4002 results for "*geneti*"

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• WGS dataset of Hepatoblastoma tumoroid biobank as a key resource for tumour genetics

  WGS dataset of Hepatoblastoma tumoroid biobank with WGS of tumor and matched tumoroids

  Dataset EGAD00001015671

• Embryonic tumour transmission in monozygotic twins

  We have a case of two siblings (twins) who were born with nodular blue rashes over their body. The first twin had a large periorbital subcutaneous mass which was diagnosed as infantile undifferentiated sarcoma. This baby was too systematically unwell for chemotherapy and died at 12 days of age. The second sibling received two cycles of emergency chemotherapy however died due to disease progression and secondary haemorrhage at 2 months of age. Post-mortem normal and tumour samples have been taken. In addition to placental tissue and parental germline DNA, the goal will be to investigate intra-uterine transfer of sarcoma and the phylogenetic relationship of tumours in both twins.

  Dataset EGAD00001015681

• Genomic and Functional Profiling of Acral Melanoma from the admixed Brazilian Population Reveals Disease Drivers and Targetable Vulnerabilities

  Acral melanoma, a subtype of melanoma characterized by its occurrence on palms, soles, and beneath the nails, presents unique challenges in diagnosis and treatment due to its distinct genetic and environmental factors. Despite recent advancements in targeted therapies for melanoma, the efficacy of treatments in acral melanoma remains limited, emphasizing the urgent need for a deeper understanding of its genetic landscape. CRISPR-based functional genomics screening has emerged as a powerful tool for uncovering genetic dependencies and potential therapeutic targets in various cancers. In this project, we present the results of CRISPR screening performed on acral melanoma cell lines to identify genes essential for cell survival and proliferation collectively termed “fitness". Through this screening approach, we aim to elucidate the molecular mechanisms underlying the pathogenesis of acral melanoma and identify novel therapeutic vulnerabilities. Our findings reveal key genetic drivers and pathways implicated in acral melanoma progression, offering potential targets for the development of precision therapies tailored to this aggressive subtype of melanoma

  Dataset EGAD00001015690

• Selection of somatic escape variants in SERPINA1 in liver tissue of patients with alpha-1 anti-trypsin deficiency - WGS

  Somatic variants accumulate in non-malignant tissues with age. Functional variants leading to clonal advantage of hepatocytes accumulate in the liver from patients with acquired chronic liver disease (CLD). Whether somatic variants are common to CLD from differing aetiologies is unknown. We analysed liver somatic variants in patients with genetic CLD from alpha-1 anti-trypsin (A1AT) deficiency or haemochromatosis. We show that somatic variants in SERPINA1, the gene encoding A1AT, are strongly selected for in A1AT deficiency, with evidence of convergent evolution. Acquired SERPINA1 variants are clustered leading to truncation or coding change at the C-terminus of A1AT. In vitro and in vivo, C-terminal truncation variants reduce disease-associated Z-A1AT polymer accumulation and disruption of the endoplasmic reticulum, supporting the C-terminal domain swap mechanism. Therefore, somatic escape variants from a deleterious germline variant are selected for in A1AT deficiency, suggesting functional somatic variants are disease-specific in CLD and point to disease-associated mechanisms.

  Dataset EGAD00001015430

• Selection of somatic escape variants in SERPINA1 in liver tissue of patients with alpha-1 anti-trypsin deficiency - Exome

  Somatic variants accumulate in non-malignant tissues with age. Functional variants leading to clonal advantage of hepatocytes accumulate in the liver from patients with acquired chronic liver disease (CLD). Whether somatic variants are common to CLD from differing aetiologies is unknown. We analysed liver somatic variants in patients with genetic CLD from alpha-1 anti-trypsin (A1AT) deficiency or haemochromatosis. We show that somatic variants in SERPINA1, the gene encoding A1AT, are strongly selected for in A1AT deficiency, with evidence of convergent evolution. Acquired SERPINA1 variants are clustered leading to truncation or coding change at the C-terminus of A1AT. In vitro and in vivo, C-terminal truncation variants reduce disease-associated Z-A1AT polymer accumulation and disruption of the endoplasmic reticulum, supporting the C-terminal domain swap mechanism. Therefore, somatic escape variants from a deleterious germline variant are selected for in A1AT deficiency, suggesting functional somatic variants are disease-specific in CLD and point to disease-associated mechanisms.

  Dataset EGAD00001015431

• Single cell transcriptional evolution of myeloid leukaemia of Down syndrome – WGS

  Abstract: Children with Down syndrome have a 150-fold increased risk of developing myeloid leukaemia (ML-DS). Unusually for a childhood leukaemia, ML-DS arises from a preleukaemic state, termed transient abnormal myelopoiesis (TAM), and via a conserved sequence of mutations. Here, we examined the relationship between the genetic and transcriptional evolution of ML-DS from a rich collection of primary patient samples through single cell mRNA sequencing, complemented by phylogenetic analyses in progressive disease. We distilled the transcriptional consequence of each genetic step in the evolution of ML-DS, showing that TAM-defining GATA1 mutations account for most of the ML-DS transcriptome, including those of progressive disease. This transcriptional backbone may thus represent a common vulnerability in ML-DS. We extracted the transcriptional difference between TAM and ML-DS which, unexpectedly, reflected features shared across childhood leukaemia. Our approach delineates the transcriptional evolution of ML-DS and provides an analytical blueprint for distilling consequences of mutations directly from patient samples.

  Dataset EGAD00001015453

• The earliest stages of neoplastic transformation in Familial Adenomatous Polyposis

  The succession of somatic genetic events associated with the conversion of a normal colorectal epithelial cell into a colorectal carcinoma constitutes a paradigmatic model of cancer development. Familial Adenomatous Polyposis (FAP) is caused by constitutional inactivating mutations in APC, the central gatekeeper gene of colorectal cancer, and is associated with a substantially increased lifetime-risk of colorectal cancer. To investigate the earliest stages of neoplastic change due to APC inactivation, we microdissected and individually whole genome sequenced 279 histologically normal and abnormal colorectal crypts from 15 individuals with FAP. Histologically normal crypts generally exhibited similar mutation burdens and mutational signatures to normal crypts from wild-type individuals of the same age, with 1/110 carrying a somatic inactivating APC mutation. By contrast, 9/18 aberrant crypt foci carried somatic APC mutations and exhibited modestly increased burdens of some mutational signatures found in normal crypts. 12/13 diminutive adenomatous polyps (less than 5mm diameter) showed somatic APC mutations and carried substantially increased mutation loads of most mutational signatures present in normal crypts. Phylogenetic trees of crypts from aberrant crypt foci and adenomatous polyps revealed that some had acquired their initiating somatic APC mutations decades previously during the first few years of life. The results catalogue the changes in somatic mutation rates, mutational processes and “driver” mutations in cancer genes during the earliest stages of colorectal neoplastic transformation initiated by APC inactivation and highlight the long periods of clonal evolution required for a cancer to develop.

  Dataset EGAD00001015471

• The earliest stages of neoplastic transformation in Familial Adenomatous Polyposis

  The succession of somatic genetic events associated with the conversion of a normal colorectal epithelial cell into a colorectal carcinoma constitutes a paradigmatic model of cancer development. Familial Adenomatous Polyposis (FAP) is caused by constitutional inactivating mutations in APC, the central gatekeeper gene of colorectal cancer, and is associated with a substantially increased lifetime-risk of colorectal cancer. To investigate the earliest stages of neoplastic change due to APC inactivation, we microdissected and individually whole genome sequenced 279 histologically normal and abnormal colorectal crypts from 15 individuals with FAP. Histologically normal crypts generally exhibited similar mutation burdens and mutational signatures to normal crypts from wild-type individuals of the same age, with 1/110 carrying a somatic inactivating APC mutation. By contrast, 9/18 aberrant crypt foci carried somatic APC mutations and exhibited modestly increased burdens of some mutational signatures found in normal crypts. 12/13 diminutive adenomatous polyps (less than 5mm diameter) showed somatic APC mutations and carried substantially increased mutation loads of most mutational signatures present in normal crypts. Phylogenetic trees of crypts from aberrant crypt foci and adenomatous polyps revealed that some had acquired their initiating somatic APC mutations decades previously during the first few years of life. The results catalogue the changes in somatic mutation rates, mutational processes and “driver” mutations in cancer genes during the earliest stages of colorectal neoplastic transformation initiated by APC inactivation and highlight the long periods of clonal evolution required for a cancer to develop.

  Dataset EGAD00001015477

• DERMATLAS: Hidradenoma papilliferum_RNAseq

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible.For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previously, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles.

  Dataset EGAD00001015480

• DERMATLAS: Hidradenoma papilliferum_WES

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible.For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previously, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles.

  Dataset EGAD00001015481

• Genetic architecture of male infertility in India

  The dataset consists of whole exome and genome sequencing data from infertile males and his parent(s) and/or sibling(s)

  Dataset EGAD00001015606

• PacBio Rare Disease Study

  This study leverages PacBio HiFi long-read sequencing technology to comprehensively analyze the genomic architecture of rare diseases. By generating highly accurate, long-read sequences, we aim to resolve complex structural variants, repeat expansions, and other genomic features that are often missed by short-read sequencing. Our approach facilitates improved variant detection and interpretation, advancing the understanding of rare disease etiology and enabling more precise genetic diagnoses.

  Dataset EGAD00001015611

• Whole-Genome Sequences from five human populations of Sudan

  This dataset provides the first high-coverage (~30X) whole-genome sequencing (WGS) data from Sudan, encompassing 125 individuals from five ethnolinguistic groups: Copts, Beja, Fulani, Fur, and Mahas. These populations represent three major linguistic families: Afro-Asiatic, Nilo-Saharan, and Niger-Congo, offering a detailed view of the country’s genetic diversity.

  Dataset EGAD00001015636

• RNAseq Atlas in HCC tumors

  The atlas provides a comprehensive exploration of genetic and transcriptomic landscapes within HCC, offering insights into key genomic alterations and gene expression patterns. The integration of DNA sequencing and RNAseq data enhances our understanding of the molecular complexity underlying HCC, potentially paving the way for targeted therapeutic strategies and biomarker discovery in the context of hepatocellular carcinoma.

  Dataset EGAD00001015341

• Exome Atlas in HCC tumors

  The atlas provides a comprehensive exploration of genetic and transcriptomic landscapes within HCC, offering insights into key genomic alterations and gene expression patterns. The integration of exome sequencing and RNAseq data enhances our understanding of the molecular complexity underlying HCC, potentially paving the way for targeted therapeutic strategies and biomarker discovery in the context of hepatocellular carcinoma.

  Dataset EGAD00001015342

• Comprehensive Deep Sequencing Atlas in HCC tumors

  The atlas aims to unravel the intricate genetic landscape of HCC, providing a detailed characterization of genomic alterations, transcriptomic profiles, and key mutations associated with liver tumors. The integration of WGS, RNAseq, and WES data offers a holistic perspective, facilitating a deeper understanding of the molecular mechanisms driving HCC pathogenesis. The resulting atlas serves as a valuable resource for researchers, clinicians, and the broader scientific community, contributing to advancements in HCC diagnostics, prognostics, and therapeutic interventions.

  Dataset EGAD00001015343

• Timing the Philadelphia chromosome and trajectory to chronic myeloid leukaemia

  We sequence >1000 whole genomes from 9 patients with CML, providing the largest sequencing dataset for this cancer. We reconstruct phylogenetic trees using somatic mutations and infer BCR::ABL1 timing and tumour growth rates. We correlate mutation landscapes and clonal trajectories with clinical features.

  Dataset EGAD00001015353

• Genomic and transcriptomic landscape of T-cell lymphoblastic lymphoma compared to T-cell acute lymphoblastic leukemia: similar subtypes and different fusions

  Due to the lower incidence of T-LBL and difficulties in obtaining diagnostic T-LBL material, extensive research on T-LBL has been hampered whereas genetic aberrations in T-ALL are thoroughly characterized. Given the similarities and differences between T-LBL and T-ALL, the question has been raised whether T-LBL and T-ALL represent two different diseases or different manifestations of the same disease. This study aims to identify the genomic and transcriptomic landscape of T-LBL and compare the findings to what is found T-ALL. Comparison of the molecular aberrations between T-LBL and T-ALL can provide insights into the overlap and differences in malignant development between the two entities, which could lead to improved risk stratification in T-LBL in order to eventually adapt T-LBL treatment protocols based on molecular-genetic prognostic factors.

  Dataset EGAD00001015357

• Solve-RD multi-omics data chud-faivre cohort

  The dataset includes short-read whole-genome sequencing (SR-WGS) data, SR-RNAseq data, OGM (Bionano) data, LR-WGS data, Epigenetics (RBSS) data and deep-WES data generated within the project Solve-RD from biosamples submitted by the group chud-faivre. The cohorts consists of 111 individuals recruited as part of Solve-RD cohorts 2-4 and aligns with ERN-ITHACA related disease entities (for a description of the Solve-RD cohorts see www.solve-rd.eu/fact-sheet-solve-rd-cohorts).

  Dataset EGAD00001015811

• On-target mutations confer resistance to WRN helicase inhibitors in Microsatellite Unstable Cancer Cells

  This study investigates genetic dependencies and resistance mechanisms to Werner helicase inhibitors (WRNi) in microsatellite-unstable (MSI) cancer models. To define determinants of WRN dependency and acquired resistance, we performed genome-wide CRISPR-Cas9 knockout screens, CRISPR base-editing mutagenesis screens targeting WRN, targeted sequencing of resistance-associated variants, bulk RNA sequencing, and whole-genome sequencing. The datasets deposited in EGA comprise raw sequencing files from CRISPR-Cas9 knockout screens, CRISPR base-editing screens, targeted DNA sequencing, RNA-seq experiments, and whole-genome sequencing of parental and drug-treated cell populations, including models with spontaneously acquired resistance. These data enable investigation of WRN synthetic lethality, genetic modifiers of WRNi response, and genomic alterations emerging under selective pressure.

  Dataset EGAD00001015822

• Genomic evolution and natural history of myeloproliferative neoplasms on therapy - triple-negative-ET

  Philadelphia-negative myeloproliferative neoplasms are chronic blood neoplasms. Treatments control blood counts but disease can progress to myelofibrosis or acute myeloid leukaemia. We performed longitudinal whole-genome and targeted sequencing in 30 patients, integrating clonal dynamics with 7,986 blood counts and clinical histories. Distinct evolutionary patterns distinguished stable from progressive disease, with leukaemic transformation arising via TP53 loss, stepwise driver mutation acquisition within complex clones, or emergence of independent leukaemic clones. In contrast, stable disease showed long-term clonal equilibrium without new drivers. Phylogenetic analysis using 203 whole-genomes of haematopoietic colonies revealed age-appropriate polyclonal haematopoiesis in triple-negative essential thrombocythaemia and germline predisposition to thrombocytosis, supporting non-neoplastic origins. Therapy-associated mutagenesis was observed, including C>G mutations following azacitidine and characteristic T>A/T>G after hydroxycarbamide exposure in blood cells, although not in skin where UV damage predominated. These findings demonstrate progression is genomically encoded years in advance and support serial monitoring and further study of treatment-related mutagenesis.

  Dataset EGAD00001016066

• Genomic evolution and natural history of myeloproliferative neoplasms on therapy - MPN_bulk

  Philadelphia-negative myeloproliferative neoplasms are chronic blood neoplasms. Treatments control blood counts but disease can progress to myelofibrosis or acute myeloid leukaemia. We performed longitudinal whole-genome and targeted sequencing in 30 patients, integrating clonal dynamics with 7,986 blood counts and clinical histories. Distinct evolutionary patterns distinguished stable from progressive disease, with leukaemic transformation arising via TP53 loss, stepwise driver mutation acquisition within complex clones, or emergence of independent leukaemic clones. In contrast, stable disease showed long-term clonal equilibrium without new drivers. Phylogenetic analysis using 203 whole-genomes of haematopoietic colonies revealed age-appropriate polyclonal haematopoiesis in triple-negative essential thrombocythaemia and germline predisposition to thrombocytosis, supporting non-neoplastic origins. Therapy-associated mutagenesis was observed, including C>G mutations following azacitidine and characteristic T>A/T>G after hydroxycarbamide exposure in blood cells, although not in skin where UV damage predominated. These findings demonstrate progression is genomically encoded years in advance and support serial monitoring and further study of treatment-related mutagenesis.

  Dataset EGAD00001016067

• Genomic evolution and natural history of myeloproliferative neoplasms on therapy - SCC_CALRmutated ET

  Philadelphia-negative myeloproliferative neoplasms are chronic blood neoplasms. Treatments control blood counts but disease can progress to myelofibrosis or acute myeloid leukaemia. We performed longitudinal whole-genome and targeted sequencing in 30 patients, integrating clonal dynamics with 7,986 blood counts and clinical histories. Distinct evolutionary patterns distinguished stable from progressive disease, with leukaemic transformation arising via TP53 loss, stepwise driver mutation acquisition within complex clones, or emergence of independent leukaemic clones. In contrast, stable disease showed long-term clonal equilibrium without new drivers. Phylogenetic analysis using 203 whole-genomes of haematopoietic colonies revealed age-appropriate polyclonal haematopoiesis in triple-negative essential thrombocythaemia and germline predisposition to thrombocytosis, supporting non-neoplastic origins. Therapy-associated mutagenesis was observed, including C>G mutations following azacitidine and characteristic T>A/T>G after hydroxycarbamide exposure in blood cells, although not in skin where UV damage predominated. These findings demonstrate progression is genomically encoded years in advance and support serial monitoring and further study of treatment-related mutagenesis.

  Dataset EGAD00001016068

• Mapping genetic variants underlying gene regulation in intestinal cell types to identify novel IBD drug targets

  Biopsies from the terminal ileum and rectum of healthy individuals and terminal ileum and blood from Crohns disease patients are collected and processed single cells and processed for single-cell RNA-sequencing using 10X Genomics 3 v3 and v3.1 and Illumina sequencing. 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 EGAD00001016069

• Multi-omics analysis of chronic active EBV infection.

  Here we performed a comprehensive multi-omics analysis (genome, transcriptome, epigenome, and single-cell transcriptome and surface proteome) to elucidate the pathogenesis of CAEBV. Our multi-omics approach highlighted the complex interplay between genetic and epigenetic factors in the pathogenesis of CAEBV and suggest novel avenues for therapeutic strategies.

  Study JGAS000735