3311 results for "*geneti*"

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• Dataset that contains runs of submission 152

  Description of runs dataset of submission 152

  Dataset EGAD50000000235

• Integrated genetic analysis of primary CNS lymphoma

  Study EGAS00001007222

• Summary statistics from genome-wide association study in glioma of 12,488 cases and 18,169 controls.

  Genome-wide association studies (GWAS) have transformed our understanding of glioma susceptibility, but individual studies have had limited power to identify risk loci. We performed a meta-analysis of existing GWAS and two new GWAS, which totaled 12,488 cases and 18,169 controls. We identified five new loci for glioblastoma (GBM) at 1p31.3 (rs12752552; P = 2.04 × 10-9, odds ratio (OR) = 1.22), 11q14.1 (rs11233250; P = 9.95 × 10-10, OR = 1.24), 16p13.3 (rs2562152; P = 1.93 × 10-8, OR = 1.21), 16q12.1 (rs10852606; P = 1.29 × 10-11, OR = 1.18) and 22q13.1 (rs2235573; P = 1.76 × 10-10, OR = 1.15), as well as eight loci for non-GBM tumors at 1q32.1 (rs4252707; P = 3.34 × 10-9, OR = 1.19), 1q44 (rs12076373; P = 2.63 × 10-10, OR = 1.23), 2q33.3 (rs7572263; P = 2.18 × 10-10, OR = 1.20), 3p14.1 (rs11706832; P = 7.66 × 10-9, OR = 1.15), 10q24.33 (rs11598018; P = 3.39 × 10-8, OR = 1.14), 11q21 (rs7107785; P = 3.87 × 10-10, OR = 1.16), 14q12 (rs10131032; P = 5.07 × 10-11, OR = 1.33) and 16p13.3 (rs3751667; P = 2.61 × 10-9, OR = 1.18). These data substantiate that genetic susceptibility to GBM and non-GBM tumors are highly distinct, which likely reflects different etiology.

  Study EGAS00001003372

• Genomic_characterisation_of_MGUS__

  he hematological malignancy multiple myeloma (MM), also called Kahler’s disease or plasma cell (PC) myeloma, is characterized by a clonal expansion of PCs originating in the bone marrow (BM). The expansion of these cells leads to an overproduction of antibodies and results in typical symptoms such as anemia, renal failure and bone lesions. All cases of MM are preceded by the asymptomatic, non-malignant pre-stage monoclonal gammopathy of undetermined significance (MGUS). Of all MGUS patients, only 1% per year will progress to MM. Despite efforts to elucidate the molecular mechanisms underlying the MGUS-to-MM progression, its pathogenesis still remains largely unknown. Additionally, the genetic profiles of MGUS patients have only been limitedly investigated due to the only incidental finding of MGUS, the difficulties in BM sampling and isolating a sufficient number of aberrant PCs from the BM aspirates of MGUS patients. Consequently, reliable biomarkers to individually predict which MGUS patients will progress to MM and which will not, are lacking. Therefore, it is highly required to study the molecular pathogenesis of MGUS and the role of genetic events in relation to the malignant transformation to MM.

  Study EGAS00001004124

• Whole_genome_sequencing_of_Italian_genetic_isolates__Friuli_Venezia_Giulia

  Low coverage whole genome sequencing of samples from individuals from Friuli Venezia Giulia, an Italian genetic isolate population.

  Study EGAS00001000252

• Low_depth_whole_genome_sequencing_across_multiple_isolated_populations

  Isolated populations have unique population genetics characteristics that can help boost power in genetic association studies for complex traits. Leveraging these advantageous characteristics requires an in-depth understanding of parameters that have shaped sequence variation in isolates. This study performs a comprehensive investigation of these parameters using low-depth whole genome sequencing (WGS) across multiple isolates.

  Study EGAS00001001597

• A Unifying Paradigm for Transcriptional Heterogeneity and Squamous Features in Pancreatic Ductal Adenocarcinoma

  Pancreatic cancer expression profiles largely reflect a classical or basal-like phenotype. The extent to which these profiles vary within a patient is unknown. We integrated evolutionary analysis and expression profiling in multiregion sampled metastatic pancreatic cancers, finding that squamous features are the histologic correlate of an RNA-seq defined basal-like subtype. In patients with coexisting basal/squamous and classical/glandular morphology, phylogenetic studies revealed that squamous morphology represented a subclonal population in an otherwise classical/glandular tumor. Cancers with squamous features were significantly more likely to have clonal mutations in chromatin modifiers, intercellular heterogeneity for MYC amplification, and entosis. These data provide a unifying paradigm for integrating basal-type expression profiles, squamous histology, and somatic mutations in chromatin modifier genes in the context of clonal evolution of pancreatic cancer.  

  Study EGAS00001003974

• Telomerase activation by genomic rearrangements in high-risk neuroblastoma

  Neuroblastoma is a malignant pediatric tumor of the sympathetic nervous system1. Roughly half of these tumors regress spontaneously or are cured by limited therapy. By contrast, high-risk neuroblastomas have an unfavorable clinical course despite intensive multimodal treatment, and their molecular basis has remained largely elusive2-4. We have performed whole-genome sequencing of 56 neuroblastomas (high-risk, n=39; low-risk, n=17) and discovered recurrent genomic rearrangements affecting a chromosomal region (5p15.22) proximal of the telomerase reverse transcriptase gene (TERT). These rearrangements occurred only in high-risk neuroblastomas (12/39, 31%) in mutually exclusive fashion with MYCN amplifications and ATRX mutations, which are known genetic events in this tumor type1,2,5. In an extended case series (n=217), TERT rearrangements defined a subgroup of high-risk tumors with particularly poor outcome. Despite the large diversity of these rearrangements, they all induced massive transcriptional upregulation of TERT. In the remaining high-risk tumors, TERT expression was also elevated in MYCN-amplified tumors, whereas alternative lengthening of telomeres was present in neuroblastomas without TERT or MYCN alterations, suggesting that telomere lengthening represents a central mechanism defining this subtype. The 5p15.22 rearrangements juxtapose the TERT coding sequence to strong enhancer elements, resulting in massive chromatin remodeling and DNA methylation of the affected region. Supporting a functional role of TERT, neuroblastoma cells bearing rearrangements or amplified MYCN exhibited both upregulated TERT expression and enzymatic telomerase activity. In summary, our findings show that remodeling of the genomic context abrogates transcriptional silencing of TERT in high-risk neuroblastoma and places telomerase activation in the center of transformation in a large fraction of these tumors.

  Study EGAS00001001308

• Canadian Prostate Cancer Genome Network

  Over 5 years, CPC-GENE will sequence the genomes of 350 intermediate risk prostate cancers to identify genetic signatures that differ in cancers that responded well to treatment compared with those that did not. CPC-GENE will also sequence multiple regions of prostate cancer from the same gland to determine if and how the genetic make-up of prostate cancer varies within an individual man’s prostate

  Study EGAS00001000900

• VIKING Health Study - Shetland

  The Viking Health Study – Shetland, together with ORCADES collectively termed VIKING, aims to identify genes influencing risk factors for common diseases such as heart disease, diabetes, glaucoma and stroke. The genetic research cohort study in Shetland was established to identify genetic variants, both common and rare, increasing risk of disease. This isolated population has a number of characteristics, the most important being the very large number of distant relatives, which are favourable for the identification of rare variants influencing disease risk. This study describes PCR-free paired end whole genome sequencing (TruSeq DNA PCR-Free, Illumina) run on a HiSeqX platform at 30X coverage on 500 individuals from VIKING. Unrelated individuals from the largest families were selected first, followed by those from smaller families, until eventually related individuals were selected to best represent the variation in the full cohort.

  Study EGAS00001003872

• Submission 58 - study_title 1

  Submission 58 - description 1

  Study EGAS50000000476

• Epigenomic profiling and transcriptomic profiling of LUAD patients tumor tissues and tumor adjacent tissues

  To provide an in-depth understanding of the epigenomic heterogeneity of LUAD, we here investigated the H3K27ac histone modification profiles of tumors and adjacent normal lung tissues from 42 LUAD patients and explored the role of epigenetic alterations in LUAD progression. We also investigated transcriptomic alterations among 36 patients tumor tissues.

  Study EGAS00001005132

• The Precision Medicine in Liver Cancer across an Asia-pacific NETwork (PLANET)

  Hepatocellular carcinoma (HCC) is the 2nd most important cause of cancer deaths in the world. The outcomes of treatment in HCC are poor compared to other common cancers because there are no good systemic therapy drugs. We designed a prospective study that will involve 5 different sites within the established Asia-Pacific Hepatocellular Carcinoma Trials Group to study both the genetics as well as immune profiles of HCC in different ethnicities. In this study, patients will be followed-up and at recurrence the tissues to understand the evolution of disease progression. Here, we presented both the genomic (DNA) and phenotypic (RNA) evolution for the first batch of 56 patients. The detailed findings will be listed in the corresponding publication soon.

  Study EGAS00001003813

• Prognostic and therapeutic significance of leukemia subtypes and minimal residual disease measurements in pediatric acute lymphoblastic leukemia treated with contemporary risk-directed trial: a cohort study

  Background Genomic analyses to identify leukemia subtypes and refinement of minimal residual disease (MRD) determination are two recent advances that would have substantial impact on the management of children with acute lymphoblastic leukemia (ALL). However, the combined application of these two approaches to determine the prognostic and therapeutic significance of MRD measurement and full spectrum of leukemia subtypes in the context of contemporary risk-directed therapy has not been studied comprehensively.MethodsBetween October 29, 2007 and March 26, 2017, 598 consecutive children with newly diagnosed ALL were enrolled in a clinical trial at St. Jude Children’s Research Hospital. Patients were provisional classified according to the presenting clinical and laboratory features including immunophenotype and cytogenetics. Patients with ETV6-RUNX1 and high hyperdiploid B-progenitor ALL were provisionally included in the low-risk groups; those with TCF3-PBX1, hypodiploidy and T-cell ALL in the standard (intermediate)-risk group; and patients with BCR-ABL1, KMT2A and early T-cell precursor ALL in the high-risk group. Final risk assignment was based primarily on MRD levels measured by flow cytometry on Day 15 (≥1%) and Day 42 (<0.01% or ≥1%) of remission induction. Using genomic classification based on cytogenetics and genomic analysis (single nucleotide polymorphism array analysis and transcriptome, exome, and genome sequencing), patients were classified into 17 subtypes. The primary aim was to determine the event-free survival, overall survival and cumulative risk of relapse according to specific leukemia subtypes and MRD levels on Days 8, 15 and 42 of remission induction. This clinical trial was registered at ClinicalTrials.gov, number NCT00549848.FindingsPatients with ETV6-RUNX1, high hyperdiploidy and DUX4-rearranged B-ALL all received low- or standard-risk therapy, and had the highest 5-year event-free survival rates: 98.4% (95% CI, 95.9-100), 95.3% (91.2-99.4), and 95.0% (84.2-100), respectively. All 142 patients with Day 8 MRD<0.01%, except two with KMT2A-rearranged ALL and one with TCF3-PBX1, were in continuous complete remission. The TCF3-PBX1, PAX5alt, T-cell, early T-cell precursor, iAMP21 and hypodiploid ALL had intermediate outcome with 5-year event-free survival rates ranging from 80.0% (39.4-100) to 88.2% (71.7-100). Patients with KMT2A-rearranged, BCR-ABL1, BCR-ABL1-like and ETV6-RUNX1-like ALL had the worst outcomes, with 5-year event-free survival rates between 64.1% (43.9-84.3) and 76.2% (51.9-100), despite most patients receiving standard- or high-risk therapy. Treatment intensification based on MRD and genotype improved outcome. Relapse did not occur in any of the patients with ETV6-RUNX1, DUX4-rearranged, TCF3-PBX1, iAMP21, ZNF384-rearranged, hypodiploid, or BCR-ABL1-like B-ALL who had day 15 MRD≥1% and received standard-risk therapy. However, day 42 MRD<0.01% did not preclude relapse in patients with intermediate-risk or unfavorable subtypes including TCF3-PBX1, PAX5alt, T-cell, iAMP21, BCR-ABL1, BCR-ABL1-like, ETV6-RUNX1-like, KMT2A-rearranged, and MEF2D-rearranged ALL, despite intensified treatment in the standard- or high-risk arms. InterpretationContemporary risk-directed treatment based on genotypes and MRD can cure virtually all patients with ETV6-RUNX1, hyperdiploid>50 and DUX4-rearranged ALL. While intensified treatment improve outcome for patients with high MRD during induction, substantial proportions of patients with intermediate-risk or unfavorable subtypes would still relapse even achieving negative MRD status at the end of induction and require novel therapeutics to improve outcome.

  Study EGAS00001004739

• PCGP Ph-like ALL

  Background: BCR-ABL1-like, or Ph-like acute lymphoblastic leukemia is characterized by a gene expression profile similar to BCR-ABL1 positive ALL, genetic alterations of lymphoid transcription factor genes, and poor outcome. Sequencing of small numbers of Ph-like ALL cases has identified genetic alterations activating kinase signaling suggesting Ph-like ALL may be amenable to treatment with tyrosine kinase inhibitors. However, the spectrum of genetic alterations in childhood and adult Ph-like ALL is incompletely understood. Methods: We performed genomic profiling of 1736 B-ALL cases and next-generation sequencing for 160 Ph-like cases. We examined the functional effects of chimeric fusion proteins in mouse cell lines. Results: The frequency of Ph-like ALL rose from 11% in children to 26% in young adults, and was associated with very poor outcome. Kinase-activating alterations were identified in 90% of Ph-like cases, most commonly fusions involving 10 kinase or cytokine receptor genes (ABL1, ABL2, CRLF2, CSF1R, EPOR, JAK2, NTRK3, PDGFRB, PTK2B and TYK2), and mutations involving FLT3, IL7R and SH2B3. Expression of ABL1, ABL2, CSF1R and JAK2 fusions resulted in cytokine-independent proliferation of cell lines and activation of pSTAT5. Cells expressing ABL1, ABL2, CSF1R and PDGFRB fusions were sensitive to dasatinib, and JAK2 fusions to ruxolitinib. Conclusions: Ph-like ALL is characterized by a diverse range of genomic alterations that converge on a limited number of kinase signaling pathways amenable to inhibition with currently available tyrosine kinase inhibitors. Trials identifying Ph-like ALL and testing the efficacy of tyrosine kinase inhibitor therapy are warranted

  Study EGAS00001000654

• Comprehensive Genomic Characterization of Refractory Multiple Myeloma Reveals a Complex Mutational and Structural Landscape Associated with Drug Resistance (H067)

  Outcome of patients with multiple myeloma (MM) refractory to immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs) is still very poor. To elucidate the genetic landscape of relapsed/refractory MM (RRMM) we performed whole genome and transcriptome sequencing of 39 heavily pretreated RRMM patients with at least double refractoriness revealing complex structural changes and a high mutational load (H067/K08K). We found a median of 67 structural variants and 116 nonsynonymous exonic mutations per patient. Assessment of oncogenic drivers showed NRAS, BRAF, TP53, KRAS, SLC4A7, FAM46C, DIS3, RB1, KMT2C, MLLT4, EWSR1, HCFC2, and COPS3 as significantly mutated. We found multiple genomic regions with bi-allelic events affecting known tumor suppressor genes, most frequently TP53, RB1, and TRAF3. Supervised analysis of mutational signatures showed a major contribution of Cosmic signature 6 associated with deficiency in DNA mismatch repair and the ‘BRCAness’ signature which coincided with mutations in genes known to confer PARP inhibitor sensitivity. Recurrently mutated gene networks included genes with relevance for PI and IMiD activity, the latter including in particular members of the Cereblon and the COP9 signalosome complex. In conclusion, this comprehensive genomic characterization revealed a complex mutational and structural landscape in RRMM and highlights potential implications for therapeutic strategies.

  Study EGAS00001004363

• Genetic control of the transcriptomic response of monocytes to bacterial and viral stimuli assessed by RNA-seq in Africans and Europeans

  Humans differ in the outcome that follows exposure to life-threatening pathogens, yet the extent of population differences in immune responses, and their genetic and evolutionary determinants, remain undefined. Here, we characterized, using RNA-sequencing, the transcriptional response of primary monocytes from Africans and Europeans to bacterial and viral stimuli - ligands activating Toll-like receptors pathways (TLR1/2, TLR4 and TLR7/8) and influenza virus - and mapped expression quantitative trait loci (eQTL). We identify multiple cis- and trans-eQTL that contribute to the marked differences in immune responses detected within and between populations, including a TLR1 master regulator that decreases expression of pro-inflammatory genes in Europeans only. We show that regulatory variants have been privileged targets of natural selection, uncovering evolutionarily advantageous mechanisms, such as attenuated inflammation. Finally, we demonstrate that admixture with Neandertals introduced regulatory variants into European genomes, affecting preferentially responses to viral challenges, and identify archaic haplotypes that contributed to population genetic adaptation.

  Study EGAS00001001895

• Human islet 3D chromatin maps provide insights into type 2 diabetes

  The transcriptional output of each cell type is controlled by thousands of enhancers, many of which contain genetic risk variants for common diseases such as type 2 diabetes (T2D). To gain insight into how enhancer variation influences diabetes risk, we created promoter capture Hi-C maps in human pancreatic islets. This linked diabetes-associated islet enhancers with their target genes, often located hundreds of kilobases away. We identified hubs that show spatial and functional connections between enhancersand target genes related to islet function and diabetes. We demonstrate that genetic variants distributed across hub enhancers have a major impact on T2D heritability, and use this knowledge to identify individuals in whom islet regulatory variation has a prominent role in T2D risk. Our results demonstrate the importance of 3D chromatin architecture for molecular interpretation of T2D genetic association signals, and define genomic spaces that harbor a distinct component of the T2D polygenic burden.

  Study EGAS00001002917

• The genomic landscape of childhood acute lymphoblastic leukaemia with intrachromosomal amplification of chromosome 21 (iAMP21-ALL)

  Intrachromosomal amplification of chromosome 21 (iAMP21) results from breakage-fusion-bridge cycles and chromothripsis defines a cytogenetic subgroup of childhood B-cell precursor acute lymphoblastic leukemia (B-ALL) cases associated with a poor prognosis. To systematically characterize the mechanism of somatic alternations in iAMP21, we perform integrated genomic, cytogenetic and transcriptomic analysis of 128 cases.

  Study EGAS00001004998

• Single cell transcriptomic landscape of pediatric B-cell acute lymphoblastic leukemia: dissection of transcriptional heterogeneity and B-cell developmental state

  Introduction: Genomic analyses of bulk ALL samples have improved our understanding of the genetic basis and risk stratification of B-ALL, but do not directly examine intratumor heterogeneity or enable inference of leukemia developmental state and cell of origin. Methods: We profiled 89 B-ALL samples by single-cell RNA-seq (scRNA-seq) (10X Genomics 5’v2) and compared them to a scRNA-seq reference map of normal human B-cell development. Results: Analysis of heterogeneity of inferred DNA copy number alterations at single cell level showed that aneuploid ALL with near haploidy and hyperdiploid harbor chromosomal losses or gains in all blasts, consistent with early, synchronous origin rather than sequential accumulation. Intra-sample heterogeneity was driven by five gene expression signatures: cell cycle, metabolism, differentiation, inflammation, refining leukemic subtyping. An atlas of B cell development was established to map B-ALL samples to specific developmental states. Hyperdiploid samples resembled pro-B cells, while MEF2D-r and TCF3::PBX1 showed high pre-B abundance. Patients with high early lymphoid abundance had poorer outcomes. Conclusions: Understanding variation in transcriptional programs and developmental states of B-ALL blasts by sc transcriptome refines existing clinical and genomic classifications and provides novel prognostic markers.

  Study EGAS00001007512

• BLUEPRINT ChIP-seq data for cells in the haematopoietic lineages, from adult and cord blood samples.

  ChIP-seq data for cells in the haematopoietic lineages, from adult and cord blood samples.

  Study EGAS00001000326

• RNA-seq study of longitudinal blood cell samples from children at risk of type 1 diabetes

  The appearance of type 1 diabetes (T1D)-associated autoantibodies is the first and only measurable parameter to predict progression toward T1D in genetically susceptible individuals. However, autoantibodies indicate an active autoimmune reaction, wherein the immune tolerance is already broken. Therefore, there is a clear and urgent need for new biomarkers that predict the onset of the autoimmune reaction preceding auto-antibody positivity or reflect progressive b-cell destruction. Here we report the mRNA sequencing–based analysis of 306 samples including fractionated samples of CD4+ and CD8+ T cells as well as CD4, CD8 cell fractions and unfractionated PBMC samples longitudinally collected from seven children who developed beta-cell autoimmunity (Case subjects) at a young age and matched control subjects.

  Study EGAS00001004071

• Whole Genome Methylation in CLL

  Study EGAS00001000272

• Submission 56 - study_title 1

  Submission 56 - description 1

  Study EGAS50000000472

• Single cell genomic variation induced by mutational processes in cancer

  How cell-to-cell copy number alterations that underpin genomic instability in human cancers drive genomic and phenotypic variation, and consequently cancer evolution, remains understudied. Here, applying scaled single cell whole genome sequencing to wildtype, TP53-deficient and TP53/BRCA1/2-deficient mammary epithelial cells (n=13,818 genomes) and primary triple negative breast (TNBC) and high grade serous ovarian cancers (HGSC) (n=22,057 genomes), we identified three distinct ‘foreground’ mutational patterns defined by cell-to-cell copy number and structural variation properties occurring in the ‘background’ of cancer-associated genomic instability. Cell and clone-specific high level amplifications (HLAMPs), parallel allele-specific copy number alterations and copy number segment length variation (serrate structural variations) exhibited measurable phenotypic and evolutionary consequences. Clone-specific HLAMPs in known oncogenes were highly prevalent in fold back inversion (FBI)-bearing tumors and associated with increased clone-to-clone phenotypic variation in gene expression inferred from matched single cell RNASeq. Parallel allele-specific alterations were linked with phylogenetically determined evolutionary diversity and clone-specific mono-allelic expression. Serrate patterns present across all clones were increased in FBI tumors, most prominently on a tetraploid background and were highly correlated with increased genomic diversity of cellular populations. Taken together, we show that cell-to-cell structural-copy number variation significantly impacts the phenotypes and evolutionary diversity of TNBC and HGSC, revealing previously hidden genomic states of cancer cells.

  Study EGAS00001006343