Search Results - EGA European Genome-Phenome Archive

CAGE analysis for endometrial carcinoma

For endometrial cancer patients, lymphadenectomy is recommended to exclude rarely metastasized cancer cells. This procedure is performed even in patients with low risk of recurrence despite the risk of complications such as lymphedema. A method to accurately identify cases with no lymph node metastases (LN-) before lymphadenectomy is therefore highly required. We approached this clinical problem by examining primary lesions of endometrial cancers with CAGE (Cap Analysis Gene Expression), which quantifies promoter-level expression across the genome. Fourteen profiles delineated distinct transcriptional networks between LN?+?and LN- cases, within those classified as having the low or intermediate risk of recurrence.

Study JGAS000124

The Role of CDX2 in Controlling ABCB1 Expression and Chemosensitivity in Human Colon Cancer

This study reports the results of RNA sequencing (RNA-seq) experiments performed on two human colon cancer cell lines (HT-29, DLD-1) that were genetically engineered to achieve either the constitutive expression (in HT-29 cells) or the selective inactivation (in DLD-1 cells) of the transcription factor CDX2, a master regulator of embryonic gut development and a key regulator of multi-lineage differentiation in adult colon epithelial cells. Our previous studies had identified lack of CDX2 expression as a prognostic biomarker of poor prognosis and a predictive biomarker of benefit from adjuvant chemotherapy in Stage-II and Stage-III colon cancer patients (Dalerba et al., NEJM, 374:211-222, 2016; PMID: 26789870). The molecular basis of these associations, however, remained poorly understood. The present study was designed to identify which genes are under the transcriptional control of CDX2, in order to clarify their role in shaping colon cancer resistance to chemotherapy. Of the two lines included in this study, the first (HT-29) is CDX2-negative at baseline, and was infected with a lentivirus vector encoding for the cDNA of the human CDX2 gene under the control of a constitutive promoter (CMV). The second line (DLD-1) is CDX2-positive at baseline, and was infected with a series of lentivirus vectors encoding for CRISPR/Cas9 constructs designed to selectively inactivate the CDX2 gene. In both cases, infected cells were purified by fluorescence-activated cell sorting (FACS), based on the differential expression of a green fluorescent reporter (EGFP) that was also encoded by the lentivirus vectors, and transcribed in tandem with either the CDX2 cDNA (HT-29) or CRISPR/Cas9 gRNAs targeting CDX2 (DLD-1). The experiments were designed to include 3 experimental replicates per condition, and to compare the transcriptional profile of genetically engineered cells with that of autologous controls (i.e., HT-29 cells infected with an "empty" version of the same lentivirus vector used to over-express CDX2, DLD-1 cells engineered with a "non-targeting" CRISPR/Cas9 gRNA). In the specific case of DLD-1 cells engineered with CRIPSR-Cas9 constructs targeting CDX2, infected cells were sorted based on the differential expression of EGFP and then plated as single-cells, in order to sub-culture three isogenic clones, all of which were genetically sequenced to confirm bi-allelic knock-out of the CDX2 gene, and confirmed to lack CDX2 protein expression by Western blot. The results of our experiments demonstrate that, in human colon epithelial cells, CDX2 controls the expression of the ABCB1 efflux pump, by positively regulating the transcription of the corresponding gene.

Study phs002903

Immunogenomics of Malignant Brain Tumors

We performed systematic and comprehensive multi-sector immunogenomic analyses on 93 samples from a cohort of 30 patients with primary or recurrent gliomas or metastatic brain tumors, representing the largest cohort of these brain cancers studied spatially to date. For each patient, we characterized multiple spatially distinct regions using whole-exome (WES), custom capture validation, RNA, and TCR-sequencing. Our findings underscore the significant differences in clonal architecture between gliomas and metastatic brain tumors which translates into distinct neoantigen landscapes and, in turn, tumor infiltrating T cell clonotypic diversity. These data therefore provide high resolution insights into the immunogenomic landscapes within malignant brain tumors which may inform tumor-specific therapeutic approaches.

Study phs002612

Phase I Clinical Trial Describing the Pharmacogenomics of Aspirin

The study protocol for both cohorts has been previously described (Journal of Thrombosis and Thrombolysis 2012:1-12). HV1 cohort: Briefly 50 healthy volunteers were exposed to two weeks of 325mg/day aspirin after which whole blood RNA was collected in PAXgene tubes and profiled by microarray before and after aspirin exposure. The pre-aspirin samples were profiled on the U133A 2.0 array and the post-aspirin samples were profiled on the U1333plus 2.0 array. HV2 cohort: Briefly 53 healthy volunteers were exposed to four weeks of 325mg/day aspirin after which whole blood RNA was collected in PAXgene tubes and profiled by U133plus 2.0 array before and after aspirin exposure.

Study phs000548

Germline

This study is part of the 'First 1,000 Days of Life and Beyond' study at the Inova Translational Medicine Institute. Whole-genome sequencing data from 1,291 parent-offspring trios was used to study the properties of clustered de novo mutations. The maternal clusters were found to be enriched in regions with accelerated maternal mutation rate and show distinct mutational signatures. For additional details, please refer to: "Germline de novo mutation clusters arise during oocyte aging in genomic regions with increased double-strand break incidence". Jakob M. Goldmann, Vladimir B. Seplyarskiy, Wendy S.W. Wong, Thierry Vilboux, Pieter B. Neerincx, Dale L. Bodian, Benjamin D. Solomon, Joris A. Veltman, John F. Deeken, Christian Gilissen, John E. Niederhuber. Nature Genetics.

Study phs001522

Clinical and genetic analysis of retinopathy of prematurity - GWAS

This project aims to identify genetic variants that contribute to the development of retinopathy of prematurity (ROP). ROP is a leading cause of childhood blindness worldwide. We have performed a genome wide association study (GWAS) using Illumina Global Screening Array (GSA) BeadChip. For this GWAS design we assembled the largest group of ROP patients described to date: around 1000 ROP patients in total. Demographic and phenotypic information associated with each sample includes gestational age, gender, ethnicity, multiple birth status, presence of ROP, and birth weight. The results of this study will help advance our understanding of the genetic susceptibility to ROP and may result in novel treatment options to slow the progression of the disease.

Study phs002020

Sweden-Schizophrenia Population-Based Case-Control Exome Sequencing

Current findings of the genetic risk of schizophrenia and bipolar disorder emerging from genome wide association studies (GWAS) support a highly polygenic model displaying the full spectrum of causal alleles that includes the extremes of rare, penetrant alleles as well as common alleles of small effect. Lower frequency polymorphism, rare variants and private mutations have eluded measurement by GWAS studies and thus association with disease. In order to create a comprehensive catalogue of low frequency or rare coding variation in individuals with psychiatric disease and to build a foundation for future genetic studies of schizophrenia and bipolar disorder, we have obtained whole exome DNA sequence from a population-based schizophrenia and bipolar disorder Swedish case-control cohort.

Study phs000473

Multiethnic Cohort Adiposity Phenotype Study (MEC-APS)

A total of 1,861 healthy men and postmenopausal women aged 60-77 years with body mass indexes (BMIs) of 17.1-46.2 kg/m2 were enrolled into the study. Stratified sampling was conducted based on sex, race/ethnicity, and six BMI categories (18.5-21.9, 22-24.9, 25-26.9, 27-29.9, 30-34.9, and 35-40 kg/m2) to balance the sample size across the wide range of BMI and optimize adjustment for total adiposity in populations with different BMI distributions. Study participants underwent body composition assessment, in person interview, blood collection, and completed a self-administered questionnaire. A genome-wide association study of obesity phenotypes was conducted among five racial/ethnic groups of the Multiethnic Cohort Study.

Study phs001689

Long-read whole genome sequencing of gastric cancer

Gastric cancer (GC) remains a significant health challenge globally, with a particularly high incidence in Asia, including Singapore. Understanding the genomic landscape of normal gastric and the different GC subtypes along with its precursor lesions such as intestinal metaplasia (IM) as well as GC metastatic sites is crucial for advancing diagnostics, prognostics, and therapeutics. Long-read sequencing technologies offer an opportunity to delve deeper into the genomic and epigenetic alterations underlying these conditions and to complement existing short-read omics data. By integrating these data with previously generated in-house multi-omics data (such as RNA sequencing and whole exome sequencing), we hope to better elucidate the molecular mechanism underlying GC initiation and progression.

Study EGAS50000001607

Illumina HiSeqX and HiSeq 2000 whole genome sequence data on 3,001 ALS samples including 212 with known C9orf72 repeat expansions

Whole genome sequence (WGS) data was generated on 3,001 samples previously quantified for the presence of the C9orf72 repeat expansion (212 expanded and 2,789 wild type), These samples were sequenced using a combination of 2x100bp reads on an Illumina HiSeq2000 and 2x150bp reads on an Illumina HiSeqX sequencer. The repeat expansions were called using ExpansionHunter to demonstrate the ability to call large repeats from high throughput, WGS data. Provided here are all read pairs where at least one of the reads aligns within 1kb of the C9orf72 repeat expansion in addition to reads aligned in pre-determined off target locations where the aligners are known to mis-align reads.

Study EGAS00001002598

ProjectMinE :llumina HiSeqX and HiSeq 2000 whole genome sequence data on 3,001 ALS samples including 212 with known C9orf72 repeat expansions

Whole genome sequence (WGS) data was generated on 3,001 samples previously quantified for the presence of the C9orf72 repeat expansion (212 expanded and 2,789 wild type), These samples were sequenced using a combination of 2x100bp reads on an Illumina HiSeq2000 and 2x150bp reads on an Illumina HiSeqX sequencer. The repeat expansions were called using ExpansionHunter to demonstrate the ability to call large repeats from high throughput, WGS data. Provided here are all read pairs where at least one of the reads aligns within 1kb of the C9orf72 repeat expansion in addition to reads aligned in pre-determined off target locations where the aligners are known to mis-align reads.

Study EGAS00001003383

Neoadjuvant chemotherapy alters the genomic landscape and immune microenvironment of breast cancers

To characterize the effects of neoadjuvant chemotherapy (NAC) on the genome, transcriptome and tumor infiltrating leukocytes (TILs), we have conducted whole exome and whole transcriptome sequencing of a comprehensive, longitudinal breast cancer cohort consisting of 146 cases and 281 paired tumor samples. In total, 52 (38%) patients achieved pathologic complete response (pCR) while 85 patients (62%) had residual disease with standard chemotherapy regimen. Tumor biopsies were collected for each patient at three time points – pre-treatment, three weeks after the first cycle of anthracycline and cyclophosphamide (AC) and at the time of surgery after 3 more cycles of AC followed by 4 cycles of taxane or taxane plus Herceptin in case of HER2+ subtype.

Study EGAS00001003354

Autoimmunity_and_immunodeficiency_COVID19

Cell Atlas of COVID-19 patients with Pre-existing Autoimmunity and Immunodeficiency conditions COVID-19 disease is characterized by hyperinflammation of the lungs and poor immune response against the virus, leading to acute respiratory distress syndrome. Patients with pre-existing medical conditions strongly correlated with poorer clinical outcomes upon SARS-CoV-2 infection. This study aims to characterize the cellular response to SARS-CoV-2 infection in controls and in patients with primary immunodeficiency and autoimmune 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/

Study EGAS00001004489

Single-cell RNA-seq data of the tumor microenvironment of lymphocyte-rich Hodgkin lymphoma and other Hodgkin lymphoma subtypes

Lymphocyte-rich classic Hodgkin lymphoma (LR-CHL) is a rare subtype of Hodgkin lymphoma. Recent technical advances have allowed for the characterization of specific crosstalk mechanisms between malignant Hodgkin Reed-Sternberg (HRS) cells and different normal immune cells in the tumor microenvironment (TME) of CHL. However, the TME of LR-CHL has not yet been characterized at single cell resolution. Here, using single cell RNA sequencing, we examined the immune cell profile of 8 cell suspension samples of LR-CHL in comparison to 20 samples of the mixed cellularity (9 cases) and nodular sclerosis (11 cases) subtypes of CHL, as well as 5 reactive lymph node controls.

Study EGAS00001005541

Using human induced pluripotent stem cell-derived oligodendrocytes to explore cellular phenotypes associated with t(1;11) translocation.

Although the underlying neurobiology of major mental illness (MMI) remains unknown, emerging evidence implicates a role for oligodendrocyte-myelin abnormalities. Here, we took advantage of a large family carrying a balanced t(1;11) translocation, which substantially increases risk of MMI, to undertake both diffusion tensor imaging (DTI) and cellular studies to evaluate the consequences of the t(1;11) translocation on white matter structural integrity and oligodendrocyte-myelin biology (this translocation disrupts among others the DISC1 gene which plays a crucial role in brain development). At a cellular level, we observe dysregulation of key pathways controlling oligodendrocyte development and morphogenesis in induced pluripotent stem cell (iPSC) case derived oligodendrocytes.

Study EGAS00001004595

Chip_seq_oesophageal_adenocarcinoma_

There is complex interplay between underlying genetic sequence and epigenetic factors, however this interplay is still illusive. Massively reconstructed cancer genomes can be used in order to better understand this relationship. Six oesophageal adenocarcinoma organoids will be sequenced using long read sequencing technologies and will be profiled for a range of epigenetic marks. Combination of genetic and epigenetic data will allow the thorough characterisation of reference cancer genomes and will provide novel insights into mechanisms of gene regulation. Description: Chip-seq Sequencing of 5 patient derived organoid cell models. Each model was derived from a piece of patient tumour taken following surgical rescetion of the tumour. All model derivations took place with the CGaP facility in Sanger.

Study EGAS00001007180

TCR- and BCR-sequencing data for The interface of malignant and immunologic clonal dynamics in high-grade serous ovarian cancer

Each tumor sample was cut into three pieces, yielding two end-pieces for cryovials and a middle portion placed in 10% buffered formalin. End pieces were homogenized manually and with a paddle blender (Stomacher). All paraffin-embedded blocks, including formalin-fixed tumor samples and molecular-fixed fallopian tubes, were sectioned and stained with hematoxylin and eosin prior to expert histopathological review to confirm the presence of high grade serous carcinoma. Homogenized end pieces were then flash frozen, and RNA was extracted using the miRNeasy Mini kit. Nanodrop was used to assess quality (260/280) and quantity. Total RNA samples were also QC checked using the Caliper HT RNA HiSens assay. Samples ranging from 60-255ng RNA were re-arrayed into a 96-well plate. 5'-RACE PCR was carried out as described in "The interface of malignant and immunologic clonal dynamics in high-grade serous ovarian cancer" (Zhang et al.). Briefly, this involved first round and nested PCR with TRB (TCR beta chain) and IGH (immunoglobulin heavy chain) gene-specific primers. The indexed libraries were sequenced on the Illumina HiSeq platform with paired-end 250bp reads using v2 chemistry reagents.

Dataset EGAD00001003985

10X whole single cell RNA-seq from pre-frontal cortex biopsy

The biopsy procedure was performed by a standard operative procedure under general anaesthesia. The placement of burr hole on the frontal lobe, opening of dura and cortex was performed in a routine fashion for VP shunt or VCS surgery. The biopsy was sharp dissected with knife through the leptomeninges, forming a tissue block consisting of cortex and subcortex, and placed in a sterile tube containing CSF. Fresh tissue sample processing was performed within the hours after surgery. The tissue was dissociated followed by red cell and debris removal and counting of the cells to be sequenced with (scRNA-seq; 10x Genomics). After dissociation only non neuronal cells were retrieved.

Study EGAS50000001058

Transcriptional profiling of ovarian tumours and cell lines

Purpose: Endogenous retroviruses (ERVs) play a role in a variety of biological processes, including embryogenesis and cancer. DNA methyltransferase inhibitors (DNMTi)-induced ERV expression triggers interferon responses in ovarian cancer cells via the viral sensing machinery. Baseline expression of ERVs also occurs in cancer cells, though this process is poorly understood and previously unexplored in epithelial ovarian cancer (EOC). Here, the prognostic and immunomodulatory consequences of baseline ERV expression was assessed in EOC. Experimental Design: ERV expression was assessed using EOC transcriptional data from TCGA and from an independent cohort (HH), as well as from untreated or DNMTi-treated EOC cell lines. LASSO logistic regression defined an ERV expression score to predict patient prognosis. Immunohistochemistry (IHC) was conducted on the HH cohort. Combination of DNMTi treatment with γδ T cells was tested in vitro, using EOC cell lines and patient-derived tumor cells. Results: ERV expression was found to define clinically relevant subsets of EOC patients. An ERV prognostic score was successfully generated in TCGA and validated in the independent cohort. In EOC patients from this cohort, a high ERV score was associated with better survival (log-rank p=0.0009) and correlated with infiltration of CD8+PD1+ T cells (r=0.46, p=0.0001). In vitro, baseline ERV expression dictates the level of ERV induction in response to DNMTi. Manipulation of ERV expression by DNMTi resulted in improved EOC cell killing by cytotoxic immune cells. Conclusions: These findings uncover the potential for baseline ERV expression to robustly inform EOC patient prognosis, influence tumor immune infiltration and affect anti-tumor immunity.

Study EGAS00001004814

Cholesterol homeostasis and lipid raft dynamics at the basis of tumor-induced immune dysfunction in chronic lymphocytic leukemia

Autologous T-cell therapies show limited efficacy in chronic lymphocytic leukemia (CLL), where acquired immune dysfunction prevails. In CLL, disturbed mitochondrial metabolism has been linked to defective T-cell activation and proliferation. Recent research suggests that lipid metabolism regulates mitochondrial function and differentiation in T cells, yet its role in CLL remains unexplored. This comprehensive study compares T-cell lipid metabolism in CLL patients and healthy donors, revealing critical dependence on exogenous cholesterol for human T-cell expansion following TCR-mediated activation. Using multi-omics and functional assays, we found that T cells present in viably frozen samples of patients with CLL (CLL T cells) showed impaired adaptation to cholesterol deprivation and inadequate upregulation of key lipid metabolism transcription factors. CLL T cells exhibited altered lipid storage, with increased triacylglycerols and decreased cholesterol, and inefficient fatty acid oxidation (FAO). Functional consequences of reduced FAO in T cells were studied using samples from patients with inherent FAO disorders. Reduced FAO was associated with lower T-cell activation but did not affect proliferation. This implicates low cholesterol levels as a primary factor limiting T-cell proliferation in CLL. Consequently, CLL T cells displayed fewer and less clustered lipid rafts, potentially explaining the impaired immune synapse formation observed in these patients. Our findings highlight significant disruptions in lipid metabolism as drivers of functional deficiencies in CLL T cells, underscoring the pivotal role of cholesterol in T-cell proliferation. This study suggests that modulating cholesterol metabolism could enhance T-cell function in CLL, presenting novel immunotherapeutic approaches to improve outcome in this challenging disease.

Study EGAS50000000933

ARDSnet and the iSPAAR Consortium: Genomic Basis of Susceptibility and Outcomes in Patients with the Acute Respiratory Distress Syndrome (ARDS)

Acute Respiratory Distress Syndrome (ARDS)/ Acute Lung Injury (ALI) is a syndrome defined by the presence of acute hypoxemic respiratory failure, bilateral pulmonary infiltrates on chest radiograph, a known clinical risk factor (e.g. sepsis, pneumonia, trauma, gastric fluid aspiration, pancreatitis, massive transfusion), and the absence of physiologic or clinical evidence of congestive heart failure. The Identification of SNPs Predisposing to Altered ALI Risk (iSPAAR) study is a multi-institutional cooperative study, funded through the NHLBI Recovery Act, that assembled samples and phenotype information from existing cohorts. The consortium included samples from patients with ARDS from the NIH NHLBI ARDS Clinical Trials Network (ARDSNet). Samples were obtained from 3 interventional treatment trials in patients with ARDS, including the Fluid and Catheter Treatment Trial (FACTT), the Albuterol to Treat Acute Lung Injury (ALTA) trial, and the Omega-3 Fatty Acid/Antioxidant Supplementation for ALI trial (Omega). In addition to ARDSnet samples, samples from the other cohorts included cases of established ARDS but also controls: critically ill patients who were at-risk for ARDS but who did not develop ARDS during their hospital course. These cohorts included the Molecular Epidemiology of Acute Respiratory Distress (MEA) Study enrolled at the Harvard University/Massachusetts General Hospital, the Systemic Inflammatory Immune Response Syndrome (SIRS) Patient Database and ICU Traumatic Injury cohorts from Harborview Medical Center, and cohorts collected from the ALI research programs at the University of Pennsylvania and the University of California, San Francisco. The Cohort is utilized in the following dbGaP sub-studies. To view genotypes, other molecular data, and derived variables collected in these sub-studies, please click on the following sub-studies below or in the "Sub-studies" box located on the right hand side of this top-level study page phs000631 ARDSnet iSPAAR Consortium. phs000334 ESP_LungGO_ALI phs000686 ALI_GeneticRisk

Study phs000631

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