22948 results for "ega"

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• The mutational landscape of skin tumours in CYLD cutaneous syndrome determined

  Patients with germline mutations in CYLD can develop hundreds of benign skin tumours called cylindromas. The development of multiple tumours within a single patient at sun-protected and sun-exposed sites, varying tumour histological patterns and grades of malignancy allow for the testing of several genetic hypothesis in relation to cutaneous carcinogenesis. By adopting the unprecedented approach of whole genome sequencing of multiple benign skin tumours within individuals in multigenerational families, we set out to study the impact of mutational diversity on models such as multistep carcinogenesis as well as non-sequential carcinogenesis. Using non-negative matrix factorisation (NMF) to discover mutational signatures, we found distinct mutational signatures in identical benign tumours (N=2 patients; n=11 tumours) at sun exposed and sun protected skin tumours within a mother and her daughter. We found recurrent mutations in epigenetic modifying genes in CCS tumours which are known to have an oncogenic dependency on Wnt signalling. We also demonstrate that cutaneous tumours that metastasize to the lung carry a a UV signature, supporting the origin from the skin. Distinct malignant tumours, such as BCC and malignant spiradenocarcinoma carried unique driver mutations. These findings add new dimensions to the existing paradigms of UV-induced skin cancer and highlight the utility of studying rare disease to gain novel insights into genetic mechanisms of tumour formation.

  Dataset EGAD00001004573

• Duplexseq of the interstrand crosslinks_WGS

  One of the most dangerous forms of DNA damage are interstrand crosslinks (ICLs), which covalently crosslink the two strands of the DNA double helix. The repair of these lesions is crucial for cellular survival due to their ability to block transcription and DNA replication. Initially, the major pathway that has been described in ICL repair involves a network of 22 genes that are mutated in a severe human genetic disease known as Fanconi Anemia (FA). Using synthetic lethality screens in the near-haploid human HAP1 cell line, we recently identified two potentially novel regulators of ICL repair, C1orf112 and THAP12. Loss of C1orf112 and THAP12 causes hypersensitivity to ICL-inducing DNA damaging agents, such as Mitomycin C (MMC). Additionally, C1orf112-depleted cells show elevated levels of micronuclei and accumulation of DNA damage in S-phase. To better understand how C1orf112 and THAP12 mediate the repair of ICLs, we want to perform mutational signature analysis, using the BotSeq method. Therefore, WT, C1orf112 and THAP12 knockout cells were cultured in vehicle or MMC treated conditions for 10 days and the genomic DNA was isolated. FANCA and FANCD2 knockout cells are taken along as controls in this experimental setting. . This dataset contains all the data available for this study on 2023-04-20.

  Dataset EGAD00001010298

• Tumor microenvironment study of ovarian granulosa cell tumors

  Adult-type granulosa cell tumors (aGCT) are rare ovarian sex cord tumors with few 41 effective treatments for recurrent disease. The objective of this study was to compare global gene expression profiles and characterize the tumor microenvironment (TME) of primary and recurrent aGCTs in order to identify correlates of disease recurrence. Total RNA sequencing was performed on 24 pathologically confirmed, cryopreserved aGCT samples, including 8 primary and 16 recurrent tumors. A total of 31 differentially expressed genes were identified between primary and recurrent aGCT. TME analysis demonstrated significantly higher fractions of neutrophils and macrophages in recurrent tumors in conjunction with significantly lower fractions of cancer-associated fibroblasts and endothelial cells.

  Study EGAS00001006478

• Reliable assessment of telomere maintenance mechanisms in neuroblastoma

  Telomere maintenance mechanisms (TMM) are a hallmark of high-risk neuroblastoma, and are conferred by activation of telomerase or alternative lengthening of telomeres (ALT). However, detection of TMM is not yet part of the clinical routine, and consensus on TMM detection, especially on ALT assessment, remains to be achieved. We here propose a workflow to reliably detect TMM in neuroblastoma. We show that unambiguous classification is feasible following a stepwise approach that determines both, activation of telomerase and ALT. The workflow proposed in this study can be used in clinical routine and provides a framework to systematically and reliably determine telomere maintenance mechanisms for risk stratification and treatment allocation of neuroblastoma patients.

  Study EGAS00001006510

• Chip_seq_oesophageal_adenocarcinoma_

  There is complex interplay between underlying genetic sequence and epigenetic factors, however this interplay is still illusive. Massively reconstructed cancer genomes can be used in order to better understand this relationship. Six oesophageal adenocarcinoma organoids will be sequenced using long read sequencing technologies and will be profiled for a range of epigenetic marks. Combination of genetic and epigenetic data will allow the thorough characterisation of reference cancer genomes and will provide novel insights into mechanisms of gene regulation. Description: Chip-seq Sequencing of 5 patient derived organoid cell models. Each model was derived from a piece of patient tumour taken following surgical rescetion of the tumour. All model derivations took place with the CGaP facility in Sanger.

  Study EGAS00001007180

• Neoadjuvant chemotherapy alters the genomic landscape and immune microenvironment of breast cancers

  To characterize the effects of neoadjuvant chemotherapy (NAC) on the genome, transcriptome and tumor infiltrating leukocytes (TILs), we have conducted whole exome and whole transcriptome sequencing of a comprehensive, longitudinal breast cancer cohort consisting of 146 cases and 281 paired tumor samples. In total, 52 (38%) patients achieved pathologic complete response (pCR) while 85 patients (62%) had residual disease with standard chemotherapy regimen. Tumor biopsies were collected for each patient at three time points – pre-treatment, three weeks after the first cycle of anthracycline and cyclophosphamide (AC) and at the time of surgery after 3 more cycles of AC followed by 4 cycles of taxane or taxane plus Herceptin in case of HER2+ subtype.

  Study EGAS00001003354

• Single-cell RNA-sequencing of CD34+ bone marrow cells from patients with SLE, healthy individuals and umbilical cord blood samples

  All immune cells that contribute to the pathogenesis of systemic lupus erythematosus (SLE) derive from adult haematopoietic stem and progenitor cells (HSPCs) within the bone marrow (BM). We reasoned that the fundamental abnormalities in the disease can be traced back to HSPCs. The aim of this study was to delineate human haematopoietic CD34+ progenitor subpopulations and to identify deregulated pathways in each subpopulation in SLE as compared to healthy controls and umbilical cord blood samples. This study revealed both quantitative-as evidenced by decreased numbers of non-proliferating early progenitors and qualitative differences- characterized by an IFN signature, which is known to drive loss of function and depletion of HSPCs.

  Study EGAS00001007317

• Intra-prostatic tumour evolution, steps in metastatic spread and histogenomic associations revealed by integration of multi-region whole genome sequencing with histopathological features

  We performed whole genome sequencing on 42 prostate cancer samples from the prostate, seminal vesicles and regional lymph nodes of five treatment-naive patients with locally advanced disease who underwent radical prostatectomy. Using cancer cell fractions computed from single nucleotide variants and copy number alterations, we reconstructed the tumour phylogenies, which in turn allowed us to infer key molecular steps in the progression of prostate cancer in these individuals. We mapped the clonal composition of cancer sampled across the prostate in each individual and inferred the routes of spread of cancer cells within the prostate and to seminal vesicles and lymph nodes.

  Study EGAS00001007438

• A standardised framework for robust fragmentomic feature extraction from cell-free DNA sequencing data

  Fragmentomic features of cell-free DNA represent promising non-invasive biomarkers for cancer diagnosis. However, a lack of systematic evaluation of biases in feature quantification has hindered the adoption of such applications. We compared features derived from whole-genome sequencing of ten healthy donors using nine library kits and ten data-processing routes, and validated them in 1,182 plasma samples from published studies. Our results clarify the variations resulting from library preparation and feature quantification methods. We designed the Trim Align Pipeline and the cfDNAPro R package as unified interfaces for data pre-processing, feature extraction, and visualisation, aiming to standardise multimodal feature engineering and integration for machine learning.

  Study EGAS00001008051

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

  Moyamoya is a progressive cerebral vasculopathy, for which genetic susceptibility factors were mainly identified in Asian populations. When associated with other medical conditions, such as neurofibromatosis type 1 (NF1), this vasculopathy is frequently reported as Moyamoya syndrome (MMS). Intriguingly, most cases of MMS-complicated NF1 have been described in Caucasians, inverting the population ratio for moyamoya vasculopathy observed in Asians, despite NF1 prevalence being constant worldwide. This study aims to investigate whether, among Caucasians, additive genetic factors may contribute to the occurrence of MMS in NF1. WES analysis has been carried out on an Italian family with co-occurrence of NF1 and MMS, as well as other cerebral vasculopathies.

  Study EGAS00001003053

• Autoimmunity_and_immunodeficiency_COVID19

  Cell Atlas of COVID-19 patients with Pre-existing Autoimmunity and Immunodeficiency conditions COVID-19 disease is characterized by hyperinflammation of the lungs and poor immune response against the virus, leading to acute respiratory distress syndrome. Patients with pre-existing medical conditions strongly correlated with poorer clinical outcomes upon SARS-CoV-2 infection. This study aims to characterize the cellular response to SARS-CoV-2 infection in controls and in patients with primary immunodeficiency and autoimmune disease. 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 EGAS00001004489

• Gastric_Mutational_Signatures__GMS_

  This study aims to characterise the mutation burdens and signatures of adult stem cells derived from different regions of the stomach in order to gain insight into the causes and preclinical evolution of the diverse cancer subtypes. Clonal populations of cells from different anatomical locations of the stomach will be derived through organoid culture and/or laser microdissection and interrogated by whole genome sequencing and/or targeted pulldown. A total of circa 300 samples from 20 – 30 donors (cancer and non-cancer patients undergoing total/partial gastrectomy) will be analysed for mutational burden and signatures and genomic findings correlated with topology, age, risk factors and different stages of pre-neoplastic or neoplastic progression.

  Study EGAS00001002938

• Genome-to-genome analysis highlights the impact of the human innate and adaptive immune systems on the hepatitis C virus

  Outcomes of hepatitis C virus (HCV) infection and treatment depend on viral and host genetic factors. We use human genome-wide genotyping arrays and new whole-genome HCV viral sequencing technologies to perform a systematic genome-to-genome study of 542 individuals chronically infected with HCV, predominately genotype 3. We show that both HLA alleles and interferon lambda innate immune system genes drive viral genome polymorphism, and that IFNL4 genotypes determine HCV viral load through a mechanism that is dependent on a specific polymorphism in the HCV polyprotein. We highlight the interplay between innate immune responses and the viral genome in HCV control.

  Study EGAS00001002324

• Genomic profiling of ovarian adult type granulosa cell tumors

  To investigate the genomic landscape of primary and recurrent ovarian adult type granulosa cell tumors, we first identified an exploratory cohort comprised of cryopreserved surgical biopsies from 24 patients (primary, n = 8; recurrent, n = 16) with 20 having matched normal tissue or peripheral blood samples. We performed whole exome sequencing (WES) on these tumor samples at 200X target coverage (mean 226; range 165-296) and also performed WES on the available normal samples. In addition, we performed cancer gene panel sequencing using the T200.1 hybrid capture platform on FFPE tissue from 55 additional patients (primary, n = 27; recurrent, n = 28), of which we sequenced matched normal tissue for a total of 44.

  Study EGAS00001002833

• Somatic point mutation data from microsatellite unstable colorectal cancers

  Microsatellite instability (MSI) leads to accumulation of an excessive number of mutations in the genome, mostly small insertions and deletions. MSI CRCs, however, also contain more point mutations than microsatellite stable (MSS) tumors, yet they have not been as comprehensively studied. To identify candidate driver genes affected by point mutations in MSI CRC, we ranked genes based on mutation significance while correcting for replication timing and gene expression utilizing an algorithm, MutSigCV. Somatic point mutation data from the exome kit-targeted area from 24 exome sequenced sporadic MSI CRCs and respective normals, and 12 whole genome sequenced sporadic MSI CRCs and respective normals were utilized. The top 73 genes were validated in 93 additional MSI CRCs.

  Study EGAS00001003101

• ProjectMinE :llumina HiSeqX and HiSeq 2000 whole genome sequence data on 3,001 ALS samples including 212 with known C9orf72 repeat expansions

  Whole genome sequence (WGS) data was generated on 3,001 samples previously quantified for the presence of the C9orf72 repeat expansion (212 expanded and 2,789 wild type), These samples were sequenced using a combination of 2x100bp reads on an Illumina HiSeq2000 and 2x150bp reads on an Illumina HiSeqX sequencer. The repeat expansions were called using ExpansionHunter to demonstrate the ability to call large repeats from high throughput, WGS data. Provided here are all read pairs where at least one of the reads aligns within 1kb of the C9orf72 repeat expansion in addition to reads aligned in pre-determined off target locations where the aligners are known to mis-align reads.

  Study EGAS00001003383

• STREP GENE: Genetics and Severe Streptococcal Infections

  This study investigated host genetic susceptibility to invasive group A streptococcal disease in the UK. Cases were either survivors recruited retrospectively through a patient group or identified from the a tissue bank at Imperial College London. Those recruited through the patient group had survived an episode of invasive GAS disease at a UK hospital since 1980 with microbiological confirmation obtained either through Public Health England or from the treating hospital. Those identified from the tissue bank had been diagnosed with invasive GAS disease at the Hammersmith Hospital, London, UK, since 2006. All cases aged less than 65 years without long-term medical conditions genome-wide genotyped using either the Illumina HumanCore or the Global Screening Array platform.

  Study EGAS00001003421

• TRACERx 100: RRBS data from a subset of the first 100 TRACERx tumours

  TRACERx (TRAcking Cancer Evolution through therapy (Rx)) is a prospective cohort study designed to investigate intratumor heterogeneity (ITH) in relation to clinical outcome, and to determine the clonal nature of driver events and evolutionary processes in early stage non-small cell lung cancer (NSCLC). This study looks at multi-region RRBS data from the TRACERx100 cohort selected for quantity of material available and high tumour purity. RRBS data was collected for 122 tumour regions across 36 patients each with matched normal. A subset of this cohort was used in a sister study looking at tumour neo-antigen promoter methylation status in NSCLC (71 tumour regions across 28 patients for a total of 99 samples).

  Study EGAS00001003484

• Multi-layered molecular characterization defines prognostic subtypes of lung adenocarcinoma in Asian never-smokers

  Multi-layered genomic studies such as the TCGA project have greatly advanced our understanding on molecular pathogenesis of lung cancer. For Asian nonsmoker patients, however, majority of studies have been limited to mutational analyses, emphasizing ethnic differences in driver mutations (e.g. more frequent EGFR mutations and ALK fusions). In essence, a comprehensive multi-layered characterization that could lead to molecular etiology and patient stratification scheme to be translated into clinical applications for this patient group is still missing. Here we report molecular profiling of tumor and matched normal tissues from 114 non-small-cell lung adenocarcinoma patients using whole exome sequencing, transcriptome sequencing, and array comparative genomic hybridization (CGH).

  Study EGAS00001003705

• Genomic Analysis of Primary Plasma Cell Leukemia reveals Complex Structural Alterations and High Risk Mutational Patterns

  Primary plasma cell leukemia (pPCL) is a rare and aggressive form of multiple myeloma (MM) that is characterized by circulating plasma cells. Overall survival remains poor despite advances of anti-MM therapy. In an attempt to identify key biological mechanisms that result in the aggressive pPCL phenotype we performed whole exome sequencing of 23 patients with pPCL. For matched non-tumor control for each patient to exclude germline variants we used CD34+ cells from stem cell harvest (n=20) or cells obtained from buccal swabs (n=3). Tumor samples were from bone marrow derived CD138+ cells. Tumor samples were compared to the germline control to identify somatic abnormalities.

  Study EGAS00001003834