3246 results for "*geneti*"

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• Identifying genetic consequences of Epstein-Barr Virus transformation by comparing an individual’s genomic DNA with that of its lymphoblastoid cell line.

  A detailed analysis of whole genomes can be now achieved with next generation sequencing. Epstein Barr Virus (EBV) transformation is a widely used strategy in clinical research to obtain an unlimited source of a subject’s DNA. Although the mechanism of transformation and immortalization by EBV is relatively well known at the transcriptional and proteomic level, the genetic consequences of EBV transformation are less well understood. A detailed analysis of the genetic alterations introduced by EBV transformation is highly relevant, as it will inform on the usefulness and limitations of this approach. We used whole genome sequencing to assess the genomic signature of a low-passage lymphoblastoid cell line (LCL). Specifically, we sequenced the full genome (40X) of an individual using DNA purified from fresh whole blood as well as DNA from his LCL. A total of 217.33 Gb of sequence were generated from the cell line and 238.95 Gb from the normal genomic DNA. We determined with high confidence that 99.2% of the genomes were identical, with no reproducible changes in structural variation (chromosomal rearrangements and copy number variations) or insertion/deletion polymorphisms (indels). Our results suggest that, at this level of resolution, the LCL is genetically indistinguishable from its genomic counterpart and therefore their use in clinical research is not likely to introduce a significant bias.

  Study EGAS00001000323

• Identification of the dismal subtype of B-ALL with dysregulation of CDX2 and UBTF

  PURPOSE: Advance in the knowledge of genomic basis of B-cell acute lymphoblastic leukemia (B-ALL) has changed the treatment approaches and diagnostic assays and improved their outcome. Despite the recent development of next generation sequencing approaches, there are still some cases that their drivers are unknown. We aimed to define and describe the characteristics of an additional B-ALL subtype by integrating genomic, transcriptomic, and epigenomic approach. METHODS: More than 2,000 B-ALL cases of RNA-seq data from from Eastern Cooperative Oncology Group (ECOG) and the American College of Radiology Imaging Network (ACRIN) (n=764), the Children's Oncology Group (COG), Munich Leukemia Laboratory (MLL) (n=280), and other several collaborators were analyzed to identify the new subtype. Whole genome sequence was performed to detect mutations, stractural variants, and copy number alterations. The tridimentional analysis of chromatin was performed with HiChIP. RESULTS: We identified the new high-risk B-ALL subtype “CDX2/UBTF” that exhibited unique gene expression profiles, which is enriched in female (77.3%), adolescents and young adults (52.6%), and relapse cohort (3.3%). CD10 negativity and IgM positivity are hallmarks of this subtype with NTRK3 expression that can be an effective marker at diagnostic approach and a potential targeted therapy with TRK and mulkinase inbitors, larotrectinib and entrectinib. Genetically, two different alterations define CDX2/UBTF. One is UBTF-ATXN7L3 fusions caused by deletion of 17q21.31, and the other is extopic CDX2 expression through the enhancer hijacking mechanism induced by deletion of 13q12.2. Other genomic features include gain of 1q and PAX5 rearrangement (PAX5-ZCCHC7), might induce upregulation of histone cluster genes and PAX5. CONCLUSION: We described the novel B-ALL subtype “CDX2/UBTF” that has unique clinical and genomic characteristics.

  Study EGAS00001005863

• 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 populationgenetics of a Croatian island isolate, in a sample of 200 subjects from the Adriatic island of Vis who wereselected to reflect islanders with at least four known ancestors in grandparental line who are original islanders.

  Study EGAS00001000336

• Integrated genomic analyses identify ARID1A and ARID1B alterations in the childhood cancer neuroblastoma

  Neuroblastomas are tumors of peripheral sympathetic neurons and are the most common solid tumor in children. To determine the genetic basis for neuroblastoma we performed whole-genome sequencing (6 cases), exome sequencing (16 cases), genome-wide rearrangement analyses (32 cases), and targeted analyses of specific genomic loci (40 cases) using massively parallel sequencing. On average each tumor had 19 somatic alterations in coding genes (range, 3-70). Among genes not previously known to be involved in neuroblastoma, chromosomal deletions and sequence alterations of chromatin remodeling genes, ARID1A and ARID1B, were identified in 8 of 71 tumors (11%) and were associated with early treatment failure and decreased survival. Using tumor-specific structural alterations, we developed an approach to identify rearranged DNA fragments in sera, providing personalized biomarkers for minimal residual disease detection and monitoring. These results highlight dysregulation of chromatin remodeling in pediatric tumorigenesis and provide new approaches for the management of neuroblastoma patients.Data Provider: Johns Hopkins Sidney Kimmel Comprehensive Cancer Center (SKCCC)

  Study EGAS00001000369

• Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma.

  follicular lymphoma (FL), the most common indolent non-Hodgkin’s lymphoma, remains incurable. A well-recognized complication of FL is its transformation to a diffuse large B-cell lymphoma (DLBCL)-morphology in a subset of patients, for which the clinical outcomes are poor. Recent genetic profiling and single case studies of donor-derived FL following stem cell transplantation had alluded to the putative existence of a ‘long lived’ tumor-initiating progenitor cell compartment from which successive disease events occurred. To chronicle the genetic changes associated with progression to transformation, we conducted whole-genome sequencing (WGS) of FL-tFL pairs and matched germline (GL) samples from six patients, a total of 20 genomes.

  Study EGAS00001000399

• Tumor suppressor miR-133a modulates the prostate cancer epigenome by repressing BAZ2A

  Our study revealed a new subgroup of prostate tumors defined by the expression of a novel prognostic marker, BAZ2A, and the first time to show the establishment of CIMP via an microRNA-epigenetic interaction in prostate tumors.

  Study EGAS00001000568

• Cell-type, allelic and genetic signatures in the human pancreatic beta cell transcriptome

  Study EGAS00001000442

• Epigenomic alterations define lethal CIMP-positive ependymomas of infancy

  Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland.

  Study EGAS00001000443

• Comprehensive analysis of atypical teratoid rhabdoid tumour (ATRT) using genomic, epigenomic and transcriptomic techniques.

  ATRTs (Atypical teratoid rhabdoid tumours) represent one of the most aggressive pediatric brain cancers, but intriguingly exhibit few other recurrently mutated loci except for SMARCB1/hSNF5. We integrated whole genome (n=15), exome, copy number, gene expression and methylation analyses to comprehensively interrogate 64 ATRTs and observed that structural events were relatively frequent in the ATRT genome (~3 tumour). In addition to SMARCB1, which was targeted by structural events in a majority (49/64) of tumours, recurrent structural alterations targeting the LRP1B, CDH13, BCR and MKL1 loci were observed. We observed novel translocation events, including 2 targeting SMARCB1 which were detected only by NGS analyses. Significantly, integration of gene expression and methylation profiles with genomic analyses revealed ATRT comprise two sub-groups with distinct clinical and genetic features. Group 1 tumours were characterized by supra-tentorial brain location, focal intragenic alterations of SMARCB1 and a pro-neural gene expression signature with evidence of NOTCH pathway activation. While Group 2 ATRTs were characterized by infra-tentorial brain location, broad SMARCB1 alterations and an activation of the BMP signalling pathway. Our findings highlight epigenetic mechanisms as important determinants of ATRT tumour phenotypes, and demonstrate for the first time that ATRTs arising in different anatomical compartments comprise distinct molecular and therapeutic sub-groups.

  Study EGAS00001000506

• Chromosome Y Philogeny in Sardinia

  Genetic variation within the male specific portion of the Y chromosome (MSY) can clarify the origins of contemporary populations, but previous studies were hampered by partial genetic information. Population sequencing of 1,204 Sardinian males identified 11,763 MSY single nucleotide polymorphisms (SNPs), of which 6,751 have not previously been observed. We constructed a MSY phylogenetic tree containing all main haplogroups found in Europe along with many Sardinian-specific lineage clusters within each haplogroup. The tree was calibrated with archaeological data from the initial expansion of the Sardinian population ~7,700 years ago. The ages of nodes highlight different genetic strata in Sardinia and reveal presumptive timing of coalescence with other human populations. We calculate a putative age for coalescence of ~180-200,000 years ago, consistent with previous mitochondrial DNA (mtDNA) based estimates.

  Study EGAS00001000532

• Analysis of DNA methylation in normal B cells and chronic lymphocytic leukemia

  Charting differences between tumors and normal tissue is a mainstay of cancer research. However, clonal tumor expansion from complex normal tissue architectures potentially obscures cancer-specific events, including divergent epigenetic patterns. Using whole-genome bisulfite sequencing of normal B cell subsets, we observed broad epigenetic programming of selective transcription factor binding sites coincident with the degree of B cell maturation. By comparing normal B cells to malignant B cells from 268 patients with chronic lymphocytic leukemia (CLL), we showed that tumors derive largely from a continuum of maturation states reflected in normal developmental stages. Epigenetic maturation in CLL was associated with an indolent gene expression pattern and increasingly favorable clinical outcomes.As second study using these samples focued on evolution and resulting intra-tumor heterogeneity in CLL. We used 450k bead-chip arrays to study DNA methylomes in 68 chronic lymphocytic leukemia (CLL) cases, including 28 serial cases. The result establishs linked evolution of epigenetic and genetic alterations in progressive disease, revealing an important aspect of the biology of epigenetics in cancer.

  Study EGAS00001000534

• Detection of Clinically Relevant Genetic Variantsin Autism Spectrum Disorderby Whole-Genome Sequencing

  Study EGAS00001000850

• A sequence-based genetic dissection of human immune cell types and implications for immune-related disease.

  The immune system is an intricate biological network mediating interactions with other organisms while preserving the integrity of our tissues. By mounting appropriate responses it protects us from a vast range of pathogens while inadvertent immune system attacks on self result in autoimmune diseases. The project aims to discover whether and to what extent the behaviour of the immune system is genetically regulated and to detect the relationships of diverse immune cells with autoimmunity. The project consists of the genetic analysis using up to ~8.2 Million variants, deriving from high density genotyping data and low pass whole genome sequencing, and quantitative levels of 95 cell types encompassing 272 immune traits, in a cohort of 1,629 individuals from four clustered Sardinian villages belonging to the SardiNIA/ProgeNIA study.

  Study EGAS00001000574

• Determination_of_cell_specific_regulatory_enhancers_in_hematopoetic_models

  The BLUEPRINT project is a large-scale project investigating epigenetic mechanisms involved in blood formation, in health and disease. The human variation workpackage (WP10) of the project seeks to characterize the effect of common sequence variation on the epigenome status of a cell. To do this, the project will use highly purified blood cells to minimise “experimental noise” and therefore enhance the power to discover modest effects. Two peripheral blood cell types, the CD14+CD16- monocyte (an important central orchestrator of adaptive immunity and a bridge between innate and adaptive immunity) and the CD65+CD9- neutrophilic granulocyte (the frontline cell for innate immunity) have been selected for this purpose. The two types of cells will be obtained at high purity from adult blood (AB) of 200 healthy males and females, respectively. Cells will be purified by using already validated and fully operational protocols that are based on density gradient centrifugation of the buffy coat obtained from whole blood, followed by magnetic bead-based purification using monoclonal antibodies against Cluster of Differentiation (CD) lineage-specific cell surface markers. This data set contains functional genomics data for gene expression and chromatin state.

  Study EGAS00001000586

• Measuring the level of relatedness between NGS datasets

  Sequencing technologies are providing increasingly detailed insight in genetic makeup are paving their way into molecular diagnostics. The field will benefit from rigorous and bias-free measures for the quality of sequence data and for the proper representation of the complexity of the original samples. While current methodologies rely on the availability of a well-characterized reference genome, we propose kMer profiling for alignment-free assessment of the quality, comparability, and complexity of sequencing datasets. We show that kMer detects technical artefacts such as high duplication rates, library chimaeras, and differences in library preparation protocols in whole-genome, whole-exome, and RNA sequencing data. Additionally, it successfully captures the complexity and diversity of microbiomes. Thus, kMer allows for a robust evaluation of the quality and complexity of sequencing data without relying on any prior information and opens the way to a more reliable biological reasoning.

  Study EGAS00001000600

• These are from Korean HCC samples with exome sequencing

  Hepatic resection is the most curative treatment option for early-stage hepatocellular carcinoma, but is associated with a high recurrence rate, which exceeds 50% at 5 years after surgery. Understanding the genetic basis of hepatocellular carcinoma at surgically curable stages may enable the identification of new molecular biomarkers that accurately identify patients in need of additional early therapeutic interventions. Whole exome sequencing and copy number analysis was performed on 231 hepatocellular carcinomas (72% with hepatitis B viral infection) that were classified as early-stage hepatocellular carcinomas, candidates for surgical resection. Recurrent mutations were validated by Sanger sequencing. Unsupervised genomic analyses identified an association between specific genetic aberrations and postoperative clinical outcomes. Recurrent somatic mutations were identified in 9 genes, including TP53, CTNNB1, AXIN1, RPS6KA3, and RB1. Recurrent homozygous deletions in FAM123A, RB1, and CDKN2A, and high-copy amplifications in MYC, RSPO2, CCND1, and FGF19 were detected. Pathway analyses of these genes revealed aberrations in the p53, Wnt, PIK3/Ras, cell cycle, and chromatin remodelling pathways. RB1 mutations were significantly associated with cancer-specific and recurrence-free survival after resection (p = 0.016 and p = 0.001, respectively). FGF19 amplifications, known to activate Wnt signalling, were mutually exclusive with CTNNB1 and AXIN1 mutations, and significantly associated with cirrhosis (p = 0.017). RB1 mutations can be used as a prognostic molecular biomarker for resectable hepatocellular carcinoma. Further study is required to investigate the potential role of FGF19 amplification in driving hepatocarcinogenesis in patients with liver cirrhosis and to investigate the potential of anti-FGF19 treatment in these patients.

  Study EGAS00001000604

• Divergence between high metastatic tumor burden and low circulating tumor DNA concentration in metastasized breast cancer

  Circulating tumor DNA (ctDNA) was reported to represent a highly sensitive biomarker of metastatic cancer disease directly reflecting tumor burden and dynamics. Here we investigated the role of ctDNA in patients with metastatic breast cancer. In an index patient with more than 100,000 circulating tumor cells (CTCs) in serial blood analyses, whole genome, exome, or targeted deep sequencing of the primary tumor, metastases, and 551 CTCs were consistent with a genetically homogeneous cancer. However, the allele fractions (AFs) of ctDNA were only 2-3% in each analysis, which did neither reflect the tumor burden nor the dynamics of this progressive disease by far. Indeed, plasma analyses of 71 further patients demonstrated highly variable AFs of mutant fragments, which frequently did not correspond to the tumor burden. These results provide insights into mechanisms involved in CTC and ctDNA release into the circulation and have important implications for diagnostic tests based on liquid biopsies.

  Study EGAS00001000625

• Genome of the Netherlands

  The Genome of the Netherlands (GoNL) Project characterizes DNA sequence variation, common and rare, for SNVs, short insertions and deletions (indels) and larger deletions in 769 individuals of Dutch ancestry selected from five biobanks under the auspices of the Dutch hub of the Biobanking and Biomolecular Research Infrastructure (BBMRI-NL). The samples come from a representative sample of 250 trio-families from all provinces in the Netherlands. The parent-offspring trios include adult individuals ranging in age from 19 to 87 years (mean=53 years; SD=16 years) from birth cohorts 1910-1994. Sequencing was done on blood-derived DNA from uncultured cells and accomplished coverage was 14-15x. Samples where contributed by LifeLines (http://lifelines.nl/lifelines-research/general), The Leiden Longevity Study (http://www.healthy-ageing.nl; http://www.langleven.net), The Netherlands Twin Registry (NTR: http://www.tweelingenregister. org), The Rotterdam studies, (http://www.erasmus-epidemiology.nl/rotterdamstudy) and the Genetic Research in Isolated Populations program (http://www.epib.nl/research/geneticepi/research.html#gip). The sequencing was carried out in collaboration with the Beijing Institute for Genomics (BGI). The analysis was done by a consortium lead by UMCG, LUMC, Erasmus MC, VU university and UMCU, see http://www.nlgenome.nl. Funding for the project was provided by the Netherlands Organization for Scientific Research under award number 184021007, dated July 9, 2009 and made available as a Rainbow Project of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL).

  Study EGAS00001000644

• A Genomics-Based Classification of Human Lung Tumors

  We characterized genome alterations in 1255 clinically annotated lung tumors of all histological subgroups to identify genetically defined and clinically relevant subtypes. More than 55% of all cases had at least one oncogenic genome alteration potentially amenable to specific therapeutic intervention, including several personalized treatment approaches that are already in clinical evaluation. Marked differences in the pattern of genomic alterations existed between and within histological subtypes, thus challenging the original histomorphological diagnosis. Immunohistochemical studies confirmed many of these reassigned subtypes. The reassignment eliminated almost all cases of large cell carcinomas, some of which had therapeutically relevant alterations. Prospective testing of our genomics-based diagnostic algorithm in 5145 lung cancer patients enabled a genome-based diagnosis in 3863 (75%) patients, confirmed the feasibility of rational reassignments of large cell lung cancer, and led to improvement in overall survival in patients with EGFR-mutant or ALK-rearranged cancers. Thus, our findings provide support for broad implementation of genome-based diagnosis of lung cancer.

  Study EGAS00001000647

• Microsatellite data show recent demographic expansions in sedentary but not in nomadic human populations in Africa and Eurasia.

  The transition from hunting and gathering to plant and animal domestication was one of the most important cultural and technological revolutions in human history. According to archeologists and paleoanthropologists, this transition triggered major demographic expansions. However, few genetic studies have found traces of Neolithic expansions in the current repartition of genetic polymorphism, pointing rather toward Paleolithic expansions. Here, we used microsatellite autosomal data to investigate the past demographic history of 87 African and Eurasian human populations with contrasted lifestyles (nomadic hunter-gatherers, semi-nomadic herders and sedentary farmers). Likely due to the combination of a higher mutation rate and the possibility to analyze several loci as independent replicates of the coalescent process, the analysis of microsatellite data allowed us to infer more recent expansions than previous genetic studies, potentially resulting from the Neolithic transition. Despite the variability in their location and environment, we found consistent expansions for all sedentary farmers, while we inferred constant population sizes for all hunter-gatherers and most herders, which could result from constraints linked to a nomadic or semi-nomadic lifestyle and/or competition for land between herders and farmers. As an exception, we inferred expansions for Central Asian herders. This might be linked with the arid environment of this area, which may have been more favorable to nomadic herders than to sedentary farmers. Alternatively, current Central Asian herders may descent from populations who have first experienced a transition from hunter-gathering to sedentary agropastoralism, and then a second transition to nomadic herding.

  Study EGAS00001000652

• Biallelic DICER1 mutations in sporadic pleuropulmonary blastoma

  Pleuropulmonary blastoma (PPB) is an extremely rare pediatric malignancy in the lung, whose pathogenesis is poorly understood, except for recent reports of frequent germline heterozygous DICER1 mutations. To investigate the genetic basis of PPB, we performed whole-exome sequencing in 7 representative PPB cases, followed by targeted deep sequencing in 12 cases with PPB. DICER1 mutations were found in 11/12 cases. Biallelic DICER1 mutations were common in PPB, in which RNase IIIb domain mutations were found in all cases with or without nonsense/frameshift mutations and were somatic in all evaluable cases. A majority of cases had mutated DICER1 alleles in germline with or without an additional somatic mutation in the remaining allele, while other cases had exclusively somatic mutations involving the RNase IIIb domain. TP53 deletions/mutations were detected in 8/12 cases. Our results highlight a unique role of the RNase IIIb domain mutations and TP53 inactivation in PPB pathogenesis.

  Study EGAS00001000662

• Integrated genomic characterization of adrenocortical carcinoma

  Adrenocortical carcinomas (ACC) are aggressive cancers originating in the cortex of the adrenal glands. Despite the overall poor prognosis, ACC outcome is heterogeneous. CTNNB1 and TP53 mutations are frequent in these tumors, but the complete spectrum of genetic changes remains undefined. Exome sequencing and SNP array analysis of 45 ACC revealed recurrent alterations in known drivers (CTNNB1, TP53, CDKN2A, RB1, MEN1) and genes not previously reported to be altered in ACC (ZNRF3, DAXX, TERT and MED12), which were validated in an independent cohort of 77 ACC. The cell-surface transmembrane E3 ubiquitin ligase ZNRF36 was the gene the most frequently altered (21%), and appears as a potential novel tumor suppressor gene related to the ß-catenin pathway. Our integrated genomic analyses led to the identification of two distinct molecular subgroups with opposite outcome. The C1A group of poor outcome ACC was characterized by numerous mutations and DNA methylation alterations, whereas the C1B group with good prognosis displayed a specific deregulation of two miRNA clusters. Thus, aggressive and indolent ACC correspond to two distinct molecular entities, driven by different oncogenic alterations.Array based dataset for this study has been made public at:http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE49280.

  Study EGAS00001000665

• Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing

  We applied multi-region exome sequencing to 10 clear cell renal carcinomas to resolve the genetic architecture, intra tumour heterogeneity and evolutionary histories of these tumours.

  Study EGAS00001000667

• Study on the consequences of prenatal famine exposure on DNA methylation.

  The potential of the epigenome to undergo environmentally-induced changes during early development is central to its postulated role in human disease. Here, we report a genome-scale view of DNA methylation differences after early gestational malnutrition that was caused by the Dutch Hunger Winter, a severe famine at the end of World War II. We adopted an annotation guided analysis of reduced-representation bisulfite sequencing data generated in 24 middle-aged individuals who had been exposed to famine in utero and 24 unexposed sibling controls. We observed differential DNA methylation primarily at genomic regions with regulatory potential, including enhancers active during early development. In-depth annotation of 181 prenatally-induced differentially methylated regions (P-DMRs) showed that they were predominantly located in gene bodies and co-occurred with histone marks denoting an active state. In line with the early gestational timing of the exposure, the P-DMRs mapped to genes that were enriched for differential expression patterns during blastocyst development and early organogenesis. Validation and further explorative analyses of 6 P-DMRs mapping to SMAD7, CDH23, INSR, RFTN1, CPT1A and KLF13 highlighted the critical role of gestational timing, indicated that differential methylation extended along pathways involved in growth, development and metabolism, and suggested associations with birth weight and serum LDL cholesterol in adulthood and confirmed an enhancer function for the INSR and CPT1A P-DMRs. Our results point toward a link between prenatal malnutrition and epigenetic modulation of growth and lipid metabolism that may underlie the adverse metabolic phenotype of exposed individuals in later life.

  Study EGAS00001000668

• Enhancer profiling to identify identifies epigenetic markers of endocrine resistance in metastatic castration resistant prostate cancer patients

  Study EGAS00001006161