3930 results for "*geneti*"

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• Cooperative activity of BRAF F595L and mutant HRAS in histiocytic sarcoma provides new insights into oncogenic BRAF signaling

  Mutations that activate the RAF-MEK-ERK signaling pathway, in particular BRAFV600E, occur in many cancers, and mutant BRAF-selective inhibitors have clinical activity in these diseases. Activating BRAF alleles are usually considered to be mutually exclusive with mutant RAS, whereas inactivating mutations in the D594F595G596 motif of the BRAF activation segment can coexist with oncogenic RAS and cooperate via paradoxical MEK/ERK activation. We determined the functional consequences of a largely uncharacterized BRAF mutation, F595L, which was detected along with an HRASQ61R allele by clinical exome sequencing in a patient with histiocytic sarcoma and also occurs in epithelial cancers, melanoma, and neuroblastoma, and investigated its interaction with mutant RAS. We demonstrate that, unlike previously described DFG motif mutants, BRAFF595L is a gain-of-function variant with intermediate activity towards MEK that does not act paradoxically, but nevertheless cooperates with mutant RAS to promote oncogenic signaling. Of immediate clinical relevance, BRAFF595L shows divergent responses to different mutant BRAF-selective inhibitors, whereas signaling driven by BRAFF595L with and without mutant RAS is efficiently blocked by pan-RAF and MEK inhibitors. Mutation data from primary patient samples and cell lines show that BRAFF595L, as well as other BRAF mutations with intermediate activity, frequently coincide with mutant RAS in a broad spectrum of cancers. These data define a novel class of activating BRAF mutations that cooperate with oncogenic RAS in a non-paradoxical fashion to achieve an optimal level of MEK-ERK signaling, extend the spectrum of patients with systemic histiocytic disorders and other malignancies who are candidates for therapeutic blockade of the RAF-MEK-ERK pathway, and underscore the value of comprehensive genetic profiling for understanding the signaling requirements of individual cancers.

  Dataset EGAD00001001384

• High-powered complex trait association mapping through whole genome sequencing of a selected subpopulation of the INGI-Val Borbera genetic isolate

  The VBSEQ project aims to combine available extensive genetic and phenotypic data to the latest high-throughput genome sequencing technology and ad hoc statistical analysis to identify new rare genetic variants underlying complex traits. Up to 100 Val Borbera samples will be sequenced to a 6x depth.

  Dataset EGAD00001000730

• Whole genome sequence of third generation family member (SFHS)

  Previously we performed deep WGS on 6 parents and 13 children from 3 large families from the Scottish Family Health Study to identify de novo mutations. This prelim is cover the additional sequencing of one grandchild from one of these three families. The inclusion of a third generation individual will provide additional experimental validation for the de novo mutations found in the initial trio. As in the previous study, the DNA will be WGS to a depth of approximately 25X to achieve this purpose.These data can only be used for the investigation of the genetic causes of the reported clinical phenotypes in these patients

  Dataset EGAD00001001454

• June 2018 data update (fastq) for reference epigenomes generated at Centre for Epigenome Mapping Technologies, Genome Sciences Center, B.C. Cancer Agency as part of the International Human Epigenome Consortium.

  June 2018 data update (fastq) for reference epigenomes generated at Centre for Epigenome Mapping Technologies (Canadian Epigenetics, Environment and Health Research Consortium), Genome Sciences Center, B.C. Cancer Agency, Vancouver, Canada as part of the International Human Epigenome Consortium.

  Dataset EGAD00001004300

• March 2016 update of Whole genome bisulfite sequencing assay data (fastq) for reference epigenomes generated at Centre for Epigenome Mapping Technologies, Genome Sciences Center, B.C. Cancer Agency as part of the International Human Epigenome Consortium.

  March 2016 update of Whole genome bisulfite sequencing assay data (fastq) for reference epigenomes generated at Centre for Epigenome Mapping Technologies (Canadian Epigenetics, Environment and Health Research Consortium), Genome Sciences Center, B.C. Cancer Agency, Vancouver, Canada as part of the International Human Epigenome Consortium.

  Dataset EGAD00001001957

• Whole genome sequencing in 1038 index cases reveals novel causative genes in pulmonary arterial hypertension

  Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within genes encoding components of the transforming growth factor-ß pathway underlie the majority of heritable forms of PAH. Identifying the missing genetic contribution is challenging, even with genes of large effect size, since it likely involves mutations in genes confined to small numbers of PAH cases. In this study, we performed whole genome sequencing, comparing 1038 PAH index cases to 6385 subjects with other rare diseases. Rare variant analysis identified mutations in novel causal genes, namely ATP13A3, AQP1 and SOX17, and provided independent validation of a critical role for GDF2 in PAH. We detected mutations predicted to be disruptive of function in most, but not all, previously reported PAH genes. Taken together these findings provide new insights into the molecular basis of PAH, and support a central role for endothelial dysregulation in disease pathogenesis.

  Dataset EGAD00001003423

• Epigenome maps of time-resolved monocyte to macrophage differentiation and innate immune memory

  Innate immune memory is the phenomenon whereby innate immune cells such as monocytes or macrophages undergo functional reprogramming after exposure to microbial components such as LPS. We apply an integrated epigenomic approach to characterize the molecular events involved in LPS-induced tolerance in a time dependent manner. ChIP-seq, RNA-seq, WGBS and ATAC-seq data were generated. This analysis identified epigenetic programs in tolerance and trained macrophages, and the potential transcription factors involved. Experimental set-up Time-course in vitro culture of human monocytes. Two innate immune memory states can be induced in culture through an initial exposure of primary human monocytes to either LPS or BG for 24 hours, followed by removal of stimulus and differentiation to macrophages for an additional 5 days. Cells were collected at baseline (day 0), 1 hour, 4 hour, 24 hour and 6 days.

  Dataset EGAD00001002693

• Whole-exome sequencing of 20 samples of actinic keratosis (10s) and cutaneous squamous cell carcinoma (10s)

  Whole-exome sequencing of 20 samples of actinic keratosis (10) and cutaneous squamous cell carcinoma (10) was performed to investigate a potential relationship between DNA methylation-based subtypes and genetic mutation patterns. 7 samples were shown to belong to the stem cell-like subclass (4 AK and 2 SCC), 12 - to the keratinocyte-like subtype (6 AK and 6 SCC) and one SCC sample is unclassified (was not included in the methylation analysis). Exome regions were captured using Agilent Low Input Exome-Seq Human v5 kit and sequenced on Illumina Hiseq4000 with paired-end 100-nucleotide reads.

  Dataset EGAD00001003765

• Comprehensive genetic analysis of Epstein-Barr virus-associated hematological malignancy

  Comprehensive genetic analyses including whole-exome sequencing, targeted sequencing, and whole-genome sequencing of the human genome and the Epstein-Barr virus (EBV) genome were performed to reveal the molecular pathogenesis of EBV-associated hematological malignancy.

  Dataset EGAD00001004286

• Congenital anosmia 1

  Congenital anosmias can be complete (the lack of a sense of smell) or specific (the inability to detect specific smells). To date, only a single recessive gene underlying complete anosmia has been identified. Here we sequenced the exomes of 10 individuals from a single family, including three with complete anosmia, across three generations to identify the genetic basis of congenital anosmia in this family. 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/

  Dataset EGAD00001002210

• Sequencing data for ICGC Oesophageal Adenocarcinoma tissue samples - 129_rnaseq

  Sequencing data for ICGC Oesophageal Adenocarcinoma tissue samples - 129_rnaseq EAC expression data - Publication Secrier & Li et al., 2016, Nature Genetics

  Dataset EGAD00001002260

• The molecular landscape of colorectal cancer reveals genetic mutations（5 cases）

  We collected tumor samples and adjacent nomal mucosae from 5 patients with colorectal cancer in surgical operation from 2014 to 2016 in the First Affiliated Hospital of Chongqing Medical University (Chongqing, China) and the Research Institute of Surgery, Third Military Medical University (Chongqing, China). the qualified captured library of each sample was then loaded on Illumina HiSeq 2000 (Illumina, San Diego, CA) platforms and subjected to high-throughput sequencing.

  Dataset EGAD00001003223

• March 2017 data update (bam/fastq) (containing H3K27ac for CEMT_87, RNA-Seq for CEMT_141, CEMT_142, CEMT_145, CEMT_146, H3K27me3, H3K9me3, H3K4me3, H3K4me1, ChIP-Seq Input for CEMT_88, CEMT_90 and CEMT_91) for reference epigenomes generated at Centre for Epigenome Mapping Technologies, Genome Sciences Center, B.C. Cancer Agency as part of the International Human Epigenome Consortium.

  March 2017 data update (bam/fastq) for reference epigenomes generated at Centre for Epigenome Mapping Technologies (Canadian Epigenetics, Environment and Health Research Consortium), Genome Sciences Center, B.C. Cancer Agency, Vancouver, Canada as part of the International Human Epigenome Consortium.

  Dataset EGAD00001003272

• Comprehensive cancer predisposition gene testing in an adult multiple primary tumor series shows a broad range of deleterious variants and atypical tumor phenotypes

  Multiple primary tumors (MPT) affect a substantial proportion of cancer survivors and may result from various causes including inherited predisposition. Currently, germline genetic testing of MPT cases for cancer predisposition gene (CPG) variants is mostly targeted by tumor type. We ascertained pre-assessed MPT cases from genetics centers (defined as ≥2 primaries by age 60 years or ≥3 by 70) and performed whole genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment/molecular investigations, pathogenic variants in moderate and high-risk CPGs were detected in 67/440 (15.2%) of probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies including structural variants at low frequency (6/440 (1.4%) of probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant) the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice site CPG variants and at least one discordant tumor type was significantly higher than a control population (χ2=43.642 P=<0.0001). 2/67 (3%) of probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Summing together variant detection rates from a similarly ascertained previous MPT case series, the present results suggest that first-line comprehensive CPG analysis in a clinical genetics referral-based MPT cohort would detect a deleterious variant in about a third of cases.

  Dataset EGAD00001004088

• Chromosome Segregation Errors Promote a Diverse Spectrum of Simple and Complex Genomic Rearrangements

  Cancer genomes are frequently characterized by numerical and structural karyotypic abnormalities. Here we combined an inducible centromere-specific inactivation approach with selection for a conditionally essential gene, a strategy we term ‘CEN-SELECT’, and show that single-chromosome missegregation during cell division can directly drive a broad spectrum of structural rearrangement types. Cytogenetic profiling revealed that missegregated chromosomes are 120-fold more susceptible to developing seven major categories of structural variants, including translocations, insertions, deletions, and reassembly into chromothriptically rearranged chromosomes. Whole-genome sequencing of clones with genetically propagatable derivative chromosomes identified complex rearrangements and copy-number alterations that can result in gene inactivation or extrachromosomal gene amplification. We conclude that chromosome segregation errors are sufficient to drive extensive structural variation that recapitulates those commonly associated with human cancers.

  Dataset EGAD00001004163

• Investigation of mutational signatures associated with DNMT3A deficiency (2019-04-03)

  Mutational signatures have been shown to be attributable to specific genetic contexts, such as mutations in DNA repair genes. DNMT3A is a DNA methyltransferase that helps maintain the DNA methylation pattern in a site-specific manner and may participate in DNA repair or the stress response. We have identified an adult individual who is a germline mosaic for a DNMT3A mutation. We have obtained clonal lymphoblastoid cells (LCLs) from the subject representing both WT and mutant lines grown in the same individual for >50 years. These clones represent a unique opportunity to examine the mutational impact of the DNMT3A mutation in a well-controlled setting. Our goal is to perform WGS on whole blood, representing the pool, as well as several WT and several mutant clones, in order to investigate the contribution of DNMT3A to mutation rates and signatures. . This dataset contains all the data available for this study on 2019-04-03.

  Dataset EGAD00001004889

• TRACERx100 metastatic samples

  Whole exome sequencing of 10 metastatic biopsies from four TRACERx100 patients (see EGA dataset EGAS00001002247), collected either after relapse or death. The data from these samples are initially published with Abbosh, C. et al. Phylogenetic ctDNA analysis depicts early stage lung cancer evolution. Nature, http://dx.doi.org/10.1038/nature22364 (2017). Abstract: Earlier detection of relapse following primary surgery for non-small cell lung cancer and the characterization of emerging subclones seeding metastatic sites might offer new therapeutic approaches to limit tumor recurrence. The potential to non-invasively track tumor evolutionary dynamics in ctDNA of early-stage lung cancer is not established. Here we conduct a patient-specific approach to ctDNA profiling in the first 100 lung TRACERx (TRAcking Cancer Evolution through therapy (Rx)) study participants, including one patient co-recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release in early-stage non-small cell lung cancer and perform tumor volume limit of detection analyses. Through blinded profiling of post-operative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients destined to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastases, providing a new approach for ctDNA driven therapeutic studies.

  Dataset EGAD00001003301

• WES analysis in identifying additive genetic factors that may contribute to the occurrence of moyamoya in neurofibromatosis type 1

  Five subjects from pedigree with co-occurrence of neurofibromatosis type 1 and moyamoya were sequenced in duplicate (0 and1). Kinship and phenotype: NF025, NF026 and NF027 were sibling all affected by neurofibromatosis type 1. NF026 also presented moyamoya. NF0262 and NF0263 were sibling both affected by neurofibromatosis type 1. NF0262 also presented moyamoya. NF026 and NF0262 were first cousins.

  Dataset EGAD00001004157

• IBD Whole Genome Sequencing Phase 1 (2018-08-03)

  We will sequence at 15X coverage the genomes of 960 IBD patients. These samples are currently onsite at Sanger and made available for sequencing via our collaboration with the UK IBD Genetics consortium. During the next quinquennium we intend to sequence the genomes of many thousand IBD patients and these 960 represent the first stage of this effort. Ultimately we will perform association tests comparing these genomes to similar numbers of control genomes to identify rare and low-frequency variants underlying IBD. . This dataset contains all the data available for this study on 2018-08-03.

  Dataset EGAD00001004272

• June 2017 data update (bam/fastq) for reference epigenomes generated at Centre for Epigenome Mapping Technologies, Genome Sciences Center, B.C. Cancer Agency as part of the International Human Epigenome Consortium.

  June 2017 data update (bam/fastq) for reference epigenomes generated at Centre for Epigenome Mapping Technologies (Canadian Epigenetics, Environment and Health Research Consortium), Genome Sciences Center, B.C. Cancer Agency, Vancouver, Canada as part of the International Human Epigenome Consortium.

  Dataset EGAD00001003414

• Exome sequencing of patients with rare neurological disorders

  Exome sequencing of patients and their families with diverse rare neurological disorders. Some families have prior linkage data identifying a specific chromosomal interval or interest, other families do not have linkage data available. Many of these families come from special populations whose demography or preference for consanguineous marriages make them particularly tractable for genetic studies.

  Dataset EGAD00001000346

• Congenital Heart Disease in UK Families

  This project aims to identify highly penetrant coding variants increasing the risk of Congenital Heart Disease (CHD) performing whole exome sequencing on DNA samples from 23 affected individuals, selected from 10 families with presumed Autosomal Recessive Inheritance. This is a collaboration with Prof. Eamonn Maher and Dr. Chirag Patel from the Department of Medical and Molecular Genetics, University of Birmingham plans to sequence 23 indexed Agilent whole exome pulldown libraries on 75Bp PE HiSeq (Illumina)

  Dataset EGAD00001000343

• ENU-NCI-H508-Cetuximab-SecondRound

  Cetuximab is a targeted monoclonal antibody against the epidermal growth factor receptor (EGFR) which is used therapeutically for the treatment of KRAS wild-type colorectal cancer (CRC). The Cetuximab sensitive KRAS wild-type CRC cell line NCI-H508 has been treated with a fixed concentration of ENU for 24 hours and then selected with Cetuximab until drug resistant clones were ready to be picked and grown up as sub-clones of the parental cell line. These will have genes causally implicated in cancer sequenced to identify common point mutations in multiple independently derived drug resistant clones as a forward genetic screen for mechanisms of resistance to Cetuximab in CRC

  Dataset EGAD00001002065

• Open Targets 020 Epigenomes of Cell Lines (2018-10-23)

  There is currently a drive to establish cell based assay systems of greater human biological and disease relevance through the use of well characterised transformed cell lines, primary cells and complex cellular models (e.g. co-culture, 3D models). However, although the field is gaining valuable experience in running more non-standard & complex cell assays for target validation and compound pharmacology studies, there is the lack of a systematic approach to determine if this expansion in cell assay models is reflected in increased human biological and disease relevance. The increasing wealth of publically available transcriptomic, and epigenome (ENCODE and Epigenome Roadmap) data represents an ideal reference mechanism for determining the relationship between cell types used for target & compound studies to primary human cells and tissues from both healthy volunteers & patients. The CTTV020 epigenomes of cell line project aims to generate epigenetic and transcriptomic profiles of cell lines and compare these with existing and newly generated reference data sets from human tissue and cell types. The aim is to identify assay systems which will provide greater confidence in translating target biology and compound pharmacology to patients. Multiple cell types commonly used within research have been grouped according to biology. Examples include erythroid, lung epithelial, hepatocyte cell types and immortalised models of monocyte / macrophage biology. 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 please see http://www.sanger.ac.uk/datasharing/ . This dataset contains all the data available for this study on 2018-10-23.

  Dataset EGAD00001004415

• A study of the molecular pathogenesis of Splenic Marginal Zone and Diffuse Large B-Cell Lymphoma

  We will perform exome sequencing on selected cases of splenic marginal zone lymphoma (SMZL) and diffuse large B-cell lymphoma (DLBCL) in order to characterise their genetic makeup and identify biomarkers for prognosis and prediction of treatment response.

  Dataset EGAD00001000410