3874 results for "*geneti*"

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• An exome sequencing approach to defining the genetic risk factors for Achilles tendinopathy

  Musculoskeletal soft tissue injuries are complex phenotypes. Case control association studies using the candidate gene approach have predominantly been used to identify risk loci for these injuries. However, the ability to identify all risk conferring variants using this approach alone is unlikely. Therefore, this study aimed to define the genetic profile of these injuries using whole exome sequencing and a customized analysis pipeline. The exomes of ten exemplar asymptomatic controls and ten exemplar cases with Achilles tendinopathy were individually sequenced using a platform that included the coverage of the untranslated regions and miRBase miRNA genes. These results provide a proof of concept for the use of a customized pipeline for the exploration of a larger genomic dataset. This approach, using previous research to guide a targeted analysis of the data has generated new genetic signatures in the biology of musculoskeletal soft tissue injuries.

  Study EGAS00001003234

• Personalised Mapping of Tumour Development in Synchronous Colorectal Cancer Patients

  We performed an in-depth characterisation of 12 tumours from 3 syCRC patients by analysing histopathological, whole genome sequencing and RNA-sequencing data. We assessed the extent of genetic overlap between synchronous tumours and examined associations between clinicopathological information and the molecular, microbial and immune features of each tumour genome.

  Study EGAS00001004413

• Papua New Guinean Genome Diversity Project

  Papua New Guinean populations have one of the highest genetic diversity of the world. Our dataset provides genomic data covering most of the Papua New Guinean territory (n=58).

  Study EGAS00001005393

• A mechanistic classification of clinical phenotypes in neuroblastoma

  Clinical courses of the pediatric tumor neuroblastoma range from fatal progression to spontaneous regression. To gain insights into the pathogenesis of these divergent subtypes, we performed massively parallel sequencing of 416 pretreatment neuroblastomas and assessed telomere maintenance mechanisms in 208/416 cases. We observed that telomere maintenance and mutations in RAS or p53 pathway genes strongly affected disease courses. Fatal outcome occurred only in the presence of telomere maintenance, whereas patients whose tumors lacked such mechanisms had excellent outcome. In patients with telomere maintenance-positive tumors, survival was dramatically inferior when additional RAS/p53 pathway mutations were present. By contrast, spontaneous regression occurred both in the presence and absence of RAS/p53 pathway mutations in patients with telomere maintenance-negative tumors. Together, our data provide a precise mechanistic classification of clinical neuroblastoma phenotypes based on telomere maintenance mechanisms and genetic alterations of the tumor.

  Study EGAS00001003244

• Genomic characterization of co-existing biliary tract intraepithelial neoplasia and carcinoma lesions reveals distinct evolutionary paths of gallbladder cancer

  Gallbladder carcinoma is the most common cancer of the biliary tract with dismal survival largely due to delayed diagnosis. Biliary tract intraepithelial neoplasia (BilIN) is the common benign tumor that is suspected to be precancerous lesions. However, the genetic and evolutionary relationships between BilIN and carcinoma remain unclear. Here we performed whole-exome sequencing of coexisting low-grade BilIN (adenoma), high-grade BilIN, and carcinoma lesions, and normal tissues from the same patients.

  Study EGAS00001005402

• Identifying transcriptional programs underlying anti-EGFR small molecule response and resistance with TraCe-seq

  Genetic and non-genetic heterogeneity within cancer cell populations represents a major challenge to anti-cancer therapies. We currently lack robust methods to determine how pre-existing and adaptive features affect cellular responses to therapies. Here, by conducting clonal fitness mapping and transcriptional characterization using expressed barcodes and single-cell RNA-sequencing, we have developed TraCe-seq, a method that captures at clonal resolution the origin, fate, and differential early adaptive transcriptional programs of cells in a complex population in response to distinct treatments. We used TraCe-seq to benchmark how next-generation dual EGFR inhibitors-degraders compare to standard EGFR kinase inhibitors in EGFR-mutant lung cancer cells. To QC the TraCe-seq strategy, single-cell RNA-seq libraries were generated from a variety of human cancer cell lines transduced with the TraCe-seq library to validate the TraCe-seq strategy. Specifically, 5 different cell lines (PC9, MCF-10A, MDA-MB-231, NCI-H358, and NCI-H1373) were each transduced with a unique TraCe-seq barcode. The transduced cells were selected with puromycin only, dissociated to single cell suspensions, and then mixed together. The complex mixture of the 5 cell lines was profiled by 10X scRNA-seq. Furthermore, transduced NCI-H1373 cells were sorted by FACS to enrich for the top 50% of eGFP positive cells, and sorted cells were cultured briefly and used to construct scRNA-seq libraries and profiled by 10x scRNA-seq. To carry out the full TraCe-seq experiment, ~600 PC9 cells carrying unique TraCe-seq barcodes were expanded over 12 doublings to establish the barcoded population. A subset of the barcoded PC9 population was used to generate scRNA-seq libraries and profiled by 10x scRNA-seq prior to treatment to establish a baseline transcription profile for each barcoded clone. The rest of the cells were then treated for four days with 1 µM erlotinib, 1 µM GNE-069, or 1 µM GNE-104 respectively. scRNA-seq libraries were then generated form the treated cells and profiled by 10x scRNA-seq.

  Study EGAS00001005405

• 46 CLL Whole Genome Sequencing Study

  Chronic lymphocytic leukaemia (CLL) consists of two biologically and clinically distinct subtypes defined by the abundance of somatic hypermutation (SHM) affecting the Ig variable heavy-chain locus (IgHV). The molecular mechanisms underlying these subtypes are incompletely understood. Here, we present a comprehensive whole-genome sequencing analysis of somatically acquired genetic events from 46 CLL patients, including a systematic comparison of coding and non-coding single nucleotide variants, copy number variants and structural variants, regions of kataegis and mutation signatures between IgHVmut and IgHVunmut subtypes.

  Study EGAS00001003254

• Combination therapies to inhibit LCK tyrosine kinase and mTOR signaling in T-cell Acute Lymphoblastic Leukemia

  Relapse and refractory T cell acute lymphoblastic leukemia (T-ALL) has a poor prognosis and new combination therapies are sorely needed. This work uncovered potent drug synergies between AKT/mTORC1 inhibitors and the general tyrosine kinase-inhibitor, dasatinib. The combination effectively curbed T-ALL growth in human cell lines and primary human T-ALL samples, and was well tolerated and effective in suppressing leukemia growth in patient-derived xenografts grown in mice. Mechanistically, dasatinib inhibited phosphorylation and activation of the lymphocyte-specific protein tyrosine kinase (LCK) to blunt the T-cell receptor (TCR) signaling pathway and when complexed with mTORC1 inhibition, induced potent T-ALL cell killing through reducing MCL-1 protein expression. Analysis of responses across T-ALL subtypes and association with specific genetic mutations or expression patterns failed to identify any obvious biomarkers or correlations in predicting therapy responses, although there appeared to be a trend toward higher TCR/LCK pathway activity in samples that exhibited synergistic therapy responses.

  Study EGAS00001005945

• Identifying the role of ID3 in DNA repair and maintenance of genome integrity

  The inhibitor of DNA-binding 3 (ID3) is a transcriptional repressor protein that limits the binding of basic helix­loop-helix (bHLH) transcription factors to DNA. Preliminary results from our lab confirm that cellular depletion of ID3 is associated with an impaired DNA damage response. we hypothesize that ID3 has the potential to epigenetically affect DNA repair. This is based on our observation that upon cellular ID3 knockdown, a reduction of chromatin-bound H4K16ac and H3K36me3.

  Study EGAS00001004478

• Fine-Scale Genomic Analyses Of Admixed Individuals Reveal Unrecognized Genetic Ancestry Components In Argentina

  Study the sub-continental origins of African, European and Native American genetic ancestries of Argentinean populations.

  Study EGAS00001004492

• Germline TP53 mutations undergo copy number gain years prior to tumor diagnosis

  Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome associated with germline TP53 mutations. We performed whole-genome sequence (WGS) analysis of tumors from 22 TP53 mutation carriers. We observed somatic mutations affecting Wnt, PI3K/AKT signaling, epigenetic modifiers and homologous recombination genes as well as mutational signatures associated with prior chemotherapy. We identified near-ubiquitous early loss of heterozygosity of TP53, with gain of the mutant allele. This occurred earlier in these tumors compared to tumors with somatic TP53 mutations, suggesting the timing of this mark may distinguish germline from somatic TP53 mutations. Phylogenetic trees of tumor evolution, reconstructed from bulk and multi-region WGS, revealed that LFS tumors exhibit comparatively limited heterogeneity. Overall, our study delineates early copy number gains of mutant TP53 as a characteristic mutational process in LFS tumorigenesis, likely arising very early in life or in utero.years prior to tumor diagnosis.

  Study EGAS00001005982

• An epigenetic single-cell atlas of IDH-mutant glioma reveals the role of ATRX in shaping tumor composition

  Recent single-cell RNA-sequencing studies have identified a hierarchy of cell types that is common to all isocitrate dehydrogenase (IDH) -mutant gliomas. This finding is somewhat paradoxical since the genetic differences between IDH-mutant astrocytomas and IDH-mutant oligodendrogliomas are prognostic, predictive of therapeutic response, and correlated with differences in immune infiltrates. To integrate these disparate findings, we constructed a single-cell atlas of 22 human IDH-mutant primary untreated grade-II/III gliomas.

  Study EGAS00001004523

• Host genotyping data from Dutch adult bacterial meningitis patients and linked bacterial genome sequences

  Streptococcus pneumoniae is a common nasopharyngeal colonizer, but can also cause life-threatening invasive diseases such as empyema, bacteremia and meningitis. Genetic variation of host and pathogen is known to play a role in invasive pneumococcal disease, though to what extent is unknown. This study includes 1146 samples of host genotyping data (genotyped and imputed) from Illumina Omni arrays. Samples were collected from adults (>16 yrs) patients with CSF confirmed bacterial meningitis in the Netherlands between 2006 and 2015. Metadata includes patient outcome, species of bacteria, and for 467 samples a link to an ENA run with the associated bacterial genome (S. pneumoniae only).

  Study EGAS00001005993

• An epigenomics time course analysis of covid19 patients from Quebec, Canada

  Investigating the cellular and epigenetic changes at play in severely ill hospitalized COVID-19 patients at admission and how it evolves with prognosis. Single-cell RNA-seq analysis done on longitudinal samples highlighted changes in the monocytic compartment, which we explored using whole-genome epigenomics methods (ATACseq abd WGBS).

  Study EGAS00001005468

• Multimodal immunogenomic biomarker analysis of tumors from pediatric patients enrolled to a phase 1-2 study of single-agent atezolizumab

  We report herein an extensive exploratory biomarker analysis of refractory tumors taken from pediatric patients prior to receiving atezolizumab monotherapy in the phase 1-2 iMATRIX-atezolizumab trial (NCT02541604). A high percentage of CD8+ T cells and elevated protein levels of programmed cell death ligand 1 (PD-L1) were associated with progression-free survival (PFS). T-cell receptor (TCR) sequencing revealed that diverse infiltrating TCR repertoire at baseline was prognostic. We found no associations between panel-based tumor mutation burden (TMB) or specific genetic aberrations with PFS in this study. Through a pan-cancer gene co-expression network analysis, we developed a novel tumor-agnostic Pediatric Cytotoxicity and Antigen Presentation (PedCAP) signature that was associated with improved PFS in the iMATRIX-atezo study. Our study highlights features of immune response in pediatric cancers when treated with immune checkpoint inhibitors and provides a multi-biomarker pediatric immunogram framework to guide prospective clinical trials in pediatric cancers.

  Study EGAS00001006004

• Novel mutations in TOP2A in gliomas

  High grade gliomas (HGGs) are aggressive, primary brain tumors with poor clinical outcomes. To better understand glioma pathobiology and find potential therapeutic susceptibilities, we designed a custom- panel 664 cancer- and epigenetics-related genes and employed targeted next generation sequencing to study the genomic landscape of somatic and germline variants in 182 glioma samples of different malignancy grades. Besides known alterations in TP53, IDH1, ATRX, EGFR genes, we found several novel variants that can be potential drivers in gliomas. In four patients from the Polish glioma cohort, we identified a novel recurrent mutation in the TOP2A gene coding for Topoisomerase 2A in glioblastomas (GBM, WHO grade IV gliomas). The mutation results in a substitution of glutamic acid (E) 948 to glutamine (Q) of TOP2 A and we predicted this E948Q substitution may affect DNA binding and a TOP2A enzymatic activity.

  Study EGAS00001004556

• Multi-omics integration reveals only minor long-term molecular and functional sequelae in immune cells of individuals recovered from COVID-19

  The majority of COVID-19 patients experience mild to moderate disease course and recover within a few weeks. An increasing number of studies characterized the long-term changes in the specific anti-SARS-CoV-2 immune responses, but how COVID-19 shapes the innate and heterologous adaptive immune system after recovery is less well known. To comprehensively investigate the post-SARS-CoV-2 infection sequelae on the immune system, we performed a multi-omics study by integrating single-cell RNA-sequencing, single-cell ATAC-sequencing, genome-wide DNA methylation profiling, and functional validation experiments in convalescent COVID-19 and healthy individuals. We showed that immune responses generally recover without major sequelae after COVID-19. However, subtle differences persist at the transcriptomic level in monocytes, with downregulation of the interferon pathway, while DNA methylation also displays moderate changes in convalescent COVID-19 individuals. However, these differences did not affect the cytokine production capacity of PBMCs upon different bacterial, viral, and fungal stimuli, although baseline release of IL-1RA and IFN?? was higher in convalescent individuals. In conclusion, despite minor differences in epigenetic and transcriptional programs, the immune system of convalescent COVID-19 patients largely recovers to the homeostatic level of healthy individuals.

  Study EGAS00001005529

• Atypical teratoid/rhabdoid tumoroids reveal subgroup-specific drug vulnerabilities

  Atypical teratoid/rhabdoid tumors (ATRTs) represent a rare, but aggressive pediatric brain tumor entity. They are genetically defined by mutations in SWI/SNF chromatin remodeling complex members SMARCB1 or SMARCA4. ATRTs can be subdivided in different molecular subgroups based on their epigenetic profiles. Although recent studies suggest that the different subgroups have distinct clinical features, subgroup-specific treatment regimens have not been developed thus far. This is hampered by the lack of pre-clinical in vitro models representative of the different molecular subgroups. Here, we describe the establishment of ATRT tumoroid models from the ATRT-MYC and ATRT-SHH subgroups. We demonstrate that ATRT tumoroids retain subtype-specific epigenetic and gene expression profiles. High throughput drug screens on our ATRT tumoroids revealed distinct drug sensitivities between and within ATRT subgroups. Our ATRT tumoroids represent the first pediatric brain tumor organoid model, providing representative pre-clinical models allowing for the development of subtype-specific therapies.

  Study EGAS00001006422

• The endometrial transcription landscape of MRKH syndrome

  The Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome (OMIM 277000) is characterized by agenesis of the uterus and upper part of the vagina in females with normal ovarian function. While genetic causes have been identified for a small subset of patients and epigenetic mechanisms presumably contribute to the pathogenic unfolding, too, the etiology of the syndrome has remained largely enigmatic. A comprehensive understanding of gene activity in the context of the disease is crucial to identify etiological components and their potential interplay. So far, this understanding is lacking, primarily due to the scarcity of samples and suitable tissue. In order to close this gap, we profiled endometrial tissue of uterus rudiments in a large cohort of MRKH patients using RNA-seq and thereby provide a genome-wide view on the altered transcription landscape of the MRKH syndrome.

  Study EGAS00001004601

• Patient-tailored design for selective co-inhibition of leukemic cell subpopulations

  The extensive primary and secondary drug resistance in many cancer types requires rational approaches to design personalized and selective combinatorial therapies that do not only show synergistic effect in overall cancer cell killing but also result in minimal toxic side effects on non-malignant cells. To address the combinatorial explosion in the number of relevant combinations, we implemented a machine learning approach that prioritizes patient-customized drug combinations with a desired synergy-efficacy-toxicity balance by combining single-cell RNA-sequencing with ex vivo single-agent testing in scarce patient-derived primary cells. When applied to two diagnostic and two refractory AML patient cases, each with a different genetic background, our integrated approach accurately predicted patient-specific combinations that were shown to result not only in synergistic cancer cell co-inhibition but were also capable of targeting specific AML cell subpopulations that emerge in differing stages of disease pathogenesis or treatment regimens. Our data-driven approach provides an unbiased means for systematic identification of personalized combinatorial regimens that selectively co-inhibit leukemic cells while avoiding inhibition of non-malignant cells, and highlight the relevance of considering cell heterogeneity for personalized cancer therapy.

  Study EGAS00001004614

• Understanding_hematopoietic_stem_cell_mobilization_and_engraftment_

  This study looks at patients undergoing gene therapy for genetic blood and immune disorders, in particular sickle cell disease. From each patient, single blood HSPC colonies are grown from patient blood mononuclear cells, bone marrow mononuclear cells, or CD34+ at multiple time points: pre gene transduction, post-transduction, and post-infusion (at several time points). Whole-genome sequencing will be performed on DNA from these colonies and somatically-acquired mutations will be called. Using these mutations, a phylogeny of these cells can be inferred and further inferences can be made about the gene therapy transduction and engraftment steps.

  Study EGAS00001004620

• Germline variants in patients with rare cancers and their implications for precision cancer medicine: experiences from the Multicenter MASTER Trial by the German Cancer Consortium (HIPO_021)

  The era of precision oncology entails an increasing amount of molecular data from tumor sequencing in research and diagnostics. In this setting, germline variant analysis may add clinical benefits for patients and family members. In this study, we evaluated germline variants from genome/exome matched tumor-blood sequencing in 1.485 advanced cancer patients within a prospective observational study carried out by the German Cancer Consortium. Included patients had cancers of rare entities (79.2%) or were under the age of 51 at first diagnosis (76.6%). Ten percent of the patients harbored pathogenic germline variants in 35 tumor predisposition genes with autosomal-dominant inheritance such as BRCA1, BRCA2, TP53, RB1, CHEK2, ATM, PALB2, SDHB etc., while 4.6% of the patients were carriers of pathogenic germline variants in 18 genes with autosomal-recessive inheritance of tumor predisposition. Based on pathogenic germline variants, 14% of the patients received genetic counselling recommendations in the molecular tumor board report. Forty five percent of pathogenic germline variants supported a molecular treatment recommendation, which was implemented for 28 patients. Furthermore, we compared our approach and results to previous studies, broadening the insight into pan cancer germline findings but also revealing differences between studies on various levels, such as cohort demographics, tumor entities, gene nominations, variant detection and variant interpretation. Our data support the importance of germline variant interpretation in precision oncology studies for patients and their families, if applicable. However, guidelines for evaluation and reporting of germline variants in the context of genetic tumor profiling need to be established and further research on the relevance of germline mutations as biomarkers for treatment recommendations is needed.

  Study EGAS00001005537

• ATAC-seq/ChIP part

  Epigenetics: ATAC-seq and ChIP-seq data

  Study EGAS00001006520

• Pediatric study using genome sequencing

  This study used whole genome sequencing to assess genome variants from DNA from pediatric individuals seen in genetics clinic who were thought to have genetic conditions.

  Study EGAS00001005553

• DLBCL NGS Genomic Datasets of non-China cohort from Phoenix Clinical Trial

  Study biopsies (n=773; 189 cases as China cohort and 584 cases as non-China cohort) underwent whole exome sequencing or targeted gene panel DNA sequencing and RNA sequencing, allowing the identification of somatic mutations. Tumors were assigned to DLBCL genetic subtypes as the MCD (n=110), BN2 (n=47) or N1 (n=28) using the LymphGen algorithm based on their somatically mutated genes. In younger patients (age≤60), ibrutinib plus R-CHOP was associated with a 100% event free survival (EFS) at 3-years in the MCD and N1 groups, whereas R-CHOP alone was associated with a 3-year EFS of 42.9% (p=0.01) and 50% (p=0.016) in the MCD and N1 groups, respectively. This analysis showed a benefit of ibrutinib with R-CHOP chemotherapy in particular genetic subtypes, providing mechanistic support for its survival benefit in younger patients with non-GCB DLBCL. The EGA collects RNA-Seq and NuGene targeted sequencing datasets of 584 cases for non-China cohort.

  Study EGAS00001005554