and gene regulatory networks inferred for IGHV-mutated vs. IGHV-unmutated samples identified characteristic differences between these two disease subtypes. In summary, we discovered widespread heterogeneity in the chromatin landscape of CLL, established a community resource for studying epigenome deregulation in leukemia, and demonstrated the feasibility of chromatin accessibility mapping in cancer cohorts and clinical research.

  Study EGAS00001001821

• UK10K NEURO FSZ

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches. These Finnish schizophrenia samples have been collected from a population cohort using national registers. The entire sample collection consists of 2756 individuals from 458 families of whom 931 are diagnosed with schizophrenia spectrum disorder, each family having at least two affected siblings. 170 families originate from an internal isolate (Kuusamo) with a three-fold lifetime risk for the trait. The genealogy of the internal isolate is well documented and the individuals form a “megapedigree” reaching to the 17th Century. All diagnoses are based on DSM-IV and for a large fraction of cases there is cognitive data. For further details/descriptions with regard to this data set please contact Tiina Paunio (tiina.paunio@thl.fi)

  Study EGAS00001000118

• 'Targeted High Throughput Sequencing in Clinical Cancer Settings: Formaldehyde fixed-paraffin embedded (FFPE) tumor tissues, input amount and tumor heterogeneity'

  "Background: Massively parallel sequencing technologies have brought an enormous increase in sequencing throughput. However, these technologies need to be further improved with regard to reproducibility and applicability to clinical samples and settings. Methods: Using identification of genetic variations in prostate cancer as an example we address three crucial challenges in the field of targeted re-sequencing: Small nucleotide variation (SNV) detection in samples of formalin-fixed paraffin embedded (FFPE) tissue material, minimal amount of input sample and sampling in view of tissue heterogeneity.Results: We show that FFPE tissue material can supplement for fresh frozen tissues for the detection of SNVs and that solution-based enrichment experiments can be accomplished with small amounts of DNA with only minimal effects on enrichment uniformity and data variance. Finally, we address the question whether the heterogeneity of a tumor is reflected by different genetic alterations, e.g. different foci of a tumor display different genomic patterns. We show that the tumor heterogeneity plays an important role for the detection of copy number variations, but is of minor importance for the detection of somatic variations.Conclusions: The application of high throughput sequencing technologies in cancer genomics opens up a new dimension for the identification of disease mechanisms. In particular the ability to use small amounts of FFPE samples available from surgical tumor resections and histopathological examinations facilitates the collection of precious tissue materials. However, care needs to be taken in regard to the locations of the biopsies taken, which can have an influence on the prediction of copy number variations. Bearing these technological challenges in mind will significantly improve many large-scale sequencing studies and will - on a long-range - result in a more reliable prediction of individual cancer therapies."

  Study EGAS00001000136

• Spiradenocarcinoma

  • Spiradenocarcinoma is a rare cutaneous sweat gland adnexal cancer with potential for aggressive behaviour. They are classified histologically into low- and high-grade tumours, with morphologically low-grade tumours thought to behave more favourably. However, limited information is available, with only 18 published cases. • We have collected morphologically low-grade spiroadenocarcinomas (one with a lung metastasis) and high-grade spiroadenocarcinomas, as well as some spiradenomas (benign lesions), cylindromas (another type of malignant cutaneous sweat gland adnexal tumour) and hybrid spiradenoma-cylindromas. • H&E-stained sections were reviewed, follow-up was obtained, and immunohistochemistry for Ki-67, p53 and, MYB has been performed. The tumours were solitary, measuring 0.8-7?cm (median: 2.7?cm), with a predilection for the head and neck of elderly patients (median age: 72 years; range 53-92) without gender bias. Histologically, the tumours were multinodular and located in deep dermis and subcutis. A pre-existing spiradenoma was present in all cases. The malignant component was characterized by expansile growth with loss of the dual cell population, up to moderate cytological atypia and increased mitotic activity (median: 10/10 HPF; range 1-28). Additional findings included squamoid differentiation (n=9), necrosis (n=7), and ulceration (n=5). P53 expression was variable and no significant differences were noted in the benign compared with the malignant parts of the tumours. In contrast, in the malignant components the Ki-67 proliferative index was slightly increased, and MYB expression was lost. Follow-up (median: 67 months; range: 13-132) available for 16 patients (84%) revealed a local recurrence rate of 19% but no metastases or disease-related mortality. • Here we wish to exome sequence these cases to define the first genomic landscape for this malignancy.

  Study EGAS00001001799

• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): Identification of VUR genes by exome sequencing

  Primary vesicoureteric reflux (PVUR), or non-syndromic VUR, is the most common type of congenital anomaly of the kidney and the urinary tract (CAKUT). PVUR is the single most important risk factor for pyelonephritis and renal parenchymal scarring in the pediatric age group. Renal parenchymal scarring due to PVUR is referred to as reflux nephropathy and is a major cause of end stage kidney disease requiring dialysis and kidney transplantation in children. PVUR shows familial aggregation; however, the specific genetic cause(s) of PVUR is unknown despite a number of linkage studies. Reasons for this include: variable expression of the disease, difficulty with case ascertainment, genetic heterogeneity and lack of large pedigrees that can facilitate locus identification. We have ascertained a large 97 member PVUR kindred spanning five generations. We performed a genome-wide linkage study (GWLS) on this family and obtained a significant genome-wide LOD score of 3.3 on chromosome 6p. We performed exome sequencing on affected individuals in the family and identified mutations in tenascin XB (TNXB) as a cause of familial VUR. The proposed studies have the following specific objectives: a) to define the role of tenascin genes in the etiology of PVUR, and b) to identify new PVUR causative genes. Our specific aims are (1) To perform mutation analysis in TNXB and other tenascins in a cohort of 200 individuals with familial and sporadic PVUR and define genotype/phenotype correlations. (2) To perform sequential genome wide linkage studies (GWLS) and whole exome/targeted sequencing in families with PVUR. Impact on public health: Identification of PVUR genes may provide a novel non-invasive diagnostic tool for a subset of children with PVUR. Furthermore, this research will provide insights into the pathogenesis of PVUR and further elucidate the pathways involved in the development of the kidney and genitourinary tract. Future studies will define the role of the genes in the etiology of other malformations of the kidney and urinary tract and also seek to unravel the mechanisms by which the identified gene causes PVUR and other malformations of the kidney and the urinary tract.

  Study phs000778

• NHLBI TOPMed: Lung Tissue Research Consortium (LTRC)

  Chronic obstructive pulmonary disease (COPD), a disease state characterized by airflow limitation that is not fully reversible, is the third leading cause of death in the U.S. COPD is a heterogeneous syndrome, with affected individuals demonstrating marked differences in lung structure (emphysema vs. airway disease); physiology (airflow obstruction); and other clinical features (e.g., exacerbations, co-morbid illnesses). Multiple genomic regions influencing COPD susceptibility have been identified by genome-wide association studies (GWAS), and rare coding variants can also influence risk for COPD. However, only a small percentage of the estimated heritability for COPD risk can be explained by known genetic loci. Like most complex diseases, COPD is influenced by multiple genetic determinants (each with modest individual effects). Emerging evidence supports the paradigm that complex disease genetic determinants are part of a network of interacting genes and proteins; perturbations of this network can increase disease risk. To identify this network, multiple Omics data will need to be analyzed with methods to account for nonlinear relationships and interactions between key genes and proteins. Our overall hypothesis is that integrated network analysis of genetic, transcriptomic, proteomic, and epigenetic data from biospecimens ranging from lung tissue to nasal epithelial cells to blood in highly phenotyped subjects will provide insights into COPD pathogenesis and heterogeneity. We will leverage the well-phenotyped, NHLBI-funded Lung Tissue Research Consortium (LTRC) to address these questions. We will perform multi-omics analysis in 1548 lung tissue and blood samples from the LTRC. With these multi-omics data, we will utilize a systems biology approach to understand relationships between multiple genetic determinants and multiple types of Omics data. We will begin by performing single Omics analyses in COPD vs. control lung, nasal, and blood samples. Next, we will integrate single Omics data with genetic variants identified by WGS to assist in fine mapping genetic determinants of COPD. We will then perform integrated network analysis of COPD with genetic and multiple Omics data using correlation-based, gene regulatory, and Bayesian networks. Subjects were recruited from Mayo Clinic, Universities of Colorado, Michigan, and Pittsburgh, and Temple University.

  Study phs001662

• AML_controls

  Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy that is most similar in expression profiles to plasmacytoid dendritic cells. However, patients often exhibit features of AML and can progress to AML. In this project, we will determine the differentially and commonly expressed genes between BPDCN and AML specimens. Available BPDCN and TET2-mutated AML specimens were taken for transcriptome microarray analysis.

  Dataset EGAD00010001726

• Comprehensive genomic analysis for AYA with acute lymphoblastic leukemia

  AYA with B-ALL showed extremely inferior outcomes when compared to children. Genetic basis undelying AYA B-ALL is largely unknown. We performed integrated analysis of RNA-seq (hum0045���JGAS000047) and target DNA-seq.

  Study JGAS000276

• Human Blastocyst 10X Single Cell RNA Sequencing

  Recent advances in human blastoids have opened new avenues for modeling early human development and implantation. One limitation of our first protocol for human blastoid generation was relatively low efficiency. We now report an optimized protocol for the efficient generation of large quantities of high-fidelity human blastoids from naive pluripotent stem cells. This enabled proteomics analysis that identified phosphosite-specific signatures potentially involved in the derivation and/or maintenance of the signaling states in human blastoids. Additionally, we uncovered endometrial stromal effects in promoting trophoblast cell survival, proliferation, and syncytialization during co-culture with blastoids and blastocysts. Side-by-side single-cell RNA sequencing revealed similarities and differences in transcriptome profiles between pre-implantation blastoids and blastocysts, as well as post-implantation cultures, and uncovered a population resembling early migratory trophoblasts during co-culture with endometrial stromal cells. Our optimized protocol will facilitate broader use of human blastoids as an accessible, perturbable, scalable, and tractable model for human blastocysts. In addition, this study is the first to use the 10X Genomics platform for human blastocysts, and we anticipate this resource will be widely used by the community as a reference for future studies.

  Study phs003122

• noninvasive lung cancer subtyping

  Accurate diagnosis of lung cancer is important for treatment decision-making. Currently, the gold standard for diagnosing histological subtypes of lung cancer relies on tumor biopsies. Recently, liquid biopsy, particularly cell-free DNA (cfDNA), has shown promising results in cancer detection and classification. In this study, we investigated the potential of cfDNA methylome for the noninvasive classification of lung cancer histological subtypes. Specifically, we focused on the two most prevalent lung cancer subtypes, lung adenocarcinoma and lung squamous cell carcinoma. Using a fragment-based marker discovery approach, we identified robust subtype-specific methylation markers from tumor samples. These markers were successfully validated in independent cohorts and associated with subtype-specific transcription activity. Leveraging these markers, we constructed a subtype classification model using cfDNA methylation profiles, achieving an AUC of 0.808 in the cross-validation and an AUC of 0.747 in the independent validation. Additionally, tumor copy number variations inferred from cfDNA methylome analysis revealed potential implications for treatment selection. In summary, our study demonstrates the potential of cfDNA methylome analysis for noninvasively lung cancer subtyping, offering insights for cancer monitoring and early detection.

  Study EGAS00001007717

• Accurate detection of tumor-specific fusion genes reveals strongly immunogenic personal neo-antigens

  Fusion genes arising from cancer-associated somatic mutations are a potential rich source for highly immunogenic neo-antigens. However, their exploitation as targets for personalized cancer immunotherapy is currently limited by the lack of computational tools allowing transcriptome-wide identification of unique fusion genes in an accurate and sensitive manner. Here, we present EasyFuse, a computational pipeline, to detect individual and cancer-specific fusion genes in next-generation-sequencing transcriptome data obtained from human cancer samples. Using machine learning, EasyFuse predicts personal fusion genes with high precision and sensitivity and outperforms previously described approaches as qualified by an unprecedented ground-truth dataset of >1500 verification experiments in relevant patient samples. By testing immunogenicity with autologous blood lymphocytes from cancer patients we detected pre-established CD4+ and CD8+ T cell responses for 10 of 21 (48%), and for 1 of 30 (3%) of identified fusion genes, respectively. In conclusion, we demonstrate accurate detection of cancer-specific fusion genes. The high frequency of T cell responses detected in cancer patients support the relevance of private fusion genes as neo-antigens for personalized immunotherapies, especially for tumors with low point mutation burdens.

  Study EGAS00001004877

• Genetic Effects on Gene Expression and Splicing during Human Neurogenesis

  Interpretation of the function of non-coding risk loci for neuropsychiatric disorders and brain-relevant traits via gene expression and alternative splicing quantitative trait locus (e/sQTL) analyses is generally performed in bulk post-mortem adult tissue. However, genetic risk loci are enriched in regulatory elements active during neocortical differentiation, and regulatory effects of risk variants may be masked by heterogeneity in bulk tissue. Here, we map e/sQTLs, and allele-specific expression in cultured cells representing two major developmental stages, primary human neural progenitors (n=85) and their sorted neuronal progeny (n=74), identifying numerous loci not detected in either bulk developing cortical wall or adult cortex. Using colocalization and genetic imputation via transcriptome-wide association, we uncover cell-type specific regulatory mechanisms underlying risk for brain-relevant traits that are active during neocortical differentiation. Specifically, we identified a progenitor-specific eQTL for CENPW co-localized with common variant associations for cortical surface area and educational attainment.

  Study phs002493

• Childhood Cancer Data Initiative (CCDI): Integrating Longitudinal Clinical, Sociodemographic and Genomic Data into the NCCR

  The goal of this study is to contribute clinical and genomic data from a large institutional cohort of pediatric cancer patients who had tumor genomic profiling between 2013 and 2019 at Dana-Farber/Boston Children's Hospital Cancer and Blood Disorders Center. Clinical data include demographics, diagnosis (classified according to the International Classification of Diseases for Oncology (ICD-O-3.2), stage, and biospecimen associated data. Tumors were sequenced with OncoPanel, a targeted next-generation DNA sequencing panel of up to 447 cancer genes for detection of single-nucleotide variants (SNV), insertions, and deletions, and copy number alterations (CNA), as well as selected intronic regions for up to 60 genes for the detection of structural variants (SV). This dataset includes a patient and sample identifier (GENIE ID) that can be used to link the genomic data included in this dataset to additional longitudinal clinical cancer data on a subset of patients that was submitted to the National Childhood Cancer Registry (NCCR).

  Study phs002677

• Rare disruptive mutations in ciliary function genes contribute to testicular cancer susceptibility

  Testicular germ cell tumor (TGCT) is the most common cancer in young men1,2. Here we aimed to identify novel risk factors for TGCT using whole-exome sequencing, which was performed on 328 affected individuals from 153 families, 634 sporadic cases and 1,644 controls. We searched for genes that were recurrently affected by rare variants (minor allele frequency <0.01) with potentially damaging effects and evidence of segregation in families. 8.7% of families carried rare disruptive mutations in the cilia-microtubule genes (CMG) as compared to 0.5% of controls3 (P=2.1x10-8). The most significantly mutated CMG was DNAAF1 with biallelic inactivation and loss of DNAAF1 expression shown in tumors from carriers. DNAAF1 as a cause of TGCT was supported by a DNAAF1Hu255h(+/-) zebrafish model with 94% penetrance for TGCT compared to 14% in wildtype fish. These data implicate cilia-microtubule inactivation as a cause of TGCT development and are the first evidence for CMGs as cancer susceptibility genes.

  Study EGAS00001001789

• Targeted sequencing of head and neck squamous cell carcinomas

  Overall survival remains very poor for patients diagnosed with head and neck squamous cell carcinoma (HNSCC). Identification of additional biomarkers and novel therapeutic strategies are important for improving patient outcome. Patient-derived xenografts (PDXs), generated by implanting fresh tumor tissue directly from patients into immune-deficient mice, recapitulate many of the features of their corresponding clinical cancers, including histopathological and molecular profiles. Using a large collection of PDX models of HNSCC we demonstrate that rapid engraftment into immune-compromised mice is highly prognostic, and show that genomic deregulation of the G1/S checkpoint pathway correlates with engraftment. Furthermore, CCND1 and CDKN2A genomic alterations are predictive of response to the CDK4/6 inhibitor abemaciclib. Overall, our study supports the pursuit of CDK4/6 inhibitors as a therapeutic strategy for a substantial proportion of HNSCC patients, and demonstrates the potential of using PDX models to identify novel targeted therapies for those patients who have the poorest outcomes.

  Study EGAS00001002979

• Human genome-wide variations in the Massim region

  The Massim, a cultural region encompassing the southeastern tip of mainland Papua New Guinea (PNG) and nearby islands, is famous for the Kula trading network, in which different valuables circulate in different directions among the islands. To explore Massim genetic history, we generated genome-wide data from across the region and found variable levels of Papuan-related (indigenous) ancestry, including a novel ancestry associated with Rossel Island, and Austronesian-related ancestry that arrived later. We find genetic evidence for different patterns of contact across PNG, the Massim, and the Bismarck and Solomon Archipelagoes for Austronesian-related vs. Papuan-related ancestry, with more geographic restriction for the latter. Moreover, Kula-practicing groups share more genetic similarity than do other groups, and this likely predates the origin of Kula, suggesting that high between-group contact facilitated the formation of Kula. Our study provides the first comprehensive genome-wide assessment of Massim inhabitants and new insights into the fascinating Kula system.

  Study EGAS00001006010

• INCLUDE: The Epidemiology of Transient Leukemia in Newborns with Down Syndrome

  The INCLUDE (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE) Project is an NIH-wide collaboration that seeks to improve health and quality-of-life for people with Down syndrome. The INCLUDE Project Data Coordinating Center and partners created the INCLUDE Data Hub, a centralized data resource that allows access to large-scale clinical and multi-omics datasets specific to Down syndrome and supports collaborative, cloud-based analysis to accelerate scientific discoveries related to Down syndrome and its co-occurring conditions.Down syndrome (DS) is associated with a remarkably high risk of childhood acute myeloid leukemia (AML), with an approximately 500-fold increased risk of the rare subtype acute megakaryoblastic leukemia. Though largely treatable, a proportion of myeloid leukemia in DS (ML-DS) patients relapse with dismal survival. ML-DS is preceded by a preleukemia, transient abnormal myelopoiesis (TAM), which presents clinically at birth and is driven by somatic truncating mutations in the erythro-megakaryocytic transcription factor gene GATA1. Up to 15% of DS newborns have TAM, and this can be fatal in up to 20% of cases. A further 10-15% of newborns with DS harbor subclonal GATA1 mutations with clinically silent disease (i.e., Silent TAM). Of the DS newborns with either TAM or Silent TAM (i.e., transient leukemia), up to 15% will acquire additional somatic mutations and progress to ML-DS. We predict that germline variation modifies the risk of developing somatic truncating GATA1 mutations, the first step towards ML-DS, however this has yet to be examined. To address this, the main aim of this X01 study is to perform the first genetic association study of GATA1 mutations in DS, through whole-genome sequencing (WGS) of 470 DS newborns in the Oxford Down Syndrome Cohort Study (ODSCS). Targeted sequencing of GATA1 has already been performed in the 470 DS newborns in the ODSCS, with 130 (28%) confirmed to harbor a somatic truncating GATA1 mutation. We will perform a genome-wide association study (GWAS) of GATA1 mutations to assess genetic variation genome-wide, in particular focusing on variants in candidate genes on the trisomic chromosome 21, RUNX1, ERG, ETS2, and DYRK1A, which have previously been associated with upregulation of GATA1. We will also carry out a chromosome X-wide association study (XWAS) to investigate genetic variation at the GATA1 gene, which resides on chromosome X. WGS data will also enable us to assess the potential role of copy number variation in the risk of transient leukemia in DS. Discovering genetic risk factors for GATA1 mutations in DS may reveal targets for new targeted therapies for TAM, and also inform the etiology of ML-DS as well as AML in the non-DS population. Finally, the ODSCS includes rich phenotypic data for the 470 DS newborns, including clinical diagnosis of TAM and other hematologic complications, complete blood counts, maternal pregnancy complications, and information on congenital heart disease and other birth defects. Thus, whole genome sequencing data in DS newborns from the ODSCS will provide a rich resource for the DS research community.

  Study phs002982

• Weighing Risks and Benefits of Laparoscopic Anti-Reflux Surgery in Patients With Idiopathic Pulmonary Fibrosis (WRAP-IPF-BioLINCC)

  Data Access NOTE: Please refer to the "Authorized Access" section below for information about how access to the data from this accession differs from many other dbGaP accessions. Objectives: To determine if the reduction of abnormal gastro-esophageal reflux (GER) with laparoscopic anti-reflux surgery will slow the progression of idiopathic pulmonary fibrosis (IPF) as measured by forced vital capacity (FVC).Background: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease of unknown cause and increasing prevalence in the United States. Aside from lung transplantation, which approximately only 1% of participants will receive, there is no FDA-approved therapy. Abnormal acid gastro-esophageal reflux (GER) has been well described in participants with IPF and is thought to play a role in the progression of the disease. The several retrospective cohort studies that have assessed the association of anti-acid therapies for GER with clinical outcomes in IPF have had inconsistent results.Participants: A total of 58 participants were enrolled.Design: The WRAP-IPF trial was a multicenter, unblinded randomized clinical trial with participants randomized to either laparoscopic anti-reflux surgery or no surgery. Participants in the no-surgery group had the option of receiving laparoscopic anti-reflux surgery from 24 weeks after randomization if their clinician deemed it medically necessary. Medications for acid GER were allowed in both groups if the clinician felt it was necessary.Participants were followed up from time of randomization to 52 weeks. All participants had study visits at baseline, 12, 24, 36, and 48 weeks, during which spirometry, 6-min walk testing, and participant-related outcome assessments were done. Participants in the surgery group had clinical visits for preoperative evaluation, laparoscopic anti-reflux surgery, and postoperative management as clinically indicated. Surgery participants additionally underwent repeat 24-hour pH testing at 24 weeks to assess the efficacy of the surgery. All participants were contacted by telephone for safety assessments at weeks 4, 8, 16, 20, 28, 32, 40, 44, and 52. All participants completed an exploratory questionnaire on reflux symptoms at baseline and 48 weeks. The primary endpoint was change in FVC from randomization (baseline) to 48 weeks. Secondary endpoints included acute exacerbation, non-elective hospitalization (both all-cause and respiratory-related), death, change in cough severity, change in dyspnea severity, change in health-related quality of life, change in 6-min walk distance, and time to selected event-driven composite endpoints of disease progression. Conclusions: In participants with IPF and abnormal acid GER, laparoscopic anti-reflux surgery is safe and well tolerated but did not significantly slow the rate of FVC decline. Further research is needed, particularly with a larger study in order to achieve sufficient statistical power, regarding the possible benefits of anti-reflux surgery in this population.Raghu G, Pellegrini CA, Yow E, et al. Laparoscopic anti-reflux surgery for the treatment of idiopathic pulmonary fibrosis (WRAP-IPF): a multicentre, randomised, controlled phase 2 trial. Reference: Raghu, et al., 2018; PMID: 30100404.

  Study phs003968

• Comparison of the performance of two commercial genome-wide association study genotyping platforms in Han Chinese Samples

  Affymetrix 6.0, Illumina OMNIExpress, and llumina Immunochip genotype data for Han Chinese population including rheumatoid arthritis cases and controls. Data is in PLINK binary format. Illumina genotype clustering was performed using Illumina’s BeadStudio software. SNPs were reclustered using the study samples, low quality subjects were removed, and a subset of clustering results were manually inspected and verified. All SNPs with GenCall scores less than 0.15 were excluded. For Affymetrix chips, clustering was performed using the program Birdseed version 2, as implemented using Affymetrix Genotyper Console v4.0, using the default quality control (QC) thresholds.

  Study EGAS00000000131

• Effects of tobacco smoking on the tumor immune microenvironment in head and neck squamous cell carcinoma

  This study was designed to measure immune cell differences between HNSCC patients according to smoking history. We measured CD3, CD8, FoxP3, PD-1 and PD-L1 for immune markers and Pancytokeratin to distinguish between tumor and surrounding tissue. We observed that current smokers have significantly lower numbers of immune cells surrounding the tumor than former or never smokers. GSEA analysis of RNAseq data from this cohort suggests that smoking is associated with reduced Interferon (IFN) Alpha and Gamma levels, and also with reduced levels of IFN-response cytokines CXCL9, 10 and 11. These results emphasize the hypothetical benefits of smoking cessation during treatment for HNSCC.

  Study phs001994

• NHLBI TOPMed - NHGRI CCDG: Massachusetts General Hospital (MGH) Atrial Fibrillation Study

  The Massachusetts General Hospital (MGH) Atrial Fibrillation Study was initiated in 2001. The study has enrolled serial probands, unaffected and affected family members with atrial fibrillation. At enrollment participants undergo a structured interview to systematically capture their past medical history, AF treatments, and family history. An electrocardiogram is performed; the results of an echocardiogram are obtained; and blood samples are obtained. For the TOPMed WGS project only early-onset atrial fibrillation cases were sequenced. Early-onset atrial fibrillation was defined as an age of onset prior to 66 years of age. Comprehensive phenotypic and pedigree data for study participants are available through dbGaP phs001001.

  Study phs001062

• Whole Exome Characterization of Squamous Cell Lung Cancers (Lung SQCC) from Appalachian Kentucky (APPKY)

  This is a pilot study of squamous cell lung cancer and matched normal tissue pairs collected (convenience sample) from patients from Central Appalachia, in Southeastern Kentucky. This study performed whole exome sequencing on tumor and matched normal DNA samples from 51 lung squamous cell carcinoma (SQCC) subjects from Appalachian Kentucky (AppKY). Somatic genomic alteration profiles were compared between the AppKY and TCGA SQCC cohorts. We found that IDH1 and PCMTD1 had higher mutation rates in AppKY versus TCGA. These findings suggest population differences in the genetics of lung SQCC between AppKY and US populations that have implications for personalized treatment for this disease.

  Study phs001651

• Spatiotemporal Transcriptome of the Human Brain

  Comprehensive knowledge about the spatiotemporal dynamics of the brain transcriptome is essential for a better understanding of neurodevelopment, sexual dimorphism, and evolution, as well as our increased susceptibility to certain brain disorders. We generated and analyzed genome-wide exon-level transcriptome data from 16 brain regions of 57 postmortem human brains, spanning from embryonic development to late adulthood and representing males and females of multiple ethnicities. We also performed genome-wide genotyping of 2.5 million SNPs and assessed genome normality for all donors. This study provides a comprehensive, publicly available dataset on the spatiotemporal human brain transcriptome and new insights into the transcriptional foundations of human neurodevelopment.

  Study phs000406

• Genome-Wide Environment Interaction Study on Neurodevelopment in Children from Mexico and Bangladesh

  Cognitive development is known to be highly heritable, but various genome wide association studies (GWAS) have failed to find common single nucleotide polymorphisms (SNPs) which can explain a large proportion of the variance in cognitive ability. We hypothesized that an interaction between genes and exposure to potentially toxic metals may account for some proportion of this missing heritability. We genotyped 749 infants in Mexico and 636 infants in Bangladesh. Criteria for inclusion into the study are given below. We then performed a Genome Wide Environmental Interaction Study (GWEIS) with neurodevelopment outcomes. There were 552,487 SNPs in common between the two cohorts.

  Study phs000996

• A Phase I/IB Study of Ipilimumab or Nivolumab in Patients With Relapsed Hematologic Malignancies After Allogeneic Hematopoietic Cell Transplantation

  Relapse after allogeneic hematopoietic stem cell transplantation (HSCT) is characterized by poor outcomes and novel therapeutic options are urgently needed. Immune checkpoint blockade using CTLA-4 and PD-1 blocking antibodies are a potential concept for reinstating a dormant graft-versus-leukemia (GvL) effect.This study investigated transcriptomic changes in biopsies obtained from patients who received immune checkpoint blockade for relapsed hematologic malignancy post-HSCT and elucidated transcriptional programs associated with successful reinvigoration of GvL. Differential gene expression analysis showed evidence of increased T cell infiltration in biopsies of responders to ipilimumab treatment and demonstrated shared gene programs between GvL and GvHD.

  Study phs002377

• Genomic analysis of head and neck squamous cell carcinoma upon acquired resistance to cetuximab

  Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (cetuximab) remain the only FDA-approved targeted therapy for patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Unfortunately, most patients develop acquired resistance to cetuximab and there is currently no further therapeutic option for these patients (unmet clinical need), thereby highlighting the need to better understand resistance-causing mechanisms. Here, we carried out whole-exome sequencing on 2 cetuximab-sensitive and -resistant patient-derived xenograft models of HNSCC. Our data reveal several genetic alterations (mutations and copy number variations) associated with acquired resistance to anti-EGFR therapy.

  Study EGAS50000000800

• CLUSTER RNAseq Study of Juvenile Idiopathic Arthritis patients in methotrexate cohort

  CLUSTER aims to discover novel disease mechanisms and biomarkers in children suffering from Juvenile idiopathic arthritis (JIA). Currently, little is known about the pathological disease mechanisms of JIA and there are no validated tools capable of predicting response or non-response to treatment. The study aims to identify biomarkers for treatment response using RNAseq technology. The samples used in this study comes from blood samples that were collected prior to patients receiving methotrexate treatment (naive). These samples were then processed for PBMC isolation followed by sorting cells into 4 different immune cell types. All of these samples were then sequenced by NovaSeq6000.

  Study EGAS50000000995

• CLUSTER Read-counts matrix of RNAseq Datasets of JIA in methotrexate cohort

  CLUSTER aims to discover novel disease mechanisms and biomarkers in children suffering from Juvenile idiopathic arthritis (JIA). Currently, little is known about the pathological disease mechanisms of JIA and there are no validated tools capable of predicting response or non-response to treatment. The study aims to identify biomarkers for treatment response using RNAseq technology. The samples used in this study comes from blood samples that were collected prior to patients receiving methotrexate treatment (naive). These samples were then processed for PBMC isolation followed by sorting cells into 4 different immune cell types. All of these samples were then sequenced by NovaSeq6000.

  Study EGAS50000001501

• The EGA joins EUCAIM, the European project powering AI and imaging in cancer research

  EUCAIM (EUropean Federation for CAncer IMages) is the cornerstone of the European Cancer Imaging Initiative, one of the flagships of the Europe’s Beating Cancer Plan (EBCP). The European Genome-Phenome Archive (EGA), as member of the EUCAIM consortium, attended the kick-off meeting organized this week in Brussels for the launch of the Initiative. The EGA will contribute to the project with the experience gained in the deployment of our federated network, the Federated EGA (FEGA), and the experience gained as partners of EuCanImage (AI4HI initiative) contributing to the definition of common data models, ontologies and data standards. The ultimate goal of the project is to unlock the power of imaging and Artificial Intelligence for the benefit of cancer patients, clinicians and researchers. The consortium will deploy a pan-European digital federated infrastructure hosting cancer-related images, and associated pathology, molecular and laboratory data from Real-World. This endeavour will provide a comprehensive dashboard for imaging data discovery, federated search, metadata harvesting, annotation and distributed data processing. EUCAIM joins 76 partners, gathering the experience and previous effort made by the different repositories of the AI4HI initiative, European Research Infrastructures and national/regional repositories. Find out more information about the EUCAIM launch here

  Blog the-ega-joins-eucaim

• Chracterising_cellur_pathways_underlying_CD3_CD28_activation_of_human_CD4__cells

  We devised an approach to disentangle the TCR and CD28 pathways upon stimulation in naive and memory primary human CD4+ T cells (Tcons) in response to defined stimulatory signals. Sorted Tcons were activated using a titration of anti-CD3 and anti-CD28 in combination as well as individually. As a control we cultured cells in the same conditions but without the stimuli. In total, we defined seven conditions from four individuals for 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/

  Study EGAS00001004147

• 2014_Lung_sq_WES

  Purpose Lung squamous cell carcinoma (SqCC) is the second most prevalent type of lung cancer. Currently, no targeted-therapeutics are approved for treatment of this cancer, largely due to lack of systematic understanding of the molecular parthenogenesis of the disease. To identify therapeutic targets and comparatively analyze them in lung SqCC, we probed somatic alterations of Korean lung SqCC. Patients and Methods We performed massively parallel whole-exome sequencing of 104 Korean lung SqCC patients’ samples with matched normal samples. In addition, copy number analysis and transcriptome analysis were conducted for a subset of these samples. Clinical association with cancer-specific somatic alterations was investigated.

  Study EGAS00001002844

• Deciphering Intratumoral Molecular Heterogeneity in Clear Cell Renal Cell Carcinoma with a Radiogenomics Platform

  Intratumoral heterogeneity (ITH) challenges the molecular characterization of clear cell renal cell Carcinoma (ccRCC) with percutaneous biopsies and is a confounding factor in selection of molecular-targeted versus immune-based therapy. Magnetic Resonance (MR) Imaging can noninvasively assess the spatial landscape of the entire tumor. To validate MRI for ITH assessment, we implemented a radiogenomic platform through a systematic imaging based co-localization approach for multi region tissue acquisition from single tumors. We investigated if the spatial changes in imaging can predict the molecular changes using transcriptome and histopathological correlatives. Our study confirmed imaging heterogeneity as a predictor of molecular heterogeneity in ccRCC.

  Study EGAS00001003846

• Chracterising_cellur_pathways_underlying_CD3_CD28_activation_of_human_CD4__cells

  We devised an approach to disentangle the TCR and CD28 pathways upon stimulation in naive and memory primary human CD4+ T cells (Tcons) in response to defined stimulatory signals. Sorted Tcons were activated using a titration of anti-CD3 and anti-CD28 in combination as well as individually. As a control we cultured cells in the same conditions but without the stimuli. In total, we defined seven conditions from four individuals for 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/

  Study EGAS00001002438

• Detection of Cancer Mutations by Urine Liquid Biopsy in Bladder Cancer Patients

  The management of bladder cancer faces multiple challenges concerning the diagnostics and fol-low-up approaches. The standard diagnostic test is invasive cystoscopy. Urine cytology and re-cently proposed urine-based biomarkers still could not replace cystoscopy, thus prompting calls for improvements. Here, we explore urine liquid biopsy to detect cancer mutations for therapeutic and prognostic assessment and subsequently evaluate the utility of urine as a suitable specimen in diagnosing bladder cancer. Our findings show that the analysis of pre-and post-operative urine enables the characterization of specific tumor mutations, which can be used to diagnose and evaluate a patient’s prognosis and therapy response.

  Study EGAS00001005758

• High Density SNP Association Analysis of Melanoma: Case-Control and Outcomes Investigation

  This research builds upon an extensive resource of melanoma cases and hospital based controls collected over several years at the U.T. M.D. Anderson Cancer Center. The goal of this research is to identify novel susceptibility and outcome-related genes for melanoma using a systematic genome-wide association-based approach. Our goal is to conduct high-density SNP association and outcome studies. This dbGaP study contains samples from 2000 European ancestry cases and 1000 European ancestry controls using the Illumina OMNI1-Quad SNP chip. As a part of an ongoing R01 project, we have epidemiological data together with candidate gene results for 1000 of the melanoma cases and the controls. With regard to the outcome aspect of our design, as part of our melanoma Specialized Program of Research Excellence (SPORE) grant, our MelCore database contains comprehensive, prospectively maintained clinical information from all melanoma patients included in the study cohort, including primary tumor histopathology and staging information, standard and investigational blood tumor markers, details of surgical and systemic therapies, and extensive follow-up information, including time to relapse or recurrence, pattern of recurrence and survival duration. Finally, we intend to collaborate with the GenoMEL collaboration so we can jointly evaluate each other's findings. The goal of our analysis will be to identify novel genetic factors predisposing the development of melanoma, as well as genetic factors controlling melanoma stage at presentation, recurrence and progression. This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org) funded by the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to melanoma through large-scale genome-wide association studies of 2000 European ancestry cases and 1000 European ancestry controls. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington.

  Study phs000187

• The National Myelodysplastic Syndromes (MDS) Study

  Myelodysplastic syndromes (MDS) are the most common cause of adult bone marrow failure in the US and occur predominantly in people over the age of 60. Much of the morbidity and mortality for MDS is due to complications from low blood counts (e.g., infections and bleeding). MDS is caused by acquired DNA mutations that occur in a patient's blood cells as they grow older. Accumulating evidence suggests that MDS patients may traverse through a series of antecedent hematopoietic conditions defined by, i) clonal hematopoiesis (i.e., detectable somatic mutations in a person's blood cells) without low blood counts, a condition that affects up to 10% of individuals 70 years old and is termed Clonal Hematopoiesis of Indeterminate Potential (CHIP), or ii) clonal hematopoiesis with low blood counts (i.e., cytopenias) but no evidence of bone marrow dysplasia, termed Clonal Cytopenia of Undetermined Significance (CCUS). Nearly all CCUS patients will develop MDS over a ten year period, highlighting the prognostic importance of this disease. A better understanding of the genetic mutations, including non-coding and structural variants (SVs), occurring in CCUS and MDS could provide valuable insight into the natural history of MDS development. The NHLBI is conducting a longitudinal, observational study to create a standardized clinical dataset linked to a prospectively collected, consistently processed, and well-characterized biospecimen repository derived from approximately 1750 participants with suspected or newly diagnosed MDS or MDS/myeloproliferative neoplasm (MPN) overlap. These volunteers will donate biological specimens (like bone marrow and blood) and medical information, including details of their symptoms, how they perceive their quality of life, the treatments they receive, and what their doctor says about the severity of their illness over time. This information will be collected at pre-determined time points for the duration of the study. Study participants may be followed for life.

  Study phs002714

• Microbiome-Host Interactions in Oral Squamous Cell Carcinoma: a Metatranscriptomic Exploratory Study

  Oral cancer (predominantly squamous cell carcinoma; OSCC) is the 14th most prevalent malignancy worldwide, accounting for more than 300,000 new cases and 145,000 deaths annually. Despite advances in cancer treatment modalities, OSCC continues to have poor prognosis with 5-year survival rates less than 50%. Although use of tobacco and alcohol consumption constitute the major risk factors, there is emerging evidence for the role of the microbiome in OSCC. However, studies on the association between the microbiome and OSCC has so far focused on compositional analysis and has been largely limited to the bacterial component of the microbiome. The aim of this study is to characterize the transcriptional activity (function) as well as composition of the multi-kingdom microbiome associated with OSCC and correlate it with the gene expression of the host using ultra-deep metatranscriptome sequencing, which will provide new insight into the role of the microbiome in OSCC and the possible mechanisms by which the tumor’s microbial community may influence on its behavior. This project comprises RNA-Seq data from twenty OSCC tumor/normal tissue pairs and twenty tongue scraping samples from healthy controls. However, due to consent constraints, the human sequences from the control data are filtered out.

  Study phs002678

• InTEAM Consortium - Alcoholic Hepatitis

  Alcoholic hepatitis (AH) is a life-threatening condition characterized by profound hepatocellular dysfunction for which targeted treatments are urgently needed. Identification of molecular drivers is hampered by the lack of suitable animal models. By performing RNA sequencing in livers from patients with different phenotypes of alcohol-related liver disease (ALD), we describe the transcriptional programs involved in disease progression. We uncovered that development of AH is characterized by the defective activity of liver-enriched transcription factors (LETFs). The PPARG predicted activation state was found increased in early forms of ALD, while AH was associated by a marked decrease in HNF4A-dependent gene expression along with a marked expression of the fetal HNF4A isoform (P2). TGFB1, a key upstream transcriptome regulator in AH, induced the use of HNF4a P2 promoter in hepatocytes, which resulted in abnormal bile acid synthesis and defective metabolic and synthetic functions. PPARG agonists partially prevented this effect. We conclude that targeting TGFB1 and epigenetic drivers that modulate HNF4A-dependent gene expression could be beneficial to improve hepatocellular function in patients with AH. The study was conducted thanks to a multicenter collaboration under the National Institute of Alcohol Abuse and Alcoholism (NIAAA)-funded consortium: Integrated Approaches for Identifying Molecular Targets in Alcoholic Hepatitis (InTEAM).

  Study phs001807

• Examination of Engineered LINE-1 Integration Events in HeLa Cells

  Long Interspsesed Element-1 (LINE1 or L1) encodes two proteins (ORF1p and ORF2p) required for its mobilization (i.e. retrotransposition) in the human genome. Human ORF2p, a 150kDa protein, has endonuclease (EN) and reverse transcriptase (RT) activities. L1 EN is classified as apurinic/apyrimidin-like endonuclease (APE) and is responsible for initiating target-site primer reverse transcription (TPRT) during the L1 retrotransposition cycle. During canonical TPRT, the L1 EN activity makes a single-strand endonucleolytic nick at a double-strand DNA target sequence in genomic DNA. The endonucleolytic nick is typically made at an L1 EN degnerate consensus cleavage sequence (5'-TTTT/A-3') exposing a free 3' hydroxy group that can be used as a primer by the ORF2p L1 RT activity to reverse transcribe the associated L1 RNA. Here, we characterized over 21,000 de novo engineered L1 retrotransposition events in HeLa cells to determine if L1 exhibits overt integration preferences in the human genome. Bru-seq of HeLa cells to determine actively transcribed regions of the genome was also performed. This Bru-seq data was used to determine if engineered L1 integration events preferentially integrate into transcribed regions of the genome, and to determine which strand during transcription may present itself as preferential during L1 retrotransposition.

  Study phs001669

• Diverse_outcomes_of_controlled_human_malaria_infection_originate_from_host_intrinsic_immune_variation_and_not_var_gene_switching

  Falciparum malaria is clinically heterogeneous and the relative contribution of parasite and host factors in shaping disease severity remains unclear. We set out to explore the interaction between host inflammation and parasite variant surface antigen (VSA) expression, asking whether this relationship underpins the variation observed in controlled human malaria infection. We uncovered marked heterogeneity in the response of naive hosts to blood challenge with some volunteers maintaining a state of immune quiescence, others triggering interferon-stimulated inflammation and a small group showing transcriptional evidence of myeloid cell suppression. Significantly, only inflammatory volunteers experienced hallmark symptoms of clinical malaria. When we then tracked temporal changes in parasite VSA expression to ask whether variants associated with severe disease preferentially expand in naive hosts (as predicted by current theory) we found that var gene profiles were essentially unchanged after 10-days of blood-stage infection. These data therefore show that the diverse clinical outcomes of CHMI largely originate from host-intrinsic variation and there is no evidence for switching or selection of var genes in naïve hosts. 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 EGAS00001003766

• Heart Failure Network - Xanthine Oxidase Inhibition for Hyperuricemic Heart Failure Patients (HFN EXACT-BioLINCC)

  ObjectivesTo determine the effect of allopurinol after 24 weeks on a composite clinical endpoint that classifies subject's clinical status (improved, worsened, unchanged) in patients with heart failure and high uric acid levels.BackgroundMorbidity and mortality rates for patients with heart failure are high, despite guideline-recommended therapy. Heart failure is characterized by an imbalance between left ventricular (LV) performance and myocardial energy consumption. There is a growing body of evidence that suggests oxidative stress contributes to ventricular and vascular remodeling, and disease progression in heart failure. Targeting potential source(s) of oxidative stress, e.g. Xanthine oxidase (XO), was the focus of recent clinical trials and epidemiological studies. Increased XO activity has been shown to lead to production of superoxide and uric acid (UA). Serum uric acid levels are included in heart failure risk scores, and hyperuricemia is present in about 25% of patients with heart failure. Hyperuricemia is associated with exercise intolerance, reduced survival, and worsening symptoms. The EXACT-HF trial tested allopurinol, an inhibitor of XO, as a potential target therapy for hyperuricemic heart failure patients.Subjects253 subjects were enrolled in the EXACT-HF study. 128 participants were randomized to the allopurinol arm, and of those participants, 119 completed the trial and 9 did not. 125 participants were randomized to the placebo arm, and of those participants, 116 completed the trial and 9 did not.DesignEXACT-HF was a multi-center, double-blind, placebo controlled, 24-week trial of allopurinol. Eligible participants had to be receiving a stable regimen for at least two weeks (3 months for beta-blockers) prior to randomization. Participants were randomized by an automated system to either the allopurinol or placebo arm, and started treatment within 12 hours of completing the baseline visit. During the first week, participants in both treatment arms received 300mg daily of the respective medications. For the following 23 weeks, participants in both treatment arms received 600mg daily of the respective medications. Patients unable to tolerate 600 mg were maintained on 300 mg.The primary endpoint was a composite clinical endpoint (CCE) that classified a subject's clinical status as improved, worsened, or unchanged at 24 weeks. The CCE was determined based on the following: death; hospitalization, emergency room visit or emergent clinic visit for worsening HF; medication change for worsening HF; and Patient Global Assessment using a 7-point scale. Secondary endpoints at 12 and 24 weeks included changes in quality of life as assessed by the Kansas City Cardiomyopathy Questionnaire, and submaximal exercise capacity as assessed by a 6-minute walk test.ConclusionsParticipants who received allopurinol had significantly less serum uric acid laboratory levels after 24 weeks; however, no significant difference was observed in the primary and secondary endpoints between the allopurinol and placebo-treated patients. Therefore, in high-risk HF patients with reduced ejection fraction and elevated uric acid levels, xanthine oxidase inhibition with allopurinol failed to improve clinical status, exercise capacity, quality of life, or LVEF at 24 weeks (Circulation. 2015 May 19; 131(20):1763-71).

  Study phs003533

• Adipose tissue macrophage dysfunction is associated with a breach of vascular integrity in NASH

  Our study describes for the first time the myeloid cell landscape in human visceral adipose tissue at single-cell level within a cohort of well-characterized patients with non-alcoholic fatty liver disease.

  Study EGAS50000000424

• SIGi001-A-13 / SAMEA104386250 WGS data

  The iPSC line SIGi001-A-13 / SAMEA104386250 has undergone whole genome sequencing. Whole genome sequencing was done using Illumina HiSeq X Five platform with a reference genome of GRCh38. Raw data as FASTQ files and analysed data as CRAM files are available for this sample, in this dataset. The iPSC line SIGi001-A-13 is available for research use at www.EBiSC.org.

  Dataset EGAD50000001031

• BIONi010-C-8 / SAMEA4454011 WGS data

  The iPSC line BIONi010-C-8 / SAMEA4454011 has undergone whole genome sequencing. Whole genome sequencing was done using Illumina HiSeq X Five platform with a reference genome of GRCh38. Raw data as FASTQ files and analysed data as CRAM files are available for this sample, in this dataset. The iPSC line BIONi010-C-8 is available for research use at www.EBiSC.org.

  Dataset EGAD50000001028

• BIONi010-C-3 / SAMEA4342740 WGS data

  The iPSC line BIONi010-C-3 / SAMEA4342740 has undergone whole genome sequencing. Whole genome sequencing was done using Illumina HiSeq X Five platform with a reference genome of GRCh38. Raw data as FASTQ files and analysed data as CRAM files are available for this sample, in this dataset. The iPSC line BIONi010-C-3 is available for research use at www.EBiSC.org.

  Dataset EGAD50000001034

• BIONi010-C-7 / SAMEA4454010 WGS data

  The iPSC line BIONi010-C-7 / SAMEA4454010 has undergone whole genome sequencing. Whole genome sequencing was done using Illumina HiSeq X Five platform with a reference genome of GRCh38. Raw data as FASTQ files and analysed data as CRAM files are available for this sample, in this dataset. The iPSC line BIONi010-C-7 is available for research use at www.EBiSC.org.

  Dataset EGAD50000001035

• BIONi010-C-6 / SAMEA4454009 WGS data

  The iPSC line BIONi010-C-6 / SAMEA4454009 has undergone whole genome sequencing. Whole genome sequencing was done using Illumina HiSeq X Five platform with a reference genome of GRCh38. Raw data as FASTQ files and analysed data as CRAM files are available for this sample, in this dataset. The iPSC line BIONi010-C-6 is available for research use at www.EBiSC.org.

  Dataset EGAD50000001037

• BIONi010-C-9 / SAMEA4454012 WGS data

  The iPSC line BIONi010-C-9 / SAMEA4454012 has undergone whole genome sequencing. Whole genome sequencing was done using Illumina HiSeq X Five platform with a reference genome of GRCh38. Raw data as FASTQ files and analysed data as CRAM files are available for this sample, in this dataset. The iPSC line BIONi010-C-9 is available for research use at www.EBiSC.org.

  Dataset EGAD50000001040

• SIGi001-A-3 / SAMEA4448571 WGS data

  The iPSC line SIGi001-A-3 / SAMEA4448571 has undergone whole genome sequencing. Whole genome sequencing was done using Illumina HiSeq X Five platform with a reference genome of GRCh38. Raw data as FASTQ files and analysed data as CRAM files are available for this sample, in this dataset. The iPSC line SIGi001-A-3 is available for research use at www.EBiSC.org.

  Dataset EGAD50000001041

• BIONi010-C-4 / SAMEA4452060 WGS data

  The iPSC line BIONi010-C-4 / SAMEA4452060 has undergone whole genome sequencing. Whole genome sequencing was done using Illumina HiSeq X Five platform with a reference genome of GRCh38. Raw data as FASTQ files and analysed data as CRAM files are available for this sample, in this dataset. The iPSC line BIONi010-C-4 is available for research use at www.EBiSC.org.

  Dataset EGAD50000001043

• EDi014-A / SAMEA4459369 WGS data

  The iPSC line EDi014-A / SAMEA4459369 has undergone whole genome sequencing. Whole genome sequencing was done using Illumina HiSeq X Five platform with a reference genome of GRCh38. Raw data as FASTQ files and analysed data as CRAM files are available for this sample, in this dataset. The iPSC line EDi014-A is available for research use at www.EBiSC.org.

  Dataset EGAD50000001051

• EDi014-B / SAMEA4459371 WGS data

  The iPSC line EDi014-B / SAMEA4459371 has undergone whole genome sequencing. Whole genome sequencing was done using Illumina HiSeq X Five platform with a reference genome of GRCh38. Raw data as FASTQ files and analysed data as CRAM files are available for this sample, in this dataset. The iPSC line EDi014-B is available for research use at www.EBiSC.org.

  Dataset EGAD50000001053

• SIGi001-A-7 / SAMEA4448730 WGS data

  The iPSC line SIGi001-A-7 / SAMEA4448730 has undergone whole genome sequencing. Whole genome sequencing was done using Illumina HiSeq X Five platform with a reference genome of GRCh38. Raw data as FASTQ files and analysed data as CRAM files are available for this sample, in this dataset. The iPSC line SIGi001-A-7 is available for research use at www.EBiSC.org.

  Dataset EGAD50000001060

• BIONi010-C-5 / SAMEA4452061 WGS data

  The iPSC line BIONi010-C-5 / SAMEA4452061 has undergone whole genome sequencing. Whole genome sequencing was done using Illumina HiSeq X Five platform with a reference genome of GRCh38. Raw data as FASTQ files and analysed data as CRAM files are available for this sample, in this dataset. The iPSC line BIONi010-C-5 is available for research use at www.EBiSC.org.

  Dataset EGAD50000001062

• BIONi010-C-2 / SAMEA4342705 WGS data

  The iPSC line BIONi010-C-2 / SAMEA4342705 has undergone whole genome sequencing. Whole genome sequencing was done using Illumina HiSeq X Five platform with a reference genome of GRCh38. Raw data as FASTQ files and analysed data as CRAM files are available for this sample, in this dataset. The iPSC line BIONi010-C-2 is available for research use at www.EBiSC.org.

  Dataset EGAD50000001068

• SIGi001-A-1 / SAMEA4451096 WGS data

  The iPSC line SIGi001-A-1 / SAMEA4451096 has undergone whole genome sequencing. Whole genome sequencing was done using Illumina HiSeq X Five platform with a reference genome of GRCh38. Raw data as FASTQ files and analysed data as CRAM files are available for this sample, in this dataset. The iPSC line SIGi001-A-1 is available for research use at www.EBiSC.org.

  Dataset EGAD50000001073

• SIGi001-A-10 / SAMEA4451117 WGS data

  The iPSC line SIGi001-A-10 / SAMEA4451117 has undergone whole genome sequencing. Whole genome sequencing was done using Illumina HiSeq X Five platform with a reference genome of GRCh38. Raw data as FASTQ files and analysed data as CRAM files are available for this sample, in this dataset. The iPSC line SIGi001-A-10 is available for research use at www.EBiSC.org.

  Dataset EGAD50000001074

• SIGi001-A-11 / SAMEA4451118 WGS data

  The iPSC line SIGi001-A-11 / SAMEA4451118 has undergone whole genome sequencing. Whole genome sequencing was done using Illumina HiSeq X Five platform with a reference genome of GRCh38. Raw data as FASTQ files and analysed data as CRAM files are available for this sample, in this dataset. The iPSC line SIGi001-A-11 is available for research use at www.EBiSC.org.

  Dataset EGAD50000001075

• SIGi001-A-12 / SAMEA104237570 WGS data

  The iPSC line SIGi001-A-12 / SAMEA104237570 has undergone whole genome sequencing. Whole genome sequencing was done using Illumina HiSeq X Five platform with a reference genome of GRCh38. Raw data as FASTQ files and analysed data as CRAM files are available for this sample, in this dataset. The iPSC line SIGi001-A-12 is available for research use at www.EBiSC.org.

  Dataset EGAD50000001076

• SIGi001-A-2 / SAMEA4451116 WGS data

  The iPSC line SIGi001-A-2 / SAMEA4451116 has undergone whole genome sequencing. Whole genome sequencing was done using Illumina HiSeq X Five platform with a reference genome of GRCh38. Raw data as FASTQ files and analysed data as CRAM files are available for this sample, in this dataset. The iPSC line SIGi001-A-2 is available for research use at www.EBiSC.org.

  Dataset EGAD50000001077

• SIGi001-A-6 / SAMEA4447426 WGS data

  The iPSC line SIGi001-A-6 / SAMEA4447426 has undergone whole genome sequencing. Whole genome sequencing was done using Illumina HiSeq X Five platform with a reference genome of GRCh38. Raw data as FASTQ files and analysed data as CRAM files are available for this sample, in this dataset. The iPSC line SIGi001-A-6 is available for research use at www.EBiSC.org.

  Dataset EGAD50000001078

• SIGi001-A-4 / SAMEA4448632 WGS data

  The iPSC line SIGi001-A-4 / SAMEA4448632 has undergone whole genome sequencing. Whole genome sequencing was done using Illumina HiSeq X Five platform with a reference genome of GRCh38. Raw data as FASTQ files and analysed data as CRAM files are available for this sample, in this dataset. The iPSC line SIGi001-A-4 is available for research use at www.EBiSC.org.

  Dataset EGAD50000001088

• SIGi001-A-5 / SAMEA4448708 WGS data

  The iPSC line SIGi001-A-5 / SAMEA4448708 has undergone whole genome sequencing. Whole genome sequencing was done using Illumina HiSeq X Five platform with a reference genome of GRCh38. Raw data as FASTQ files and analysed data as CRAM files are available for this sample, in this dataset. The iPSC line SIGi001-A-5 is available for research use at www.EBiSC.org.

  Dataset EGAD50000001092

• SIGi001-A-8 / SAMEA4448777 WGS data

  The iPSC line SIGi001-A-8 / SAMEA4448777 has undergone whole genome sequencing. Whole genome sequencing was done using Illumina HiSeq X Five platform with a reference genome of GRCh38. Raw data as FASTQ files and analysed data as CRAM files are available for this sample, in this dataset. The iPSC line SIGi001-A-8 is available for research use at www.EBiSC.org.

  Dataset EGAD50000001093

• SIGi001-A-9 / SAMEA4447499 WGS data

  The iPSC line SIGi001-A-9 / SAMEA4447499 has undergone whole genome sequencing. Whole genome sequencing was done using Illumina HiSeq X Five platform with a reference genome of GRCh38. Raw data as FASTQ files and analysed data as CRAM files are available for this sample, in this dataset. The iPSC line SIGi001-A-9 is available for research use at www.EBiSC.org.

  Dataset EGAD50000001095

• Illumina short-reads and 10X Genomics linked-reads sequencing data for MCF7 and a primary breast tumor sample

  This dataset contains whole genome sequencing data from Illumina short-reads sequencing (2X150bp) and 10X Genomics linked-reads sequencing. Both the sequencing technologies were used to sequence MCF7 cell line and a primary breast triple-negative cancer sample. The fastq of paired-end reads for both the samples sequenced with both the technologies is available.

  Dataset EGAD00001005724

• Whole Genome Sequencing of INTERVAL (2019-06-12)

  15x Whole Genome Sequencing of 15,000 individuals from the INTERVAL study cohort, phase III. 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 2019-06-12.

  Dataset EGAD00001005086

• Genetic screening of GPI-anchor protein synthesis

  This study will analyse the guide sequence which were used for making mutations in the Cas9-expressing cells. We used GeCKO v2 library which were released by Feng Zhang, 2014. 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 EGAD00001001928

• Australia and New Guinea haplotype phasing (2017-06-27)

  Whole-genome sequencing and phasing of admixed Aboriginal Australian genomes and Papua New Guinean genomes using 10x Genomics Chromium technology. 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 please see http://www.sanger.ac.uk/datasharing/ This dataset contains all the data available for this study on 2017-06-27.

  Dataset EGAD00001003407

• Isotype-resolved sequencing of B-cell receptor in health and disease (2017-09-13)

  Sequencing of B-cell receptor repertoires in healthy individuals and patients with chronic lymphocytic leukemia. 1) 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 please see http://www.sanger.ac.uk/datasharing/ This dataset contains all the data available for this study on 2017-09-13.

  Dataset EGAD00001003748

• Spatially resolved cellular and molecular drivers of cardiac remodelling in healthy and failing human hearts: Adult RNA (2025-07-31)

  Cell Atlas of the diseased human heart. 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 2025-07-31.

  Dataset EGAD00001015668

• Germline and Somatic Genetic Landscape of Pediatric Rhabdomyosarcoma

  Dynamic approaches that integrate population-based research and molecular biology are needed to explain the mechanisms underlying pediatric rhabdomyosarcoma (RMS) and to determine novel prevention strategies. RMS, the most common soft-tissue sarcoma in children and adolescents, has one of the poorest 5-year survival rates among all pediatric cancers (less than 65%). One of the strongest risk factors for RMS is having a cancer predisposition syndrome. The syndromes that are most commonly seen among those with RMS are Li-Fraumeni, neurofibromatosis type 1, Costello, Noonan, and DICER1. Based on smaller clinic-based studies, only about 7% of RMS cases are thought to be associated with the genes responsible for these syndromes. However, there have been no population-based assessments to support this estimate. Even in the most recent large-scale evaluations of germline mutations in predisposition genes among children with cancer, very few RMS cases were included (43 cases). Furthermore, no distinctions were made between the major histologic subtypes of RMS: embryonal (eRMS) and alveolar (aRMS), which display differences in terms of age distribution, incidence, and cytogenetics. For instance, nearly 80% of alveolar cases are driven by a chromosomal translocation between either PAX3 or PAX7 and FOXO1, whereas these fusions are not seen in embryonal cases. In fact, RMS research is shifting from categorization based on histology to fusion status (eRMS is overwhelmingly fusion-negative). Another limitation in previous studies has been the inability to evaluate the frequency of de novo germline mutations (DNMs) in cancer predisposition genes due to the absence of any well-characterized cohorts of RMS case-parent trios. Therefore, a major gap in our understanding of the role of cancer predisposition in pediatric RMS that limit translational impact is there have been no population-based assessments to determine the true impact of these mutations on pediatric RMS, which limits clinical sequencing guidelines and surveillance protocols in these children.Overall Project Strategy: The objective of this project is to advance our understanding of the relationship between cancer predisposition genes and pediatric RMS. Our central hypotheses are: 1) mutations in cancer predisposition genes are more common than expected in children with RMS; and 2) children with fusion-negative tumors have a higher burden of germline mutations than those with fusion-positive tumors. The framework for this study relies on >600 well annotated samples collected from newly diagnosed RMS patients and stored in the Children’s Oncology Group (COG) Biopathology Center.

  Study phs002304

• De Novo Mutation Rates at the Single-Mutation Resolution in the Human Genome

  We developed a method to measure the origination rates of target mutations of choice and applied it to the HbS and nearby mutations in the human beta-globin (HBB) gene, as well as to the equivalent mutations in the nearly identical delta-globin (HBD) gene in sperm cells from African and European donors. Specifically, after extracting DNA from the sperm of the donors, each sample is enriched for the HbS mutation and nearby mutations by the restriction enzyme Bsu36I, which cleaves the wild-type (WT) sequence CCTGAGG at positions 16–22 of HBB and the homologous positions of HBD while leaving the HbS mutant and other mutants in these positions intact. Next, unique barcodes are attached to the DNA fragments from these Bsu36I-treated samples in order to reduce error by consensus sequencing of copies originating from the same original fragment. To determine how many target WT sequences have been removed (scanned) by Bsu36I digestion and hence to be able to calculate the de novo mutation rate, we run a second reaction in parallel for each donor. This reaction involves the same steps as the former reaction except for digestion by Bsu36I (Bsu36I-untreated). Spiking into the Bsu36I-treated and untreated samples known amounts of mock HBB-like DNA molecules that are fully resistant to Bsu36I digestion allows to calculate in the sequence analysis stage the Bsu36I-enrichment score based on the change in their frequency between the two treatments, which in turn is used to calculate the number of scanned WT sequences. Our results show significant correspondence between de novo mutation rates and past observations of alleles in carriers, showing that mutation rates vary substantially in a mutation-specific manner that contributes to the site frequency spectrum. We also found that the overall point mutation rate is significantly higher in Africans than Europeans in the HBB region studied. Finally, the rate of the 20A>T mutation, called the “HbS mutation” when it appears in HBB, is significantly higher than expected from the genome-wide average for this mutation type. Nine instances were observed in the African HBB ROI, where it is of adaptive significance, representing at least three independent originations, and no instances were observed in the European HBB ROI or in the European or African HBD ROI.12 consented subjects; samples from two subjects were pooled

  Study phs002391

• Transdisciplinary Studies of Genetic Variation in Colorectal Cancer(CORECT): Meta-analysis

  This study is part 2 of 2 for Schumacher et al, Nat Communication. 2015 Jul 7;6:7138. Part 2 is the pooled meta-analysis of 29 different studies of 37,955 European (18,299 Cases/19,656 Controls) participants using eight different genotyping platforms/variations. table, th, td { border: 1px solid black; border-collapse: collapse; } Study Name Participants Platform CFR-1 2976 Illumina 1M, 1M Duo, Omni1 CFR-2 3053 Affymetrix Axiom MECC 1 982 Illumina Omni 2.5 MECC2 1940 Affymetrix Axiom Kentucky 2172 Affymetrix Axiom ACS/CAPII 1086 Affymetrix Axiom Melbourne 1008 Affymetrix Axiom Newfoundland 672 Affymetrix Axiom ASTERKSI 1895 Illumina 300K COLO23 212 Illumina 300K DACHS1 3417 Illumina 300K DACHS2 1173 Illumina OmniExpress DALS1 1416 Illumina 550k/610K DALS2 874 Illumina 300K HPFS1 457 Illumina OmniExpress HPFS2 348 Illumina OmniExpress HPFS AA 658 Illumina OmniExpress MEC 674 Illumina 300K NHS1 1168 Illumina OmniExpress NHS2 340 Illumina OmniExpress NHSAA 1091 Illumina OmniExpress OFCCR 1172 Affymetrix 100k/500K PHS 771 Illumina OmniExpress PMH 402 Illumina 300K PLCO1 2509 Illumina 550k/610K PLCO2 901 Illumina 300K VITAL 573 Illumina 300K WHI1 1999 Illumina 550k/610K WHI2 573 Illumina 300K Since this study is a meta-analysis no corresponding phenotype, pedigree, sample, subjects, or primary molecular data are available. Each contributing study/platform will have fulfilled its own DBGAP submission commitment. This DBGAP entry is for European participants in the the pooled meta-analysis exclusively.

  Study phs001499

• Targeted Linked-Read DNA-seq Analysis of Castration-Resistant Prostate Cancers

  Androgen receptor (AR) inhibition is standard of care for advanced prostate cancer (PC). However, its efficacy is limited by progression to castration-resistant PC (CRPC), usually due to AR re-activation via mechanisms that include AR amplification and structural rearrangement. These two classes of AR alterations often co-occur in CRPC tumors, but it is unclear whether this reflects intercellular or intracellular heterogeneity of AR. It is important to resolve the mechanisms of AR genomic rearrangements to develop new therapies and predictive biomarkers for PC. We developed a targeted linked-read DNA sequencing assay to interrogate alterations in AR and a panel of genes known to be amplified or mutated in CRPC. Linked-read DNA-sequencing libraries were generated using the 10X Genomics Chromium platform and subjected to hybridization enrichment using a custom-designed Agilent SureSelect bait panel. Post-capture DNA-seq libraries were pooled and sequenced on an Illumina HiSeq 2500 using 2x150 bp settings. This targeted linked-read DNA-seq assay was used to interrogate a set of 6 benchmarking samples harboring known AR gene rearrangements and other alterations in AR, as well a panel of 6 patient-derived xenograft CRPC tumors and 23 clinical CRPC tumors. In this cohort, we identified a subset of samples that developed complex, multiply-rearranged AR gene structures in conjunction with very high AR copy number. The data that will be made available through dbGaP are raw FASTQ files.

  Study phs003343

• Conserved features of TERT promoter duplications reveal an activation mechanism that mimics hotspot mutations in cancer

  Mutations in the TERT promoter are the single most common non-coding mutation in cancer and represent the genetic underpinnings of tumor cell immortality. Beyond the two most common point mutations, G228A and G250A, which selectively recruit the ETS factor GABP to activate TERT, the significance of other variants in the TERT promoter are unknown. We identified duplications of wildtype sequence within the core promoter region of TERT in 7 different cancer types that have strikingly similar features including size, insertion position, and inclusion of one of the native ETS motifs. Each duplication activates the TERT promoter to a similar level as G228A and G250A and is critically dependent on the insertion site. The GABP tetramer binds to the TERT duplicated promoter sequence by virtue of the native ETS motif and its duplicated version with precise spacing, and it is necessary for the transcriptional activation by all duplications tested. Spatiotemporal analysis in a multifocal glioblastoma shows the duplication is clonal and its activation of TERT is readily detectable at the single cell level and in bulk tumor tissue. We conclude that recurrent TERT promoter duplications of the native ETS sequence are functionally and mechanistically equivalent to the hotspot mutations that confer tumor cell immortality. The shared mechanism of these divergent somatic genetic alterations suggests a strong selective pressure for recruitment of the GABP tetramer to activate TERT.

  Study EGAS00001006118