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• ChIP sequencing for β-catenin and histone modifications in HCC cell lines and organoids with CTNNB1 mutations

  CTNNB1 mutation is a major driver of HCC, particularly in metabolic-associated subtype. This study utilized patient-derived tumour organoids and cell lines harbouring various endogenous CTNNB1 mutations to comprehensively map the transcriptional repertoire regulated by mutant β-catenin through ChIP-seq under normal and fatty conditions. Genome-wide binding patterns of β-catenin were integrated with ChIP-seq data for histone modifications H3K27ac and H3K27me3 to assess active and repressive chromatin states. Oleic acid treatment was used to model fatty conditions.

  Study EGAS50000001274

• Res1_H23_exp2_MC_13_07_22

  8 samples are cell pellets for genomic DNA extraction. CRISPR PCR1 and PCR2 indexing - Please use standard Kosuke primers.

  Study EGAS00001006683

• Whole_Exome_Sequencing_for_Characterization_of_Disease_Causing_Mutations_in_two_Pakistani_Families_Suffering_from_Autosomal_Recessive_Ocular_Disorders_

  We propose to use whole exome Agilent solutionprobes and paired end Illumina sequencing to sequence 4 individualsfrom two families suffering from novel autosomal recessive disease[microphthalmia, MOP (OMIM %251600) and non-syndromic persistenthyperplastic primary vitreous, PHPV (OMIM %611311)]. Selectedcandidate variants will subsequently be genotyped in the remainingfamily members in Pakistan with the aim of identifying the rarehomozygous recessive mutations responsible for the disease phenotype. 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 EGAS00001000026

• NHLBI TOPMed: Diabetes Heart Study (DHS) African American Coronary Artery Calcification (AA CAC)

  The Diabetes Heart Study (DHS) is a family-based study enriched for type 2 diabetes (T2D). The cohort included 1443 European American and African American participants from 564 families with multiple cases of type 2 diabetes (Bowden et al., 2010. Review of Diabetic Studies 7:188-201. PMID: 21409311). The cohort was recruited between 1998 and 2006. Participants were extensively phenotyped for measures of subclinical CVD and other known CVD risk factors. Primary outcomes were quantified burden of vascular calcified plaque in the coronary artery, carotid artery, and abdominal aorta all determined from non-contrast computed tomography scans.

  Study phs001412

• Extracorporeal Life Support Survival in a Pediatric Hematopoietic Cellular Transplant Recipient with Presumed Graft Versus Host Disease-Related Fulminant Myocarditis

  We report the case of a 15-year-old female with hypodiploid pre-B acute lymphoblastic leukemia status post allogeneic hematopoietic stem cell transplantation (HCT) from a matched unrelated male donor who presented on transplant day +75 with cardiac arrest due to ventricular fibrillation associated with fulminant myocarditis. Using conventional diagnostics, an exhaustive search for microbial pathogens in the heart biopsy as well as nasopharynx, blood, urine, and endotracheal aspirate was performed but did not uncover a candidate pathogen. The family consented to a research study for the use of unbiased next-generation genomic sequencing for pathogen identification in the myocardial biopsy. DNA sequencing was performed on 1.5 x 108 sequencing pairs and no microbial pathogens were identified. Interestingly, a significant component of Y-chromosomal human DNA was identified, suggesting infiltration of at least 10 donor leukocytes per host cell. This finding is grossly consistent with the lymphocyte:myocyte ratio in the biopsy according to visual inspection at 40x magnification. This case merits discussion due to (1) her survival after 17 days of veno-arterial extracorporeal life support (ECLS) and (2) the possibility of cardiotropic graft versus host disease (GVHD).

  Study phs001336

• SDR-seq_06_BCL

  SDR-seq_BCL data access. Two follicular lymphoma (FL) primary patient samples and one germinal center subtype diffuse large B-cell lymphoma (GCB) primary patient sample. FL1 and GCB1 are sequenced in Run1. FL2 is sequenced in Run2.

  Dataset EGAD50000000551

• Copy number profiles detected by shallow coverage WGS

  We performed shallow coverage whole genome sequencing on 147 glioma samples and analyzed their copy number profile. The coverage of each sample is about 2. Data are presented as VCF files which describe the copy number segments and their log2 ratio.

  Dataset EGAD00001005062

• The Cancer Dependency Map (DepMap)

  The Cancer Dependency Map (DepMap) aims to accelerate precision cancer medicine by creating a comprehensive map of tumor vulnerabilities. The DepMap project genomically profiles a wide range of cancer models and characterizes them for their sensitivity to genetic and compound perturbations. The data is computationally analyzed to create a systematic overview of the genetic dependencies and compound sensitivities of cancer types and the predictive biomarkers that point to patient populations most likely to benefit from targeting of these vulnerabilities. The DepMap public portal has become a comprehensive resource to identify cancer vulnerabilities by providing datasets at scale, cutting-edge computational tools, and sophisticated visualization tools that together have accelerated the discovery of novel targets and biomarkers. Please visit Depmap.org to access the public portal.

  Study phs003444

• Fragmentomic features of individuals with different cfDNA concentrations

  The goal of this study is to explore fragmentomic patterns that vary between individuals of different concentrations of total cell-free DNA in plasma. We have selected a large cohort of individuals (ethnically Chinese men with a median age of 54 years, IQR 49-57) who were part of a screening of a large-scale clinical study to screen for nasopharyngeal carcinoma. Differences in fragmentomic features provided insights into the modulation of cfDNA levels in blood circulation. Fragmentomic and machine learning systems adopted in this study have also been applied to assess the quantity of cfDNA species of clinical interest, including the fraction of circulating fetal and tumor DNA, from pregnancy cases and individuals with hepatocellular carcinoma, respectively.

  Study EGAS50000000692

• Assessment of de novo copy number variations in Italian patients with schizophrenia.

  We investigated de novo CNVs in the whole genomic DNA of schizophrenia patients and their parents and, specifically, in putative enhancer motifs.Study participants were part of a wider multicenter study, involving an Italian cohort of schizophrenia patients recruited by members of INRP - Italian Network for Research on Psychoses.Whole genomic DNA obtained from 46 family trios of schizophrenia probands was analyzed using the Enhancer Chip, a customized array CGH developed using the Agilent SurePrint G3 8X60K format, which is able to investigate the whole genome with a 300Kb resolution, specific disease loci at a tenfold higher resolution, and that was highly enriched in probes in more than 1.250 enhancer elements selected from the Vista Enhancer Browser (PLoS One. 2012;7(12):e52264).

  Study EGAS00001002159

• Prediction of homologous recombination deficiency identifies colorectal tumors sensitive to PARP inhibition

  BRCAness is a well-established feature in breast, ovarian, prostate and pancreatic carcinomas, our recent findings indicate that up to 15% of colorectal cancers (CRC) also harbor defects in the HR pathway, presenting promising opportunities for innovative therapeutic strategies in CRC patients. We developed a new tool called HRDirect, which builds upon the HRDetect algorithm and is able to predict HRD from reference-free tumor samples. We validated HRDirect using matched breast cancer and CRC patient samples. Subsequently, we assessed its efficacy in predicting response to the PARP inhibitor olaparib by comparing it with two other commercial assays: AmoyDx HRD by Amoy Diagnostics and the TruSight Oncology (TSO) _500 HRD panel by Illumina NGS technology. While all three approaches successfully identified the most PARPi-sensitive CRC models, HRDirect demonstrated superior precision in distinguishing resistant models compared to AmoyDX and TSO500-HRD, which exhibited overlapping scores between sensitive and resistant cells. Furthermore, we propose integrating HRDirect scoring with ATM immunohistochemical analysis as part of our "composite biomarker approach" to enhance the identification of HRD tumors, with an immediate translational and clinical impact for CRC personalized treatment.

  Study EGAS50000000426

• Heterogeneity of IKZF1 genomic alterations and risk of relapse in childhood B-cell precursor acute lymphoblastic leukemia

  Purpose Genomic alterations of IKZF1 are common and associated with adverse clinical features in B-ALL, but the relationship between the type of IKZF1 alteration, disease subtype and outcome are incompletely understood. Patients and Methods We used transcriptome and genomic sequencing, and SNP microarray data to determine leukemia subtype and genomic alterations for 688 pediatric patients with B-ALL enrolled into St. Jude Total Therapy 15 and 16 studies. Results IKZF1 alterations were identified in 115 (16.7%) patients, commonly in BCR::ABL1 (78%) and CRLF2-rearranged, BCR::ABL1-like B-ALL (70%), and were associated with five-year cumulative incidence of relapse (CIR) of 14.8 ± 3.3% compared to 5.0 ± 0.9% for patients without any IKZF1 alteration (P < 0.0001). IKZF1 deletions of exon 4-7 (P = 0.0002), genomic IKZF1plus with any IKZF1 deletion (P = 0.006) or with focal IKZF1 deletion (P = 0.0007), and unfavorable genomic subtypes (P < 0.005) were independently adversely prognostic. Patients with both IKZF1 exon 4-7 deletion and unfavorable genomic subtype had a significantly increased risk of relapse (HR = 58.3; 95% CI, 11.9 – 285.4, P < 0.0001) whereas IKZF1 sequence mutations were not independently predictive of outcome. Conclusions Genomic IKZF1plus with any IKZF1 deletion, IKZF1 deletion of exon 4-7, and unfavorable subtype confer increased risk of relapse. The combination of unfavorable genomic subtype and IKZF1 deletion of exon 4-7 identified patients at greatest risk of relapse despite MRD-directed therapy. The type of IKZF1 alteration together with subtype are informative for risk stratification and predict response in patients with B-ALL.

  Study EGAS50000000106

• Heterogeneity and evolution of DNA mutation rates in microsatellite stable colorectal cancer. Higher mutation rates (MR) in metastatic tumours

  Building on the observation that MR appears to be a unique and inheritable feature of each cancer cell, we explored whether MR is subject to selective pressure during cancer progression. These data suggest that a higher MR is selected during CRC metastatic progression.

  Study EGAS50000000147

• Microvascular Permeability, Inflammation, and Lesion Physiology in Endometriosis: A Microphysiological Systems Approach

  The goal of the study is to identify novel molecular pathways involved in the etiology of endometriosis and to develop in vitro model systems to enable the study of the mechanisms regulating reproductive function. Using a physiomimetic modeling approach, primary tissue samples of the human endometrium derived from patients diagnosed with and without endometriosis and/or endometriotic diseases (e.g. adenomyosis) were used for secondary analysis using multi-omic systems biology analysis and to build tissue engineered models. We performed single cell RNA sequencing (scRNA-Seq, N=6)) to study the cellular and transcriptomic composition of the endometrial tissue microenvironment and proteomics (LC-MS/MS) to study protein-level signaling pathways and the matrisome of the native endometrium. Systems biology analysis of these datasets helped identified a putative dysregulated inflammatory signaling pathway in endometriosis patients compared to controls. Moreover, subsets from these scRNA-Seq and proteomic datasets were used to aid the design of a synthetic extracellular matrix hydrogel as an in vitro platform for the culture of endometrial cells. Tissue-engineered synthetic PEG hydrogel enables the simultaneous co-culture of endometrial epithelial organoids and stromal fibroblasts in a fully defined, 3D, and tunable environment. We demonstrated that the in vitro co-culture model recapitulates key phenotypic processes observed across the human menstrual cycle in response to sex hormone stimulation through both biochemical and transcriptomic (bulk RNA-sequencing) analysis. This model will enable future mechanistic studies that examine origins of endometriotic disease phenotypes. The transcriptomic data generated for this study including the scRNA-Seq data from primary human endometrial tissues and the bulk RNA-Seq datasets from the experimental co-culture models is available through dbGAP.

  Study phs003326

• A sequence-based genetic dissection of human immune cell types and implications for immune-related disease.

  The immune system is an intricate biological network mediating interactions with other organisms while preserving the integrity of our tissues. By mounting appropriate responses it protects us from a vast range of pathogens while inadvertent immune system attacks on self result in autoimmune diseases. The project aims to discover whether and to what extent the behaviour of the immune system is genetically regulated and to detect the relationships of diverse immune cells with autoimmunity. The project consists of the genetic analysis using up to ~8.2 Million variants, deriving from high density genotyping data and low pass whole genome sequencing, and quantitative levels of 95 cell types encompassing 272 immune traits, in a cohort of 1,629 individuals from four clustered Sardinian villages belonging to the SardiNIA/ProgeNIA study.

  Study EGAS00001000574

• Genome‐wide postnatal changes in immunity following fetal inflammatory response

  The fetal inflammatory response (FIR) increases the risk of perinatal brain injury, particularly in extremely low gestational age newborns (ELGANs, &lt; 28 weeks of gestation). One of the mechanisms contributing to such a risk is a postnatal intermittent or sustained systemic inflammation (ISSI) following FIR. The link between prenatal and postnatal systemic inflammation is supported by the presence of well‐established inflammatory biomarkers in the umbilical cord and peripheral blood. However, the extent of molecular changes contributing to this association is unknown. Using RNA sequencing and mass spectrometry proteomics, we profiled the transcriptome and proteome of archived neonatal dried blood spot (DBS) specimens from 21 ELGANs. Comparing FIR‐affected and unaffected ELGANs, we identified 782 gene and 27 protein expression changes of 50% magnitude or more, and an experiment‐wide significance level below 5% false discovery rate. These expression changes confirm the robust postnatal activation of the innate immune system in FIR‐affected ELGANs and reveal for the first time an impairment of their adaptive immunity. In turn, the altered pathways provide clues about the molecular mechanisms triggering ISSI after FIR, and the onset of perinatal brain injury.

  Study EGAS00001003635

• Evolution of an adenomacarcinoma in response to selection by targeted kinase inhibitors

  Background - Adenocarcinomas of the tongue are rare and represent the minority (20-25%) of salivary gland tumors affecting the tongue. We investigated the utility of massively parallel sequencing to characterize an adenocarcinoma of the tongue, before and after treatment. Results - In the pre-treatment tumor we identified 7,629 genes within regions of copy number gain. 1,078 genes exhibited increased expression relative to the blood and unrelated tumors and four genes contained somatic protein-coding mutations. Our analysis suggested the tumor cells were driven by the RET oncogene. Genes whose protein products are targeted by the RET inhibitors sunitinib and sorafenib correlated with being amplified and or highly expressed. Consistent with our observations administration of sunitinib was associated with stable disease lasting 4 months, after which the lung lesions began to grow. Administration of sorafenib and sulindac provided disease stabilization for an additional 3 months after which the cancer progressed and new lesions appeared. A recurring metastasis possessed 7,288 genes within copy number amplicons, 385 genes exhibiting increased expression relative to other tumours and 9 new somatic protein coding mutations. The observed mutations and amplif ications were consistent with therapeutic resistance arising through activation of the MAPK and AKT pathways. Conclusions - We conclude that complete genomic characterization of a rare tumour has the potential to aid in clinical decision making and identifying therapeutic approaches where no established treatment protocols exist. These results also provide direct in-vivo genomic evidence for mutational evolution within a tumor under drug selection and potential mechanisms of drug resistance accrual.

  Study EGAS00000000074

• Circulating Tumor DNA Analysis in ERBB2-Amplified Colorectal Cancer: Biomarker Analysis of the MyPathway Trial

  Combination of two HER2-directed antibodies, pertuzumab and trastuzumab (P+T), has antitumor activity in HER2-positive colorectal cancer (CRC). Although liquid biopsies are increasingly being used in clinical oncology, the association between tumor and circulating tumor DNA (ctDNA) ERBB2 status and ctDNA monitoring for early response and resistance are unknown. Eighty-five patients with ERBB2-amplified and/or overexpressed CRC were treated with P+T in the MyPathway trial; 42 had ctDNA testing at Cycle 1 Day 1 (C1D1), and 38 had longitudinal plasma tested for ctDNA. We analyzed the ctDNA vs tissue ERBB2 concordance, genomic co-alterations, and ctDNA dynamics and association with response. Forty-one (98%) of 42 patients had genomic alterations detected in ctDNA at C1D1, and 29 (69%) had ERBB2 amplification in ctDNA. There was a strong correlation between ERBB2 copy number on next-generation sequencing in tissue and C1D1 ERBB2 ctDNA copy number. Thirty-seven percent achieved a molecular response by C3D1 on P+T, which was associated with prolonged progression-free survival and overall survival (OS). CDKN2A and KRAS mutations were associated with shorter OS, and a trend was seen with PIK3CA mutations. Several emerging co-alterations were identified in ctDNA at progression, including in the MAPK and PI3K pathways and other tyrosine receptor kinases. ctDNA can detect ERBB2 amplification in many, but not all, patients with ERBB2 amplification detected in tumor samples. ctDNA molecular response was associated with better survival, and ctDNA co-alterations may offer insights into mechanisms of intrinsic and acquired resistance.

  Study EGAS50000000916

• Diagnostic Exome Sequencing in Persons with Severe Intellectual Disability

  Intellectual disability is a common condition that carries lifelong severe medical and developmental consequences. The causes of intellectual disability (ID) remain unknown for the majority of patients due to the extensive clinical and genetic heterogeneity of this disorder. De novo mutations may play an important role in ID as most individuals with ID present as isolated cases without family history and/or clear syndromic indication. In addition, the involvement of such mutations have recently been demonstrated in a small number of individuals with ID. Here we evaluate the diagnostic potential and role of de novo mutations in a cohort of 100 patients with ID of unknown cause using family-based exome sequencing.

  Study EGAS00001000287

• Guardians_of_the_genome__protecting_DNA_from_endogenous_sources_of_damage_

  Analysis of mutational signatures caused by DNA repair defects in human induced pluripotent stem (iPS) cells. A reference human iPS cell line will be used for genetic manipulation to introduce homozygous knockouts of 100 genes known to be involved in or connected to DNA repair or DNA editing. Following a defined period of growth after homozygous knockout of each gene, sub clones will be generated and sequenced. The progenitor “parental” IPS cell line will be used to generate reference sequence data, in order to determine the mutational signature acquired due to the gene knockout. This is a pilot study to investigate the effects of oxygen conditions and growth period on mutations acquired

  Study EGAS00001000874

• PCA Atlas Visium spatial transcriptomics data (FASTQs, spaceranger BAMs and Visium mapping tables)

  This dataset contains Visium spatial transcriptomics data for the PCA Atlas study EGAS00001008332. It includes: - Raw Visium FASTQ runs (EGAR00004172272–EGAR00004172283) for all libraries. - spaceranger alignment BAM analyses for those libraries where BAM output was generated. - visium.csv: a slide-level mapping table linking Visium slide samples to EGA sample accessions, sequencing runs/experiments and spaceranger BAM analyses. - visium_tma.csv: a TMA mapping table describing how mini-TMA slides relate slide-level Visium libraries to tissue-level samples/cores. Together these objects provide the raw and aligned Visium data and the technical/biological mappings needed to understand and reuse the spatial transcriptomics component of the PCA Atlas. High resolution histology images are available from the following Zenodo repository, along with additional spaceranger outs for each slide: - https://zenodo.org/records/17411292

  Dataset EGAD00001015796

• TDP43 proteinopathy leads to divergent cryptic splicing in the cortex and spinal cord

  Mislocalization of the nuclear TAR DNA-binding protein 43 (TDP43) is a hallmark of ALS and FTD which leads to de-repression and inclusion of cryptic exons, promising biomarkers of TDP43 pathology in a spectrum of neurodegenerative diseases. However, most cryptic exons to date have been identified from in vitro models or a single cortical FTD dataset, and little is known about cryptic splicing in the spinal cord, or within different neuronal subtypes. We meta-analyzed published bulk RNAseq datasets representing 1,778 RNAseq profiles of ALS and FTD post-mortem tissue, and in vitro models with experimentally depleted TDP43. We identified 142 cryptic splices, including 76 novel events. We found a novel pattern of spinal cord cryptic splicing, validated in an independent cohort by qPCR, which differed significantly from cortical and in vitro splicing. Finally, leveraging multiple public single-nucleus RNAseq datasets of ALS and FTD motor and frontal cortex, we confirmed the elevation of cortical-enriched splices in disease and localized them to layer-specific neuronal populations. This catalog of cryptic splices could inform efforts to develop biomarkers for tissue-specific and cell type-specific TDP43 pathology.

  Study EGAS50000000575

• Next Generation Mendelian Genetics: Muscle Hypertrophy

  The NHGRI Next Generation Mendelian Genetics project uses exome resequencing to identify variants in unsolved Mendelian diseases. Samples were collected from a single, multi-generational family with the same phenotype of exaggerated muscular development (muscular hypertrophy) and strength characterized by reduced fat pad thickness under the skin. All family members deny "body building" activities, and are so far negative for known gene mutation that have been identified as associated with excessive muscle development. All family members have examples of demonstrating extraordinary strength occurring both in childhood and old age. No negative associated phenotype traits with the muscle hypertrophy phenotype have been identified.

  Study phs000541

• Mechanism of Decitabine response in MDS/AML patients

  Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) with complex or monosomy karyotype show high prevalence of TP53 mutations (TP53m), poor response to induction chemotherapy and adverse outcome. These diseases may respond to decitabine but the mechanisms are presently unclear. This study investigates MDS/AML patients who were treated with decitabine for 10 days in a Phase II clinical trial. Serial samples were collected from patients before and at completion of decitabine treatment, morphologic remission and relapse. The samples were interrogated using single-cell transcriptomics to investigate potential interactions between leukemic and immune populations."

  Study EGAS50000000924

• RNAseq profile of monomorphic epitheliotropic intestinal T-cell lymphoma and enteropathy associated T-cell lymphoma

  Background : Enteropathy-associated T-cell lymphoma (EATL) and monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) are aggressive malignancies with limited treatment options and poor prognosis. Our research on MEITL has uncovered its genetic portrait including hallmark SEDT2 mutations, expanded its pathological spectrum, and identified molecular biomarkers influencing patients’ outcome. In this study, we aimed to establish and clarify the similar and diverging features of EATL. Methods : A large combined cohort of patients with EATL (n=30) and MEITL (n=52) was assembled and tumor samples were used for whole-exome and RNA sequencing profiling.

  Study EGAS50000001125

• Whole Exome Sequencing of monomorphic epitheliotropic intestinal T-cell lymphoma and enteropathy associated T-cell lymphoma

  Background : Enteropathy-associated T-cell lymphoma (EATL) and monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) are aggressive malignancies with limited treatment options and poor prognosis. Our research on MEITL has uncovered its genetic portrait including hallmark SEDT2 mutations, expanded its pathological spectrum, and identified molecular biomarkers influencing patients’ outcome. In this study, we aimed to establish and clarify the similar and diverging features of EATL. Methods : A large combined cohort of patients with EATL (n=30) and MEITL (n=52) was assembled and tumor samples were used for whole-exome and RNA sequencing profiling.

  Study EGAS50000001126

• Understanding_hematopoietic_stem_cell_mobilization_and_engraftment_

  This study looks at patients undergoing gene therapy for genetic blood and immune disorders, in particular sickle cell disease. From each patient, single blood HSPC colonies are grown from patient blood mononuclear cells, bone marrow mononuclear cells, or CD34+ at multiple time points: pre gene transduction, post-transduction, and post-infusion (at several time points). Whole-genome sequencing will be performed on DNA from these colonies and somatically-acquired mutations will be called. Using these mutations, a phylogeny of these cells can be inferred and further inferences can be made about the gene therapy transduction and engraftment steps.

  Study EGAS00001004620

• RNA004 Nanopore DRS of peripheral blood

  Direct RNA Sequencing offers the capability of standard transcriptomic analyses + RNA modification analysis, which holds promising applications for future clinical workflows. To this end, we tested the newly available RNA004 kit from ONT on human peripheral blood and provide orthogonal GLORI and IVT measurement for benchmarking of m6A-detection. The samples are from peripheral blood of a healthy control, taken at three different timepoints.

  Dataset EGAD50000001710

• IL-10 signalling and macrophage gene expression (2019-08-28)

  Study to stimulate WT and IL-10RB mutant macrophages with LPS in presence or absence of recombinant IL-10 and compare their gene expression profiles by RNASeq These data are part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/ . This dataset contains all the data available for this study on 2019-08-28.

  Dataset EGAD00001005300

• Merged analysis-ready bam files: HiSeq sequencing of matched tumour/normal DNA samples from Pancreatic Ductal Adenocarcinoma cases

  Additional sequencing data for 173 donors in EGAS00001000154, a study of Pancreatic Ductal Adenocarcinoma. WGS libraries were used for high-cellularity cases, WXS sequencing to high depth on low-cellularity cases. HiSeq 2xxx platform was used in all cases. The analysis files associated with this dataset are merged, de-duplicated bams aligned against GRCh37, one tumour and one normal bam per donor.

  Dataset EGAD00001002192

• Cross-site Concordance Evaluation of Tumor DNA and RNA Sequencing Platforms of CIMAC-CIDC Network

  The Cancer Immune Monitoring and Analysis Centers (CIMACs) and the Cancer Immunologic Data Commons (CIDC)&nbsp; has engaged in efforts to harmonize Whole-exome (WES) and RNA-sequencing (RNA-seq) data from three different experimental platforms (MD Anderson, NCI MoCha lab, and Broad Institute) and are using a series of developed pipelines to process the early trial samples. To evaluate the consistency of tumor WES and RNA-seq profiling platforms across different centers, the CIMACs-CIDC conducted a systematic harmonization study. DNA and RNA were centrally extracted from fresh frozen (FF) and formalin-fixed paraffin-embedded (FFPE) non-small cell lung carcinoma (NSCLC) tumors and distributed to three centers for WES and RNA-seq profiling

  Study phs002295

• Genome Asia 100K Project

  The underrepresentation of non-European individuals in human genetic studies so far has limited the diversity of individuals in genomic datasets and led to reduced medical relevance for a large proportion of the world’s population. Population-specific reference genome datasets as well as genome-wide association studies in diverse populations are needed to address this issue. Here we describe the pilot phase of the GenomeAsia 100K Project. This includes a whole-genome sequencing reference dataset from 1,739 individuals of 219 population groups and 64 countries across Asia. We catalogue genetic variation, population structure, disease associations and founder effects. We also explore the use of this dataset in imputation, to facilitate genetic studies in populations across Asia and worldwide.

  Study EGAS00001002921

• IBD Whole Genome Sequencing (2019-08-14)

  Whole genome sequences at 15X depth of patients with Inflammatory Bowel Disease. 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 2019-08-14.

  Dataset EGAD00001005254

• Validation of AML Mutational Screening

  We recently worked-up a pulldown protocol for studying 21 genes recurrently mutated in AML (Study1770). Our manuscript is currently under revision and to address the reviewers' comments we need to validate some mutations by re-sequencing. In this add-on study we will be using PCR followed by MiSeq for this purpose.

  Dataset EGAD00001000445

• Isotype-resolved sequencing of B cell receptor in measles virus infection (2017-09-13)

  Isotype-resolved sequencing of B cell receptor in measles virus infection 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 EGAD00001003749

• Genome-wide Rare Variant Score Associates With Morphological Subtypes of Autism Spectrum Disorder

  Defining different genetic subtypes of Autism Spectrum Disorder (ASD) can help predict developmental outcomes. Based on minor physical and major congenital anomalies, we categorized 325 Canadian children with ASD into dysmorphic and non-dysmorphic subgroupings. We developed a method to calculate a genome-wide rare variant score (GRVS) from whole-genome sequencing (WGS) data for each ASD proband. GRVS is a sum of the number of variants in morphology-associated coding and non-coding regions, weighted by their effect sizes. Probands with dysmorphic ASD had a significantly higher GRVS compared to those with non-dysmorphic ASD (P= 0.027). Using the polygenic transmission disequilibrium test, we observed an over-transmission of ASD-associated common variants in non-dysmorphic ASD probands (P= 2.9×10-3). We replicated our findings using 442 ASD probands that had accompanying morphology data in the Simons Simplex Collection. Our findings provide support for an alternative genomic classification of ASD subgroups using morphology data, which may inform intervention protocols.

  Study EGAS00001005753

• Defined Lifestyle and Germline Factors Predispose Asian Populations to Gastric Cancer

  Gastric cancer (GC) is one of the leading causes of cancer mortality throughout the world, with the highest incidence in east-Asia. Although the somatic genetics of GC has extensively been characterized by recent advances in cancer genome sequencing, the germline and environmental effects on GC and their ethnic differences have poorly been understood. Here, we performed genomic scale trans-ethnic analysis of 531 GC cases (319 Asian and 212 non-Asians), by integrating east-Asian and public GC datasets. There is one distinct GC subclass with clear alcohol-associated mutation signature and strong Asian specificity, and almost all the cases in the subclass are attributable to alcohol intake behavior, smoking habit, and Asian-specific ALDH2 defective allele. Alcohol-related GCs have low mutation burden and a characteristic immune profile of increased B-cell infiltration into the tumor area in relation to cancer cell-intrinsic CXCL13 chemokine expression. In addition to germline variants of genes involved in BRCA pathways, we found frequent (7.4%) germline CDH1 variants among Japanese GCs. Most of them were attributed to a few recurrent SNVs shared by both Japanese and Koreans, suggesting the existence of common ancestral events and widespread distributions of these pathogenic variants among east-Asian populations. Specifically, approximately one-fifth of diffuse-type GCs were attributable to the combination of alcohol intake and defective-ALDH2 allele or to germline CDH1 variants. These results revealed uncharacterized impacts of germline variants and their interplays with lifestyles in the high incidence areas.

  Study JGAS000229

• Defined Lifestyle and Germline Factors Predispose Asian Populations to Gastric Cancer

  Gastric cancer (GC) is one of the leading causes of cancer mortality throughout the world, with the highest incidence in east-Asia. Although the somatic genetics of GC has extensively been characterized by recent advances in cancer genome sequencing, the germline and environmental effects on GC and their ethnic differences have poorly been understood. Here, we performed genomic scale trans-ethnic analysis of 531 GC cases (319 Asian and 212 non-Asians), by integrating east-Asian and public GC datasets. There is one distinct GC subclass with clear alcohol-associated mutation signature and strong Asian specificity, and almost all the cases in the subclass are attributable to alcohol intake behavior, smoking habit, and Asian-specific ALDH2 defective allele. Alcohol-related GCs have low mutation burden and a characteristic immune profile of increased B-cell infiltration into the tumor area in relation to cancer cell-intrinsic CXCL13 chemokine expression. In addition to germline variants of genes involved in BRCA pathways, we found frequent (7.4%) germline CDH1 variants among Japanese GCs. Most of them were attributed to a few recurrent SNVs shared by both Japanese and Koreans, suggesting the existence of common ancestral events and widespread distributions of these pathogenic variants among east-Asian populations. Specifically, approximately one-fifth of diffuse-type GCs were attributable to the combination of alcohol intake and defective-ALDH2 allele or to germline CDH1 variants. These results revealed uncharacterized impacts of germline variants and their interplays with lifestyles in the high incidence areas.

  Study JGAS000228

• Effect of ETS2 modulation on chromatin accessibility and enhancer activity in inflammatory (TPP) macrophages

  This dataset consists of H3K27ac ChIP-seq and ATAC-seq in primary human macrophages following modulation of ETS2 expression. There are three datasets: H3K27ac ChIP-seq in ETS2-edited and unedited inflammatory (TPP) macrophages, H3K27ac ChIP-seq in ETS2-overexpressing and control M0 macrophages, and ATAC-seq in ETS2-edited and unedited inflammatory macrophages. For editing experiments, monocytes were transfected with CRISPR-Cas9 ribonucleoproteins containing a gRNA that was validated to edit ETS2, or a non-targeting control gRNA. Inflammatory macrophage differentiation was performed using conditions that model chronic inflammation (TPP): 3 days GM-CSF (50ng/mL) followed by 3 days GM-CSF, TNFa (50ng/mL), PGE2 (1mg/mL), and Pam3CSK4 (1mg/mL). For overexpression experiments, controlled overexpression of ETS2 mRNA or control mRNA (an equivalent amount of mRNA encoding the reverse complement of ETS2 – thereby controlling for the quantity, length and purine/pyrimidine composition of the transfected RNA but with a transcript that would not be translated) was induced in resting, non-activated (M0) macrophages by transfecting 500ng mRNA. To minimise non-specific activation due to the transfected RNA, in vitro transcription was performed using co-transcriptional capping (to minimise uncapped products), and incorporating modified, minimally immunogenic nucleotides (replacing uridine with N1-methyl-pseudouridine and cytidine with methylcytidine). After 18 hours, transfected cells were were activated with low dose LPS and harvested 6 hours later. For H3K27ac ChIP-seq, cells were harvested, cross-linked, quenched, lysed, and sheared. Immunoprecipitation of histone-DNA complexes was performed overnight at 4C with rotation using an anti-H3K27ac antibody and the SimpleChIP Plus Sonication ChIP kit (Cell Signaling Technology). Following reverse cross-linking, 50ng of immunoprecipitated DNA or input DNA were used to prepare sequencing libraries using the iDeal Library Preparation kit (Diagenode), according to manufacturer instructions. 10 PCR cycles were used for the amplification step and size selection was not performed. The quality and molarity of all libraries was assessed using a BioAnalyzer 2100 (Agilent) and the libraries were sequenced on an Illumina NovaSeq 6000. Raw data are provided as raw and aligned sequencing reads from H3K27ac-bound DNA and the input chromatin. ATAC-seq in TPP macrophages was performed using the Omni-ATAC protocol (Corces et al 2017) with the following modifications: cell number was increased to 75,000 cells, cell lysis time was increased to 5 minutes; volume of Tn5 transposase in the transposition mixture was doubled; duration of the transposition step was extended to 40 minutes. Sequencing libraries were prepared by PCR with the NEBNext Ultra II Q5Master Mix (NEB) as described previously (Corces et al 2017). Amplified libraries were cleaned using AMPure XP beads (Beckman Coulter). Sequencing reads were trimmed using TrimGalore! (Phred score 24), filtered to remove reads < 20 bp and aligned to the human genome (hg19) using Burrows-Wheeler Aligner (BWA). Aligned reads were converted to BAM files, sorted and indexed using SAMtools (Li et al, 2009). PCR duplicates and unmapped reads were removed, and the resulting BAM files were re-sorted and indexed. Raw data are provided as 100 bp paired-end Illumina reads from n = 3 donors for each experiment. BAM files are also provided.

  Study EGAS50000000109

• Genome-wide Association Study of Myasthenia Gravis

  The purpose of this project was to conduct a genome-wide associate study to search for the genetic factors that predispose to myasthenia gravis. The rationale for this study lies in the fact that, although the immunological and physiological processes affecting the neuromuscular junctions of myasthenia gravis patients are well understood, the spectrum of genetic factors that predispose to myasthenia gravis and influence its disease manifestations are not well known. Identification of the myasthenia gravis-related genes will shed light on the fundamental cellular events underlying myasthenia gravis, and will provide focus for research aimed at developing therapies that alter the natural course of the disease. A consortium of fourteen institutions in North America collected DNA samples from 1028 people diagnosed with autoimmune myasthenia gravis. Relevant clinical data have been collected for each patient, including age of onset, severity of disease, response to drug therapy, personal and family history of other autoimmune diseases. Genotyping of the case cohort was performed in the Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD. Genotyping of the case cohort was performed using the HumanOmniExpress-12v1_C SNP array manufactured by Illumina Inc. For the control cohort, we downloaded genotype data from dbGAP (accession phs000196.v2.p1) for 1,998 US neurologically normal individuals. The control cohort had been previously genotyped at the Center for Inherited Disease Research at Johns Hopkins University on HumanOmni1-Quad version 1.0B beadchips (Illumina) as part of the NeuroGenetics Research Consortium GWAS of Parkinson&#39;s disease. Analyses were confined to the 677,673 autosomal SNPs that were common to both chips. Of the 1028 samples which were genotyped, 21 samples were excluded due to mismatched genders, 9 were excluded due to low genotype call rate, 5 samples were excluded as duplicates, and 25 samples were excluded as ethnic outliers. The remaining 972 samples were used in analysis.

  Study phs000726

• 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&#39;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

• Coverage bias and sensitivity of variant calling for four whole-genome sequencing technologies

  Massively parallel sequencing has revolutionized research in cancer genetics and genomics and enhanced our understanding of natural human genetic variation. Recently, Lam et al. have performed a detailed comparison of two next-generation sequencing technologies with respect to their sensitivity to call single nucleotide variants (SNV) and indels. Here, we sequenced two tumor/normal pairs obtained from two paedriatic medulloblastoma patients with Life Technologies’ SOLiD 4 and 5500xl SOLiD, Illumina’s HiSeq2000, and Complete Genomics’ technology. We then compared their ability to call SNVs with high confidence. As gold standard for SNV calling, we used genotypes determined by an Affymetrix SNP array. Additionally, we performed a detailed analysis of how evenly each technology covers the genome and how the reads are distributed across functional genomic regions. Finally, we studied how a combination of data from different technologies might help to overcome the limitations in SNV calling by any of the four technologies alone.

  Study EGAS00001000274

• Korea Epigenome Project(KEP), Korea National Research Institute of Health(KNIH)

  The KEP was launched in 2012 to produce 50 epigenomic sets on Korean chronic diseases related target cells with the participation on Internationsl Human Epigenome Consortium(IHEC) of which focus is constructing 1000 reference epigenome map on 250 human cell type. The objective of the KEP was to provide a comprehensive epigenomic map of Korean chronic disease-related target tissues. Single cells were isolated from the pancreas, fat and kidney. Islet, ductal, acinar, and beta cells from the pancreas were purified into a single homogenous cell type using flow-assisted cell sorting technique. Adipocytes and pre-adipocytes were purified from fat, using Percoll gradient centrifugation technique. Mesangial, distal tubule, proximal tubule, podocytes, and collecting duct cells from the kidney were collected using mechanical sieving and immunostaining methods. Each cell type was derived from normal tissue or those with diabetes, obesity, or chronic kidney disease. Sixty reference epigenome datasets of pancreatic, fat, kidney cells were produced. Cell types such as the islets, and beta from the pancreas, adipocytes, pre-adipocytes from fat tissue, podocyte, mesangial, tubules from kidney were used for primary target to produce a Korean metabolic reference epigenome. And the bisulfite converted-whole genome sequencing, Infinium 450k DNA methylation bead array, mRNA, miRNA-Sequencing were performed to produce a comprehensive epigenomic map. The aim of roadmap reports is preparation of Long-term and Mid-term Technology Roadmaps for Korean Human Epigenome Project towards a competitive execution of International Epigenome Project and successful expansion of the research outcomes. Roadmap reports reviewed on recent technological development of DNA methylation and histone modification analysis, emerging new trends in epigenome medicine, plans for hardware and software analysis systems aimed to epigenome analysis, medical expert opinion on target cells and isolation scheme, bioinformatics expert opinion on analytical tools, new ideas for a putative epigenome studies, trends in single cell epigenome analysis. In conclusion, roadmap report suggested several projects for the future KNIH epigenome research in collaboration with epigenome research group. These are including refocusing the goals of KNIH-driven research in identification of disease mechanism, development of new studies on GWAS-EWA, higher priority on the epigenomic studies of human primary cells, establishment of collaborative relationship with tissue banking centers, establishment of mapping centers and data analysis portals, establishment of Korean Epigenome Research Consortium, establishment of steering committee governing both research and funding, launching of additional funding for epigenomic researches.

  Study EGAS00001001774

• Error-corrected flow-based sequencing at whole genome scale and its application to circulating cell-free DNA profiling

  Differentiating sequencing errors from true variants is a central genomics challenge calling for error suppression strategies that balance costs when sparse material or ultra-rare variants require high-accuracy methods. For example, circulating cell-free DNA (ccfDNA) sequencing for cancer monitoring is limited by sparsity of circulating tumor DNA (ctDNA), abundance of genomic material in samples, library preparation error rates and sequencing errors. Whole-genome sequencing (WGS) can overcome the low abundance of ccfDNA by integrating signal across the mutation landscape, but higher cost limits adoption compared with targeted panels, where ccfDNA abundance limits maximal coverage depths. Here we applied deep (~120x) lower-cost WGS (Ultima Genomics) with analytic error correction for tumor-informed ctDNA detection within the part-per-million range. We further developed high-coverage duplex error-corrected WGS of ccfDNA, achieving 7.7x10-8 error rates, to assess disease burden in melanoma and urothelial cancer patients without matched tumor sequencing. Together, we show that deeply sequenced error-corrected WGS accurately calls somatic variants, demonstrating the feasibility of WGS for tumor-informed and tumor-agnostic ctDNA detection.

  Study EGAS50000000844

• Custom long non-coding RNA capture enhances detection sensitivity in different human sample types.

  Long non-coding RNAs (lncRNAs) are a heterogeneous group of transcripts that lack protein coding potential and display regulatory functions in various cellular processes. As a result of their cell- and cancer-specific expression patterns, lncRNAs have emerged as potential diagnostic and therapeutic targets. The accurate characterization of lncRNAs in bulk transcriptome data remains challenging due to their low abundance compared to protein coding genes. To tackle this issue, we describe a unique short-read custom lncRNA capture sequencing approach that relies on a comprehensive set of 565,878 capture probes for 49,372 human lncRNA genes. This custom lncRNA capture approach was evaluated on various sample types ranging from artificial high-quality RNA mixtures to more challenging formalin-fixed paraffin-embedded tissue and biofluid material. The custom enrichment approach allows the detection of a more diverse repertoire of lncRNAs, with better reproducibility and higher coverage compared to classic total RNA-sequencing.

  Study EGAS00001005418

• SHANK2 mutations associated with Autism Spectrum Disorder cause hyperconnectivity of human neurons

  Heterozygous loss-of-function mutations in the synaptic scaffolding gene SHANK2 are strongly associated with autism spectrum disorder (ASD). To investigate their effect on synaptic connectivity, we generated cortical neurons from induced pluripotent stem cells (iPSC) derived from neurotypic and ASD-affected donors. We developed Sparse coculture for Connectivity (SparCon) assays where SHANK2 and control neurons were differentially labeled and sparsely seeded together on a lawn of unlabeled control neurons. We observed striking increases in dendrite length, dendrite complexity, total synapse number, and frequency of spontaneous excitatory postsynaptic currents. These findings were phenocopied in gene-edited homozygous SHANK2 knockout cells and rescued by gene correction of an ASD SHANK2 muation, supporting a role for SHANK2 as a regulator of connectivity in developing human neurons. Dendrite length increases were exacerbated by IGF1, TG003, or BDNF, and suppressed by DHPG treatment. The transcriptome in these isogenic SHANK2 neurons was deeply perturbed in synapse, plasticity, and neuronal morphogenesis gene sets and ASD gene modules, and activity-dependent dendrite extension was impaired. Our unexpected findings provide evidence for hyperconnectivity and profoundly altered transcriptome in SHANK2 neurons derived from ASD subjects.

  Study EGAS00001003436

• Use of new methodologies to achieve a thorough molecular characterization in pediatric acute leukemia

  In childhood leukemia, a better genetic characterization is needed to define new clinic-biological entities, refine the risk-stratification of patients and help to reduce the toxicity by applying a risk-directed therapy. This project aims to obtain information that will allow us to personalize the management of pediatric patients with leukemia as much as possible, so that we can offer a complete diagnosis, a sensitive follow-up and a more targeted treatment to the real risk of each case. The use of massive genome analysis technologies such as transcriptome sequencing (RNA-Sequencing) will allow a comprehensive biological characterization of pediatric leukemia patients, especially those cases that we have not been able to characterize by conventional diagnostic techniques. We believe that the RNA-Seq technique will allow us to identify new biomarkers that will be useful for: 1) defining new biological entities with their own clinical behavior; 2) refining the stratification of patients into risk groups; 3) finding targets for a better follow-up of MRD and 4) identifying therapeutic targets for the application of targeted therapies to reduce toxicity. PI: Camós-Guijosa, Mireia; Vega-García, Nerea Funding: PI21/00213 Instituto de Salud Carlos III (ISCIII)

  Study EGAS50000000701

• Long read whole genome sequencing data from brain postmortem tissue

  Dataset consisting of 172 whole genome sequencing runs from healthy controls and Parkinson's disease patients. The data was sequenced on Oxford Nanopore (PromethION) platform. The data has been mapped to T2T-CHM13v2.0 reference genome. The data processing pipeline is available on the following link: [https://zenodo.org/records/13385065](https://zenodo.org/records/13385065). The data is in CRAM format and subet of donors also have information on C (hydroxy)methylation (MM and ML tag). The reads are also phased (HP tag).

  Dataset EGAD50000001349

• Activating AKT1 and PIK3CA mutations in metastatic castration-resistant prostate cancer

  This dataset contains all available targeted exon sequencing bam files from our study, "Activating AKT1 and PIK3CA mutations in metastatic castration-resistant prostate cancer". Patient identifiers are denoted by the first segment of the sample aliases (e.g. "P1"), and additional information is appended to reflect which serial sample is referenced (1st, 2nd, 3rd, etc.), and whether the sample represents cell-free DNA ("cfdna") or paired white-blood cell control ("WBC"). All samples were sequenced using Illumina technology.

  Dataset EGAD00001006122

• Field effect of healthy and diseased livers (2019-04-08)

  Recent work in the Campbell group has revealed somatic mutations present in normal, non-cancerous human skin. A subset of the mutations conferred selective advantages to the host cells, leading to clonal expansions and raising the risk for future cancer development. Capturing such somatic mutations in normal tissue is important to advance our understanding about carcinogenesis and could provide prospective medical insights. In this project, our goal is to detect somatic mutations in normal (pre-cancerous) liver tissue. Using Laser Microdissection technology, we will dissect individual liver lobules from patient samples and submit these to sequencing. For each patient sample, we aim to sequence multiple lobules to characterise the mutagenic burden. Samples will be taken from patients with different liver disease aetiologies, including alcoholism and obesity, with a view on distinguishing the prevalent mutation types occurring in each disease context. We will perform targeted sequencing, initially using the WTSI cancer panel. Later we aim to use a novel bait set that captures both cancer genes as well as genes relevant to the non-cancerous samples (ie. genes implicated in hereditary disorders, immune sequences). . This dataset contains all the data available for this study on 2019-04-08.

  Dataset EGAD00001004941