22951 results for "ega"

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• Genome-wide cell-free DNA biological patterns in patients with cancer

  The structure of cell-free DNA (cfDNA) is altered in the blood of cancer patients. From whole genome sequencing we retrieved the cfDNA fragment-end composition using a new software (FrEIA), as well as the cfDNA size and tumor fraction in three independent cohorts (n=925 cancer from >10 types and 321 control samples). At 95% specificity, we detect 72% of cancer samples using at least one cfDNA measure, including 64% of early-stage cancer (n=220). cfDNA detection correlates with a shorter overall (p=0.018) and recurrence-free (p=0.006) survival in patients with resectable esophageal adenocarcinoma. Integrating cfDNA measures with machine learning in an independent test set (n=396 cancer, 90 controls) achieve a detection accuracy of 82% and AUROC of 96%. In conclusion, harnessing the biological features of cfDNA can improve at no-extra cost the diagnostic performance of liquid biopsies.

  Study EGAS00001007400

• RNA sequencing in primary inflammatory (TPP) macrophages following deletion of a disease-associated gene desert at chr21q22, disruption of ETS2, or treatment of ETS2-edited macrophages with a HIF1α stabiliser.

  GWAS studies in five different inflammatory diseases have identified a strong genetic association at a gene desert at the chr21q22 locus. We have shown that this locus contains a monocyte/macrophage-specific enhancer that regulates ETS2 - a gene whose role in primary human monocytes/macrophages is incompletely understood. We therefore used a CRISPR-Cas9-based approach to delete the enhancer region or to disrupt ETS2, and performed RNA-sequencing to examine the transcriptional consequences. One effect of ETS2 disruption was upregulation of genes involved in aerobic respiration and oxidative phosphorylation. We therefore treated ETS2-edited inflammatory macrophages with roxadustat, a HIF1α stabiliser that can promote glycolysis via HIF1α-mediated metabolic reprogramming, and performed RNA-sequencing to determine whether this drug might rescue the transcriptional effects of ETS2 disruption.

  Study EGAS00001007553

• Cancer of Low survival and UnMet Need – Pathologist Initiated

  Despite significant advances in diagnostic cancer histopathology, a subset of tumors remain unable to be classified using WHO criteria. The resulting diagnostic uncertainty can result in inappropriate clinical management and negative patient outcomes. We investigated whether combining histopathology with whole genome and transcriptome sequencing (WGTS) could improve the classification of tumors that posed diagnostic dilemmas despite extensive histopathology and standard molecular work-up at a quaternary oncology center. We successfully sequenced 45 tumors from an initial set of 54 unclassified tumors (83% success rate). A confident diagnosis was made for 38/45 tumors (84%). Additionally, potential treatment targets were identified in 21/45 tumors (47%). Theoretical comparison with alternative assays demonstrated that WGTS was uniquely capable of detecting critical diagnostic findings in 15/38 tumors (39%). This work supports augmenting histopathology and standard molecular pathology with WGTS in the classification of difficult-to-diagnose tumors.

  Study EGAS00001008112

• Single-cell and spatial transcriptomic profiling of hormone-naïve localised prostate cancer

  Localised prostate cancers (PCa) are heterogeneous and multifocal, with diverse outcomes. Current prognostic methods are epithelium-centric, overlooking the complex cellular landscape within the tumour microenvironment (TME), which remains incompletely characterised. We performed a comprehensive analysis of cancerous and adjacent-benign cores from 24 patients with hormone therapy-naïve localised PCa using single-cell RNA-sequencing. By integrating copy number variation and transcriptional signatures, we classified epithelial cells across a malignant spectrum, revealing widespread molecular perturbation. We found an expansion of Club cell phenotypes, suggestive of Luminal dedifferentiation. We also performed a detailed annotation of stromal phenotypes, focusing on fibroblasts, and identified a novel peri-neural fibroblast population. Spatial transcriptomics elucidated the precise anatomical distribution of CAFs within the PCa TME. This study provides a valuable foundation for advancing our understanding of PCa pathobiology and developing a comprehensive cellular model of the disease.

  Study EGAS00001008332

• Digital tEchnology For Lung Cancer Treatment

  The aim of the DEFLeCT project (Digital tEchnology For Lung Cancer Treatment) is to generate a technological platform for precision medicine in order to set predictive personalised algorithms for patient diagnosis and therapy. All resectable patients having histologically confirmed stage IB-IIIA non-small cell lung cancer(NSCLC) will be enrolled in the PROMOLE study, a related and ongoing observational prospective clinical study, for tissue sampling. A large biobank of lung cancer samples and the corresponding healthy tissues and biological components (ie, blood, stools, etc.) with complete clinical, pathological and molecular information will be collected. The project will lay the basis of a knowledge hub and qualified technology aimed not only at answering the medical and scientific community's questions, but also meant to be useful to individual patients by predicting the response to adjuvant and second-line drugs in case of relapse of the disease.

  Study EGAS00001007219

• Raw human sequencing data for “Characterization of intestinal immune responses in generalized human and murine lipodystrophy”

  This dataset contains raw FASTQ files generated from peripheral blood and intestinal biopsy samples collected for the study “Characterization of intestinal immune responses in generalized human and murine lipodystrophy.” Peripheral blood sequencing was performed on samples from three healthy donors as controls and from a patient with acquired generalized lipodystrophy and Crohn’s disease (AGLCD) at two distinct timepoints. Intestinal biopsy–derived immune cells were sequenced from three individuals with Crohn’s disease as disease controls, as well as from the AGLCD patient (single timepoint). The data include paired-end FASTQ files derived from single-cell RNA sequencing and T-cell receptor repertoire profiling, enabling analyses of immune composition, transcriptional states, and clonal T-cell expansion. All data are controlled-access human genomic datasets and require appropriate authorization for secondary use.

  Study EGAS50000001517

• A small cell lung cancer genome reports complex tobacco exposure signatures

  Cancer is driven by mutation. Worldwide, tobacco smoking is the major lifestyle exposure that causes cancer, exerting carcinogenicity through 60 chemicals that bind and mutate DNA. Using massively parallel sequencing technology, we sequenced a small cell lung cancer cell line, NCI-H209, to explore the mutational burden associated with tobacco smoking. 22,910 somatic substitutions were identified, including 132 in coding exons. Multiple mutation signatures testify to the cocktail of carcinogens in tobacco smoke and their proclivities for particular bases and surrounding sequence context. Effects of transcription-coupled repair and a second, more general expression-linked repair pathway were evident. We identified a tandem duplication that duplicates exons 3-8 of CHD7 in-frame, and another two lines carrying PVT1-CHD7 fusion genes, suggesting that CHD7 may be recurrently rearranged in this disease. These findings illustrate the potential for next-generation sequencing to provide unprecedented insights into mutational processes, cellular repair pathways and gene networks associated with cancer.

  Study EGAS00000000051

• Geographical structure and differential natural selection among North European populations

  European populations and epidemiological cohorts are of special significance in the current era of genomic research aiming to characterize the background of common human diseases. The genome sequence, detailed information of genetic variations between individuals, high-throughput molecular technologies and novel statistical strategies create new possibilities to define genetic and life-style risk factors behind common health problems. Studies of large population cohorts are needed to transform the genetic information to detailed understanding of the predisposing factors in diseases affecting most human populations. European twin cohorts provide a unique competitive advantage for investigations of the role of genetics and environment or life style in the etiology of common diseases. This project will apply and develop new molecular and statistical strategies to analyze unique European twin and other population cohorts to define and characterise the genetic, environmental and life-style components in the background of health problems like obesity, migraine, coronary heart disease and stroke, representing major health care problems worldwide.

  Study EGAS00000000033

• HG_Retroduplications_in_Neurodevelopmental_Disorders

  Mobile genetic Elements (MEs) are pieces of DNA which, through an RNA intermediate, can generate new copies of themselves elsewhere in the host genome. Additionally, MEs can facilitate the duplication of non-ME transcripts, typically genes, through the mechanism of retroduplication. In humans, several disorders have been directly attributed to ME-derived mutagenesis but not to retroduplication events. We propose to whole genome sequence the 7 individuals with putative de novo gene retroduplications in order to identify the site of insertion. This sequencing will serve two primary purposes: 1.) Identify the first documented case of a de novo retrogene insertion event causing a disease in humans 2.) provide additional whole genome sequencing of undiagnosed probands recruited into the DDD 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 EGAS00001002907

• NOWAC blood-based breast cancer case-control study

  Tumor-host interactions extend beyond the local microenvironment and cancer development largely depends on the ability of malignant cells to hijack and exploit the normal physiological processes of the host. Although abnormalities in a host’s systemic immunity are associated with increased cancer susceptibility, the functional interplay between tumor cells and circulating immune cells in regulating tumorigenic responses is unclear. We employed the Norwegian Women and Cancer study, a large prospective population-based cohort study, to identify gene expression changes in blood cells that provide a robust and reproducible diagnostic signal specific to breast cancer patients. We further show that circulating blood cells in breast cancer patients are enriched in genes involved in systemic immunosuppression and the motility, metabolism, growth, and proliferation of immune cells. By mining of the cancer-associated blood transcriptome, we identified immune mediators or biomarkers that could permit early detection of breast cancer and open avenues to novel targeted immunotherapies.

  Study EGAS00000000134

• Origination of Ovarian Cancer is Dependent on Specific Aneuploidy Landscape

  Ovarian high-grade serous carcinoma (HGSC), a highly chromosomally instable malignancy, develops through sequential stages of precursors in fallopian tubes including histologically unremarkable but TP53 mutated clones (p53 signature) and serous tubal intraepithelial carcinoma (STIC). Here, we applied RealSeqS to assess aneuploidy in 127 microdissected tubal regions. We found nearly all p53 signatures lost the entire Chr17 chromosome, offering a “two-hit” mechanism of both TP53 and BRCA1 in BRCA1 germline mutation carriers. Proliferatively active STICs harbor gains of 19q12 (CCNE1), 19q13.2, 8q24 (MYCyc), or 8q arm, while proliferatively dormant STICs show 22q loss. Based on aneuploidy patterns in a training set (n= 67), we developed an algorithm, REAL-FAST, to classify NFTE and STICs into 5 clusters. In an independent validation set (n= 72), REAL-FAST was able to detect STIC/HGSC with high sensitivity and specificity. Taken together, REAL-FAST promises a molecular test for diagnosing HGSC precursor lesions based on specific aneuploidy patterns.

  Study EGAS00001007220

• Colon cancer targeted sequencing study contaning WBCs, primary tumor tissue and plasma samples

  In the setting of localized colon cancer (CC), circulating tumor DNA (ctDNA) monitoring in plasma has shown potential for detecting minimal residual disease (MRD) and predicting higher risk of recurrence. With the tumor-only sequencing approach, however, germline variants may be misidentified as somatic variations, precluding the possibility of tracking in up to 11% of patients due to a lack of known somatic mutations. In this study comprising 148 prospectively recruited localized CC patients, a custom 29-gene panel was utilized to sequence both tumor tissue and matched white blood cells (WBCs) to enhance the accuracy of sequencing results. Performing targeted sequencing of paired tumor tissue and WBCs samples detected additional somatic mutations and increased the number of patients eligible for MRD tracking in plasma, although MRD detection sensitivity was not increased. Furthermore, the germline testing approach revealed the presence of pathogenic germline variants, thereby helping identify patients at elevated risk of hereditary cancer syndromes.

  Study EGAS50000000059

• Oxidative DNA damage and ubiquitin proteasome system dysfunction underpins neurodegeneration in young adults with a DNA repair disorder

  Xeroderma pigmentosum (XP) is caused by defective nucleotide excision-repair of DNA damage. This results in hypersensitivity to ultraviolet light and increased skin cancer risk, as sunlight-induced photoproducts remain unrepaired. However, many XP patients also display early-onset neurodegeneration, which leads to premature death. The mechanism of neurodegeneration is unknown. Here, we investigate XP neurodegeneration using pluripotent stem cells derived from XP patients and healthy relatives, performing functional multi-omics on samples during neuronal differentiation. We have identified substantially increased levels of 5',8-cyclopurine and 8-oxopurine in XP neuronal DNA secondary to marked oxidative stress. Furthermore, we find endoplasmic reticulum stress is upregulated, and, critically, XP neurons exhibit inappropriate downregulation of the protein clearance ubiquitin-proteasome system (UPS). Chemical enhancement of UPS activity improves phenotypes, albeit inadequately, implying that early detection/prevention strategies are necessary to produce clinically impactful outcomes. Thus, we develop an early detection assay predicting neurodegeneration in at-risk patients.

  Study EGAS50000000160

• Oxidative DNA damage and ubiquitin proteasome system dysfunction underpins neurodegeneration in young adults with a DNA repair disorder

  Xeroderma pigmentosum (XP) is caused by defective nucleotide excision-repair of DNA damage. This results in hypersensitivity to ultraviolet light and increased skin cancer risk, as sunlight-induced photoproducts remain unrepaired. However, many XP patients also display early-onset neurodegeneration, which leads to premature death. The mechanism of neurodegeneration is unknown. Here, we investigate XP neurodegeneration using pluripotent stem cells derived from XP patients and healthy relatives, performing functional multi-omics on samples during neuronal differentiation. We have identified substantially increased levels of 5',8-cyclopurine and 8-oxopurine in XP neuronal DNA secondary to marked oxidative stress. Furthermore, we find endoplasmic reticulum stress is upregulated, and, critically, XP neurons exhibit inappropriate downregulation of the protein clearance ubiquitin-proteasome system (UPS). Chemical enhancement of UPS activity improves phenotypes, albeit inadequately, implying that early detection/prevention strategies are necessary to produce clinically impactful outcomes. Thus, we develop an early detection assay predicting neurodegeneration in at-risk patients.

  Study EGAS50000000162

• Oxidative DNA damage and ubiquitin proteasome system dysfunction underpins neurodegeneration in young adults with a DNA repair disorder

  Xeroderma pigmentosum (XP) is caused by defective nucleotide excision-repair of DNA damage. This results in hypersensitivity to ultraviolet light and increased skin cancer risk, as sunlight-induced photoproducts remain unrepaired. However, many XP patients also display early-onset neurodegeneration, which leads to premature death. The mechanism of neurodegeneration is unknown. Here, we investigate XP neurodegeneration using pluripotent stem cells derived from XP patients and healthy relatives, performing functional multi-omics on samples during neuronal differentiation. We have identified substantially increased levels of 5',8-cyclopurine and 8-oxopurine in XP neuronal DNA secondary to marked oxidative stress. Furthermore, we find endoplasmic reticulum stress is upregulated, and, critically, XP neurons exhibit inappropriate downregulation of the protein clearance ubiquitin-proteasome system (UPS). Chemical enhancement of UPS activity improves phenotypes, albeit inadequately, implying that early detection/prevention strategies are necessary to produce clinically impactful outcomes. Thus, we develop an early detection assay predicting neurodegeneration in at-risk patients.

  Study EGAS50000000158

• scRNAseq data of CAP

  Fastq files from scRNAseq data of cancer associated pericytes-like from 3 patients. CAP were isolated from a total of 3 primary BC (surgical residues prior to any treatment) by using BDFACS ARIA III sorter (BD Biosciences). BC were collected directly from the operating room after surgical specimen macroscopic examination and selection of areas of interest by a pathologist. Samples were cut into small pieces (around 1 mm3) and digested in CO2-independent medium (Gibco #18045-054) supplemented with 150 μg/mL liberase (Roche #05401020001) and Dnase I (Roche #11284932001) for 40 min at 37°C with shaking (180 rpm). After digestion, cells were processed and stained as described above (#Flow Cytometry analysis of BC samples). CAP fibroblasts were then gated on the Live/Dead negative fraction and defined as EPCAM- CD45- CD31- CD235a- FAPMed CD29High. CAP scRNA-seq: Upon isolation, CAP cells were directly collected into RNase-free tubes (Thermo Fisher Scientific, #AM12450) precoated with DMEM (GE Life Sciences, #SH30243.01) supplemented with 10% FBS (Biosera, #1003/500). Single-cell capture, lysis, and cDNA library construction were performed using Chromium system from 10X Genomics, with the following kits: Chromium Single Cell 3′ Library & Gel Bead Kit v2 kit (10X Genomics, #120237) and Chromium Single Cell A Chip Kits (10X Genomics, #1000009). Generation of gel beads in Emulsion (GEM), barcoding, post GEM-reverse transcription cleanup and cDNA amplification were performed according to the manufacturer’s instructions. Cells were loaded accordingly on the Chromium Single cell A chips, and 12 cycles were performed for cDNA amplification. cDNA quality and quantity were checked on Agilent 2100 Bioanalyzer using Agilent High Sensitivity DNA Kit (Agilent, #5067-4626) and library construction followed according to 10X Genomics protocol. Libraries were next run on the Illumina HiSeq (for patients P1) and NovaSeq (for patients P2–3) with a depth of sequencing of 50,000 reads per cell.

  Dataset EGAD50000000321

• Karyotype Evolution in Response to Chemoradiotherapy and Upon Recurrence of Esophageal Adenocarcinomas

  The genome of esophageal adenocarcinoma (EAC) is highly unstable and might evolve over time. Here, we track karyotype evolution in EACs in response to treatment and upon recurrence through multi-region and longitudinal analysis. To this end, we introduce L-PAC, a bio-informatics technique that allows inference of absolute copy number aberrations (CNA) of low-purity samples by leveraging information of high-purity samples from the same cancer. Quantitative analysis of matched absolute CNAs reveals that the amount of karyotype evolution induced by chemoradiotherapy (CRT) is predictive for early recurrence and depends on the initial level of karyotype intra-tumor heterogeneity. We observe that CNAs acquired in response to CRT are partially reversed back to the initial state upon recurrence. CRT hence alters the fitness landscape to which tumors can adjust by adapting their karyotype. Together, our results indicate that karyotype plasticity contributes to therapy resistance of EACs.

  Study EGAS00001007711

• Multiomic spatial landscape of innate immune cells at central nervous system borders

  The innate immune compartment of the human central nervous system (CNS) is highly diverseand includes several immune cell populations such as macrophages that are frequent in the brain parenchyma (microglia) and less numerous at the brain interfaces as CNS-associated macrophages (CAMs).Due to their scantiness and particular location, little is known about the presence of temporally and spatially restricted CAM subclasses during development, health and perturbation. Here, we combined single-cell RNA-sequencing, time-of-flight mass cytometry and single-cell spatial transcriptomics with fate mapping and advanced immunohistochemistry to comprehensively characterize the immune system at human CNS interfaces. We also provide a comprehensive analysis of resident and engrafted myeloid cells in the brains of 15 individuals with peripheral blood stem cell transplantation, revealing compartment-specific engraftment rates across different CNS interfaces... Our results highlight myeloid diversity at the interfaces of the human CNS with the periphery and provide insights into the complexities of the human brain’s immune system.

  Study EGAS50000000030

• Immunomodulatory effects and improved outcomes with cisplatin- vs carboplatin-based chemotherapy plus atezolizumab in urothelial cancer

  In metastatic urothelial cancer (mUC), cisplatin versus carboplatin leads to durable disease control in a subset of patients. The IMvigor130 trial reveals more favorable effects with atezolizumab combined with gemcitabine and cisplatin (GemCis) versus gemcitabine and carboplatin (GemCarbo). This study investigates the immunomodulatory effects of cisplatin as a potential explanation for these observations. Our findings indicate that improved outcomes with GemCis versus GemCarbo are primarily observed in patients with pretreatment tumors exhibiting features of restrained adaptive immunity. Additionally, GemCis versus GemCarbo ± atezolizumab induces transcriptional changes in circulating immune cells, including upregulation of antigen presentation and T-cell activation programs. In vitro experiments demonstrate that cisplatin, compared with carboplatin, exerts direct immunomodulatory effects on cancer cells, promoting dendritic cell activation and antigen-specific T cell killing. These results underscore the key role of immune modulation in cisplatin's efficacy in mUC and highlight the importance of specific chemotherapy backbones in immunotherapy combination regimens.

  Study EGAS50000000104

• Improved detection of colibactin-induced mutations by genotoxic E. coli in organoids and colorectal cancer

  Co-culture of intestinal organoids with a colibactin-producing pks+ E. coli strain (EcC) revealed mutational signatures also found in colorectal cancer (CRC). E. coli Nissle 1917 (EcN) remains a commonly used probiotic, despite harboring the pks operon and inducing double strand DNA breaks. We determine the mutagenicity of EcN and three CRC-derived pks+ E. coli strains with an analytical framework based on sequence characteristic of colibactin-induced mutations. All strains, including EcN, display varying levels of mutagenic activity. Furthermore, a machine learning approach attributing individual mutations to colibactin reveals that patients with colibactin-induced mutations are diagnosed at a younger age and that colibactin can induce a specific APC mutation. These approaches allow the sensitive detection of colibactin-induced mutations in ~12% of CRC genomes and even in whole exome sequencing data, representing a crucial step towards pinpointing the mutagenic activity of distinct pks+ E. coli strains.

  Study EGAS50000000212