3241 results for "*geneti*"

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• InsPIRE islets

  We explored the relationship between genetic variants influencing predisposition to type 2 diabetes (T2D) and related glycemic traits, and human pancreatic islet transcription using RNA-Seq and genotyping data from 420 islet donors and 26 FAC sorted beta-cells.

  Study EGAS00001003997

• Whole Exome Sequencing of Spanish Patients diagnosed with rare ophtalmogenetic disorders: Macular Dystrophy, Retinitis Pigmentosa and Leber's congenital amaurosis.

  Study EGAS00001004084

• UCSF Pediatric Bithalamic Glioma Genome Project

  Brain tumors are the most common solid tumors of childhood, and the genetic drivers and optimal therapeutic strategies for many of the different subtypes remain unknown. We performed targeted next-generation sequencing of approximately 500 cancer-associated genes on a cohort of 13 pediatric bithalamic diffuse gliomas, a lethal brain tumor of childhood for which the genetic basis is largely unknown. We identified that bithalamic diffuse gliomas harbor frequent mutations in the EGFR oncogene in the absence of accompanying gene amplification and only rare histone H3 mutation. These EGFR mutations were either small in-frame insertions within exon 20 (intracellular tyrosine kinase domain) or missense mutations within exon 7 (extracellular ligand-binding domain). Accompanying alterations included frequent TP53 mutation, CDK6 amplification or CDKN2C mutation, and BCOR and BCORL1 mutation or deletion.

  Study EGAS00001004033

• Germline elongator mutations in sonic hedgehog medulloblastoma

  Cancer genomics has illuminated a wide spectrum of genes and core molecular processes contributing to human malignancy. Still, the genetic and molecular basis of many cancers remains only partially explained. Genetic predisposition accounts for 5-10% of cancer diagnoses and genetic events cooperating with known somatic driver events are poorly understood. Analyzing established cancer predisposition genes in medulloblastoma (MB), a malignant childhood brain tumor, we recently identified pathogenic germline variants that account for 5% of all MB patients. Here, by extending our previous analysis to include all protein-coding genes, we discovered and replicated rare germline loss-of-function (LoF) variants across Elongator Complex Protein 1 (ELP1) on 9q31.3 in 15% of pediatric MBSHH cases, thus implicating ELP1 as the most common MB predisposition gene and increasing genetic predisposition to 40% for pediatric MBSHH. Inheritance was verified based on parent-offspring and pedigree analysis, which identified two families with a history of pediatric MB. ELP1-associated MBs were restricted to the molecular SHHa subtype and were characterized by universal biallelic inactivation of ELP1 due to somatic loss of chromosome 9q. The majority of ELP1-associated MBs exhibited co-occurring somatic PTCH1 (9q22.32) alterations, suggesting that ELP1-deficiency predisposes to tumor development in combination with constitutive activation of SHH signaling. ELP1 is an essential subunit of the evolutionary conserved Elongator complex, whose primary function is to enable efficient translational elongation through tRNAs modifications at the wobble (U34) position. Biochemical, transcriptional, and proteomic analyses revealed that ELP1-associated MBSHH are characterized by a destabilized core Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response (UPR), consistent with deregulation of protein homeostasis due to Elongator-deficiency in model systems. Our findings suggest that genetic predisposition to proteome instability is a previously underappreciated determinant in the pathogenesis of pediatric brain cancer. These results provide strong rationale for further investigating the role of protein homeostasis in other pediatric and adult cancer types and potential opportunities for novel therapeutic interference.

  Study EGAS00001004126

• An integrative model of pathway convergence in genetically heterogeneous blast crisis chronic myeloid leukemia (CML)

  Targeted therapies against the BCR-ABL1 kinase have revolutionized treatment of chronic phase (CP) chronic myeloid leukemia (CML). In contrast, management of blast crisis (BC) CML remains challenging because BC cells acquire complex molecular alterations that confer stemness features to progenitor populations and resistance to BCR-ABL1 tyrosine kinase inhibitors. Comprehensive models of BC transformation have proved elusive because of the rarity and genetic heterogeneity of BC, but are important for developing biomarkers predicting BC progression and effective therapies. To better understand BC, we performed an integrated multiomics analysis of 74 CP and BC samples using whole-genome and exome sequencing, transcriptome and methylome profiling, and chromatin immunoprecipitation followed by high-throughput sequencing. Employing pathway-based analysis, we found the BC genome was significantly enriched for mutations affecting components of the polycomb repressive complex (PRC) pathway. While transcriptomically, BC progenitors were enriched and depleted for PRC1- and PRC2-related gene sets respectively. By integrating our data sets, we determined that BC progenitors undergo PRC-driven epigenetic reprogramming toward a convergent transcriptomic state. Specifically, PRC2 directs BC DNA hypermethylation, which in turn silences key genes involved in myeloid differentiation and tumor suppressor function via so-called epigenetic switching, whereas PRC1 represses an overlapping and distinct set of genes, including novel BC tumor suppressors. On the basis of these observations, we developed an integrated model of BC that facilitated the identification of combinatorial therapies capable of reversing BC reprogramming (decitabine+PRC1 inhibitors), novel PRC-silenced tumor suppressor genes (NR4A2), and gene expression signatures predictive of disease progression and drug resistance in CP.

  Study EGAS00001001751

• Dissection of the molecular complexity of colorectal cancer in pre-clinical models identifies predictive signatures of sensitivity to EGFR inhibitors

  Colorectal carcinoma (CRC) is a heterogeneous tumour entity, with only a fraction of the tumours responding to currently available therapies. A detailed understanding of the biology and genetics of CRC is a prerequisite for precision medicine. To address this challenge in clinical oncology, the OncoTrack consortium recruited 106 CRC patients (stages I-IV) and developed an integrated pre-clinical platform analysing drug sensitivity in the established matched patient-derived in vivo and in vitro models, 46 three-dimensional cell cultures and 59 xenografts, recapitulating many of the molecular features of the donor tumours. We generated extensive omics information on patient tumours and their derived models used to generate a compendium of drug sensitivity data. We could distinguish tumour molecular sub-groups responding differently to therapy and identified a novel independent predictor of sensitivity to the EGFR inhibitor cetuximab. The findings reported here will advance our understanding of CRC and its response to therapy.

  Study EGAS00001001752

• High-resolution analyses of human sperm dynamic methylome reveals thousands of novel age-related epigenetic alterations

  Age-dependent modifications of the germ cells epigenome remain poorly understood. Our objective was to assess the DNA methylation profile of human spermatozoa during aging. A cohort study was designed to investigate the effects of age and fertility status on sperm DNA methylation.

  Study EGAS00001004168

• Sex-biased patterns shaped the genetic history of Roma

  Whole mtDNA sequences and Y chromosomes from Roma and Non-Roma European samples.

  Study EGAS00001004207

• Expression-Based Subtypes Define Pathologic Response to Neoadjuvant Immune-Checkpoint Inhibitors in Muscle-Invasive Bladder Cancer

  Checkpoint immunotherapy (CPI) has increased survival for some patients with advanced stage bladder cancer (BCa). However, most patients do not respond. Here, we characterized the tumor and immune microenvironment in pre- and post-treatment tumors from the PURE01 neoadjuvant pembrolizumab immunotherapy trial, using a consolidative approach that combined transcriptional and genetic profiling with digital spatial profiling.

  Study EGAS00001005549

• Ashkenazi Jewish Leukoencephalopathy

  Genetic leukoencephalopathies (gLEs) are a group of heterogeneous disorders with white matter abnormalities in the central nervous system (CNS). Patients affected with gLEs have brain white matter defects that can be seen in MRI and exhibit variable neurologic phenotypes including motor impairment, hypotonia, pyramidal dysfunction, dystonia and/or dyskinesias, ataxia, seizures, cortical blindness, optic atrophy, and impaired cognitive development. The exact causes in half of gLEs are unknown. We studied three unrelated families affected with an undiagnosed gLE and discovered a homozygous germline mutation c.2536T>G in VPS11 by whole exome sequencing, a gene involved in membrane trafficking and fusion of the lysosomes and endosomes, as a novel cause of a new gLE syndrome.

  Study EGAS00001001767

• Characterization of a human iPSC-derived endocrine pancreas model

  Directed differentiation of stem cells offers a scalable solution to the need for human cell models recapitulating islet biology and T2D pathogenesis. We profiled mRNA expression at six stages of an induced pluripotent stem cell (iPSC) model of endocrine pancreas development from two donors, and characterized the distinct transcriptomic profiles associated with each stage. Established regulators of endodermal lineage commitment, such as SOX17 (log2 fold change [FC] compared to iPSCs=14.2, p-value=4.9x10-5) and the pancreatic agenesis gene GATA6 (log2 FC=12.1, p-value=8.6x10-5), showed transcriptional variation consistent with their known developmental roles. However, these analyses highlighted many other genes with stage-specific expression patterns, some of which may be novel drivers or markers of islet development. For example, the leptin receptor gene, LEPR, was most highly expressed in published data from in vivo-matured cells compared to our endocrine pancreas-like cells (log2 FC=5.5, p-value=2.0x10-12), suggesting a role for the leptin pathway in the maturation process. Endocrine pancreas-like cells showed significant stage-selective expression of adult islet genes, including INS, ABCC8, and GLP1R, and enrichment of relevant GO-terms (e.g. "insulin secretion"; odds ratio=4.2, p-value=1.9x10-3): however, principal component analysis indicated that in vitro-differentiated cells were more immature than adult islets. Integration of the stage-specific expression information with genetic data from T2D genome-wide association studies revealed that 46 of 82 T2D-associated loci harbor genes present in at least one developmental stage, facilitating refinement of potential effector transcripts. Together, these data show that expression profiling in an iPSC islet development model can further understanding of islet biology and T2D pathogenesis.

  Study EGAS00001001803

• Khoe-San genomes reveal unique variation and confirm deepest population divergence in Homo sapiens

  The southern African indigenous Khoe-San populations harbor the most divergent lineages of all living peoples. Exploring their genomes is key to understanding deep human history. We sequenced 25 full genomes from five Khoe-San populations, revealing many novel variants, that 25% of variants are unique to the Khoe-San, and that the Khoe-San group harbors the greatest level of diversity across the globe. In line with previous studies, we found several gene-regions with extreme values in genome-wide distributions, potentially caused by natural selection early in the modern human lineage and more recent in time. These gene-regions included immunity-, sperm-, brain-, diet- and muscle-related genes. When accounting for recent admixture, all Khoe-San groups display genetic diversity approaching the levels in other African groups and a reduction in effective population size starting around 100,000 years ago. Hence, all human groups show a reduction in effective population size commencing around the time of the Out-of-Africa migrations, which coincides with changes in the paleoclimate records, changes that potentially impacted all humans at the time.

  Study EGAS00001004459

• 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

• Survival Benefit and Genetic Profile of Pemetrexed as Initial Chemotherapy in Selected Chinese Patients with Advanced Lung Adenocarcinoma

  We retrospectively collected patients (n=1047) enrolled in the Chinese Patient Assistance Program from multiple centers who received pemetrexed alone or combined with platinum as initial chemotherapy and continued pemetrexed maintenance therapy for advanced lung adenocarcinoma from November 2014 to June 2017. The outcomes were duration of treatment (DOT) and overall survival (OS). Clinical features were analyzed for their influence on the treatment effect and prognosis. Next-generation sequencing (NGS) was performed to identify genetic biomarkers associated with the efficacy of pemetrexed. The median DOT was 9.1 months (95% CI: 8.5-9.8), and the median OS was 26.2 months (95% CI: 24.2-28.1). OS was positively correlated with DOT (r=0.403, P<0.001). Multivariable analysis showed that smoking status and Eastern Cooperative Oncology Group (ECOG) performance status (PS) were independently associated with DOT; smoking status, ECOG PS, targeted therapy, and EGFR/ALK/ROS1 status were independently associated with OS. NGS in 22 patients with available samples showed genes with high mutation rates were: TP53 (54.5%), EGFR (50.0%), MYC (18.2%), PIK3CA (13.6%). When grouped based on progression-free survival (PFS) reported in the PARAMOUNT study, the DOT >6.9 months set was associated with PIK3CA, ALK, BRINP3, CDKN2A, CSMD3, EPHA3, KRAS, and RB1 mutations, while ERBB2 mutation was observed only in the DOT ≤6.9 months set. This study shows that initial chemotherapy with pemetrexed is an effective regimen for advanced lung adenocarcinoma in selected Chinese patients. There is no specific genetic profile predicting the benefit of pemetrexed found by NGS. Biomarkers predicting the efficacy of pemetrexed need further exploration.

  Study EGAS00001004546

• SNP array files, IDAT files, from 34 members of a Family with a high prevalence of psychosis

  We investigated the genetic causes of major mental disorders (MMDs) including schizophrenia, bipolar disorder I, major depressive disorder, and attention deficit hyperactive disorder, in a large family pedigree from Alpujarras, South of Spain, a region with a high prevalence of psychotic disorders. We applied a systematic genomic approach based on karyotyping (N=4), genotyping by genome-wide SNP array (N=33), whole-exome sequencing (N=4), and whole-genome sequencing (N=12). We performed genome-wide linkage analysis, family-based association analysis, and polygenic risk score estimates. Significant linkage was obtained at chromosome 9 (9q33.1-33.2, LOD score= 4.11), a suggestive region that contains five candidate genes ASTN2, BRINP1, C5, TLR4, and TRIM32, previously associated to MMDs. Comprehensive analysis associated the MMD phenotype with genes of the immune system with dual brain functions. Moreover, the psychotic phenotype was enriched for genes involved in synapsis. These results should be considered once studying the genetics of psychiatric disorders in other families, especially the ones from the same region, since founder effects may be related to the high prevalence.

  Study EGAS00001004592

• Multisample genomic analysis of solid childhood cancers using high resolution SNP-arrays, Whole Exome Sequencing and Targeted Deep Sequencing.

  We mapped the prevalence of genetically distinct clones over 248 regions in 54 childhood cancers. This revealed that primary tumors can simultaneously follow up to four evolutionary patterns in different anatomic areas. The most common pattern consists of a fluctuating presence over anatomic space of subclones with very few mutations. The second most common is a surprisingly stable coexistence, over vast areas, of clones with different changes in chromosome numbers. This is contrasted by a third, less frequent, pattern where a novel clone harboring driver mutations or structural chromosome rearrangements completely replaces its progenitor. The fourth and rarest pattern is the local emergence of a myriad of clones with TP53 inactivation. Strikingly, death from disease was limited to tumors exhibiting the two latter, most dynamic patterns.

  Study EGAS00001002662

• Epigenome and transcriptome profiling of chronic lymphocytic leukemia patients

  Chronic lymphocytic leukemia (CLL) is characterized by substantial clinical heterogeneity, despite relatively few genetic alterations. To provide a basis for studying epigenome deregulation in CLL, we established genome-wide chromatin accessibility maps for 88 CLL samples from 55 patients using the ATAC-seq assay, and we also performed ChIPmentation and RNA-seq profiling for ten representative samples. Based on the resulting dataset, we devised and applied a bioinformatic method that links chromatin profiles to clinical annotations. Our analysis identified sample-specific variation on top of a shared core of CLL regulatory regions. IGHV mutation status – which distinguishes the two major subtypes of CLL – was accurately predicted by the chromatin profiles, and gene regulatory networks inferred for IGHV-mutated vs. IGHV-unmutated samples identified characteristic differences between these two disease subtypes. In summary, we discovered widespread heterogeneity in the chromatin landscape of CLL, established a community resource for studying epigenome deregulation in leukemia, and demonstrated the feasibility of chromatin accessibility mapping in cancer cohorts and clinical research.

  Study EGAS00001001821

• Identification of 19 novel loci reveals gene regulatory mechanisms determining susceptibility to testicular germ cell tumour

  Testicular germ cell tumour (TGCT) is the most common cancer in young men1,2, and is characterised by strong inherited genetic risk factors3. Here we have undertaken large-scale genome wide association study (GWAS) for TGCT, encompassing ~7,500 cases and ~23,000 controls, through the Oncoarray consortium. We identified 19 novel loci, approximately doubling the number of known TGCT risk loci to 44 (P<5x10-8)4-14 and conduct deep, high-throughput functional annotation of all risk loci. We establish a network of physical interactions for all risk SNPs to candidate casual genes in 3D space, using high-throughput chromosome conformation capture techniques (HiC) in TGCT cells. Firstly, functional evidence reveals widespread disruption of developmental transcriptional regulators, consistent with failed primordial germ cell differentiation as an initiating step in TGCT oncogenesis15. We secondly observe multiple risk loci associated with defective microtubule assembly, compatible with the high level of aneuploidy observed in TGCTs, suggesting gross chromosomal instability. Finally KIT-MAPK signalling features as a recurrently dysregulated pathway. In summary our findings substantially increase the number of known TGCT risk alleles, and provides a functional basis for disease susceptibility.

  Study EGAS00001001836

• Whole exome sequencing of Finnish hereditary breast cancer families

  A remarkable proportion of factors causing genetic predisposition to breast cancer (BC) are unknown in non-BRCA1/2 families. Exome sequencing was performed for 13 high-risk Finnish hereditary breast and/or ovarian cancer (HBOC) families to detect variants contributing to BC susceptibility

  Study EGAS00001001835

• Genome-wide quantification of rare somatic mutations in normal human tissues using massively parallel sequencing

  We present Bottleneck Sequencing System (BotSeqS), a nextgeneration sequencing method that simultaneously quantifies rare somatic point mutations across the mitochondrial and nuclear genomes. BotSeqS combines molecular barcoding with a simple dilution step immediately prior to library amplification. We use BotSeqS to show age and tissue-dependent accumulations of rare mutations and demonstrate that somatic mutational burden in normal tissues can vary by several orders of magnitude, depending on biologic and environmental factors. We further show major differences between the mutational patterns of the mitochondrial and nuclear genomes in normal tissues. Lastly, the mutation spectra of normal tissues were different from each other, but similar to those of the cancers that arose in them. This technology can provide insights into the number and nature of genetic alterations in normal tissues and can be used to address a variety of fundamental questions about the genomes of diseased tissues.

  Study EGAS00001001838

• Therapeutic Targeting of Ependymoma as Informed by Oncogenic Enhancer Profiling

  Genomic sequencing has driven precision-based oncology therapy; however, genetic drivers remain unknown or non-targetable for many malignancies, demanding alternative approaches to identify therapeutic leads. Ependymomas are chemotherapy-resistant brain tumours, which, despite genomic sequencing, lack effective molecular targets. Here, we mapped active chromatin landscapes in 42 primary ependymomas in two non-overlapping primary ependymoma cohorts. Enhancer regions revealed novel oncogenes, molecular targets, and pathways, which when subjected to small molecule inhibitor or shRNA treatment, increased survival and slowed proliferation in mouse and neurosphere patient-derived models of ependymomas. This study represents one of the largest enhancer mapping study of any cancer type to date, and provides a framework for target and drug discovery for other cancers recalcitrant to therapeutic development because of their lack of known genetic drivers.

  Study EGAS00001002696

• The dataset of Southeast Borneo individuals (Banjar and Ngaju ethnic groups) was used as comparative data to determine the Asian parental population of the Malagasy. Our study found strong support for an origin of the Asian ancestry of Malagasy among the Banjar.

  Malagasy genetic diversity results from an exceptional proto-globalisation process that took place over a thousand years ago across the Indian Ocean. Previous efforts to locate the Asian origin of Malagasy have highlighted Borneo broadly as a potential source, but so far no firm source populations have been identified. Here, we have generated genome-wide data from two Southeast Borneo populations, the Banjar and the Ngaju, together with published data compiled from populations across the Indian Ocean region. We find strong support for an origin of the Asian ancestry of Malagasy among the Banjar. This group emerged from the long-standing presence of a Malay Empire trading post in Southeast Borneo, which favoured admixture between the Malay and an autochthonous Borneo group, the Ma’anyan. Reconciling genetic, historical and linguistic data, we show that the Banjar, in Malay-led voyages, were the most probable Asian source among the analysed groups in the founding of the Malagasy gene pool.

  Study EGAS00001001841

• Whole-genome sequencing of two probands with hereditary spastic paraplegia reveals novel splice-donor region mutation and known pathogenic mutation in SPG11

  Hereditary spastic paraplegias (SPG) are a group of heterogeneous neurodegenerative disorders, which are often presented with overlapping phenotypes such as progressive paraparesis and spasticity. To assist the diagnosis of SPG subtypes, next-generation sequencing is often used to provide supporting evidence. In this study, we report the case of two probands from the same family with SPG symptoms, including bilateral lower limbs weakness, unsteady gait, cognitive decline, dysarthria and slurring of speech since age of 14. Subsequent whole-genome sequencing revealed that the patients are compound heterozygous for mutations in SPG11 gene, including the paternally inherited c.6856C>T (p.Arg2286*) mutation and the novel maternally inherited c.2316+5G>A splice donor region mutation. Mutations in SPG11 are the common cause of autosomal recessive Spastic Paraplegia type 11. According to the ClinVar database, there are already 101 reported pathogenic mutations in SPG11 that are associated with SPG. To our knowledge, this is the first report of SPG11 mutations in our local population. Novel splice mutation identified in this study would enrich the catalog of SPG11 mutations, potentially leading to better genetic diagnosis of SPG.

  Study EGAS00001001849

• Recurrent somatic JAK-STAT mutations within a novel RUNX1-mutated pedigree

  The acquisition of somatic mutations is an emerging field of investigation in familial leukemia. Currently, genetic profiles in familial MDS/AML are considered analogous to sporadic disease, although the patterns of clonal evolution within families are poorly defined. We performed whole exome profiling of tumour samples from a novel RUNX1 mutated family, to determine the stepwise evolution of MDS/AML across 4 young siblings. Three siblings developed monocytic AML/RAEB2 at 5 years of age, with hepatosplenomegaly and somatic mutations upregulating JAK-STAT signalling, the latter are typically detected in <5% of sporadic MDS/AML. Two siblings acquired the canonical JAK2 V617F mutation, while another acquired a unique missense mutation of SH2B3, a negative regulator of JAK2. Notably, 2/3 siblings demonstrated dosage amplification of these mutations due to acquired uniparental disomy of chromosomes 9p and 12q (encompassing JAK2 and SH2B3, respectively). All 4 siblings were heterozygous for the 46/1 JAK2 haplotype associated with predisposition to sporadic V617F myeloproliferative disorders, which likely influenced the acquisition of JAK2 mutations. Our findings provide further evidence that relatives with shared germline mutations may acquire somatic mutations in a non-random manner leading to convergent patterns of disease evolution.

  Study EGAS00001001862

• Summary statistics of meta-analysis using two genome-wide association study of inflammatory bowel disease in Koreans.

  Inflammatory bowel disease (IBD), a chronic inflammatory disorder of the gastrointestinal tract, is thought to develop due to dysregulated mucosal immune responses to gut flora in genetically susceptible individuals. Crohn’s disease (CD) and ulcerative colitis (UC) are the two major subtypes of IBD. To identify additional susceptibility loci for IBD in Asians, we performed meta-analyses using two genome-wide association studies.

  Study EGAS00001005026