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• Spatial map of microglia states across CNS diseases

  Microglia are the key immune cells involved in virtually all diseases of the central nervous system (CNS). Here, we generated a novel large-scale single-cell RNA-sequencing-derived taxonomy through the analysis of > 1 million CNS cells enriched for myeloid cells across > 15 different pathologies and conditions. Disease-associated human microglia, together with CNS-associated macrophages and monocytes, were differentiated iteratively into 27 superclusters and 192 clusters. This top-down approach, in combination with targeted and genome-wide subcellular spatial transcriptomics, enabled us to examine and compare the spatial interactome of the identified superclusters and clusters within and across pathologies. Our data provide new insights into the spatial dynamics of the endogenous CNS immune system during development, health and disease in humans.

  Study EGAS50000001289

• Multiplexed biomarkers dynamically detect heterogeneous residual neuroblastoma cell clone activity in the bone marrow niche

  Our objective was to develop a patient-specific, genomics-informed minimal residual disease (MRD) monitoring strategy for pediatric high-risk neuroblastoma using individualized multiplexed mediator-probe PCR (MP-PCR) assays. Tumor-specific somatic mutations or structural variants were identified through hybrid-capture panel sequencing. We examined tumor material from 8 patients, including 11 primary tumor samples, 3 of which represent spatially distinct primary tumor samples and 2 samples obtained at relapse. Provided are FASTQ data files, bam and bambai files, as well as breakpoint spanning and encompassing read (enspan) bam and bambai files. Sequencing bam data files are aligned to GRCh37.p13 reference genome (processed). Sequencing data were aligned to the GRCh37.p13 reference genome and processed using validated pipelines.

  Study EGAS50000001581

• 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

• Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma.

  follicular lymphoma (FL), the most common indolent non-Hodgkin’s lymphoma, remains incurable. A well-recognized complication of FL is its transformation to a diffuse large B-cell lymphoma (DLBCL)-morphology in a subset of patients, for which the clinical outcomes are poor. Recent genetic profiling and single case studies of donor-derived FL following stem cell transplantation had alluded to the putative existence of a ‘long lived’ tumor-initiating progenitor cell compartment from which successive disease events occurred. To chronicle the genetic changes associated with progression to transformation, we conducted whole-genome sequencing (WGS) of FL-tFL pairs and matched germline (GL) samples from six patients, a total of 20 genomes.

  Study EGAS00001000399

• The 3D evolution of glioma cell populations

  Study description: A detailed understanding of heterogeneity in solid tumors has been limited due to insufficient sampling and a lack of knowledge from where within the tumor the sample was taken from. We present here a novel resource - the 3D Glioma Atlas - in which we record the precise, three-dimensional (3D) coordinate for each of 8-20 spatially-distinct samples obtained from each patient tumor.By revealing how genetic alterations and tumor cell states are patterned in glioma in 3D space, our Atlas shows that genetic diversity is more regionally confined in indolent as compared to aggressive tumors, that recurrent tumors have a greater density of genetic diversity, and that more aggressive tumors have greater tumor-wide transcriptomic heterogeneity.

  Study EGAS00001003710

• H3Africa - Respiratory Microbiota of African Children

  Shotgun metagenomic sequencing of nasopharyngeal (NP) samples, from children enrolled in a PCV13-vaccinated South African birth cohort was used to explore strain-level pneumococcal colonization patterns and transmission dynamics, and associated antimicrobial-resistance determinants. NP swabs were collected at two-week intervals from birth through the first year of life from 137 infants. Pneumococcal isolates were serotyped and tested for phenotypic antimicrobial resistance. 196 NP samples from a subset of 23 infants were then selected based on changes in serotype or antimicrobial resistance. DNA was extracted directly from the enriched NP samples and shotgun metagenomic sequencing performed. Reads were assembled and aligned against reference pneumococcal genomes. in silico pneumococcal capsular, multilocus sequence typing, and resistome analyses were performed.

  Study EGAS00001004401

• DPY30_ChIP_seq

  H9 human embryonic stem cells (hESCs) were cultured in feeder-free chemically-defined conditions in medium containing 10ng/ml Activin A and 12ng/ml FGF2 (Vallier L. 2011, Methods in Molecular Biology, 690: 57–66). Chromatin immunoprecipitation was performed as described in Brown S. et al. 2011. Stem Cells 29: 1176–85 by using 5ug of anti-DPY30 antibody (Sigma, cat. number HPA043761). This protocol was performed in control hESCs (expressing a scrambled shRNA) and in hESCs stably expressing an shRNA against DPY30 (Sigma, clone n. TRCN0000131112).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 EGAS00001001132

• RNA-seq study of longitudinal blood cell samples from children at risk of type 1 diabetes

  The appearance of type 1 diabetes (T1D)-associated autoantibodies is the first and only measurable parameter to predict progression toward T1D in genetically susceptible individuals. However, autoantibodies indicate an active autoimmune reaction, wherein the immune tolerance is already broken. Therefore, there is a clear and urgent need for new biomarkers that predict the onset of the autoimmune reaction preceding auto-antibody positivity or reflect progressive b-cell destruction. Here we report the mRNA sequencing–based analysis of 306 samples including fractionated samples of CD4+ and CD8+ T cells as well as CD4, CD8 cell fractions and unfractionated PBMC samples longitudinally collected from seven children who developed beta-cell autoimmunity (Case subjects) at a young age and matched control subjects.

  Study EGAS00001004071

• Targeted next-generation sequencing detects novel gene-phenotype associations and expands the mutational spectrum in cardiomyopathie

  Cardiomyopathies are a heterogeneous group of primary diseases of the myocardium,including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), andarrhythmogenic right ventricular cardiomyopathy (ARVC), with higher morbidity andmortality. These diseases are genetically diverse and associated with rare mutations ina large number of genes, many of which overlap among the phenotypes. To betterinvestigate the genetic overlap between these three phenotypes and to identify newgenotype-phenotype correlations, we designed a custom gene panel consisting of 115genes known to be associated with cardiomyopathic phenotypes and channelopathies.A cohort of 38 unrelated patients, 16 affected by DCM, 14 by HCM and 8 by ARVC,was recruited for the study on the basis of more severe phenotypes and family historyof cardiomyopathy and/or sudden death.

  Study EGAS00001002506

• Whole genome sequencing of 50 trios, where the child is affected with ID, and the parents are unaffected

  50 trios were whole genome sequenced with Complete Genomics to a depth of 80x. Each trio the child was affected with severe ID, and the parents were unaffected. All trios were negative for array, targetted gene and whole exome screening.

  Study EGAS00001000769

• Comprehensive genetic analysis of uveal melanoma heterogeneity during metastatic progression

  Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Despite improvement of diagnosis and treatment of the primary tumor, there is no effective treatment of metastatic disease and approximately half of patients will die within one year or less following metastases detection. Tumor heterogeneity has been proposed as a key factor of drug resistance. However, it has been scarcely studied in UM. The present project aims searching for specific drivers of the metastatic progression, describing the genomic and transcriptomic landscape of metastatic UM, exploring tumor heterogeneity and investigating its role in drug resistance. Thus whole exome sequencing and transcriptomics have been performed on constitutional, primary tumor and metastatic samples from 28 UM patients.

  Study EGAS00001002761

• Genomic characterization of esophageal squamous cell carcinoma reveals critical genes underlying tumorigenesis and poor prognosis

  The genetic mechanisms underlying the poor prognosis of esophageal squamous cell carcinoma (ESCC) are not well understood. In this study, we comprehensively characterized somatic mutations, copy number alterations (SCNAs)/structural variants (SVs) found in ESCC from sequencing 10 whole-genome and 57 whole-exome matched tumor-normal pairs. We identified multiple somatic mutations seen previously in known cancer pathways and identified candidate genes for ESCC including VANGL1 and MIR4707. A survival analysis based on the expression profiles of 321 ESCC individuals indicated that the somatically altered genes we found were significantly associated with ESCC poorer survival. Subsequently, we performed functional studies to validate the roles of the altered genes in tumor proliferation and metastasis.

  Study EGAS00001001723

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

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

  Study EGAS00001003572

• 16 Year Life History and Genomic Evolution of an ER+ HER2- Breast Cancer

  We reconstructed the genomic evolution through the sixteen year history of an ER+ HER2- breast cancer patient to investigate molecular mechanisms of disease relapse and treatment resistance after long term exposure to hormonal therapy. Genomic and transcriptomic profiling was performed on primary breast tumor (2002), initial recurrence (2012) and liver metastasis (2015) tumor samples. Cell free DNA analysis was performed at eleven timepoints (2015-2017).This phylogenetic reconstruction of the life history of a single patient's cancer as well as monitoring tumor progression through liquid biopsies with the detection of a resistant clone harboring a de-novo ESR1 E380Q mutation allowed for uncovering the molecular mechanisms leading to initial relapse, metastatic spread and treatment resistance.

  Study EGAS00001004624

• Aberrant ERBB4-SRC Signaling as a Hallmark of Group 4 Medulloblastoma Revealed by Integrative Phosphoproteomic Profiling

  The four main medulloblastoma subgroups are characterized by distinct biology, clinicopathological features and clinical outcomes. While the WNT and SHH subgroups are characterized by clearly defined aberrant signaling of developmental pathways, the underlying biology of Group 3 and 4 remains poorly understood. Here, we delineate distinct post-translational regulation orchestrating active oncogenic signaling networks in Groups 3 and 4. Specifically, aberrant ERBB4-SRC signaling constitutes a novel hallmark feature of Group 4, with great promise as a novel oncogenic mechanism and potential vulnerability for therapeutic intervention in the most common subgroup. Altogether, this novel integrative proteogenomic landscape demonstrates the added value of proteomics and phosphoproteomics analysis to discover and exploit unexpected oncogenic mechanisms in medulloblastoma and beyond.

  Study EGAS00001002757

• 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

• Heterogeneous metabolic signatures are linked to cancer cell differentiation in colorectal cancer

  Colorectal cancer (CRC) is characterized by functional intratumor heterogeneity that shares many similarites with the hierarchical organization of the normal intestinal epithelium. In order to relate transcriptional subtypes to functional tumor cell heterogeneity we applied scRNA-seq to 12 patient-derived CRC spheroid cultures. We identified shared expression programs that relate to intestinal lineages and revealed metabolic signatures that are linked to cancer cell differentiation. In addition, we validated and complemented sequencing results by quantitative microscopy using live-dyes and multiplexed RNA fluorescence in situ hybridization, thereby revealing metabolic compartmentalization and potential cell-cell interactions. FInally, we demonstrate functional differences between metabolically distinct lineage subtypes that might have strong implications for future treatment strategies of CRC.

  Study EGAS00001004064

• Targeted deep sequencing on Pediatric MDS

  Targeted NGS using custom panels with SAMD9, SAMD9L genes and 22 single nucleotide polymorphisms (SNP) on chromosome 7q (allele frequency >35% in all ethnic sub-populations in gnomAD) (Ampliseq #IAD10417) was performed in 667/669 cases. Additionally, 559 cases were sequenced using 28 pediatric MDS genes (GATA2, RUNX1, HOXA9, CEBPA, GATA1, KRAS, NRAS, CBL, PTPN11, ASXL1, EZH2, SETBP1, FLT3, KIT, JAK2, JAK3, CSF3R, MPL, SH2, BCOR, BCORL1; RAD21, STAG2, CTCF, TP53, PTEN, CALR, VPS45; Ampliseq #IAD51150). Libraries for targeted NGS were prepared using NEBNext Ultra II DNA library prep kit (New England BioLabs, cat#E7645S/L) per manufacturer’s instruction and samples were sequenced on an Illumina Miseq 2000 with 2 x 150 bp reads. The BAM files are uploaded here.

  Study EGAS00001005431

• Temporal stability of circulating microRNAs in human serum

  Circulating microRNA biomarkers for disease have been subject to extensive research. However, insufficient consideration of variability in the healthy population has led to few markers achieving the performance necessary in independent follow-up studies to be taken forward to clinical practice. To investigate the natural variation of circulating microRNA over time, we performed small RNA sequencing in a longitudinal study of 66 women with no history of cancer, and determined the distribution and dynamics (via intraclass correlation coefficients, ICCs) of the miRNA profile over 3 time points sampled across 2-5 years. We also investigate abundances in circulation, as well as the impact of normalization, age, BMI, and other sample collection factors on microRNA measurements from small RNA sequencing.

  Study EGAS00001003221

• Effect of 28-day administration of Urolithin A to sedentary elderly on muscle gene expression

  Urolithin A (UA) is a natural dietary, microflora derived, metabolite shown to stimulate mitophagy and improve muscle health in old animals and pre-clinical models of aging. UA was administered for 28-day in a first-in-human clinical trial to sedentary elderly subjects. Muscle biopsies were collected before the first dosing, and at the end of the 28-day period, under fasted conditions. Gene expression was measured by microarray. Gene-set enrichment analysis of the gene expression data showed that UA increased the transcription of mitochondrial related genesets. These observed effects on mitochondrial biomarkers show that UA induces a molecular signature of improved mitochondrial and cellular health following regular oral consumption in humans.

  Study EGAS00001003638

• Reconstruction of the personal information from human genome reads in gut metagenome sequencing data

  Human DNA present in fecal samples can result in a small number of human reads in gut shotgun metagenomic sequencing data. However, it is currently unclear how much personal information can be reconstructed from such reads and this has not been quantitatively evaluated. Such a quantitative evaluation is necessary to clarify the ethical concerns related to data sharing and to enable the efficient use of human genetic information in stool samples, such as for research and forensics. Here, we used genomic approaches to reconstruct personal information from fecal metagenomes of 343 Japanese individuals with associated human genotype data. Our approach can be used to quantify the personal information contained within gut metagenome data.

  Study EGAS00001007027

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

  By investigating an intergenic haplotype on chr21q22, independently linked to inflammatory bowel disease (IBD), ankylosing spondylitis, primary sclerosing cholangitis and Takayasu’s arteritis, we discover that the causal gene, ETS2, is a master regulator of inflammatory responses in human macrophages and delineate how the risk haplotype increases ETS2 expression. Using a database of cellular signatures, we identified drugs that could modulate this pathway. To validate the anti-inflammatory activity of one class of small molecules ex vivo, we obtained biopsies from patients with active IBD and cultured these biopsies with a selective, non-ATP competitive MEK inhibitor (PD-0325901), infliximab (positive control), or DMSO (vehicle control) for 18 hours, then performed RNA sequencing.

  Study EGAS00001007534

• Somatic mutations and single cell transcriptomes reveal the root of malignant rhabdoid tumours

  Like many childhood cancers, malignant rhabdoid tumours (MRT) are thought to arise from aberrant foetal development. Although MRT predominantly exhibit a mesenchymal phenotype, it has been suggested that the foetal root of MRT lies in neural crest development. Here, we combine phylogenetic analyses of MRT, single cell mRNA assays, and functional experiments in patient-derived MRT organoids, to define the embryological origin of MRT and explore therapeutic avenues that may drive MRT differentiation. Phylogenetic analyses from the distribution of somatic mutations revealed that MRT were related to neural crest-derived, but not to mesodermal tissues, providing direct evidence of the neural crest origin of MRT in humans. In MRT organoids, reversal of the principal driver event underpinning MRT, SMARCB1 loss, induced differentiation along mesenchymal pathways. Together, these findings placed MRT cells on a developmental trajectory of neural crest to mesenchyme conversion, and defined the transcriptional changes underpinning MRT differentiation. Searching perturbation databases for agents that mimic these mRNA changes, we identified HDAC and mTOR inhibition as potential differentiation agents. Treatment of MRT organoids with this drug combination induced proliferation arrest with transcriptional changes akin to SMARCB1 re-expression. Our study defines the embryological root of MRT and proposes a differentiation treatment for this often fatal childhood cancer.

  Dataset EGAD00001006296

• Molecular characterization of NASH-HCC

  We collected 80 NASH-HCCs formalin fixed paraffin-embedded (FFPE) samples from 5 different institutions. NASH was diagnosed in FFPE samples by at least two expert pathologists following a described histological algorithm (Bedossa et al., Hepatology, 2012). All NASH patients included in the study were HBV- and HCV-negative. Patients reporting alcohol consumption ≥ 20 g/day for women and 30 g/day for men, as well as patients with a known liver disease superimposed to NASH were excluded. Tumour and paired non-tumour gDNA of NASH-HCC FFPE samples was submitted to Whole Exome Sequencing (WES). Exome capture and sequencing library preparation were performed using the SureSelect Human All Exon V5, no UTR hybridization capture kit from Agilent (Target Size 50 Mb). Libraries were sequenced on an Illumina HiSeq 4000 instrument with 100-bp paired-end reads.

  Dataset EGAD00001007524

• MutWP1: CRUK Grand Challenge Mutographs of Cancer: pancreas (2019-04-03)

  The Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Different patterns of somatic mutation are generated by the different environmental, lifestyle and genetic factors that cause cancer, many of them are still unknown. Within Mutographs, the International Agency for Research on Cancer is coordinating the recruitment of 5000 individuals with cancer (colorectal, renal, pancreatic, oesophageal adenocarcinoma or oesophageal squamous cancers) across 5 continents to explore whether different mutational signatures explain marked variation in incidence. In brief, through an international network of collaborators around the world, biological materials are collected, along with demographic, histological, clinical and questionnaire data. Whole genome sequences of tumour-germline DNA pairs are generated at the Wellcome Trust Sanger Institute (Illumina HiSeqX, 40X and 20X depth respectively). Somatic mutational signatures are subsequently extracted by non-negative matrix factorisation methods and correlated with risk factors data. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development. . This dataset contains all the data available for this study on 2019-04-03.

  Dataset EGAD00001004893