13384 results for ""pdc"+"heritage+language"+census+study"

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• The interface of malignant and immunologic clonal dynamics in high-grade serous ovarian cancer

  High-grade serous ovarian cancer exhibits extensive intratumoral heterogeneity coupled with widespread intraperitoneal disease. Despite this, metastatic spread of tumor clones is non-random, implying the existence of local microenvironmental factors that shape tumor progression. We interrogated the molecular interface between tumorinfiltrating lymphocytes (TIL) and cancer cells in 143 samples from 21 patients using whole-genome sequencing, immunohistochemistry, histologic image analysis, gene expression profiling, and T- and B-cell receptor sequencing. We identify 3 immunologic response categories, which frequently co-exist within individual patients. Furthermore, epithelial CD8+ TIL were inversely associated with malignant cell diversity, evidenced by subclonal neoepitope elimination and spatial tracking between tumor and T-cell clones. Intersecting mutational signatures and immune analysis showed that foldback inversion genomic aberrations lead to worse outcomes even in the presence of cytotoxic TIL (n=433). Thus, regional variation in immune contexture mirrors the pattern of intraperitoneal malignant spread, provoking new perspectives for treatment of this challenging disease.

  Study EGAS00001002839

• Whole Exome sequencing of Gingivo-buccal Cancer : ICGC-India Project_Batch04

  Whole Exome Sequencing of Gingivo-buccal Cancer: ICGC-India ProjectAs a part of the ICGC, India has undertaken genomic studies on gingivobuccal cancer of the oral cavity, which is the most prevalent form of cancer among men in India. There are various known environmental (life-style) correlates of this cancer, the most important of which are tobacco chewing and HPV infection. Exome of paired DNA samples – isolated from the tumor tissue and from the blood of 47 patients – have been performed to catalog germline and somatic mutations. Association between each observed genomic alteration and exposure to environmental risk factors is being explored. Detailed clinical characterization of the patients, collection of data on demographic and environmental exposures, and isolation of DNA samples from blood and tumor tissues collected from each patient are being done at the Advanced Centre for Research, Treatment and Education on Cancer, Mumbai. Whole exome sequencing is being performed at the National Institute of Biomedical Genomics, Kalyani.

  Study EGAS00001002852

• Somatic_mutation_and_clonal_evolution_normal_breast_tissue_WGS

  Cancer is a genetic disease caused by an accumulation of mutations, however many of these mutations have been identified in pathologically normal tissue. We aim to use laser-capture microscopy (LCM) to sample individual clones from breast tissue to identify whether cancer-associated mutations appear in this normal tissue, assess the mutational burden present, and identify the mutational processes causing these mutations. We will sample from a wide age range of individuals (<20 to >70 years old) to determine whether these processes differ in pre- and post-menopausal women. We will also be comparing the tissue from healthy individuals (samples from breast reduction surgery) to those at elevated risk of breast cancer (mastectomy from BRCA1/2 patients) and those who have breast cancer (adjacent normal, distal normal, and tumour tissue from mastectomy). This will allow us to determine how these processes are different between these groups of individuals, and gain insight into the earliest stages of tumour development.

  Study EGAS00001002857

• Somatic_mutation_and_clonal_evolution_normal_breast_tissue_TGS

  Cancer is a genetic disease caused by an accumulation of mutations, however many of these mutations have been identified in pathologically normal tissue. We aim to use laser-capture microscopy (LCM) to sample individual clones from breast tissue to identify whether cancer-associated mutations appear in this normal tissue, assess the mutational burden present, and identify the mutational processes causing these mutations. We will sample from a wide age range of individuals (<20 to >70 years old) to determine whether these processes differ in pre- and post-menopausal women. We will also be comparing the tissue from healthy individuals (samples from breast reduction surgery) to those at elevated risk of breast cancer (mastectomy from BRCA1/2 patients) and those who have breast cancer (adjacent normal, distal normal, and tumour tissue from mastectomy). This will allow us to determine how these processes are different between these groups of individuals, and gain insight into the earliest stages of tumour development.

  Study EGAS00001002858

• A Genomics-Based Classification of Human Lung Tumors

  We characterized genome alterations in 1255 clinically annotated lung tumors of all histological subgroups to identify genetically defined and clinically relevant subtypes. More than 55% of all cases had at least one oncogenic genome alteration potentially amenable to specific therapeutic intervention, including several personalized treatment approaches that are already in clinical evaluation. Marked differences in the pattern of genomic alterations existed between and within histological subtypes, thus challenging the original histomorphological diagnosis. Immunohistochemical studies confirmed many of these reassigned subtypes. The reassignment eliminated almost all cases of large cell carcinomas, some of which had therapeutically relevant alterations. Prospective testing of our genomics-based diagnostic algorithm in 5145 lung cancer patients enabled a genome-based diagnosis in 3863 (75%) patients, confirmed the feasibility of rational reassignments of large cell lung cancer, and led to improvement in overall survival in patients with EGFR-mutant or ALK-rearranged cancers. Thus, our findings provide support for broad implementation of genome-based diagnosis of lung cancer.

  Study EGAS00001000647

• CTCF/cohesin-binding sites are frequently mutated in cancer

  Cohesin is present in almost all active enhancer regions, where it is associated with transcription factors. Cohesin frequently colocalizes with CTCF (CCCTC-binding factor), affecting genomic stability, expression and epigenetic homeostasis. Cohesin subunits are mutated in cancer, but CTCF/cohesin-binding sites (CBSs) in DNA have not been examined for mutations. Here we report frequent mutations at CBSs in cancers displaying a mutational signature where mutations in A•T base pairs predominate. Integration of whole-genome sequencing data from 213 colorectal cancer (CRC) samples and chromatin immunoprecipitation sequencing (ChIP-exo) data identified frequent point mutations at CBSs. In contrast, CRCs showing an ultramutator phenotype caused by defects in the exonuclease domain of DNA polymerase ɛ (POLE) displayed significantly fewer mutations at and adjacent to CBSs. Analysis of public data showed that multiple cancer types accumulate CBS mutations. CBSs are a major mutational hotspot in the noncoding cancer genome.

  Study EGAS00001003010

• Whole Exome Sequencing of 60 tumor/normal matched liver Cancers (HCC)

  The French ICGC project on liver tumors is coordinated by Pr Jessica Zucman-Rossi and funded by Inca (French Institute for Cancer). The aim of the present project is to identify the catalog of somatic and germline mutations in liver tumors using whole genome (WGS) and whole exome sequencing (WGS), integrated with DNA methylation and RNA sequencing (RNA-seq) data. The present series corresponds to 60 whole exome tumor/normal pairs with matched RNA-seq. Hepatocellular carcinoma (HCC) accounts for more than 90% of liver cancers, and is a major health problem. It is the 3rd cause of cancer-related mortality. Advances in genomic analyses have formed a comprehensive understanding of different underlying pathobiological layers resulting in hepatocarcinogenesis. Thus, the development of next-generation sequencing technologies has made it possible to generate more comprehensive catalogues of somatic alteration events (single nucleotide substitutions, structural variations, and epigenetic changes) in liver cancer genome than ever before.

  Study EGAS00001003063

• Understanding human fetal pancreas development using subpopulation sorting and RNA sequencing

  To decipher the populations of cells present in the human fetal pancreas and their lineage relationships, we developed strategies to isolate pancreatic progenitors, endocrine progenitors and endocrine cells. Transcriptome analysis of the individual populationsrevealed a large degree of conservation among vertebrates in the drivers of gene expression changes occurring at different steps of differentiation, althoughnotably, sometimes, different members of the same gene family are expressed. The transcriptome analysis establishes a resource to identify novel genes and pathways involved in human pancreas development. Single cell profiling further captured intermediate stages ofdifferentiation and enabled us to decipher the sequence of transcriptional events occurring during human endocrine differentiation. Furthermore, we evaluate how well individual pancreatic cells derived in vitro from human pluripotent stem cells mirror the natural processoccurring in human fetuses. This comparison uncovers a few differences at the progenitor steps, a convergence at the steps of endocrine induction and the current inability to fully resolve endocrine cell subtypes in vitro.

  Study EGAS00001003127

• FBSeq: RNA sequencing of human fetal brain.

  RNA sequencing of 120 human fetal brains (aged 12-19 post-conception weeks) was performed as part of a Medical Research Council (U.K.) funded project (MR/L010674/2) to investigate genetic effects on gene expression in the developing human brain and their role in neuropsychiatric disorders. Human fetal brain tissue from elective terminations of pregnancy was provided by the Human Developmental Biology Resource (HDBR) (http://www.hdbr.org), with ethical approval (#08/H0712/34), and with consent for use of fetal material for medical research provided by female donors. Total RNA was extracted from half of the available brain tissue from each fetus using Tri-Reagent and treated with TURBO DNase. RNA-Seq libraries were prepared using 1µg of purified total RNA and the Illumina TruSeq Stranded Total RNA Library Prep kit, following ribosomal RNA depletion. Libraries were sequenced on the Illumina HiSeq 2500 or HiSeq 4000 systems, generating at least 50 million read pairs per sample.

  Study EGAS00001003214

• A spatiotemporal organ-wide gene expression and cell atlas of the developing human heart

  The process of cardiac morphogenesis in humans is incompletely understood. Its full characterization requires a deep exploration of the organ-wide orchestration of gene expression with a single-cell spatial resolution. Here, we present a molecular approach that reveals the comprehensive transcriptional landscape of cell types populating the embryonic heart at three developmental stages, and which maps cell type-specific gene expression to specific anatomical domains. Spatial Transcriptomics identified unique gene profiles corresponding to distinct anatomical regions in each developmental stage. Human embryonic cardiac cell types identified by single-cell RNA-sequencing confirmed and enriched the spatial annotation of embryonic cardiac gene expression. In situ sequencing was then used to refine these results and create spatial subcellular map for the three developmental phases. Finally, we generated a publicly available web resource of the human developing heart to facilitate future studies on human cardiogenesis.

  Study EGAS00001003996

• MutWP5__CRUK_Mutographs_of_Cancer__Breast__Reduction_Mammoplasty__Exome_

  Cancer is a genetic disease caused by an accumulation of mutations, however many of these mutations have been identified in pathologically normal tissue. We aim to use laser-capture microscopy (LCM) to sample individual clones from breast tissue to identify whether cancer-associated mutations appear in this normal tissue, assess the mutational burden present, and identify the mutational processes causing these mutations. We will sample from a wide age range of individuals (<20 to >60 years old) to determine whether these processes differ in pre- and post-menopausal women. We will also be comparing the tissue from healthy individuals (samples from breast reduction surgery) to those at elevated risk of breast cancer (mastectomy from BRCA1/2 patients) and those who have breast cancer (adjacent normal, distal normal, and tumour tissue from mastectomy). This will allow us to determine how these processes are different between these groups of individuals, and gain insight into the earliest stages of tumor development.

  Study EGAS00001003313

• Single_cell_analysis_T_cell_activation

  We isolated naïve and memory T cells from healthy donors and cultured them in resting and stimulated conditions. We performed scRNA sequencing to assess T cell actiavtaion and perform sceQTL analysis. Major challenges for translating GWAS variants to function include identification of the disease relevant cell types in which the associated variants function. We have shown that immune-disease variants are functional in CD4+ T cell activation, and understanding how GWAS variants affect the activation efficiency is critical for development of new therapies. To perform sceQTL analysis of naïve and memory T cell activation, here we stimulated T cells and profiled single cell transcriptome at different time points following stimulation. We mapped sceQTLs affecting cell activation. 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 EGAS00001003479

• MutWP5__CRUK_Mutographs_of_Cancer__BRCA_Carriers___WG__Novaseq_

  Cancer is a genetic disease caused by an accumulation of mutations, however many of these mutations have been identified in pathologically normal tissue. We aim to use laser-capture microscopy (LCM) to sample individual clones from breast tissue to identify whether cancer-associated mutations appear in this normal tissue, assess the mutational burden present, and identify the mutational processes causing these mutations. We will sample from a wide age range of individuals (<20 to >60 years old) to determine whether these processes differ in pre- and post-menopausal women. We will also be comparing the tissue from healthy individuals (samples from breast reduction surgery) to those at elevated risk of breast cancer (mastectomy from BRCA1/2 patients) and those who have breast cancer (adjacent normal, distal normal, and tumour tissue from mastectomy). This will allow us to determine how these processes are different between these groups of individuals, and gain insight into the earliest stages of tumor development.

  Study EGAS00001003523

• MutWP5__CRUK_Mutographs_of_Cancer__Breast__Reduction_Mammoplasty___WG__Novaseq_

  Cancer is a genetic disease caused by an accumulation of mutations, however many of these mutations have been identified in pathologically normal tissue. We aim to use laser-capture microscopy (LCM) to sample individual clones from breast tissue to identify whether cancer-associated mutations appear in this normal tissue, assess the mutational burden present, and identify the mutational processes causing these mutations. We will sample from a wide age range of individuals (<20 to >60 years old) to determine whether these processes differ in pre- and post-menopausal women. We will also be comparing the tissue from healthy individuals (samples from breast reduction surgery) to those at elevated risk of breast cancer (mastectomy from BRCA1/2 patients) and those who have breast cancer (adjacent normal, distal normal, and tumour tissue from mastectomy). This will allow us to determine how these processes are different between these groups of individuals, and gain insight into the earliest stages of tumor development.

  Study EGAS00001003524

• High number of somatic mutations found in the healthy blood compartment of a 115-year-old woman reveals oligoclonal hematopoiesis

  The somatic mutation burden in healthy white blood cells (WBCs) is not well known. Based on deep whole genome sequencing, we estimate that ~450 somatic mutations accumulated in the non-repetitive genome within the healthy blood compartment of a 115-year old woman. The detected mutations appear to have been harmless passenger mutations: they were enriched in non-coding, AT-rich regions that are not evolutionarily conserved, and they were depleted for genomic elements where mutations might have favorable or adverse effects on cellular fitness, such as regions with actively transcribed genes.The distribution of variant allele frequencies of these mutations suggests that the majority of the peripheral white blood cells were offspring of two related hematopoietic stem cell (HSC) clones. Moreover, telomere lengths of the WBCs were significantly shorter than telomere lengths from other tissues. Together, this suggests that the finite lifespan of HSCs, rather than somatic mutation effects, may lead to hematopoietic clonal evolution at extreme ages.

  Study EGAS00001000660

• Single-cell RNA-seq of immune cells sorted from human melanoma tumors

  Tumor immune cell compositions play a major role in response to immunotherapy but the heterogeneity and dynamics of immune infiltrates in human cancer lesions remain poorly characterized. Here we identify conserved intratumoral CD4 and CD8 T cell behaviors in scRNA-seq data from 25 melanoma patients. We discover a large population of CD8 T cells showing continuous progression from an early effector "transitional" into a dysfunctional T cell state. CD8 T cells that express a complete cytotoxic gene set are rare, and TCR sharing data suggest their independence from the transitional and dysfunctional cell states. Notably, we demonstrate that dysfunctional T cells are the major intratumoral proliferating immune cell compartment and that the intensity of the dysfunctional signature is associated with tumor-reactivity. Our data demonstrate that CD8 T cells previously defined as exhausted, are in fact a highly proliferating, clonal and dynamically differentiating cell population within the human tumor microenvironment.

  Study EGAS00001003363

• MutWP5__CRUK_Mutographs_of_Cancer__BRCA_Carriers___Exome__Novaseq_

  Cancer is a genetic disease caused by an accumulation of mutations, however many of these mutations have been identified in pathologically normal tissue. We aim to use laser-capture microscopy (LCM) to sample individual clones from breast tissue to identify whether cancer-associated mutations appear in this normal tissue, assess the mutational burden present, and identify the mutational processes causing these mutations. We will sample from a wide age range of individuals (<20 to >60 years old) to determine whether these processes differ in pre- and post-menopausal women. We will also be comparing the tissue from healthy individuals (samples from breast reduction surgery) to those at elevated risk of breast cancer (mastectomy from BRCA1/2 patients) and those who have breast cancer (adjacent normal, distal normal, and tumour tissue from mastectomy). This will allow us to determine how these processes are different between these groups of individuals, and gain insight into the earliest stages of tumor development.

  Study EGAS00001003526

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

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

  Study EGAS00001000721

• Integrated genetic and epigenetic analysis defines novel molecular clusters in rhabdomyosarcoma

  Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood. To unravel the genetic/epigenetic basis of RMS, we studied 60 RMS cases using whole exome/transcriptome sequencing, copy number (CN) profiling, and DNA methylome analysis. Based on DNA methylation patterns, RMS was clustered into 4 distinct subtypes, which exhibited remarkable correlation with mutation/CN profiles, histological phenotypes, and clinical behaviors. A1 and A2 subtypes, especially A1, largely corresponded to alveolar histology with frequent PAX3/7 fusions and alterations in cell cycle regulators. In contrast, mostly showing embryonal histology, both E1 and E2 subtypes were characterized by high frequency of CN alterations and/or allelic imbalances, FGFR4/RAS/AKT pathway mutations and PTEN mutations/methylation and in E2, also by p53 inactivation. Despite generally poor prognosis in RMS, patients in E1 cluster exceptionally showed excellent prognosis. Our results highlight the close relationship between DNA methylation status and gene mutations and biological behavior in RMS.

  Study EGAS00001000884

• Control iPSC lines with clinically annotated genetic variants for versatile multi-lineage differentiation

  Induced Pluripotent Stem Cells (iPSC) derived from healthy individuals are important controls for disease modeling studies. To create a resource of genetically annotated iPSC, we reprogrammed footprint-free lines from four volunteers in the Personal Genome Project Canada (PGPC). Multilineage directed differentiation efficiently produced functional cortical neurons, cardiomyocytes and hepatocytes. Pilot users further demonstrated line versatility by generating kidney organoids, T-cells and sensory neurons. A frameshift knockout was introduced into MYBPC3 and these cardiomyocytes exhibited a hypertrophic phenotype as expected. WGS annotation of PGPC lines revealed on average 20 coding variants. Importantly, nearly all annotated PGPC and HipSci lines harboured at least one pre-existing or acquired variant with cardiac, neurological or other disease associations. Overall, PGPC lines were efficiently differentiated by multiple users into cell types found in six tissues for disease modelling, and clinical annotation highlighted variant-preferred lines for use as unaffected controls in specific disease settings.

  Study EGAS00001003684

• SeqControl: Process Control for DNA Sequencing

  As next-generation sequencing (NGS) continues to increase in speed and throughput, routine clinical and industrial application draws steadily closer. These “production” uses of NGS will require enhanced quality-monitoring and quality-control to optimize output and reduce costs. We therefore developed a framework called SeqControl for predicting sequencing quality and coverage using a set of 15 metrics describing overall coverage, coverage distribution, base-wise coverage and base-wise quality. Using whole-genome sequences of 27 prostate cancers and 26 normal references we derive multivariate models that predict sequencing quality and depth. SeqControl robustly predicts how much sequencing is required to reach a given coverage depth (AUC = 0.993), accurately classifies clinically relevant formalin-fixed paraffin-embedded samples and makes predictions from as little as 1/8 of a lane of sequencing data (AUC = 0.967). These techniques can be immediately incorporated into existing NGS pipelines to monitor data quality in real-time. SeqControl represents a first step towards statistical process-control for NGS.

  Study EGAS00001000899

• Single cell transcriptomic analysis of the immune cell compartment in the human small intestine and in Celiac disease

  Celiac disease is an autoimmune disorder in which ingestion of dietary gluten triggers an immune reaction in the small intestine leading to destruction of the lining epithelium. Current treatment focusses on lifelong adherence to a gluten-free diet. Gluten-specific CD4+ T cells and cytotoxic intraepithelial CD8+ T cells have been proposed to be central in disease pathogenesis. Here we use unbiased single-cell RNA-sequencing and explore the heterogeneity of CD45+ immune cells in the human small intestine. We show altered myeloid cell transcriptomes present in active celiac lesions. CD4+ and CD8+ T cells transcriptomes show extensive changes and we define a natural intraepithelial lymphocyte population that is reduced in celiac disease. We show that the immune landscape in Celiac patients on a gluten-free diet is only partially restored compared to control samples. Altogether, we provide a single cell transcriptome resource that can inform the immune landscape of the small intestine during Celiac disease.

  Study EGAS00001003751

• Patient-Derived Lung Cancer Organoid

  Lung cancer shows substantial genetic and phenotypic heterogeneity across individuals, driving a need for personalized medicine. Here we report lung cancer organoids and normal bronchial organoids established from patients tissues comprising five histological subtypes of lung cancer and non-neoplastic bronchial mucosa as in vitro models representing individual patient. The lung cancer organoids recapitulate the tissue architecture of the primary lung tumours and maintain the genomic alterations of the original tumours during long-term expansion in vitro. The normal bronchial organoids maintain cellular components of normal bronchial mucosa. Lung cancer organoids respond to drugs based on their genomic alterations: a BRCA2 mutant organoid to olaparib, an EGFR mutant organoid to erlotinib, and an EGFR mutant/MET amplified organoid to crizotinib. Considering the short length of time from organoid establishment to drug testing, our newly developed model may prove useful for predicting patient-specific drug responses through in vitro patient-specific drug trials.

  Study EGAS00001003786

• Genetic_profiling_of_mucosal_melanoma

  Primary mucosal melanomas (MMs) arise from melanocytes located in mucosal membranes lining the respiratory, gastrointestinal and urogenital tracts. MMs frequently present late and have a poor prognosis; the 5-year survival rate is only 14%. MM makes up only ~1.4% of all melanomas and it is this rarity that makes knowledge of the genetic changes that contribute to its pathogenesis limited to a small number of exome/genome studies and other targeted studies. Thus to investigate the somatic alterations and mutation spectra in MM genomes, we have extracted genomic DNA from formalin-fixed, paraffin-embedded (FFPE) human MMs, and subjected them to whole exome sequencing. Given the propensity of MM to metastasize, we will also be sequencing metastatic MM lesions; primary and metastatic lesions from the same individual represent an excellent opportunity to identify potential drivers of metastasis in MM. Finally we will sequence ‘normal’ DNA from the same individual, where possible, to exclude germline variations.

  Study EGAS00001001115

• CTCF-dependent enhancer hijacking by the EVI1 oncogene in leukemia

  Chromosomal rearrangements are a frequent cause of oncogene deregulation in human malignancies. Overexpression of EVI1 is found in a subgroup of acute myeloid leukemia (AML) with 3q26 chromosomal rearrangements which are often therapy resistant. In a cohort of primary t(3;8)(q26;q24) AML samples we observed the translocation of a MYC super-enhancer to EVI1. We generated a patient-based t(3;8)(q26;q24) model in vitro using CRISPR-Cas9 technology and demonstrated hyper-activation of EVI1 by the hijacked MYC super-enhancer. One MYC super-enhancer element in particular, which recruits early hematopoietic regulators, is critical for EVI1 expression and enhancer-promoter interaction. This interaction is facilitated by a CTCF-bound motif upstream of the EVI1 promoter that acts as an enhancer-docking site in t(3;8) AML. Genomic analyses of 3q26-rearranged AML samples point to a common mechanism by which EVI1 uses this CTCF-bound enhancer-docking site to hijack early hematopoietic enhancers.

  Study EGAS00001004808