3413 results for "*geneti*"

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• Whole genome sequencing of EBV Associated Nasopharyngeal Carcinoma

  Interplay between EBV infection and acquired genetic alterations during nasopharyngeal carcinoma (NPC) development remains vague. Here we report a comprehensive genomic analysis of 70 NPCs, combining whole-genome sequencing (WGS) of microdissected tumor cells with EBV oncogene expression to reveal multiple aspects of cellular-viral co-operation in tumorigenesis. Genomic aberrations along with EBV-encoded LMP1 expression underpin constitutive NF-κB activation in 90% of NPCs. A similar spectrum of somatic aberrations and viral gene expression undermine innate immunity in 79% of cases and adaptive immunity in 47% of cases; mechanisms by which NPC may evade immune surveillance despite its pro inflammatory phenotype. Additionally, genomic changes impairing TGFBR2 promote oncogenesis and stabilize EBV infection in tumor cells. Fine-mapping of CDKN2A/CDKN2B deletion breakpoints reveals homozygous MTAP deletions in 32-34% of NPCs that confer marked sensitivity to MAT2A inhibition. Our work concludes that NPC is a homogeneously NF-κB-driven and immune-protected, yet potentially druggable, cancer.

  Study EGAS00001004705

• Geographical structure and differential natural selection among North European populations

  European populations and epidemiological cohorts are of special significance in the current era of genomic research aiming to characterize the background of common human diseases. The genome sequence, detailed information of genetic variations between individuals, high-throughput molecular technologies and novel statistical strategies create new possibilities to define genetic and life-style risk factors behind common health problems. Studies of large population cohorts are needed to transform the genetic information to detailed understanding of the predisposing factors in diseases affecting most human populations. European twin cohorts provide a unique competitive advantage for investigations of the role of genetics and environment or life style in the etiology of common diseases. This project will apply and develop new molecular and statistical strategies to analyze unique European twin and other population cohorts to define and characterise the genetic, environmental and life-style components in the background of health problems like obesity, migraine, coronary heart disease and stroke, representing major health care problems worldwide.

  Study EGAS00000000033

• MRCA and MRCE SNP genotypes

  Gene expression levels can be an important link DNA between variation and phenotypic manifestations. Our previous map of global gene expression based on approximately 400K SNPs and 50K transcripts in 400 sib pairs from the MRCA family panel has been widely used to interpret the results of GWAS. Here, we more than double the size of our initial dataset with expression data on 550 additional individuals from the MRCE family panel using the Illumina whole genome expression array. We have used new statistical methods for dimension reduction to account for non-genetic effects in estimates of expression levels and we have also included SNPs imputed from the 1000 Genomes Project. Our methods reduced false discovery rates and increased the number of eQTLs mapped either locally or at a distance (i.e. in cis or trans) from 1,534 in the MRCA dataset to 4,452 (with <5% FDR). Imputation of 1000 Genomes SNPs further increased the number of eQTLs to 7,302. Using the same methods and imputed SNPs in the newly acquired MRCE dataset we identified eQTLs for 9000 genes. The combined results identify strong local and distant effects for transcripts from 14,177 genes. Our eQTL database (http://www.hsph.harvard.edu/faculty/liming-liang/software/eqtl/) based on these results is freely available to help define the function of disease-associated variants.

  Study EGAS00000000137

• Determination of the molecular nature of the Vel blood group by exome sequencing

  The genetic basis of the Vel group is yet to be determined. We have collected DNA samples from about 90 Vel negative blood donors by phenotyping 270,000 donors. Understanding the genetic basis of the Vel group could have clinical significance as transfusion of Vel positive blood to Vel negative recipients with anti-Vel can cause severe and acute haemolytic transfusion reactions.

  Study EGAS00001000069

• PAS Pedigrees: Identification of novel genetic variants contributing to cardiovascular disease in pedigrees with premature atherosclerosis.

  The heritability of CVD has been estimated to be between 40 and 55%. Due to the low MAF, PAS-causing mutations cannot be identified by indirect genotyping because their presence cannot be inferred from common haplotypes, as has been done successfully to uncover common risk variants by GWAS. It has been shown by Ng et al that the causative gene for rare syndromes can be unequivocally identified by sequencing the exomes of only four cases and eight controls. We expect exome sequencing to result in a high number of mutations and non-causitive coding variants.

  Study EGAS00001000052

• Investigation of the genetic basis of the rare syndrome Post-Transfusion Purpura (PTP)

  The Post-Transfusion Pupura (PTP) syndrome although rare has severe side effects for 5-10 cases per annum in the UK as a result of transfusion. High quality DNA has been isolated from either whole blood or from cryopreserved mononuclear cells of 4 patients in order to study our postulation that the condition is caused by a loss-of-function mutation in a specific gene.

  Study EGAS00001000053

• Unraveling_the_genetic_basis_of_a_collagen_migration_defect_in_patients_with_a_combined__platelet_dysfunction_and_reduced_bone_density

  In this project we study cases from unrelated pedigrees that present at a young age with a phenotype which inludes hypotonia and hypodensity of bones, a chronic elevation of some liver and muscle enzymes as well as abnormal platelet number and volume. We aim to use exome sequencing to discover the causative variants reponsible for these defects.

  Study EGAS00001000093

• 'Targeted High Throughput Sequencing in Clinical Cancer Settings: Formaldehyde fixed-paraffin embedded (FFPE) tumor tissues, input amount and tumor heterogeneity'

  "Background: Massively parallel sequencing technologies have brought an enormous increase in sequencing throughput. However, these technologies need to be further improved with regard to reproducibility and applicability to clinical samples and settings. Methods: Using identification of genetic variations in prostate cancer as an example we address three crucial challenges in the field of targeted re-sequencing: Small nucleotide variation (SNV) detection in samples of formalin-fixed paraffin embedded (FFPE) tissue material, minimal amount of input sample and sampling in view of tissue heterogeneity.Results: We show that FFPE tissue material can supplement for fresh frozen tissues for the detection of SNVs and that solution-based enrichment experiments can be accomplished with small amounts of DNA with only minimal effects on enrichment uniformity and data variance. Finally, we address the question whether the heterogeneity of a tumor is reflected by different genetic alterations, e.g. different foci of a tumor display different genomic patterns. We show that the tumor heterogeneity plays an important role for the detection of copy number variations, but is of minor importance for the detection of somatic variations.Conclusions: The application of high throughput sequencing technologies in cancer genomics opens up a new dimension for the identification of disease mechanisms. In particular the ability to use small amounts of FFPE samples available from surgical tumor resections and histopathological examinations facilitates the collection of precious tissue materials. However, care needs to be taken in regard to the locations of the biopsies taken, which can have an influence on the prediction of copy number variations. Bearing these technological challenges in mind will significantly improve many large-scale sequencing studies and will - on a long-range - result in a more reliable prediction of individual cancer therapies."

  Study EGAS00001000136

• An exome sequencing pilot study of HIV elite-long term non progressors and rapid progressors

  A pilot study examining genetic determinants associated with elite long term non progression and rapid progression using exome sequencing of individuals at the extremes of the distribution of HIV control and progression. Data can only be used for HIV related research.

  Study EGAS00001000057

• Intra-tumor heterogeneity and clonal evolution patterns towards platinum-resistant high-grade serous ovarian cancer

  Although many high-grade serous ovarian carcinoma (HGSOC) patients are initially sensitive to the standard-of-care platinum-based therapy, intra-tumor heterogeneity may fuel selection towards platinum-resistant clones over subsequent lines of therapy. We performed whole-exome coupled to ultra-deep re-sequencing and copy number alteration (CNA) profiling on 31 matched diagnosis and relapse tumors from HGSOC patients treated with platinum. Genetic heterogeneity within tumor pairs varied extremely, with some recurrent tumors being identical and others completely different from the primary tumor. All primary tumors showed evidence of homologous recombination (HR)-deficiency, but none of them carried reactivating mutations in the HR pathway at relapse, also not when becoming resistant to subsequent lines of platinum. We did also not identify other mutations, CNAs or pathways that were enriched in platinum-resistant clones. However, a platinum score consisting of 13 CNAs correlated significantly with platinum-free interval (PFI) after first-line therapy in multiple cohorts of &gt;450 primary HGSOCs. A relative increase of this score in the relapsed tumor correlated with a change in PFI during subsequent therapy. Clonal evolution under platinum therapy contributes to genetic heterogeneity within tumor pairs, implicating that genetic tests linked to targeted treatment options for recurrent HGSOC need to be performed on biopsies collected at relapse. Platinum resistance of an initially platinum-sensitive HR-deficient HGSOC at relapse is not caused by reactivation of the HR pathway, suggesting that these tumors are still responsive to PARP inhibitors, instead, several chromosomal aberrations contribute to a score predictive of disease outcome under platinum therapy, both in first and subsequent lines of platinum therapy.

  Study EGAS00001001244

• Screening_for_human_epigenetic_variation_at_CpG_islands

  Many human characteristics, including susceptibility to disease, are determined genetically. An unexplored alternative to such genetic determination concerns epigenetic mechanisms such as DNA methylation. CpG islands (CGIs) are generally constitutively hypomethylated, however there are circumstances in which they become heavily methylated and, when coincident with a gene promoter, this invariably causes transcriptional silencing. CGI methylation occurs in normal tissues during processes such as X-inactivation, but abnormal patterns of methylation have also been implicated in disease. The vast majority of evidence relates to cancer, where silencing of multiple genes in this way appears to be a causal contributor to the cancer state. To address the role and extent of CGI methylation in ‘normal’ and diseased cells we applied MBD-affinity purification in conjunction with next generation sequencing in a panel of human brain autopsy samples. These samples represent a panel of individuals as well as specific brain regions and neurological pathologies.

  Study EGAS00001000074

• Genetic landscape of pediatric ETV6-RUNX1 acute lymphoblastic leukemia

  Abstract in preparation

  Study EGAS00001001314

• Genetic landscape of pediatric high hyperdiploid acute lymphoblastic leukemia

  Abstract in preparation

  Study EGAS00001001316

• ATRX mutant neuroblastoma is sensitive to EZH2 inhibition via modulation of neuronal differentiation.

  Mutations and structural alterations of the SWI/SNF-like chromatin remodeler ATRX have been reported at high frequency in a number of adult and pediatric tumors1. However, the consequences of ATRX (Alpha Thalassemia/Mental Retardation, X-linked) mutations in cancer and their underlying epigenetic sensitivities remain ill defined. Particularly intriguing are the large N-terminal deletions of ATRX in neuroblastoma that generate in-frame fusion (IFF) proteins1–3 devoid of key chromatin interaction domains. Here we demonstrate that neuroblastoma cells harbouring ATRX IFFs have distinct gene expression programs compared to neuroblastoma cells that are wild type for ATRX. This is due in part to H3K27me3-mediated silencing of REST (RE1 Silencing Transcription Factor) target genes involved in neuronal differentiation. In turn, we find that ATRX IFF cells display exquisite sensitivity to EZH2 inhibition in both adherent and tumorsphere conditions, due in part to derepression of neurogenesis genes, including REST targets. Examination of the epigenomic landscape of a pediatric neuroblastoma tumor harboring an ATRX IFF revealed that H3K27me3 occupies a subset of REST target genes that are transcriptionally silenced, and are sensitive to EZH2 inhibition in our cell-based assays. Thus, our study greatly advances our understanding of indolent neuroblastoma and identifies EZH2 inhibition as a potential therapy for patients with ATRX mutant disease. Further, these studies may be applicable to other ATRX mutant pediatric malignancies, particularly those carrying similar structural alterations of ATRX.

  Study EGAS00001002507

• BLUEPRINT Hematopoietic Stem/Progenitor Cell Methylomes

  Study EGAS00001002070

• Germline and somatic SMARCA4 mutations characterize small-cell carcinoma of the ovary, hypercalcemic type.

  Small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is the most common undifferentiated ovarian malignancy in women under 40 years1. We sequenced the exomes of six individuals from three SCCOHT families. After discovering segregating deleterious germline mutations in SMARCA4 in all three families, we tested DNA from a fourth family, which also possessed a segregating SMARCA4 germline mutation. All familial tumors sequenced harboured either a somatic mutation or loss of the wild-type allele. Immunohistochemical (IHC) analysis of these and additional familial and non-familial cases showed loss of the SMARCA4 protein (BRG1) in 38/40 tumors overall. Sequencing of cases with available DNA revealed at least one germline or somatic deleterious SMARCA4 mutation in 30/32 cases. Additionally, the SCCOHT cell line BIN-67 contained bi-allelic deleterious mutations in SMARCA4. Our findings identify alterations in SMARCA4 as the major cause of SCCOHT, which could lead to genetic counseling and new treatment approaches.

  Study EGAS00001000721

• Spatial heterogeneity in medulloblastoma

  Spatial heterogeneity of transcriptional and genetic markers between physically isolated biopsies of a single tumor poses major barriers to the identification of biomarkers and the development of targeted therapies that will be effective against the entire tumor. We analyzed the spatial heterogeneity of multiregional biopsies from 35 patients, using a combination of transcriptomic and genomic profiles. Medulloblastomas (MBs), but not high-grade gliomas (HGGs), demonstrated spatially homogeneous transcriptomes, which allowed for accurate subgrouping of tumors from a single biopsy. Conversely, somatic mutations that affect genes suitable for targeted therapeutics demonstrated high levels of spatial heterogeneity in MB, malignant glioma, and renal cell carcinoma (RCC). Actionable targets found in a single MB biopsy were seldom clonal across the entire tumor,which brings the efficacy of monotherapies against a single target into question. Clinical trials of targeted therapies for MB should first ensure the spatially ubiquitous nature of the target mutation.

  Study EGAS00001001014

• 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

• 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

• Integrative analysis of small cell lung cancer

  Small-cell lung cancer (SCLC) is an aggressive lung tumor subtype. We conducted integrated analysis of genome sequencing, transcriptome, and copy number analysis and found an extremely high mutation rate of 7.4±1 protein-changing mutations per million basepairs. Evidence for inactivation of TP53 and RB1 was found in all sequenced cases. Furthermore, we identified recurrent mutations in CREBBP, EP300, and MLL, observed mutations in PTEN, in SLIT2, and EPHA7, as well as focal amplifications of the FGFR1 locus. As a major feature of SCLC we found mutation in histone modifying genes, observed genome alterations that are therapeutically tractable, and provide a framework for identifying biologically relevant genes in the context of a high mutation rate. Peifer et al., 2012, Nature Genetics.

  Study EGAS00001000299

• 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

• 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

• Functional_characterisation_of_CpG_islands_in_human_and_mouse_tissues

  Tissue-specific methylation patterns suggest a role for CpG island (CGI) methylation in differentiation and cell-type-specific gene regulation. We have applied CXXC affinity purification (CAP), MBD affinity purification (MAP) and chromatin immunoprecipitation (ChIP) in combination with solexa sequencing to investigate the extent and functional significance of CGI methylation in sperm, blood, cerebellum and ES cells for both human and mouse.

  Study EGAS00001000075

• Screening_for_abnormal_CGI_methylation_in_primary_colorectal_tumours

  A common hallmark of neoplastic cells is abnormal acquisition of CpG island (CGI) methylation and the silencing of associated gene promoters. To determine the extent and distribution of CGI methylation in colorectal cancer, we solexa sequenced MBD affinity purified DNA prepared from five colorectal tumours and matched colon mucosa from the same individuals.

  Study EGAS00001000076

• Poly(A) RNA sequencing of hepatocellular carcinoma tumors and their matched noncancerous liver tissues

  Background &amp; Aims: The differentiation of distinct multifocal hepatocellular carcinoma (HCC): multicentric disease vs. intrahepatic metastases, in which the management and prognosis varies substantively, remains problematic. We aim to stratify multifocal HCC and identify novel diagnostic and prognostic biomarkers by performing whole genome and transcriptome sequencing, as part of a multi-omics strategy Methods: A complete collection of tumour and somatic specimens (intrahepatic HCC lesions, matched non-cancerous liver tissue and blood) were obtained from representative patientswith multifocal HCC exhibiting two distinct postsurgical courses. Whole-genome and transcriptome sequencing with genotyping were performed for each tissue specimen to con-trast genomic alterations, including hepatitis B virus integrations, somatic mutations, copy number variations, and structural variations. We then constructed a phylogenetic tree to visualise individual tumour evolution and performed functional enrichment analyses on select differentially expressed genes to elucidate biological processes involved in multifocal HCC development. Multi-omics data were integrated with detailed clinicopathological information to identify HCC biomarkers, which were further validated using a large cohort of HCC patients (n = 174).Results: The multi-omics profiling and tumour biomarkers could successfully distinguish the two multifocal HCC types, while accurately predicting clonality and aggressiveness. The dual specificity protein kinase TTK, which is a key mitotic checkpoint regulator with links to p53 signaling, was further shown to be a promising overall prognostic marker for HCC in the large patient cohort.Conclusions: Comprehensive multi-omics characterisation of multifocal tumour evolution may improve clinical decision-making, facilitate personalised medicine, and expedite identification of novel biomarkers and therapeutic targets in HCC.

  Study EGAS00001002337