3329 results for "*geneti*"

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• Circulating Genomic Determinants of Treatment Failure in Hodgkin Lymphoma

  In this study, we show that the plasma representation of mutations exceeds the bulk tumor representation in most cases, making classic Hodgkin Lymphoma (cHL) particularly amenable to noninvasive profiling. Leveraging single-cell transcriptional profiles of cHL tumors, we demonstrate hazard ratios (HRs) circulating tumor DNA (ctDNA) shedding to be shaped by DNASE1L3, whose increased tumor microenvironment-derived expression drives high ctDNA concentrations. Using this insight, we comprehensively profile 366 patients, revealing two distinct cHL genomic subtypes with characteristic clinical and prognostic correlates, as well as distinct transcriptional and immunological profiles. Furthermore, we identify a novel class of truncating IL4R-mutations that are dependent on IL13 signaling and therapeutically targetable with IL4R blocking antibodies. Finally, we demonstrate the clinical value of pre- and on-treatment ctDNA levels for longitudinally refining cHL risk prediction, and for detection of radiographically occult minimal residual disease. Collectively, these results support the utility of noninvasive strategies for genotyping and dynamic monitoring of cHL as well as capturing molecularly distinct subtypes with diagnostic, prognostic, and therapeutic potential.Methods utilized include a) targeted genotyping of baseline plasma samples, b) whole exome sequencing (WES) of baseline plasma samples, c) epigenetic expression inference from cell-free DNA-sequencing (EPIC-Seq) to infer gene expression from cell-free DNA (cfDNA) fragmentation profiles, d) ctDNA tracking in on-treatment samples, e) RNA-Sequencing, and f) Phased variant Enrichment and Detection Sequencing (PhasED-Seq).All patients were treated at cancer centers across Europe and North America between 2011 and 2020. The following 3 cancer centers, Stanford (CA, USA), Bellinzona [Confoederatio Helvetica (CH) or Switzerland], and Leuven (Belgium), were included. The 6 clinical trial collectives included in this study are the Phase III trial AHOD1331 trial (NCT02166463) and the Phase II cHOD17 study (NCT03755804) for enrolled pediatric patients, the Phase III AHL2011 (NCT01358747), the Phase II BREACH trial (NCT02292979), a pilot study evaluating concurrent Pembrolizumab with AVD (Doxorubicin, also known as Adriamycin, Vinblastine, and Dacarbazine; NCT03331341), and a Phase II study evaluating PVAB (Prednisone, Vinblastine, Doxorubicin and Bendamustine; NCT02414568) in older patients (61 years and older). In addition, lymph node specimens from a biorepository at St. Jude Children's Research Hospital (TN, USA) were included.

  Study phs003435

• Investigating Genetics in Suspected Congenital Syndromes

  We employed forward and reverse genetics to identify individuals with heterozygous JAK1 variants associated with autoimmune and inflammatory diseases. We first recruited six unrelated probands and seven affected family members presenting with a range of autoimmune and inflammatory conditions. Whole exome sequencing revealed 4 different variants spanning all domains of the JAK1 protein: FERM domain (chr1: 64873438-G>A; c.415C>T; p.E139K), SH2 domain (chr1: 64855641-G>A; c.1516C>T; p.R506C), pseudokinase domain (chr1: 64845529-C>T; c.2099G>A; p.S700N, and kinase domain (chr1: 64838479-C>T; c.2953G>A; p.V985I). We then performed a systematic review of electronic health records of the BioME BioBank database and identified 43 additional individuals with at least one of these JAK1 variants. Comparing variant-positive and variant-negative individuals, our study revealed increased occurrences of autoimmunity, atopy, colitis, and dermatitis in patients harboring these JAK1 gain-of-function variants. We have deposited in dbGaP the whole exome sequencing files of the 43 patients identified in the BioME biobank, as well as their phenotype information.

  Study phs003453

• Breast Cancer in Blacks: Impact of Genomics, Healthcare Use and Lifestyle on Outcomes (BRIGHT)

  Young Black females bear a disproportionate burden of breast cancer (BC) mortality compared to White females and are underrepresented in clinical studies. It remains critical to understand factors that contribute to the high mortality from BC among young Black females in order to improve outcomes. The higher BC mortality rate among young Black females with breast cancer is partially attributed to the disproportionately higher proportions who develop the aggressive triple-negative breast cancer (TNBC). In addition to biologic factors, timely access to care, and lifestyle factors contribute to this disparity. Consequently, we sought to evaluate the interplay between biologic and non-biologic contributors to BC outcomes (i.e., BC disease-free survival (DFS)), and to better characterize the highly aggressive TNBC among young Black females based on distinct molecular subtypes. Ultimately, it is critical to assess both biologic and non-biologic factors to fully understand and address existing health disparities in this population. Through prior and subsequent recruitment of a population-based study of young Black females diagnosed with invasive breast cancer spanning 2009-2016, we: 1) assessed the contribution of biologic and non-biologic factors on BC-DFS observed among young Black females with BC, and 2) investigated molecular features of the subgroup with TNBC. Through this study, consented participants were asked to provide a saliva sample from which DNA was extracted for germline analyses, including germline inherited cancer genetic testing and Infinium Expanded Multi-Ethnic Genotyping Array. Breast cancer tumor specimens were also collected, and tumor RNA was extracted from viable FFPE tumor samples. Tumor RNA analyses included gene expression profiling through NanoString PAM50.Data that will be available through dbGaP for this study include SNP array data and PAM50 data.

  Study phs003466

• Genetic Markers of Lipids in Indians: A Validation Study of Most Relevant Findings of Genome-Wide Association Studies

  We aimed to validate the GWAS loci (identified in European populations) related to serum lipid levels (total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and very low-density lipoprotein cholesterol (VLDL-C)) in the Indian population originally recruited to examine the 20-year trend of cardiometabolic risk factors in rural and urban areas around National Capital region in India. Isolated DNA was processed for genotyping of 12 established GWAS variants using multiplex Sequenom Mass ARRAY technology. We examined the association of these genetic variants with different lipid levels and found association of eight variants for lipid levels. We also derived weighted genetic risk scores (wGRAS) using the validated variants. The wGRS for triglycerides and VLDL-C was derived based on four associated variants (rs174546 at FADS1, rs17482753 at LPL, rs2293889 at TRPS1, rs4148005 at ABCA8, rs4420638 at APOC1) which was associated with 36.31 mg/dL elevated triglycerides and VLDL-C (β=0.95, SE=0.16, pTRPS1 and rs4147536 at ADH1B) was associated with 40.62 mg/dL higher total cholesterol (β=1.01, SE=0.23, pTRPS1, rs4147536 at ADH1B, rs4420638 at APOC1 and rs660240 at CELSR2). The wGRS derived from five associated variants (rs174546 and FADS1, rs17482753 at LPL, rs4148005 at ABCA8, rs4420638 at APOC1 and rs7832643 at PLEC) was associated with 10.64 mg/dL lower HDL-C (β= -0.87, SE =0.14, pThe phenotypic and genotypic data will be made available on the dbGaP portal for access.

  Study phs003469

• PIEZO1 Loss of Function Compound Heterozygous Mutation in the Rare Congenital Human Disorder Prune Belly Syndrome

  Prune Belly Syndrome (PBS) is a rare congenital myopathy that is incompletely understood genetically. In this IRB approved study, one white Non-Hispanic 35 year-old male PBS proband was prospectively enrolled and phenotyped. Blood lymphocyte DNA from the proband underwent paired-end Whole Exome Sequencing using the Illumina SureSelect kit and HiSeq2500 sequencer with data pipeline analysis. We aligned the subject's sequence against the GRCh38/hg19 assembly and variant calling was performed using data training sets from the 1000 Genomes Project, Omni 2.5 M SNP microarray, and HapMap phase 3.3. These variants were filtered for rare minor allele frequency ( 0.9, CADD score > 20, GERP > 4, MutationTaster = “DC”, Mutation Assessor = “M” or “NE”, and Vest > 3.00. Rare and novel candidate functional variants were screened in the ClinVar database for prior association with smooth muscle myopathy (SMM). Only variants that met these criteria were included for further analysis. Confirmed variants had inheritance analysis performed on available samples. Our WES analysis identified novel compound heterozygous variants in the PIEZO1 gene. We conducted an extensive functional analysis of the PIEZO1 PBS variants that revealed loss-of-function characteristics. Thus, PIEZO1 mutations may be causal for PBS. Our WES data will be available through dbGaP.

  Study phs003475

• Postmortem Analysis of the Caudate Nucleus in Schizophrenia

  This postmortem study examines genomic signatures (gene, transcript, exon, and exon-exon junction) in the caudate nucleus of individuals with or without psychiatric illnesses. We characterized genetic and epigenetic changes across the lifespan of 443 donor subjects, including 245 individuals without psychiatric illness, 154 individuals with schizophrenia, and 44 individuals with bipolar disorder. The subjects are 210 from African and 233 from European ancestries. Combining expression quantitative trait loci (eQTL) analysis, Mendelian randomization with the latest schizophrenia genome-wide association study (GWAS), transcriptome-wide association study (TWAS) and differential expression analysis, we identified many genes associated with schizophrenia risk, including potentially the dopamine D2 receptor short isoform. We found that antipsychotic medication has an extensive influence on caudate gene expression. We constructed caudate nucleus gene expression networks that highlight interactions involving schizophrenia risk. These analyses provide a resource for the study of schizophrenia and insights into risk mechanisms and potential therapeutic targets. There are 120 subjects in this study which are also present in the study phs000417.

  Study phs003495

• Identification of Host Genetic Factors That Are Determinant for the Development of Severe Forms of COVID-19

  We conducted whole exome sequencing (WXS) on 21 cases of Multisystem Inflammatory Syndrome in Children (MIS-C) related to COVID-19 from Brazil. All patients who were hospitalized underwent serum (ELISA) and molecular (RT-PCR) testing for SARS-CoV-2, and the main clinical symptoms associated with SARS-CoV-2 infection were collected. During hospitalization, data on complications, medical interventions, and laboratory findings were also collected. Our results revealed in an unprecedented way the occurrence of several rare loss-of-function variants in the NLRP12 gene among the affected children, and three other SNVs, predicted to be highly pathogenic, were identified in the IL17RC gene. An additional nonsense variant, in the IFNA10 gene, was identified in a single patient. Through in vitro functional analysis, we unequivocally demonstrated that these mutations impact NF-kB activation. These findings are similar to those observed in NLRP12-associated systemic autoinflammatory disorders, characterized by altered innate immune response, with increased NF-κB activation and excessive production of inflammatory cytokines. To our knowledge, our study is the first to provide a plausible molecular mechanism for MIS-C involving inborn errors in NLRP12. We suggest that some patients with MIS-C may benefit from Interleukin (IL)-1 pathway blockade treatments.

  Study phs003512

• Cell Type-Specific and Disease-Associated eQTL in the Human Lung

  This study was conducted to investigate the genetic control of gene expression in a cell-type and context-specific manner in the human lung. We performed single-cell RNA-sequencing (scRNA-seq) of lung tissue from 66 Interstitial Lung Disease (ILD) cases and 48 unaffected donors. Employing a pseudo-bulk approach, we mapped expression quantitative trait loci (eQTL) across 38 cell types. The scRNA-seq data presented here include previously published (PMID 34262047) and unpublished samples. ILD tissue samples were obtained from lungs removed at the time of lung transplantation at either Vanderbilt University Medical Center (VUMC) or the Norton Thoracic Institute (NTI). Control tissue samples were obtained from lungs declined for organ donation either at the Donor Network of Arizona (DNA) or VUMC. The self-reported ethnicities of donors were 66.7% European, 9.6% African American, 17.5% not available (N/A), and 6.1% other. The smoking history includes 46.5% ever smoker, 29.8% never smoker, 23.7% N/A. For genotyping, flash-frozen tissue in DNA/RNA shield was homogenized via a bullet blender. Genomic DNA was extracted using Zymo Quick DNA/RNA microprep plus kit. Library preparation and low-pass Whole Genome Sequencing (WGS) were carried out at TGen or by Gencove Inc. At TGen, libraries were prepared using PCR-free Watchmaker kits (Watchmaker Genomics) with 200 ng input. Genomes were sequenced on NovaSeq at low coverage (typically 0.4–1x). The resulting sequence data were processed and imputed using Gencove's imputation platform.

  Study phs003521

• Integrating Genomic and Transcriptomic Data to Identify Breast Cancer Susceptibility Genes

  Genetic factors play an important role in the etiology of both sporadic and familial breast cancer. Since 2007, common genetic variants in ~200 loci have been identified in genome-wide association studies (GWAS) in relation to breast cancer risk. However, it is often difficult to translate GWAS findings to disease prevention and treatment since causal genes in the large majority of GWAS-identified loci are unknown. Furthermore, a large fraction of breast cancer heritability remains unexplained. Recent studies suggest that nearly 80% of disease heritability can be explained by genetic variants regulating gene expression. Herein, we propose three well-powered transcriptome-wide association studies (TWAS) to systematically investigate the association of breast cancer risk with gene expression across the transcriptome of African, Asian and European descendants. In Aim 1, we will perform RNA sequencing and high-density genotyping assays using normal breast tissue samples, and build race-specific gene expression prediction models using data from 1000 women of African, Asian and European descent. These models will be applied to the GWAS data generated from approximately 320,000 breast cancer patients and controls to impute gene expression for association analyses of predicted gene expression with risk of breast cancer overall, and by estrogen receptor and HER2 status. In Aim 2, we will select the top 50 genes identified in Aim 1 for in vitro functional assays to assess their influence on major cell functions related to cancer biology. In Aim 3, we will evaluate whether TWAS-identified genes may express differently in normal breast tissues and breast cancer tissues collected from African, Asian, and European descendants to assess whether these genes may contribute to racial differences in breast cancer risk by molecular subtypes. With strong methodology and a large sample size, we believe that this proposed study should be able to identify and characterize a large number of novel genes related to breast cancer risk. Uncovering breast cancer susceptibility genes will greatly improve the understanding of the genetic and biological basis for breast cancer and accelerate the translation of genetic findings to disease prevention and patient care.

  Study phs003535

• Action to Control Cardiovascular Risk in Diabetes (ACCORD - Imaging)

  Available DataAction to Control Cardiovascular Risk in Diabetes (ACCORD-Imaging), provides access to ECG signals data from the ACCORD clinical trial. The clinical phenotyping and outcomes data from the trial are associated with ACCORD-BioLINCC, phs003551.ObjectivesThe purpose of this study was to determine if intensive glycemic control, multiple lipid management and intensive blood pressure control could prevent major cardiovascular events (myocardial infarction, stroke or cardiovascular death) in adults with type 2 diabetes mellitus. Secondary hypotheses included treatment differences in other cardiovascular outcomes, total mortality, microvascular outcomes, health-related quality of life and cost-effectiveness.BackgroundGlycemia Trial:Patients with type 2 diabetes mellitus die of cardiovascular disease (CVD) at rates two to four times higher than non-diabetic populations of similar demographic characteristics. They also experience increased rates of nonfatal myocardial infarction and stroke. With the growing prevalence of obesity in the United States, CVD associated with type 2 diabetes is expected to become an even greater public health challenge in the coming decades than it is now. Expected increases in event rates will be associated with a concomitant rise in suffering and resource utilization.The ACCORD study investigated whether intensive therapy to target normal glycated hemoglobin (HbA1c) levels would reduce cardiovascular events in patients with type 2 diabetes who had either established cardiovascular disease or additional cardiovascular risk factors when compared to standard therapy (HbA1c between 7.0% and 7.9%). A separate analysis investigated whether reduction of blood glucose concentration decreases the rate of microvascular complications in these patients.Lipid Therapy Trial:Patients with type 2 diabetes mellitus have an increased incidence of atherosclerotic cardiovascular disease attributable, in part, to associated risk factors such as dyslipidemia. This is characterized by elevated plasma triglyceride levels, low levels of high-density lipoprotein (HDL) cholesterol and small, dense low-density lipoprotein (LDL) particles. The ACCORD Lipid Therapy trial was designed to test the effect of a therapeutic strategy that uses a fibrate to raise HDL-C and lower triglyceride levels and uses a statin for treatment of LDL-C reduce the rate of CVD events compared to a strategy that only uses a statin for treatment of LDL-C on cardiovascular outcomes in patients with type 2 diabetes that were at high risk for cardiovascular disease.Blood Pressure Trial:Diabetes mellitus increases the risk of cardiovascular disease at every level of systolic blood pressure. Because cardiovascular risk in patients with diabetes is graded and continuous across the entire range of levels of systolic blood pressure, even at prehypertensive levels, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommended beginning drug treatment in patients with diabetes who have systolic blood pressures of 130 mm Hg or higher, with a treatment goal of reducing systolic blood pressure to below 130 mm Hg. There is, however, a paucity of evidence from randomized clinical trials to support these recommendations. The ACCORD Blood Pressure trial tested the effect of a target systolic blood pressure below 120 mm Hg on major cardiovascular events among high-risk persons with type 2 diabetes compared to a strategy that targeted a SBP of EYE Substudy:Diabetic retinopathy, an important microvascular complication of diabetes, is a leading cause of blindness in the United States. Randomized, controlled clinical trials in cohorts of patients with type 1 diabetes and those with type 2 diabetes have shown the beneficial effects of intensive glycemic control and intensive treatment of elevated blood pressure on the progression of diabetic retinopathy. Elevated serum cholesterol and triglyceride levels have been implicated, in observational studies and small trials, as additional risk factors for the development of diabetic retinopathy and visual loss. The ACCORD EYE Substudy evaluated the effects of the ACCORD medical strategies on the progression of diabetic retinopathy in a subgroup of trial patients.MIND Substudy:Studies suggest that older persons with type 2 diabetes have at least twice the likelihood of developing late-life cognitive impairment or dementia compared to those without. The mechanisms underlying these cognitive disorders are increasingly thought to reflect a mixed pathology pattern with contributions from vascular, neurodegenerative and neurovascular processes. Pathophysiological mechanisms that have been described include inflammation, oxidative stress, energy imbalance, protein misfolding, glucocorticoid-mediated effects and differences in genetic susceptibilities. The ACCORD MIND substudy took as a premise that early intervention with the ACCORD therapeutic strategies to improve glycemic control could mitigate the adverse effects of type 2 diabetes on the brain.Subjects10,251 patients with type 2 diabetes and HbA1c concentrations of 7.5% or more participated in the trial. Of these patients, 5518 were assigned to the lipid therapy arm and 4733 to the blood pressure arm. EYE Substudy:A subgroup of 2856 patients was evaluated for the effects of the ACCORD interventions at 4 years on the progression of diabetic retinopathy. Patients who, at baseline, had a history of proliferative diabetic retinopathy that had been treated with laser photocoagulation or vitrectomy were excluded.MIND Substudy:A subgroup of 2977 patients was evaluated for cognitive function and brain volume. The ACCORD MIND substudy excluded patients aged DesignPatients were randomly assigned to undergo either intensive glycemic control (targeting a glycated hemoglobin level EYE Substudy:EYE Substudy patients were evaluated at two standardized and comprehensive eye examinations for the effects of the ACCORD interventions at 4 years on the progression of diabetic retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study Severity Scale (as assessed from seven-field stereoscopic fundus photographs, with 17 possible steps and a higher number of steps indicating greater severity) or the development of diabetic retinopathy necessitating laser photocoagulation or vitrectomy.MIND Substudy:The cognitive primary outcome, the Digit Symbol Substitution Test (DSST) score, was assessed at baseline, 20 and 40 months. Total brain volume (TBV), the primary brain structure outcome, was assessed with MRI at baseline and 40 months in a sub-set of 632 patients. All patients with follow-up data were included in the primary analyses.ConclusionsGlycemia Trial:As compared with standard therapy, the use of intensive therapy to target normal glycated hemoglobin levels for 3.5 years increased mortality and did not significantly reduce major cardiovascular events. (NEJM. 2008; 358(24): 2545-59).Microvascular Outcomes of the Glycemia Trial:Intensive therapy did not reduce the risk of advanced measures of microvascular outcomes, but delayed the onset of albuminuria and some measures of eye complications and neuropathy. Microvascular benefits of intensive therapy should be weighed against the risk of increased total and cardiovascular disease-related mortality, increased weight gain, and higher risk for severe hypoglycemia. (Lancet. 2010; 376(9739): 419-30)Lipid Therapy Trial:The combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infarction or nonfatal stroke, as compared with simvastatin alone. These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority of high-risk patients with type 2 diabetes (NEJM. 2010; 362(17): 1563–1574).Blood Pressure Trial:In patients with type 2 diabetes at high risk for cardiovascular events, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events (NEJM. 2010; 362: 1575-1585).EYE Substudy:Intensive glycemic control and intensive combination treatment of dyslipidemia, but not intensive blood-pressure control, reduced the rate of progression of diabetic retinopathy (NEJM. 2010; 363: 233-244).MIND Substudy:Although significant differences in TBV favored the intensive therapy, cognitive outcomes were not different. Combined with the unfavorable effects on other ACCORD outcomes, MIND findings do not support using intensive therapy to reduce the adverse effects of diabetes on the brain in patients similar to MIND patients (Lancet Neurol. 2011; 10(11): 969–977).

  Study phs003562

• Human genomic and phenotypic synthetic data for the study of rare diseases

  The purpose of this dataset is to facilitate development of technical implementations for rare disease data integration, analysis, discovery, and federated access. This synthetic dataset includes clinical and genomic data from 6 rare disease cases. It consists of 18 whole genomes (6 index cases with their parents) which have genetic background based on public human data sequenced in the context of the Illumina Platinum initiative (Eberle, MA et al. (2017)) and made available by the HapMap project (https://www.genome.gov/10001688/international-hapmap-project). In each of the cases, real causative variants correlating with the phenotypic data provided were spiked-in. The cases included in this synthetic dataset correspond to the following type of disorders: CASE 1- Congenital myasthenic syndrome (Autosomal Dominant -de novo variant) CASE 2- Macular dystrophy (Autosomal Dominant) CASE 3- Muscular dystrophy (Autosomal Recessive-compound heterozygous variants) CASE 4- Mitochondrial disorder (Autosomal Recessive-consanguineous case - homozygous variant) CASE 5- Breast cancer (Autosomal Dominant) CASE 6- Similar as case 1 for patient matchmaking tests: Congenital myasthenic syndrome (Autosomal Dominant-de novo variant) For each case you will be able to download the following data: clinical information (phenopackets per individual and pedigree per family), raw genomic data (FASTQ and BAMs) and processed genomic data (vcfs). When using the data, the following should be acknowledged: the RD-Connect GPAP (https://platform.rd-connect.eu/), EC H2020 project EJP-RD (grant # 825575), EC H2020 project B1MG (grant # 951724) and Generalitat de Catalunya VEIS project (grant # 001-P-001647).

  Study EGAS00001005702

• Structural variant analysis of homologous recombination-deficient genomes

  Homologous recombination (HR) deficiency causes DNA breaks and cytogenetic aberrations. Paradoxically, the types of DNA rearrangements specifically associated with HR-deficient cancers only minimally impact chromosomal structure. Addressing this, we combined a genome graph analysis of short-read whole genome sequencing (WGS) profiles across thousands of tumors with deep linked-read (LR) WGS of 46 BRCA1 or BRCA2 mutant breast cancers to discover a distinct class of HR deficiency-enriched rearrangements called reciprocal pairs. LR WGS showed that reciprocal pairs with identical rearrangement orientations gave rise to one of two distinct chromosomal outcomes, distinguishable only with long molecule data. While one (cis) outcome corresponded to the copy and pasting of a small segment to a distant site, a second (trans) outcome was a quasi-balanced translocation or multi-megabase inversion with substantial (10kb) duplications at each junction. The full spectrum of reciprocal pair outcomes could be explained by an HR-independent replication restart repair mechanism. LR WGS additionally identified single-strand annealing (SSA) as a BRCA2-deficiency specific repair pathway in human cancers. Replication restart- and SSA-associated SVs improved BRCA1- vs. BRCA2- deficiency classification and identified metastatic cancer cases with favorable chemotherapy responses. Our data reveal classes of BRCA1- and BRCA2-deficiency specific rearrangements as drivers of cytogenetic aberrations in HR deficient cells.

  Study EGAS00001007186

• Population_dynamics_in_abnormal_haematopoiesis

  Background: Our recent study has made direct insight into the clonal dynamics of blood cell production in an unperturbed setting in a human. Using whole genome sequencing to track acquired somatic mutations, we were able to construct a phylogenetic tree of different stem and progenitor cells and used this tree to determine the dynamics of mature blood cell production in longitudinal samples. These data set the baseline for understanding population dynamics in abnormal haematopoiesis, and how malignant clones outcompete their normal counterparts to drive haematological malignancies. Aim: This study will measure population dynamics in abnormal human haematopoiesis in patients with clonal blood stem cell disorders. Methods: From patient bone marrow or peripheral blood, we have isolated colonies grown from single blood stem cells/progenitors. Colony DNA will be analysed by whole-genome sequencing to build (or populate) a phylogenetic tree to determine clonal relationships and track stem cell contribution to mature blood cell production. These data will also reveal disease-associated genomic features (mutational burden and mutational signatures) in haematopoietic cells.

  Study EGAS00001003181

• H3Africa - Genomic Characterization and Surveillance of Microbial Threats in West Africa

  Viral diseases are remarkably heterogeneous in their presentation and clinical course. Although diseases such as Lassa Fever and Ebola Virus Disease are thought to be severe and rapidly fatal, they can often present with mild symptoms or remain asymptomatic. Host genetic variability is likely an important mediator of this heterogeneity. Complete characterization of the clinical, laboratory, and host genetic features of these illnesses is not only imperative to rapid diagnosis and effective clinical care, but also important for further scientific study. In this project, we propose to address this need through deep characterization of the clinical and laboratory features of viral disease and through study of genetic mediators of resistance to Lassa Fever and Ebola Virus Disease. Will carry out deep clinical characterization and laboratory assessment of viral febrile cases at two West African Collaborative Centers, and will use this data to develop prognostic models using cutting-edge tools in exploratory data visualization and machine learning. Investigate host genetic factors of Lassa Fever and Ebola Virus Disease through genome-wide association studies. We will then develop field-deployable genotyping assays for the top-associated variants, and apply them in new cohorts to replicate our findings and investigate patterns of genetic resistance in clinical subgroups. This project can shed light on the clinical manifestations of viral illness and their host genetic mediators, leading to potential new insights in disease biology and pathophysiology. We will also create a rich resource of clinical, laboratory, and genetic data for these illnesses in two countries in West Africa, which will serve as a foundation for advancing the clinical care and scientific study of viral disease in the region.

  Study EGAS00001007250

• The Genetic Landscape of Ocular Adnexa MALT Lymphoma Reveals Frequent Aberrations in NFAT and MEF2B Signaling Pathways

  A comprehensive constellation of somatic non-silent mutations and copy number (CN) variations in ocular adnexa marginal zone lymphoma (OAMZL) is unknown. By utilizing whole-exome sequencing in 69 tumors we define the genetic landscape of OAMZL. Mutations and CN changes in CABIN1 (30%), RHOA (26%), TBL1XR1 (22%), and CREBBP (17%) and inactivation of TNFAIP3 (26%) were among the most common aberrations. Candidate cancer driver genes cluster in the B-cell receptor (BCR), NFkB, NOTCH and NFAT signaling pathways. One of the most commonly altered genes is CABIN1, a calcineurin inhibitor acting as a negative regulator of the NFAT and MEF2B transcriptional activity. CABIN1 deletions enhance BCR-stimulated NFAT and MEF2B transcriptional activity, while CABIN1 mutations enhance only MEF2B transcriptional activity by impairing binding of mSin3a to CABIN1. Our data provide an unbiased identification of genetically altered genes that may play a role in the molecular pathogenesis of OAMZL and serve as therapeutic targets.

  Study EGAS00001006631

• ATAC-seq/ChIP part

  Epigenetics: ATAC-seq and ChIP-seq data

  Study EGAS00001006520

• 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.

  Study EGAS00001006545

• Genomic evolution and transcriptional changes in the evolution of prostate cancer into neuroendocrine and ductal carcinoma types (RNAseq)

  Prostate cancer is typically of acinar adenocarcinoma type but can occasionally present as neuro-endocrine and/or ductal type carcinoma. These are associated with clinically aggressive disease and the former often arises on a background of androgen deprivation therapy, although it can al-so arise de novo. Two prostate cancer cases were sequenced by exome capture from archival tis-sue. Case 1 was de novo small cell neuroendocrine carcinoma and ductal adenocarcinoma with 3 longitudinal samples over 5 years. Case 2 was a single time point after development of treatment related neuroendocrine prostate carcinoma. Case 1 showed whole genome doubling in all sam-ples and focal amplification of AR in all samples except the first time point. Phylogenetic analysis revealed a common ancestry for the ductal and small cell carcinoma. Case 2 showed 13q loss (involving RB1) in both adenocarcinoma and small cell carcinoma regions, and 3p gain, 4p loss, 17p loss (involving TP53) in the latter. By using highly curated samples, we demonstrate for the first time that small cell neuroendocrine and ductal prostatic carcinoma can have a common an-cestry and the process of evolution over time. We highlight whole genome doubling in a patient with prostate cancer relapse, reinforcing its poor prognostic nature.

  Study EGAS00001007428

• SudanMitoSeq: Sudanese mitochondrial sequencing

  In various contexts, mitochondrial function or dysfunction can be linked to mitochondrial genome variations. The use of mitochondrial genetics thus promises personalized diagnostics and treatments. In order to devise specific precision medicine approaches based on mitochondrial genetic variation and to test them within clinical studies, control data is indispensable. Such control data needs to comprehensively cover genetic variation commonly observed and thus expected. In the context of this study we assessed whether current, world-wide mitochondrial data sufficiently represents the region of North and East Africa, that is, whether current reference data is ready for precision medicine in this region. Towards this, we sequenced mitochondrial genomes of 159 Sudanese individuals provided as part of this EGA study and analyzed them together with various other, publicly available data concerning mitochondrial variation. For details, please refer to the publication.

  Study EGAS00001005669

• Genomic evolution and transcriptional changes in the evolution of prostate cancer into neuroendocrine and ductal carcinoma types

  Prostate cancer is typically of acinar adenocarcinoma type but can occasionally present as neuro-endocrine and/or ductal type carcinoma. These are associated with clinically aggressive disease and the former often arises on a background of androgen deprivation therapy, although it can al-so arise de novo. Two prostate cancer cases were sequenced by exome capture from archival tis-sue. Case 1 was de novo small cell neuroendocrine carcinoma and ductal adenocarcinoma with 3 longitudinal samples over 5 years. Case 2 was a single time point after development of treatment related neuroendocrine prostate carcinoma. Case 1 showed whole genome doubling in all sam-ples and focal amplification of AR in all samples except the first time point. Phylogenetic analysis revealed a common ancestry for the ductal and small cell carcinoma. Case 2 showed 13q loss (involving RB1) in both adenocarcinoma and small cell carcinoma regions, and 3p gain, 4p loss, 17p loss (involving TP53) in the latter. By using highly curated samples, we demonstrate for the first time that small cell neuroendocrine and ductal prostatic carcinoma can have a common an-cestry and the process of evolution over time. We highlight whole genome doubling in a patient with prostate cancer relapse, reinforcing its poor prognostic nature.

  Study EGAS00001007412

• Revealing active mutational processes in tumours using DigiPico/MutLX at unprecedented accuracy

  Active mutational processes in a tumor result in genetic micro-heterogeneity that can determine the tumor’s evolutionary trajectory. Identification of these processes by studying micro-heterogeneity can unveil novel aspects of tumor evolution with potential therapeutic implications. Such studies, however, are inherently problematic because of the discovery of excessive false positive mutations. Here we report the optimization and validation of a robust whole genome sequencing and analysis pipeline (DigiPico/MutLX) that virtually eliminates false positive results. Using our method, we identified, for the first time, a sub-clonal local hyper-mutation (kataegis) event in a recurrent ovarian carcinoma, which was unidentifiable from the bulk WGS data of the same tumor. Overall, we propose DigiPico/MutLX method as a powerful framework for the reliable study of genetic micro-heterogeneity in tumor and normal tissues.

  Study EGAS00001003555

• Whole genome sequencing with linked reads of pediatric glioblastoma samples

  Pediatric glioblastoma (pGBM) is a lethal cancer with no effective therapies. To understand mechanisms of tumor evolution in this cancer, we performed whole genome sequencing with linked reads on longitudinally resected pGBM samples. Our analyses showed that all diagnostic and recurrent samples were collections of genetically diverse subclones. Clonal composition rapidly evolved at recurrence, with less than 8% of non-synonymous single nucleotide variants being shared in diagnostic-recurrent pairs. In order to track the origins of the mutational events we observed in pGBM, we generated whole genome datasets for two patients and their parents. These trios showed that genetic variants could be (i) somatic, (ii) inherited from a healthy parent, or (iii) arose de novo in the germlines of pGBM patients. Analysis of variant allele frequencies supported a model of tumor growth involving slow-cycling cancer stem cells that give rise to fast-proliferating progenitor-like cells and to non-dividing cells. Interestingly, radiation and anti-mitotic chemotherapeutics did not increase overall tumor burden upon recurrence. These findings support an important role for slow-cycling stem cell populations in contributing to recurrences, since slow-cycling cell populations are expected to be less prone to genotoxic stress induced by these treatments and to accumulate few mutations. Our results highlight the need for new targeted treatments that account for the complex functional hierarchies and genomic heterogeneity of pGBM.

  Study EGAS00001003432

• Egyptref: An integrated personal and population-based Egyptian genome reference

  North African individuals are not represented in current genetic data sets. To address this issue, we generated an integrated personal and population-based Egyptian genome reference called Egyptref. Towards this end, we performed a human de novo assembly of an Egyptian individual using long PacBio reads (99x genome coverage) and polished it using Illumina short reads (90x). Variants were phased using 10x Genomics linked reads (80x). This personal genome was complemented with whole genome sequencing-based variant data of 109 further Egyptians and mitochondrial haplogroups from mtDNA sequencing of 326 further Egyptians (of which 100 individuals from EGAD00001001372/EGAD00001001380) to obtain a population-based genome. We used Egyptref for assessing the impact of genetic variation, e.g. by integration of blood RNA sequencing data of the assembly individual.

  Study EGAS00001004303

• Genotype data from 'Evidence of the interplay of genetics and culture in Ethiopia'

  Study EGAS00001005171

• Evolutionary predictability of genetic versus non genetic resistance to anticancer drugs in melanoma

  Therapy resistance arises from heterogeneous drug-tolerant persister cells or minimal residual disease (MRD) through genetic and nongenetic mechanisms. A key question is whether specific molecular features of the MRD ecosystem determine which of these two distinct trajectories will eventually prevail. We show that, in melanoma exposed to MAPK therapeutics, emergence of a transient neural crest stem cell (NCSC) population in MRD concurs with the development of nongenetic resistance. This increase relies on a GDNF-dependent signaling cascade, which activates the AKT survival pathway in a focal adhesion kinase (FAK)-dependent manner. Ablation of the NCSC population through FAK inhibition delays relapse in patient-derived tumor xenografts. Strikingly, all tumors that ultimately escape this treatment exhibit resistance-conferring genetic alterations and increased sensitivity to ERK inhibition. These findings identify an approach that abrogates the nongenetic resistance trajectory in melanoma and demonstrate that the cellular composition of MRD deterministically imposes distinct drug resistance evolutionary paths.

  Study EGAS00001005314