3968 results for "*geneti*"

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• RNA-sequencing of six Pilocytic astrocytoma tumors

  Pilocytic astrocytoma (PA) is the most common pediatric brain tumor. A recurrent feature of PA is deregulation of the mitogen activated protein kinase (MAPK) pathway most often through KIAA1549-BRAF fusion, but also by other BRAF- or RAF1-gene fusions and point mutations (e.g. BRAFV600E). These features may serve as diagnostic and prognostic markers, and also facilitate development of targeted therapy. The aim of this study was to characterize the genetic alterations underlying the development of PA tumor in six cases, and evaluate methods for fusion oncogene detection. Using a combined analysis of RNA sequencing and copy number variation data we identified a new BRAF fusion involving the 5’ gene fusion partner GTF2I (7q11.23), not previously described in PA. The novel GTF2I-BRAF 19-10 fusion was found in one case, while the other five cases harbored the frequent KIAA1549-BRAF 16-9 fusion gene. Comparing fusion detection methods, Fluorescence in situ hybridization with BRAF break apart probe was the most sensitive method for detection of the two different BRAF rearrangements (GTF2I-BRAF and KIAA1549-BRAF). Our finding of a novel BRAF fusion in PA further emphasis the important role of B-Raf in tumorigenesis of these tumor types. Also, the growing list of BRAF/RAF gene fusions suggests these to be informative tumor markers in molecular diagnostics, which could guide future treatment strategies.

  Study EGAS00001002149

• 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

• Family-based GWAS for CRSwNP

  AbstractOur goal was to identify genetic markers and genes associated with susceptibility to chronic rhinosinusitis with nasal polyps using a family-based genome-wide association study.MethodsPatients with CRSwNP and controls were recruited. SNP association values were generated using DFAM (implemented in PLINK) and Efficient Mixed Model Association eXpedited (EMMAX).

  Study EGAS00001002665

• Genetics of Microcephalic Osteodysplatics Primordial Dwarfism

  This project aims to find causal variants in 50 patients diagnosed with Microcephalic Osteodysplastic Primordial Dwarfism (MOPD), of presumed recessive inheritance performing whole exome sequencing to ~50x mean depth. This is a collaboration with Prof A. Jackson, MRC Human Genetics Unit, Edinburgh

  Study EGAS00001000064

• Samples from the Greek island of Crete, MANOLIS cohort

  Genome-wide association studies of complex traits have been successful in identifying common variant associations, but a substantial heritability gap remains. The field of complex trait genetics is shifting towards the study of low frequency and rare variants, which are hypothesised to have larger effects. The study of these variants can be empowered by focusing on isolated populations, in which rare variants may have increased in frequency and linkage disequilibrium tends to be extended. This work focuses on isolated populations from Greece. Sequencing is very efficient in isolated populations, because variants found in a few samples will be shared by others in extended haplotype contexts, supporting accurate imputation.

  Study EGAS00001000067

• Whole genome bisulfite sequencing of hepatitis B virus-associated hepatocellular carcinoma tumor and non-cancerous samples

  To understand comprehensive epigenetic alterations in hepatitis B virus-associated HCC, we have conducted a whole genome bisulfite sequencing of 5 tumor samples and 3 non-cancerous samples (3 pairs and 2 tumors).

  Study EGAS00001002230

• An Unusual Genomic Variant of Pancreatic Ductal Adenocarcinoma with an Indolent Clinical Course

  We describe a patient with biopsy-proven locally advanced pancreatic ductal adenocarcinoma (PDA) who underwent a modified course of gemcitabine and stereotactic body radiation therapy. Whole exome sequencing of this patient's tumor revealed a simple genome landscape with no evidence of mutations, copy number changes, or structural alterations in genes most commonly associated with PDA, i.e. KRAS, CDKN2A, TP53 or SMAD4. An analysis of germline DNA revealed no pathogenic variants of significance. Whole exome and whole genome sequencing identified a somatic mutation of RNF213 and an inversion/deletion of CTNNA2 as the genetic basis of this PDA. Although PDA is classically characterized by a predictable set of mutations, these data suggest that alternate genetic paths to PDA may exist, which can be associated with a more indolent clinical course.

  Study EGAS00001002192

• UK10K NEURO FSZNK

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches. This Finnish schizophrenia sample set has been collected from a population cohort using national registers. The entire sample collection consists of 2756 individuals from 458 families of whom 931 are diagnosed with schizophrenia spectrum disorder. Families outside Kuusamo (n=288) all had at least two affected siblings. All diagnoses are based on DSM-IV and for a large fraction of cases there is cognitive data.For further details/descriptions with regard to this data set please contact Tiina Paunio (tiina.paunio@thl.fi)

  Study EGAS00001000119

• UK10K_RARE_NEUROMUSCULAR

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches. The neuromuscular disorder samples are part of the “rare disease” group, and will undergo exome sequencing. For further information with regard to this cohort please contact Francesco Muntoni (f.muntoni@ucl.ac.uk).

  Study EGAS00001000101

• Genome-wide DNA methylation profiles by MeDIP-seq of cord blood cells and cord blood mononuclear cells obtained from twins conceived through in vitro fertilization and naturally conceived controls

  The study included 47 newborn twins conceived though in vitro fertilisation (IVF) and 60 non-IVF-conceived twins from the Peri/postnatal Epigenetic Twins Study (PETS). Cord blood was collected at birth and used to process mononuclear cells. Whole blood cells (WBCs) from cord blood of 98 twins (40 IVF and 58 non-IVF) and cord blood mononuclear cells (CBMCs) of 82 twins (35 IVF and 47 non-IVF) were subjected to DNA methylation profiling. Methylated DNA immunoprecipitation followed by deep sequencing (MeDIP-seq) was applied to generate genome-wide DNA methylation profiles in a total of 180 samples. Single-end reads were mapped onto hg19 using BWA. Methylation levels were quantified using MEDIPS and used to identify IVF-associated differentially methylated regions.

  Study EGAS00001002248

• This study explored and validated the clinical application of targeted NGS of circulating tumor DNA in identifying tumor-specific mutations and uncovering clinical actionable targets in a variety of solid tumors in large patient cohorts.

  Cancer is a disease of genetic alterations. Comprehensive genetic diagnosis is needed to match each patient to appropriate cancer therapy. However, acquisition of representative tumor samples is invasive and often infeasible. Circulating tumor DNA (ctDNA) is a promising non-invasive biomarker for cancer mutational profiling. Here we implemented targeted next generation sequencing (NGS) with a customized pan-cancer gene panel on 605 clinical ctDNA samples in multiple cancer types. Overall, tumor-specific mutations were identified in 87% of ctDNA samples, with mutation spectra highly concordant with their matched tumor tissues. 71% of patients have at least one clinical actionable mutation with 76% of which have suggested drugs approved or in clinical trials. In particular, our study reveals a unique mutation spectrum in Chinese lung cancer patients, which could be used to guide treatment decision and monitor the appearance of drug-resistant mutations. Taken together, our study demonstrated the clinical utility of target NGS-based ctDNA mutational profiling to guide cancer treatment decision.

  Study EGAS00001002251

• UK10K NEURO ASD SKUSE

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches. This sample set of UK origin consists of clinically identified subjects with Autism Spectrum Disorders, mostly without intellectual disability (ie. Verbal IQs >70). The subjects represent children and adults with Autism, Asperger syndrome or Atypical Autism, identified according to standardized research criteria (ADI-algorithm, ADOS). A minority has identified comorbid neurodevelopmental disorders (e.g. ADHD). Family histories are available, with measures of broader phenotype in first-degree relatives.For further information on this cohort please contact David Skuse (d.skuse@ucl.ac.uk).

  Study EGAS00001000114

• Whole exome sequencing of cell-free DNA reveals temporo-spatial heterogeneity and identifies treatment-resistant clones in neuroblastoma

  Background: Neuroblastoma (NB) displays important clinical and genetic heterogeneity, with emergence of new mutations at tumor progression. Patients and Methods: To study clonal evolution during treatment and follow-up, an innovative method based on circulating cell-free DNA (cfDNA) analysis by whole exome sequencing (WES) paired with target sequencing was realized in sequential liquid biopsy samples of 19 NB patients. Results: WES of the primary tumor and cfDNA at diagnosis showed overlap of Single Nucleotide Variants (SNVs) and Copy Number Alterations (CNAs), with 41% and 93% of all detected alterations common to the primary NB and cfDNA. CfDNA WES at a second time point indicated a mean of 22 new SNVs for patients with progressive disease. Relapse-specific alterations included genes of the MAPK pathway and targeted the protein kinase A signaling pathway. Deep coverage target sequencing of intermediate timepoints during treatment and follow-up identified distinct subclones. For 17 seemingly relapse-specific SNVs detected by sequencing detected these alterations in minor subclones, with relapse-emerging SNVs targeting genes of neuritogenesis and cell cycle. Furthermore a persisting, resistant clone with concomitant disappearance of other clones was identified by a mutation in the ubiquitin protein ligase HERC2. Conclusion: Modelisation of mutated allele fractions in cfDNA indicated distinct patterns of clonal evolution, with either a minor, treatment-resistant clone expanding to a major clone at relapse, or minor clones collaborating towards tumor progression. Identification of treatment-resistant clones will enable development of more efficient treatment strategies.cfDNA WES at relapse but not tumor or cfDNA WES at diagnosis, deep coverage target.

  Study EGAS00001002705

• UK10K NEURO IMGSAC

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches.The IMGSAC cohort is an international collection of families containing children ascertained for ASDs (autism spectrum disorders). The affected individuals are have been phenotyped, including using the ADI-R and ADOS instruments. Individuals with a past or current medical disorder of probable etiological significance or TSC have been excluded. Where possible, karyotyping has been performed on one affected individual per family to exclude Fragile X syndrome. Many of the samples have been genotyped, using the Affymetrix 10k and Illumina 1M platforms. All samples to be included in the current study are of UK origin.For further information on this cohort please contact Jeremy Parr (jeremy.parr@newcastle.ac.uk).

  Study EGAS00001000120

• UK10K_NEURO_MUIR

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches.The sample selection consists of subjects with schizophrenia (SZ), autism, or other psychoses all with mental retardation (learning disability). The samples were initially collected under the leadership of Walter J Muir (deceased), now with Prof. Blackwood, Dr McKechanie and Prof McIntosh as custodians. These subjects represent the intersection of severe forms of neurodevelopmental disorders, appear to have a higher rate of familiality of SZ than typical, and are likely to have more serious and penetrant forms of mutations.For further information on this cohort please contact Andrew McIntosh (andrew.mcintosh@ed.ac.uk).

  Study EGAS00001000122

• The_life_history_of_colorectal_cancer_metastases_study_WGS_X10

  Whole genome sequencing of a series of metastasis collected from 2 patients at autopsy will be used to construct a life history of the cancer, including phylogenetic relationship between the different metastases an also whether there is evidence of convergence towards common biological processes that underpin the metastatic process but though different mutational events

  Study EGAS00001000864

• We performed whole-exome sequencing and whole epigenome sequencing (RRBS) of samples collected from different time points during radiotherapy from thirty-four ESCC patients. We compared the genetic and epigenetic features of the different time biopsy samples to reveal the changes in ESCC received radiotherapy.

  We performed whole-exome sequencing and whole epigenome sequencing (RRBS) of samples collected from different time points during radiotherapy from thirty-four ESCC patients. We compared the genetic and epigenetic features of the different time biopsy samples to reveal the changes in ESCC received radiotherapy.

  Study EGAS00001002719

• Triple_Negative_Breast_Cancer_Whole_Genomes

  We propose to definitively characterise the somatic genetics of Triple negative breast cancer through generation of comprehensive catalogues of somatic mutations in 500 cases by high coverage genome sequencing coupled with integrated transcriptomic and methylation analyses.

  Study EGAS00001000092

• Genetic_Overlap_between_Metabolic_and_Psychiatric_disease

  The Genetic Overlap between Metabolic and Psychiatric Diseases (GOMAP) study comprises samples from four patient groups: 964 schizophrenia samples, 921 type 2 diabetes patients, 582 patients with comorbid schizophrenia and type 2 diabetes and 280 samples with another psychiatric diagnosis.

  Study EGAS00001002723

• Evolutionary analysis of pancreatic cancer and coexistent precursor lesions using whole exome sequencing data

  Most adult carcinomas develop from noninvasive precursor lesions, a progression that is supported by genetic analysis. Further, the evolution of these lesions contextualizes the dynamics of advanced stage disease. We analyzed the somatic variants of co-existing pancreatic cancers and precursor lesions sampled from distinct regions of the same pancreas. After inferring evolutionary relationships, we found that the ancestral cell had initiated and clonally expanded to form one or more lesions, and that subsequent driver gene mutations eventually led to a pancreatic cancer. We also found that this multi-step progression generally spans many years. Our data suggest that independent, high-grade pancreatic lesions observed in a histologic cross section often represent a single neoplasm that can spread and colonize the ductal system, accumulating spatial and genetic divergence over time.

  Study EGAS00001002778

• MutWP1__CRUK_Grand_Challenge_Mutographs_of_Cancer__pancreas

  The Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Different patterns of somatic mutation are generated by the different environmental, lifestyle and genetic factors that cause cancer, many of them are still unknown. Within Mutographs, the International Agency for Research on Cancer is coordinating the recruitment of 5000 individuals with cancer (colorectal, renal, pancreatic, oesophageal adenocarcinoma or oesophageal squamous cancers) across 5 continents to explore whether different mutational signatures explain marked variation in incidence. In brief, through an international network of collaborators around the world, biological materials are collected, along with demographic, histological, clinical and questionnaire data. Whole genome sequences of tumour-germline DNA pairs are generated at the Wellcome Trust Sanger Institute (Illumina HiSeqX, 40X and 20X depth respectively). Somatic mutational signatures are subsequently extracted by non-negative matrix factorisation methods and correlated with risk factors data. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development.

  Study EGAS00001002726

• UK10K RARE COLOBOMA

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches. Ocular coloboma is the most common significant developmental eye defect with an incidence of ~1 in 5,000 live births. It results from failure of optic fissure closure during embryogenesis. The position and extent of the fusion failure dictates the clinical appearance and functional effect. ~30% of coloboma cases are associated with other systemic malformations. These UK10K samples will mostly comprise isolated coloboma cases without systemic involvement (aka non-syndromal coloboma). There is strong evidence from family studies that coloboma has a major genetic component with autosomal dominance being the most common pattern of inheritance. However, many cases are isolated or show complex patterns of familial clustering. The genes responsible for isolated coloboma are largely unknown, but in a small number of families mutations in SHH, CHX10, and PAX6 have been identified indicating marked genetic heterogeneity. Thus in addition to the clinical benefits of achieving a molecular diagnosis there are also major scientific advantages to identifying coloboma genes, as these are likely to provide insights into the complex process of optic fissure closure, that is critical to normal eye development. In the longer term, understanding the molecular basis of the disease may provide clues to therapeutic strategies.For further information with regard to this cohort please contact David Fitzpatrick (david.fitzpatrick@ed.ac.uk).

  Study EGAS00001000127

• UK10K_RARE_FIND

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches. The Raymond samples will be part of the “rare disease” group, and will undergo exome sequencing. For further information with regard to this cohort please contact Lucy Raymond (flr24@cam.ac.uk).

  Study EGAS00001000128

• Himalayan_population_genetic_study

  We genotyped 770 individuals belonging to 49 populations from Nepal, Bhutan, North India or Tibet at over 500,000 SNPs genomewide to investigate the demographic history of the region and the genetic adaptations to the harsh environment. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001002731

• X chromosomal genetic variants are associated with childhood obesity

  Current genetic association studies are usually focused on autosomal variants only, and the sex chromosomes are often neglected. In recent years, a number of statistical techniques and strategies have been widely described making much easier overcoming X-chromosome technical hurdles and including this region within genetic studies. Tenomodulin (TNMD) is a Xq22 chromosome anti angiogenic locus which has been recently linked to different obesity-related phenotypes. These results have not been replicated to date. Given these facts, we have conducted a genetic association analysis in Spanish children population including seven TNMD SNPs as potential candidate markers for obesity and metabolic dysfunctions. Additionally genotypes for another locus located in the X chromosome, the SLC6A14, have been included in the dataset. A total of 915 DNA samples from 258 normal weight, 177 overweight and 480 obese Spanish children (438 males, 477 females) were genotyped for seven TNMD SNPs and one SLC6A14 SNP. Associations with anthropometric measurements and glucose metabolism were investigated.

  Study EGAS00001002738