11989 results for "cancer rna-seq"

in 20.89 milliseconds.

• V4_panel_bait_design_test

  Targeted gene screen of FFPEs, cell lines and primary tumours for testing the new V4 Cancer gene panel.

  Study EGAS00001001808

• Lung_Progression_versus_Regression_Whole_Genome_Sequencing

  Around 50 samples of pre-invasive lung cancer lesions showing subsequent clinical and pathological progression or regression

  Study EGAS00001000837

• In_Situ_Transcription_whole_genome_sequencing

  Whole genome sequencing of multifocal breast cancer regions. Intention to use this data to inform in-situ transcription analysis.

  Study EGAS00001001971

• The_identification_of_genetic_vulnerabilities_in_head_and_neck_cancers_for_the_development_of_novel_therapies

  CRISPR/Cas9 lethality screens in a set of Asian head and neck cancer cell lines to identify novel targets.

  Study EGAS00001002204

• Targeting the bicarbonate transporter SLC4A4 overcomes immunosuppression and immunotherapy resistance in pancreatic cancer

  Targeting the bicarbonate transporter SLC4A4 overcomes immunosuppression and immunotherapy resistance in pancreatic cancer

  Study EGAS00001006334

• A Genome Wide Scan of Lung Cancer and Smoking

  The majority of cases of lung cancer are the culmination of a dynamic process that begins with smoking initiation, proceeds through dependency and smoking persistence, continues with lung cancer development and ends with progression to disseminated disease or response to therapy and survival. We are conducting a whole genome study of lung cancer and smoking to examine critical steps in lung cancer progression. This study is a genome-wide association study (GWAS) to investigate the genetic determinants of lung cancer risk. The study design efficiently allows identification of genes that also contribute to smoking persistence and outcome from lung cancer using a single GWAS of 5,900 subjects using the primary GENEVA dataset, derived from two studies. The first is the Environment and Genetics in Lung Cancer Etiology Study (EAGLE), a population-based, biologically intensive, case-control study from the Lombardy region of Italy including ~2000 newly diagnosed lung cancer cases and ~2000 age-, gender- and region- matched controls. The second is the Prostate, Lung, Colon and Ovary Study (PLCO) Cancer Screening Trial from which we have selected ~850 lung cancer cases and ~850 controls, also matched on age and gender. Understanding the basis for the well-established hereditary component of lung cancer and smoking persistence could provide new insights into etiology, prevention, and treatment, and have an enormous impact on public health. The same GWAS genotyping data in the two studies will be used to investigate the genetic determinants of smoking persistence. Specifically, we will analyze current smokers and former smokers from EAGLE and PLCO for diverse smoking phenotypes, including persistence of smoking as well as ever/never smoking comparisons, quitting attempts, and the Fagerström index of tobacco addiction. PLCO participants are all European-Americans and EAGLE involves subjects from Italy. EAGLE is a case-control study and contains 3937 phenotyped subjects. PLCO is a screening trial with a cohort design and contains 1651 phenotyped subjects. 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 lung cancer and smoking through large-scale genome-wide association studies of population-based samples of lung cancer cases and 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 phs000093

• Enabling sensitive and precise detection of ctDNA through somatic copy number aberrations in breast cancer

  Cell-free DNA (cfDNA) extracted from peripheral blood has emerged as a crucial biomarker source in oncology research. To enhance the detection of somatic copy number alterations (SCNAs) and circulating tumor DNA (ctDNA), we developed eSENSES, a 2Mb breast cancer-targeted NGS panel. It includes 15,000 genome-wide SNPs, 500 focal SNPs in breast cancer driver regions, and exons from 81 commonly altered genes, alongside a custom computational approach. eSENSES provides a reliable, powerful and cost-effective tool for monitoring disease progression and guiding therapeutic decisions in breast cancer patients.

  Study EGAS50000000793

• High-depth whole genome sequencing of 51 premalignant breast lesions

  Ductal carcinoma in situ (DCIS) is a non-obligate precursor lesion of breast cancer, representing 20-25% of newly diagnosed breast cancer lesions. It is currently not possible to predict which DCIS patients will progress to invasive breast cancer. The samples deposited here are part of a larger study using high-depth whole-genome sequencing (WGS) to investigate the somatic mutation genomic landscape of DCIS. Comprehensive evaluation of DCIS genomes aims to uncover biological insights into breast cancer progression and potential opportunities to stratify DCIS patients for personalised treatment options or active surveillance.

  Study EGAS50000001436

• Microsatellite unstable colorectal cancers

  Immune escape has been recognised as one of the hallmarks of cancer. Overcoming this immunomodulatory process by tumour cells has become a major therapeutic target. Here we utilize organoid technology to study immune-cancer interactions and assess immunomodulation by colorectal cancer (CRC). Transcriptional profiling and flow cytometry revealed that organoids maintain differential expression of immunomodulatory molecules present in primary tumours. Finally, we established a method to model antigen-specific epithelial cell killing and cancer immunomodulation in vitro using CRC organoids co-cultured with cytotoxic T cells. Our method may serve as a first step to rebuilding the tumor microenvironment in vitro.

  Study EGAS00001003366

• Sequencing data for oesophageal and related samples - OACs release 5 (RNA)

  Dataset EGAD00001005383

• Sequencing data for oesophageal and related samples - Normals release 6 (RNA)

  Dataset EGAD00001005376

• APCIM_Nanostring_HD

  Expression of immune related genes in 12 healthy donors. Expression assessed by analyzing whole blood-derived RNA samples using a Nanostring nCounter Immunology V2 panel (579 genes)

  Dataset EGAD00010002554

• Sequencing data for oesophageal and related samples - BOs release 6 (RNA)

  Dataset EGAD00001005377

• Sequencing data for oesophageal and related samples - OACs release 4 (RNA)

  Dataset EGAD00001004021

• RNA sequencing study for 8 pairs of primary NSCLCs and distant metastases

  This study is to understand of the molecular mechanisms driving metastasis.

  Study EGAS00001004078

• Non-small cell lung cancer sequencing

  Study EGAS00001005499

• Cancer-Restricted Cryptic Antigens Are Targets for T Cell Recognition

  Subjects included patients with pancreatic cancer, at least 18 years of age, who were recruited from outpatient clinics and inpatient units at Dana-Farber Cancer Institute and Brigham and Women's Hospital.Bulk and single-cell transcriptomic profiling of human pancreatic cancer patient samples (direct from tumor or profiling of patient-derived organoids) was performed. Patient-derived pancreatic cancer organoids were profiled in the presence or absence of interferon-gamma stimulation. Healthy-donor CD8 T lymphocytes were ex vivo primed and expanded with candidate non-canonical (cryptic) peptide antigens. Single-cell transcriptomic profiling with paired T cell receptor (TCR) sequencing and molecularly-barcoded HLA tetramers enabled deconvolution and identification of cryptic antigen-reactive TCRs.

  Study phs003887

• Sequencing data of tumor tissue obtained from GANNET53 study patients

  The GANNET53 clinical trial evaulated novel treatment options for ovarian cancer patients with platinum-resistant relapse. Archival fresh-frozen paraffin embedded tissue was available from 131 of the 133 enrolled patients. NGS sequencing aimed at assessing the mutational spectrum of key ovarian cancer genes (with a focus on TP53), and their relevance for therapy resistance. From available FFPE samples, DNA was extracted and NGS sequenced using the SureSeq™ Ovarian Cancer Panel and the NGS Library Preparation kit covering all exons of 7 key ovarian cancer genes BRCA1, BRCA2,TP53, PTEN, ATM, ATR, NF1 for single nucleotide variants (SNV) and indels. Finally, sequence data from 118 individual FFPE tumor tissue samples were generated.

  Study EGAS50000000935

• BRAF_and_MEK_resistant_cell_line_clones

  The Sanger Institute has the largest collection of genetically-characterised cancer cell lines world-wide (we have collected >1000 human cancer cell lines which are being screened against >400 cancer therapeutics (http://www.sanger.ac.uk/genetics/CGP/translation). These lines have been characterized to the level of gene copy number, gene expression and cancer gene mutation sequence data. This has enabled us to select melanoma lines with varying BRAF mutational status and that show sensitivity to a range of BRAF inhibitors. Sensitive lines are being used to generate resistant clones by serial exposure to increasing concentrations of BRAF and MEK inhibitors and these are being characterised by genome-wide copy number analysis as well as by whole exome sequencing.

  Study EGAS00001000172

• EMBARCAM BC360 PROJECT

  This dataset is related to the EMBARCAM BC360 PROJECT. A total of 106 breast cancer samples, from Pregnancy-Associated Breast Cancer (PABC) (n=57) and non-PABC (n=49) patients, were analysed using the nCounter Breast Cancer 360 V2 panel on the NanoString platform. All samples were FFPE tumor samples from breast cancer patients, derived from GEICAM/2012-03, GEICAM/2017-07, and EpiGEICAM studies, sponsored by GEICAM.

  Dataset EGAD00010002709

• Cancer Research UK Manchester Institute/ Cancer Research UK National Biomarker Centre Data Access Committee

  Cancer Research UK Manchester Institute/Cancer Research UK National Biomarker Centre Data Access Committee is created to • Review and approve data access requests. • Ensure data security and compliance with institutional and legal obligations. • Maintain accurate records of access decisions For questions or further information, please contact: Chair of the Data Access Committee: Caroline Wilkinson Email: dac@cruk.manchester.ac.uk

  Dac EGAC50000000795

• RRBS sequencing data of ovarian cancer, breast cancer, control tissues, and white blood cell DNA.

  The dataset comprises 8 breast cancer, 11 ovarian cancer, 1 benign tumour, 18 normal tissue, 2 endometrium, and 23 white blood cell samples. Genome wide methylation analysis was performed by Reduced Representation Bisulfite Sequencing (RRBS) on Illumina HiSeq 2500. Data is provided as FASTQ files

  Dataset EGAD00001003822

• ATAC-seq for 2 samples

  This dataset contains ATACseq data from ta primary sample and a patient derived model (PDX) of the novel FOXF1/FENDRR ALL subtype. All the 2 samples are in bam file type.

  Dataset EGAD50000001791

• DNA-seq from plasma of 14 liver transplantation patients

  We performed DNA sequencing on the plasma of 14 liver transplantation patients to study the liver DNA in the plasma.

  Study EGAS00001003116

• 5hmC enrichment in human monocyte differentiation

  This dataset consists of 5hmC capture-seq data from human monocytes, monocyte-derived dendritic cells. It includes two biological replicates and three time points. Including controls, the dataset comprises 10 samples in total.

  Dataset EGAD00001006603

• RRBS - MBD4-deficient AML

  Reduced Representation Bisulfite Sequencing for WEHI-AML-1 and WEHI-AML-2. RRBS libraries were made with the NuGEN Ovation RRBS Methyl-Seq System. Bisulfite conversion was performed with the Qiagen Epitect kit. Sequencing was performed on an Illumina HiSeq2500.

  Dataset EGAD00001003567

• DEEP-IHEC-release-2017

  Raw data files for the German Epigenome Project (DEEP), IHEC/EpiRR submission of 2017. metadata available at: http://deep.dkfz.de/#/experiments

  Dataset EGAD00001003974

• combined ChIPseq (H3, modifications and TF)

  ChIPseq data for 31 CLL samples (12 controls, 19 tumor) of the CancerEpiSys-PRECiSe project; containing histone H3, histone modifications and transcription factor binding sites (CTCF, EBF1).

  Dataset EGAD00001005969

• Epigenetic subtypes of neuroblastoma - ChIPseq

  In the absence of recurrent gene mutations, evidence accumulates that epigenetic deregulation plays a prominent role in neuroblastoma biology. Here we provide genome wide H3K27ac profiles in 60 primary neuroblastoma samples.

  Dataset EGAD00001006285

• CAGE-seq of frontal post-mortem human brain tissue of patients with FTD and healthy controls

  CAGE-sequencing was performed on frontal post-mortem human brain tissue of patients with FTD caused by mutations in GRN, MAPT or C9orf72 and healthy controls.

  Dataset EGAD00001006843

• The Genomic Landscape of Prostate Cancer Brain Metastases

  Study EGAS00001004557

• Cancer Research UK manchester Institute Cancer Biomarker Centre

  Dac EGAC00001001765

• Cancer Registry of Norway - NIPH Data Access Committee for CRCbiome datasets

  The Cancer Registry of Norway - NIPH appointed Data Access Committee for the CRCbiome datasets - The microbiome as a colorectal cancer screening biomarker. https://www.mn.uio.no/sbi/english/groups/rounge-group/crcbiome/.

  Dac EGAC50000000121

• Massachusetts General Hospital Cancer Center DAC for high-throughput microfluidic enrichment from whole leukopak for CTC-based liquid biopsy

  Whole genome sequencing and whole exome sequencing data of circulating tumor cells isolated from patients with metastatic prostate cancer and liver cancer.

  Dac EGAC50000000423

• Colorectal_organoids_and_tumour_tissue

  Whole genome sequencing of single cell derived organoids from normal colon tissue and colorectal cancer.

  Study EGAS00001000881

• Analyses of IACS-010759 treatment resistance on breast cancer bone metastases

  Identification of biological mecanisms involved in resistance of breast cancer bone metastases to IACS treatment.

  Study EGAS00001006429

• Environmental Influences on Child Health Outcomes (ECHO) - PATHWAYS - Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE)

  Pregnant women are exposed daily to multiple chemical and non-chemical stressors, including air pollutants, phthalates, and psychosocial stress. The Developmental Origins of Health and Disease model (DOHaD) states that exposure to these stressors in pregnancy affects fetal development in a manner that impacts offspring health across the life course. Yet epidemiologic data in these areas is limited, particularly with U.S. samples. It is also poorly understood whether these exposures prenatally affect childhood neurodevelopment and airway health in an independent or combined manner, and likely moderators of effects, such as the sex of the child, are infrequently addressed. We propose to unify three diverse extant pregnancy cohorts: TIDES (N=717, 2010-12), GAPPS (N=1133, 2012-16), and CANDLE (N=1385, 2007-11), for a combined sample size of 3235 mother-child dyads in the PATHWAYS study. PATHWAYS will investigate how chemical (air pollutants and phthalates) and non-chemical (psychosocial stress) exposures during pregnancy are related to placental gene expression (transcriptome) and childhood neurodevelopment and airway health (at ages 4-6, 8-9, and 10-11 years). Each cohort has rich resources of prenatal data and banked specimens (urine, blood, and placenta) that will be harmonized for the PATHWAYS study and will contribute to the ECHO consortium. We will develop a national model with high spatiotemporal resolution of key air pollutants and assess urinary markers of maternal exposure. A composite measure will capture multilevel maternal psychosocial stress across pregnancy, and urinary phthalate and blood stress hormone [Corticotropin-releasing hormone (CRH)] levels in the second and third trimesters will provide individual assessment of those exposures in potential critical periods. We will characterize the placental transcriptome using RNA sequencing (RNA-Seq) and will assess neurodevelopment and airway health prospectively into middle childhood. PATHWAYS will examine how these prenatal exposures are related to the placental transcriptome and child health outcomes in main effect and interactive models, with emphasis on sex-specific associations. For both neurodevelopment and airway health, we propose to measure both phenotypic precursors of health outcomes (i.e. fluid cognition, lung function growth), which yield dimensional tests of proposed associations, as well as clinically meaningful and policy relevant outcomes (i.e. asthma, mental health). Our study is powered to assess interactive effects of chemical and non-chemical stressors and will be the first study to characterize how prenatal environmental exposures relate to placental transcriptome pathways in relation to childhood health outcomes. This represents a significant scientific advance in testing DOHaD hypotheses. Major contributions to the ECHO Consortium include: 1) the development of a state of the art national model of air pollution, 2) a large, diverse pregnancy cohort with extensive biorepositories and extant prenatal and postnatal biomarkers, placental transcriptome, psychosocial and environmental data, and 3) an experienced, interdisciplinary team that will contribute meaningfully to the ECHO program of work.The sequencing data in this submission pertains only to the 794 subjects from the CANDLE study for whom placental tissue transcriptomics was performed.

  Study phs003619

• Environmental Influences on Child Health Outcomes (ECHO) - PATHWAYS - Global Alliance to Prevent Prematurity and Stillbirth (GAPPS)

  Pregnant women are exposed daily to multiple chemical and non-chemical stressors, including air pollutants, phthalates, and psychosocial stress. The Developmental Origins of Health and Disease model (DOHaD) states that exposure to these stressors in pregnancy affects fetal development in a manner that impacts offspring health across the life course. Yet epidemiologic data in these areas is limited, particularly with U.S. samples. It is also poorly understood whether these exposures prenatally affect childhood neurodevelopment and airway health in an independent or combined manner, and likely moderators of effects, such as the sex of the child, are infrequently addressed. We propose to unify three diverse extant pregnancy cohorts: TIDES (N=717, 2010-12), GAPPS (N=1133, 2012-16), and CANDLE (N=1385, 2007-11), for a combined sample size of 3235 mother-child dyads in the PATHWAYS study. PATHWAYS will investigate how chemical (air pollutants and phthalates) and non-chemical (psychosocial stress) exposures during pregnancy are related to placental gene expression (transcriptome) and childhood neurodevelopment and airway health (at ages 4-6, 8-9, and 10-11 years). Each cohort has rich resources of prenatal data and banked specimens (urine, blood, and placenta) that will be harmonized for the PATHWAYS study and will contribute to the ECHO consortium. We will develop a national model with high spatiotemporal resolution of key air pollutants and assess urinary markers of maternal exposure. A composite measure will capture multilevel maternal psychosocial stress across pregnancy, and urinary phthalate and blood stress hormone [Corticotropin-Releasing Hormone (CRH)] levels in the second and third trimesters will provide individual assessment of those exposures in potential critical periods. We will characterize the placental transcriptome using RNA sequencing (RNA-Seq) and will assess neurodevelopment and airway health prospectively into middle childhood. PATHWAYS will examine how these prenatal exposures are related to the placental transcriptome and child health outcomes in main effect and interactive models, with emphasis on sex-specific associations. For both neurodevelopment and airway health, we propose to measure both phenotypic precursors of health outcomes (i.e., fluid cognition, lung function growth), which yield dimensional tests of proposed associations, as well as clinically meaningful and policy relevant outcomes (i.e., asthma, mental health). Our study is powered to assess interactive effects of chemical and non-chemical stressors and will be the first study to characterize how prenatal environmental exposures relate to placental transcriptome pathways in relation to childhood health outcomes. This represents a significant scientific advance in testing DOHaD hypotheses. Major contributions to the ECHO Consortium include: 1) the development of a state of the art national model of air pollution, 2) a large, diverse pregnancy cohort with extensive biorepositories and extant prenatal and postnatal biomarkers, placental transcriptome, psychosocial and environmental data, and 3) an experienced, interdisciplinary team that will contribute meaningfully to the ECHO program of work.The sequencing data in this submission pertain only to the 408 subjects from the GAPPS study for whom placental tissue transcriptomics was performed.

  Study phs003620

• Human Liver Cohort (HLC)

  The Human Liver Cohort (HLC) study aimed to characterize the genetic architecture of gene expression in human liver using genotyping, gene expression profiling, and enzyme activity measurements of Cytochrom P450. The HLC was assembled from a total of 780 liver samples screened. DNA samples were genotyped on the Affymetrix 500K SNP and Illumina 650Y SNP genotyping arrays. Only data from those samples which were collected postmortem are accessible through this submission. These 228 samples represent a subset of the 427 samples included in the Human Liver Cohort Publication (Schadt, Molony et al. 2008, PMID: 18462017). RNA samples were profiled on a custom Agilent 44,000 feature microarray composed of 39,280 oligonucleotide probes targeting transcripts representing 34,266 known and predicted genes, including high-confidence, noncoding RNA sequences. Gene Expression data for the samples from which it could be obtained is available in GEO under accession number GSE9588. Results and networks will be made available for download from Sage Bionetworks.

  Study phs000253

• Functional Genomic Landscape of Acute Myeloid Leukemia

  The implementation of targeted therapies for acute myeloid leukemia has been challenged by complex mutational patterns within and across patients as well as a dearth of pharmacologic agents for most mutational events. The initial findings from the Beat AML program were from a cohort of 672 tumor specimens collected from 562 patients. Additional patients have been added in subsequent versions. We assessed these specimens using whole exome sequencing, RNA-sequencing, and ex vivo drug sensitivity analyses. Our data reveal novel mutational events not previously detected in AML. We show association of drug response with mutational status, including instances of drug sensitivity that are specific to combinatorial mutational events. Integration with RNA-sequencing also revealed gene expression signatures, which predict a role of specific gene networks in drug response. Collectively, this report offers a dataset, accessible by the Beat AML data viewer (www.vizome.org), that can be leveraged to address clinical, genomic, transcriptomic, and functional inquiries into the biology of AML.

  Study phs001657

• Unraveling the heterogeneity of multiple myeloma identifies therapy resistant subpopulation with vulnerability to the splicing pathway intervention

  Intra-tumor heterogeneity underlies the therapy resistance of multiple myeloma (MM). However, its details remain unknown. Here, we performed single-cell RNA sequencing coupled with VDJ targeted sequencing on highly purified bone marrow lineage marker-negative CD38+ MM cells from patients at diagnosis and in remission. This approach successfully subdivided MM cells into distinct clusters, unraveling their heterogeneity and plasticity on the axis of cell surface CD138 expression. Notably, unique clusters were identified in the minor CD138-negative population that resisted therapies. CRISPR/Cas9 screening of upregulated genes in the resistant population identified their vulnerability to the splicing pathway inhibition, among which RNA-binding protein 39 (RBM39) appeared to be overexpressed in the resistant population and involved in aberrant splicing. Genetic and pharmacological inhibition of RBM39 exerted a profound synthetic lethal effect on them. Our results unveil an uncharacterized subpopulation associated with therapy resistance and provide a novel therapeutic strategy targeting the splicing pathway in MM.

  Study JGAS000723

• Somatic mutations in ALS genes in the motor cortex of sporadic ALS patients

  Several lines of evidence suggest that amyotrophic lateral sclerosis (ALS) pathology starts focally and spreads within the central nervous system (CNS). We leveraged DNA and RNA sequencing data from ALS autopsy tissue to explore the presence of somatic mosaic variants in sporadic ALS (sALS) cases. Deep targeted sequencing of known ALS disease genes from motor cortex tissue revealed enrichment of somatic variants in sALS compared to familial ALS (fALS) with a monogenic cause and an increased pathogenicity of mosaic mutations in known ALS mutational hot spots. Experimental validation of the variants identified that the somatic FUS variant p.E516X leads to nucleo-cytoplasmic mislocalization and aggregation. Additionally, somatic variant calling from single-cell RNA-sequencing data of sALS tissue showed an accumulation of somatic variants in excitatory neurons. Collectively, using a multi-modal approach, our findings suggest that somatic mutations within the motor cortex, especially in excitatory neurons, may contribute to the development of sALS.

  Study EGAS00001008104

• Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas

  RNA polymerase II mediates the transcription of all protein-coding genes in eukaryotic cells, a process that is fundamental to life. Genomic mutations in this enzyme have not been previously linked to any pathology in humans, a testament to its indispensable role in cell biology. Based on a combination of next-generation genomic analyses of 775 meningiomas, we report that recurrent somatic p.Gln403Lys or p.Leu438_His439del mutations in POLR2A, which encodes the catalytic subunit of RNA polymerase II1, are sufficient to hijack this essential enzyme and drive neoplasia. POLR2A mutant tumors reveal dysregulation of key meningeal identity genes, including WNT6 and ZIC1/ZIC42,3. In addition to POLR2A, NF2, SMARCB1, TRAF7, KLF4, AKT1, PIK3CA and SMO4-8, we also report somatic mutations in AKT3, PIK3R1, PRKAR1A, and SUFU in meningiomas. Our results identify a role for essential transcriptional machinery in driving tumorigenesis and define mutually exclusive meningioma subgroups with distinct clinical and pathological features.

  Study EGAS00001001916

• RNA-Seq of PBMC's from rUTI Patients and Healthy Controls

  Recurrent urinary tract infections (rUTIs) are a major health burden worldwide, with history of infection being a significant risk factor. While the gut is a known reservoir for uropathogenic bacteria, the role of the microbiota in rUTI remains unclear. We conducted a year-long study of women with and without history of rUTIs, from whom we collected urine, blood and monthly fecal samples for multi-omic interrogation. The rUTI gut microbiome was significantly depleted in microbial richness and butyrate-producing bacteria compared to controls, reminiscent of other inflammatory conditions, though Escherichia coli gut and bladder dynamics were comparable between cohorts. Blood samples revealed signals of differential systemic immunity, leading us to hypothesize that rUTI susceptibility is in part mediated through a syndrome involving the gut-bladder axis, comprising gut dysbiosis and differential immune response to bacterial bladder colonization, manifesting in symptoms. This work highlights the potential for microbiome therapeutics to prevent and treat rUTIs.  (Reprinted from medrxiv.org ) 

  Study phs002728

• Rna-Seq Leiomyosarcoma subtypes

  Leiomyosarcomas (LMS) are genetically heterogeneous tumors differentiating along smooth muscle lines. Currently, LMS treatment is not informed by molecular subtyping and is associated with highly variable survival. While disease site continues to dictate clinical management, the contribution of genetic factors to LMS subtype, origins, and timing are unknown. Here we analyzed 70 genomes and 130 transcriptomes of LMS, including multiple tumor regions and paired metastases. Molecular profiling highlighted the extremely early origins of LMS. Three specific subtypes of LMS develop from distinct lineages of smooth muscle cells. Of these, dedifferentiated LMS with high immune infiltration and tumors primarily of gynaecological origin acquired the highest burden of genomic mutation and are associated with worse survival. Homologous recombination defects lead to genome-wide mutational signatures, and a corresponding sensitivity to PARP and other DNA damage response inhibitors, suggesting a novel therapeutic strategy for LMS. Finally, by phylogenetic reconstruction, we present evidence that clones seeding lethal metastases arise decades prior to LMS diagnosis.

  Study EGAS00001004783

• RNA-seq from human embryonic tissues (additional samples 2018)

  How the genome activates or silences transcriptional programmes governs organ formation. Little is known about this in human post-implantation embryos undermining our ability to benchmark the fidelity of in vitro stem cell differentiation or cell programming, or interpret noncoding variation as potential causes of disease. Here, by studying histone modification we identified genome-wide open chromatin states and active repression across thirteen tissues during human organogenesis. We integrated the data with transcription to build the first view of how promoter states from nearly 20,000 genes differentially regulate alternative organ fates, arguing against bivalency during human organogenesis. The data illustrate tissue-specific as well as complex patterns of enhancer activity functional in zebrafish and impute master transcription factors. Overlaying 739 noncoding de novo mutations in patients allowed phenotypic correlation of developmental disorders to unanticipated target genes. Taken together, the data provide a comprehensive genomic framework for understanding normal and abnormal human development.

  Study EGAS00001003738

• Single-cell RNA-seq and spatial transcriptomics data for the sarcoidosis baseline project

  Granulomas are lumps of immune cells that can form in various organs. Most granulomas appear unstructured, yet they have some resemblance to lymphoid organ formation. To better understand granuloma formation, we performed single-cell sequencing and spatial transcriptomics on granulomas from patients with sarcoidosis and bioinformatically reconstructed the underlying gene-regulatory networks. We discovered an immune stimulatory environment in granulomas that repurposed transcriptional programs associated with lymphoid organ development. Granuloma formation followed characteristic spatial patterns and involved genes linked to immunometabolism, cytokine and chemokine signaling, and extracellular matrix remodeling. Three cell types emerged as key players in granuloma formation: metabolically reprogrammed macrophages, cytokine-producing Th17.1 cells, and fibroblasts with inflammatory and tissue remodeling phenotypes. Pharmacological inhibition of one of the identified processes attenuated granuloma formation in a sarcoidosis mouse model. We show that human granulomas adopt characteristic aspects of normal lymphoid organ development in aberrant combinations, indicating that granulomas constitute aberrant lymphoid organs.

  Study EGAS00001006970

• Linking the epigenetic landscape in chronic lymphocytic leukemia to deregulated chromatin networks

  Aberrant chromatin features and epigenetic signaling emerge as an important part of the tumor disease state in chronic lymphocytic leukemia (CLL). However, an integrative analysis of the malignant chromatin landscape is currently missing. Here, we mapped DNA-methylation, nucleosome position, 7 histone modifications, ATAC-seq and the transcriptome in primary CD19+ sorted B-cells from the peripheral blood of CLL patients in comparison to non-malignant lymphocytes of healthy donor reference samples. On the > 50 kb scale we identified global differences with respect to DNA methylation, nucleosome positioning and histone modifications in CLL. Furthermore, a chromatin state annotation was developed to identify deregulated chromatin features of promoters and enhancers in CLL. By integrating these findings with an ATAC-seq based transcription factor binding analysis we identified a set of promoters and enhancers specific to CLL that were enriched in certain transcription factors binding motifs and genes of the BCR signaling pathway. Thus, our study provides an in-depth map of the CLL chromatin landscape and links chromatin state changes at promoters and enhancers to deregulated pathways.

  Study EGAS00001002518

• A Single-cell Atlas of Progressive TKI Resistance in Chronic Myeloid Leukemia

  High-dimensional scRNA seq and CyTOF were used to identify features predictive of treatment outcome at diagnosis. An optimal TKI response was characterised by erythroid lineage skewing of the CD34+ HSPC compartment. While TKI-resistant CP was reminiscent of a BC-like state, where HSPCs were enriched for inflammation, stemness and quiescence. We designed a machine-learning approach which assessed the prognostic potential of all 32 sub-populations of our scRNA seq dataset. LSCs and NK populations harboured the highest prognostic power at diagnosis. Within the LSCs, erythroid lineage priming and MYC activation were features of an optimal and poor TKI responses, respectively. With the NK cell compartment, apart from a higher abundance of NK cells in TKI optimal responders, a memory-like HLA-DR+ adaptive NK and KLRC1+ NK populations were hallmarks of an optimal and poor TKI responses, respectively. Mechanistically, both cell intrinsic and extrinsic mechanisms contributed towards the higher sensitivity of EPs to TKI therapy. In summary, our high-dimensional single-cell atlas of TKI resistance highlights pivotal transcriptional features associated with TKI-resistance disease, some of which have the potential to be exploited as biomarkers.

  Study EGAS00001005509

• Multi-Region WES of Metastatic Colorectal Cancer

  Study EGAS00001003573