4051 results for "*geneti*"

in 61.91 milliseconds.

• Understanding_the_development_of_resident_memory_T_cells__Trm__in_the_human_small_intestine_using_integrative_multiomic_approaches__Adult_RNA

  Animal studies have demonstrated that resident memory T (Trm) cells provide enhanced protective responses to a broad array of tissue-tropic pathogens, thus making Trm cells promising targets for novel vaccination strategies. However, the biological pathways that enable the long-term survival of Trm cells are poorly understood in humans. Here, we will employ a unique human intestinal transplantation setting that allows us to study the retention of persistent T cells in the grafts and the temporal development of resident T-cell populations from recruited recipient T cells. We will integrate high resolution transcriptomics, epigenetics, proteomics and immune repertoire single-cell data from purified intestinal T cells. These single-cell multiomics approaches will uncover the diversity and differentiation of the T cell populations in the human intestine, allowing us to temporally resolve the generation and maintenance of gut resident T cells.

  Study EGAS00001008257

• Peruvian Population Genomics: Unraveling the Genetic Landscape and Admixture Dynamics of Urban Populations

  Genome-wide study of human populations living in Peruvian urban areas

  Study EGAS00001008264

• Molecular subtypes of pancreatic neuroendocrine tumors mutated in MEN1/DAXX/ ATRX explain biological variability

  Pancreatic Neuroendocrine Tumors (PanNETs) most probably arise from the islets of Langerhans, although direct evidence is still lacking. About 40% of non-functioning (NF) PanNETs harbour mutations in MEN1, often in conjunction with alterations in DAXX/ATRX. Despite the homogeneous genetic background, the ADM (mutation in DAXX/ATRX and MEN1) group is heterogeneous regarding molecular features and response to treatment. To explore the molecular and clinical heterogeneity within this group, we integrated transcriptomic and DNA methylation data from 36 and 93 samples, respectively. Using a multi-omic approach we described a two-level hierarchy separating PanNET subtypes mutated in MEN1, DAXX and ATRX. First, DNA methylation discriminates ADM-PanNET from PanNET mutated in MEN1 only (α-like). Compared to α-like, all ADM tumors exhibit DNA methylation changes at enhancer and lowly methylated regions as well as at peri-centromeric and telomeric regions, associated with alternative lengthening of telomeres, increased chromosomal instability, and enhanced proliferative capacity. At a second level, transcriptomic analysis revealed three distinct ADM subtypes: ADM hypoxic, ADM NST (No Special Type), and ADM immunosuppressive. The ADM hypoxic subtype is characterized by strong hypoxia signature, likely regulated epigenetically. The ADM NST subtype appears to be primarily driven by epigenetic changes that promote proliferation. The ADM immunosuppressive is highly enriched in immune component and strong metastasis-like signature. While all the three subtypes are highly associated with liver metastasis formation and invasion, the ADM immunosuppressive are significantly smaller (<2.5 cm p.value=0.023) despite displaying aggressive molecular features. By defining these three novel ADM subtypes, our study provides a refined framework for understanding PanNET heterogeneity. This classification underscores potential diagnostic markers and highlights distinct biological vulnerabilities that may inform the development of subtype-tailored therapeutic strategies.

  Study EGAS00001008272

• Immunodeficiency syndrome caused by LCP1 mutations

  Severe congenital neutropenia (SCN) is characterized by neutropenia, recurrent infections and an increased leukemia risk. Multiple genetic defects underlying SCN have been identified, but a genetic diagnosis is still lacking in a significant proportion of patients. Here, we report three independent pedigrees with autosomal dominant variants in LCP1. Variants c.740-1G>T and c.740-20_744del resulted in the same alternatively spliced RNA product, causing an in-frame deletion (p.A247_E254del). Variant c.509C>T in the third pedigree resulted in p.S170L. Variant carriers suffer from neutropenia, poor or complete lack of response to G-CSF treatment, and variable degrees of lymphopenia. Patients with A247_E254del presented with tetraploid cells in the bone marrow, indicative of disturbed cytokinesis. In one of these kindreds, two individuals developed acute leukemia. G-CSF non-responsiveness and defective cell cycling were repaired upon correction of the LCP1 A247_E254del variant in patient-derived induced pluripotent stem cells, supporting the monogenic origin of the disease. Indicative of their gain-of-function, both A247_E254del and S170L variants increased F-actin bundling and formation of abnormal protrusions. Single-cell transcriptome analysis of A247_E254del bone marrow-derived hematopoietic stem and progenitor cells (HSPCs) showed deregulation of signaling pathways controlling mitosis in multi-lineage and lymphoid-primed HSPC subsets. We conclude that activating LCP1 variants cause a new autosomal dominant hematopoietic disorder. Depending on the consequences of the LCP1 variants for protein structure, patients may suffer from G-CSF refractory severe neutropenia, lymphopenia, defective cytokinesis and predisposition to leukemia.

  Study EGAS00001008293

• Duplex sequencing in NF2-related schwannomatosis

  Background: Schwannomatosis (SWN) is a rare tumor predisposition syndrome caused by pathogenic variants in NF2, SMARCB1, or LZTR1. Mosaicism contributes to up to 30% of de novo NF2-related cases, but its role in SMARCB1- and LZTR1-related SWN remains unclear. Accurate molecular classification is critical for clinical management, yet overlapping phenotypes complicate diagnosis. Because standard diagnostics have limited sensitivity and often require tumor tissue, we evaluated whether ultra-sensitive duplex sequencing of blood-derived DNA improves mosaic variant detection in SWN. Methods: We developed a duplex sequencing assay targeting NF2, SMARCB1, and LZTR1 and analyzed 102 individuals with suspected SWN previously negative for constitutional pathogenic variants, along with 35 controls. Results: Duplex sequencing identified low-level mosaic NF2 pathogenic variants in 11% of cases (11/102), with variant allele frequencies as low as 0.06%. In all patients with available tumor material (8/11), blood and tumor findings were concordant. No mosaic pathogenic variants were detected in SMARCB1 or LZTR1. Controls showed no deleterious variants except one LZTR1 splice-site variant. Conclusions: Duplex sequencing enables robust detection of ultra-low-frequency NF2 variants in SWN and complements existing diagnostic workflows. This approach may reduce dependence on tumor tissue in NF2-related SWN, improve differential diagnosis, and support patient management and genetic counseling.

  Study EGAS00001008298

• Epigenetic profiling of acute myeloid leukemia

  To investigate the epigenetic heterogeneity of acute myeloid leukemia (AML), we analyzed a cohort of AML patients using ATAC-seq (n=1563), targeted-capture sequencing (n=1563), and RNA-seq (n=1398). Subsets of cases were also analyzed using EPIC DNA methylation array (n=424), ChIP-seq (for H3K27ac (n=234), H3K27me3 (n=217), SMC1 (n=209), CTCF (n=218), and RPB1 (n=220)), and single-cell RNA- and ATAC-seq (n=36).

  Study EGAS00001008315

• H3Africa - Deciphering Developmental Disorders in Africa

  Developmental disorders are typically rare conditions, causing an impairment in physical, learning, language, or behavioural areas. Genetic heterogeneity and highly variable clinical manifestations make diagnosing developmental disorders particularly challenging. Developmental disorders are increasing in prevalence in low- and middle-income countries, partly due to effective prevention and treatment of infectious diseases leading to a decrease in childhood mortality. New sequencing technologies are used effectively in the diagnosis of rare diseases and results can impact clinical practice significantly. Despite this international trend, very little implementation of these new approaches has taken place in low-resource settings, especially in Africa. The Deciphering Developmental Disorders in Africa (DDD-Africa) study aims to take advantage of an unbiased genotype-driven approach to improve healthcare services for patients. The study aims to recruit and perform detailed clinical phenotyping and exome sequencing (ES) on 500 African patients with a developmental disorder in whom a genetic diagnosis has not been confirmed. Where available, parents are also included in sequencing efforts. The project has two active research sites in Johannesburg (South Africa) and Kinshasa (Democratic Republic of Congo) representing diversity in geography, clinical, socio-economic, genetic and environmental factors.

  Study EGAS00001008319

• Taste Receptor Gene Variants: Body Mass Index (BMI) and Longevity

  We evaluated differences in genotype and allele frequencies at the TAS1R2, TAS1R3, TAS2R38, and CD36 single-nucleotide polymorphisms (SNPs) and their associations with BMI and sex in two genetically and environmentally distinct populations: a cohort of near centenarian participants and a control cohort.

  Study EGAS00001008403

• Transcriptional and translational alterations induced by BET protein inhibition and its combination with Omaveloxolone in acute myeloid leukemia

  The inhibition of bromodomain and extra-terminal domain (BET) protein family achieved promising preclinical results as epigenetic therapy in acute myeloid leukemia (AML). However, clinical data showed a limited activity of bromodomain inhibitor (BETi) as single agent. We aimed to investigate the role of hypoxia in the response of AML cells to BET inhibition in order to identify a novel therapeutic combination targeting leukemia stem-progenitor cells (LSPCs) in their niche. BETi maintained an anti-proliferative and pro-apoptotic activity at low oxygen concentration by modulating the leukemic transcriptional, translational and metabolic programs towards reduced ribosome biogenesis, altered polyamine metabolism and activation of a TNF- via NF-B signature at translational level, especially in hypoxic conditions. Accordingly, Omaveloxolone, a clinical-stage NF-B inhibitor and NFR2 activator approved for Friedreich’s ataxia, significantly enhanced the efficacy of BETi against AML cell lines in hypoxia and normoxia by reducing cell viability and enhancing apoptosis. At molecular level, the drug combination converged to the downregulation of MYC, the DNA replication and oxidative phosphorylation signatures while forcing the expression of antioxidant genes. Overall, the combination of BETi and Oma disrupts key metabolic and transcriptional programs essential to AML cell survival and LSPC maintenance in the hypoxic microenvironment.

  Study EGAS00001008404

• Brazilian biorepository to support genome-wide association studies of colorectal, breast, and cervical cancer

  This study established a large-scale Brazilian biorepository to support cancer GWAS, replication studies, and polygenic risk score (PRS) evaluation for colorectal, breast, and cervical cancers. 4,062 participants have been enrolled, including cancer cases and cancer-free controls. Genotyping was performed in 2,844 participants using the Axiom 850K PMDA Array. Genetic ancestry inference confirmed Brazil’s highly admixed genetic background, with predominant European, followed by African, Native American, and Asian contributions. This biorepository provides a scalable resource to enable replication of genetic associations, assess the transferability of polygenic risk scores, and advance precision medicine in underrepresented populations.

  Study EGAS00001008408

• Genomic and fragmentomic landscapes of cell-free DNA in aging and disease

  Genome-wide analyses of cell-free DNA (cfDNA) are beginning to be used for non-invasive disease diagnosis, but these approaches have not been explored for detection of aging-related diseases. We used low coverage whole genome sequencing (1-2x) to assess variation in cfDNA fragmentomes across 1446 individuals of varying ages with different comorbidities and genetic risk profiles. Analysis of cfDNA fragment characteristics revealed changes in overall concentration and size distributions, as well as alterations in genome-wide fragmentation profiles, chromosomal representation, repeat element landscapes, end-positions, and coverage at epigenetic regions in the circulation of aging individuals. cfDNA fragmentome characteristics were uniquely altered in a variety of human morbidities, including vascular, neurologic, and inflammatory diseases, and were independent predictors of patient outcomes in separate prospectively collected discovery (n=570) and validation (n=231) cohorts. cfDNA fragmentome-based analyses detected Alzheimer’s disease in aging individuals with varying germline risk profiles (n=645). These results identify changes in cfDNA fragmentomes in aging populations and highlight the potential of cfDNA liquid biopsies to provide snapshots of an individual’s physiologic state in health and disease.

  Study EGAS00001008470

• Spatial Omics Resolves Adrenergic and Mesenchymal Cell States in Neuroblastoma

  Neuroblastoma is a pediatric cancer arising from the developing sympathoadrenal lineage. Although cell lines derived from neuroblastoma patients have features of either adrenergic (ADRN) or mesenchymal (MES) cells, identifying MES cells in patient tumors is challenging and controversial. Here, to characterize intra- and inter-patient cellular heterogeneity, we analyze 54 neuroblastoma tumors spanning broad clinical, genetic, and histologic features using single-cell/single-nucleus RNA-sequencing (sc/snRNA-seq), bulk RNA-sequencing, spatial transcriptomics, and spatial proteomics. We show that tumor cells occupy distinct cellular neighborhoods separated from nonmalignant immune and stromal cells, yet established cell line-derived gene expression signatures fail to identify MES neuroblastoma cells. We therefore develop ADRN/MES signatures from early passage orthotopic patient-derived xenografts, enabling identification of MES tumor cells, validated by transcriptomic, epigenomic, proteomic, ultrastructural and functional assays. In patients, high MES gene expression correlates with worse event-free and overall survival. Together, this study provides a framework for defining clinically relevant neuroblastoma cell states.

  Study EGAS00001008537

• A nationwide prospective randomized trial for diagnosing developmental disorders demonstrates whole-genome sequencing outperforms whole-exome sequencing.

  Whole-exome (WES) or whole-genome (WGS) sequencing are recommended as first- or second-tier molecular tests for patients with developmental disorders (DD), but the clinical utility of WGS continues to be debated. This prospective randomized trial involving all Belgian Human Genetics centers compared the standard of care (SoC) - combining WES and microarray or shallow WGS - with WGS for 567 individuals with unexplained DD. The diagnostic yield of WGS was 39.8% (113/284) vs 30% for SoC (85/283) (p=0.015), mainly due to an increased detection of single nucleotide variants and indels (+8.7%). WGS also enabled the detection of three non-coding (potential) pathogenic variants. Diagnostic yield was higher for females (45.5%, 97/213) compared to males (28.5%, 101/354) (p<0.001). De novo variants were found for 23.6% of patients. Analysis of inherited variants in genes associated with autosomal dominant phenotypes contributed more to the diagnostic yield (3.9%) than X-linked variants (1.9%), and to a similar extent as autosomal recessive variants (4.1%). This nationwide study demonstrates WGS outperforms WES for the diagnosis of patients with DD in a decentralized hospital setting and well-characterized cohort. The results also highlight the importance of evaluating autosomal dominant inherited variants in genomics analyses for DD.

  Study EGAS50000002018

• Distinct immune and genomic signatures predict resistance to ibrutinib therapy in Waldenström macroglobulinemia

  In this study, we investigate the complex interplay between tumour-acquired genetic features and the composition of the microenvironment in the promotion of ibrutinib resistance in WM patients by integrating single-cell RNA sequencing (scRNAseq) and whole-genome sequencing (WGS), to examine bone marrow tumour and immune compartments from 37 symptomatic WM patients treated with ibrutinib.

  Study EGAS50000001586

• Egypt Genome Project - high coverage whole genome sequencing

  All humans outside Africa are descendants of the same single exit, usually dated at 50-70 thousand years ago. However, the route taken out of Africa is still debated. The two main candidates are a northern route via Egypt and the Levant, or a southern route via Ethiopia and the Arabian Peninsula. We are generating genetic data to evaluate these two possibilities. In this study we propose to generate high-coverage sequencing data for 3 Egyptian samples.

  Dataset EGAD00001001380

• Cooperative activity of BRAF F595L and mutant HRAS in histiocytic sarcoma provides new insights into oncogenic BRAF signaling

  Mutations that activate the RAF-MEK-ERK signaling pathway, in particular BRAFV600E, occur in many cancers, and mutant BRAF-selective inhibitors have clinical activity in these diseases. Activating BRAF alleles are usually considered to be mutually exclusive with mutant RAS, whereas inactivating mutations in the D594F595G596 motif of the BRAF activation segment can coexist with oncogenic RAS and cooperate via paradoxical MEK/ERK activation. We determined the functional consequences of a largely uncharacterized BRAF mutation, F595L, which was detected along with an HRASQ61R allele by clinical exome sequencing in a patient with histiocytic sarcoma and also occurs in epithelial cancers, melanoma, and neuroblastoma, and investigated its interaction with mutant RAS. We demonstrate that, unlike previously described DFG motif mutants, BRAFF595L is a gain-of-function variant with intermediate activity towards MEK that does not act paradoxically, but nevertheless cooperates with mutant RAS to promote oncogenic signaling. Of immediate clinical relevance, BRAFF595L shows divergent responses to different mutant BRAF-selective inhibitors, whereas signaling driven by BRAFF595L with and without mutant RAS is efficiently blocked by pan-RAF and MEK inhibitors. Mutation data from primary patient samples and cell lines show that BRAFF595L, as well as other BRAF mutations with intermediate activity, frequently coincide with mutant RAS in a broad spectrum of cancers. These data define a novel class of activating BRAF mutations that cooperate with oncogenic RAS in a non-paradoxical fashion to achieve an optimal level of MEK-ERK signaling, extend the spectrum of patients with systemic histiocytic disorders and other malignancies who are candidates for therapeutic blockade of the RAF-MEK-ERK pathway, and underscore the value of comprehensive genetic profiling for understanding the signaling requirements of individual cancers.

  Dataset EGAD00001001384

• Understanding population genetics and patterns of genome-wide heterozygosity in a sample of the Croatian isolated populations (ESGIDalmatians)

  Using high-throughput sequencing technologies and analytical tools, we conduct an exome sequencing study that will help understand the population genetics of a Croatian island isolate, in a sample of 200 subjects from the Adriatic island of Vis who were selected to reflect islanders with at least four known ancestors in grandparental line who are original islanders.

  Dataset EGAD00001001387

• ESGI-Exome sequencing in Circulating Tumor Cells to determine therapy related markers

  The objectives of this project are the identification of markers related to cancer therapy resistance in the blood of breast cancer patients and to study the genetic changes in cancer cells during this development of resistance. Whole genome amplified DNA from Circulating Tumor Cells (CTCs), selected during the course of systemic treatment from blood of metastatic breast cancer patients, will be exome sequenced . The patients selected for this study did not respond to therapy.

  Dataset EGAD00001001425

• TGS - Comprehensive Molecular Characterization of Colorectal Cancer Metastases (2015-07-02)[MOSAIC]

  Systematic next generation sequencing efforts are beginning to define the genomic landscape across a range of primary tumours, but we know very little of the mutational evolution that contributes to disease progression. We therefore propose to obtain a comprehensive description of genomic, transcriptomic and epigenomic changes in a cohort of matched primary and metastatic colorectal cancers, and additionally to explore the extent to which those mutations identified as recurrent in the metastatic setting are able to subvert normal biological processes using both genetically engineered mouse models and established cancer cell lines. This study will enable us to define to what extent primary tumour profiling can capture the biological processes operative in matched metastases as well as the significance of intratumoural heterogeneity. This dataset contains all the data available for this study on 2015-07-02.

  Dataset EGAD00001001426

• SCLC study Peifer et al. - RNAseq dataset

  SCLC - RNA sequencing data Publication Peifer et al., 2012, Nature Genetics

  Dataset EGAD00001001431

• MINCR is a MYC-induced lncRNA able to modulate MYC’s transcriptional network in Burkitt lymphoma cells

  Despite the established role of the transcription factor MYC in cancer, little is known about the impact of a new class of transcriptional regulators, the long non-coding RNAs (lncRNAs), on the way MYC is able to influence cellular transcriptome. To this aim we have intersected RNA-sequencing data from two MYC-inducible cell lines and from a cohort of 91 mature B-cell lymphomas carrying, or not carrying, genetic variants resulting in MYC over-expression. By this approach, we identified 13 lncRNAs differentially expressed in IG-MYC-positive Burkitt lymphoma and regulated in the same direction by MYC in the model cell lines. Among them we focused on a lncRNA that we named MINCR, for MYC-Induced long Non-Coding RNA, showing a strong correlation with MYC expression in MYC-positive lymphomas and also in pancreatic ductal adenocarcinomas. To understand its cellular role we performed RNA interference (RNAi) experiments and found that MINCR knock-down is associated with a reduction in cellular viability, due to an impairment in cell cycle progression. Differential gene expression analysis following RNAi showed a strongly significant enrichment of cell cycle genes among the genes down-regulate following MINCR knock-down. Interestingly these genes are enriched in MYC binding sites in their promoters, suggesting that MINCR acts as a modulator of MYC transcriptional program. Accordingly, following MINCR knock-down, we observed a reduction in the binding of MYC to the promoters of selected cell cycle genes. Finally we provide evidences that down-regulation of AURKA, AURKB and CTD1 may explain the reduction in cellular proliferation observed upon MINCR knock-down. We therefore suggest that MINCR is a newly identified player in the MYC transcriptional network able to control the expression of cell cycle genes.

  Dataset EGAD00001001441

• Atypical teratoid/rhabdoid tumors (ATRT) are comprised of three epigenetic subgroups with distinct enhancer landscapes

  Atypical teratoid/rhabdoid tumor (ATRT) is one of the most common brain tumors in infants and young children. Although the prognosis of ATRT patients is poor, some patients respond very well to current treatments, suggesting inter-tumor molecular heterogeneity. To investigate this further, we genetically and epigenetically analyzed a large cohort of ATRTs (n = 170). Three distinct molecular subgroups of ATRTs, associated with differences in demographics, tumor location and type of SMARCB1 alterations, were identified using DNA-methylation or gene expression analyses. Whole genome DNA- and RNA-sequencing found no other recurrent mutations explaining the differences between subgroups. However, whole genome bisulfite-sequencing and H3K27Ac ChIP-sequencing of primary tumors revealed clear differences in methylation patterns and enhancer landscapes, leading to the identification of subgroup-specific regulatory networks.

  Dataset EGAD00001001444

• Whole genome sequence of third generation family member (SFHS)

  Previously we performed deep WGS on 6 parents and 13 children from 3 large families from the Scottish Family Health Study to identify de novo mutations. This prelim is cover the additional sequencing of one grandchild from one of these three families. The inclusion of a third generation individual will provide additional experimental validation for the de novo mutations found in the initial trio. As in the previous study, the DNA will be WGS to a depth of approximately 25X to achieve this purpose.These data can only be used for the investigation of the genetic causes of the reported clinical phenotypes in these patients

  Dataset EGAD00001001454

• Neuroblastoma relapse trio series from the AMC

  The majority of neuroblastoma patients have tumors that initially respond to chemotherapy, but a large proportion of patients will experience therapy-resistant relapses. The molecular basis of this aggressive phenotype is unknown. Whole genome sequencing of 23 paired diagnostic and relapsed neuroblastomas showed clonal evolution from the diagnostic tumor with a median of 29 somatic mutations unique to the relapse sample. Eighteen of the 23 relapse tumors (78%) showed RAS-MAPK pathway mutations. Seven events were detected only in the relapse tumor while the others showed clonal enrichment. In neuroblastoma cell lines we also detected a high frequency of activating mutations in the RAS-MAPK pathway (11/18, 61%) and these lesions predicted for sensitivity to MEK inhibition in vitro and in vivo. Our findings provide a rationale for genetic characterization of relapse neuroblastoma and show that RAS-MAPK pathway mutations may function as a biomarker for new therapeutic approaches to refractory disease.

  Dataset EGAD00001001360

• Egypt Genome Project - low coverage whole genome sequencing

  All humans outside Africa are descendants of the same single exit, usually dated at 50-70 thousand years ago. However, the route taken out of Africa is still debated. The two main candidates are a northern route via Egypt and the Levant, or a southern route via Ethiopia and the Arabian Peninsula. We are generating genetic data to evaluate these two possibilities. In this study we propose to generate low-coverage sequencing data for 100 Egyptian samples.

  Dataset EGAD00001001372