3955 results for "*geneti*"

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• Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment.

  Temozolomide (TMZ) increases the overall survival of patients with glioblastoma (GBM), but its role in the clinical management of diffuse low-grade gliomas (LGG) is still being defined. DNA hypermethylation of the O 6 -methylguanine-DNA methyltransferase (MGMT) promoter is associated with an improved response to TMZ treatment, while inactivation of the DNA mismatch repair (MMR) pathway is associated with therapeutic resistance and TMZ-induced mutagenesis. We previously demonstrated that TMZ treatment of LGG induces driver mutations in the RB and AKT-mTOR pathways, which may drive malignant progression to secondary GBM. To better understand the mechanisms underlying TMZ-induced mutagenesis and malignant progression, we explored the evolution of MGMT methylation and genetic alterations affecting MMR genes in a cohort of 34 treatment-naïve LGGs and their recurrences. Recurrences with TMZ-associated hypermutation had increased MGMT methylation compared to their untreated initial tumors and higher overall MGMT methylation compared to TMZ-treated non-hypermutated recurrences. A TMZ-associated mutation in one or more MMR genes was observed in five out of six TMZ-treated hypermutated recurrences. In two cases, pre-existing heterozygous deletions encompassing MGMT, or an MMR gene, were followed by TMZ-associated mutations in one of the genes of interest. These results suggest that tumor cells with methylated MGMT may undergo positive selection during TMZ treatment in the context of MMR deficiency.

  Study EGAS00001001179

• Molecular_characterization_of_invasive_lobular_carcinoma

  Invasive lobular carcinoma (ILC) is the second most common histological subtype of breast cancer accounting for 10-15% of cases. ILC differs from invasive ductal carcinoma (IDC)with respect to epidemiology, histology, and clinical presentation. Moreover, ILC is lesssensitive to chemotherapy, more frequently bilateral, and more prone to form gastrointestinal, peritoneal, and ovarian metastases than IDCs. In contrast to IDC, the prognostic value ofhistological grade (HG) in ILC is controversial. One of the three major components of histological grading (tubule formation) is missing in ILC which hinders the process of gradingin this histological subtype and results in the classification of approximately two thirds of ILC as HG 2.Over the last decade, a number of gene expression signatures have shed light onto breast cancer classification, allowing breast cancer care to become more personalized. Withrespect to the management of estrogen receptor (ER)-positive breast cancer, several gene expression signatures provide prognostic and/or predictive information beyond what is possible with current classical clinico-pathological parameters alone. Nevertheless, most studies using gene expression signature have not considered different histologic subtypesseparately. Recently, a comprehensive research program has elucidated some of the biological underpinnings of invasive lobular carcinoma. Genetic material extracted from 200 ILC tumor samples were studied using gene expression profiling and identified ILCmolecular subtypes. These proliferation-driven gene signatures of ILC appear to have prognostic significance. In particular, the Genomic Grade (GG) gene signature improved upon HG in ILC and added prognostic value to classic clinico-pathologic factors. In addition this study demonstrated that most ILC are molecularly characterized as luminal-A (~75%)followed by luminal-B (~20%) and HER2-positve tumors (~5%). Moreover, we investigated the prognostic value of known gene signatures/ gene modules in the same cohort of ILC. As a second step within the scope of this project, we aim to investigate the interactionsbetween somatic ILC tumor mutations to observed transcriptome findings. To this end, we aim to perform somatic mutation analysis for the ILC tumors for which Affymetrix gene expression profiling is available. To this end, we will use a gene screen assay, which specifically interrogates the mutational status of a few hundreds of cancer genes. We believe that this pioneering effort will be fundamental for a tailored treatment of ILC withimprovement in patients' outcome.

  Study EGAS00001000292

• A sequence-based genetic dissection of human immune cell types and implications for immune-related disease.

  The immune system is an intricate biological network mediating interactions with other organisms while preserving the integrity of our tissues. By mounting appropriate responses it protects us from a vast range of pathogens while inadvertent immune system attacks on self result in autoimmune diseases. The project aims to discover whether and to what extent the behaviour of the immune system is genetically regulated and to detect the relationships of diverse immune cells with autoimmunity. The project consists of the genetic analysis using up to ~8.2 Million variants, deriving from high density genotyping data and low pass whole genome sequencing, and quantitative levels of 95 cell types encompassing 272 immune traits, in a cohort of 1,629 individuals from four clustered Sardinian villages belonging to the SardiNIA/ProgeNIA study.

  Study EGAS00001000574

• Assessing the impact of low frequency coding variants on disease risk using the Exomechip

  Following several rounds of Genome Wide Association (GWA) scans and subsequent meta-analyses of results multiple risk loci have been identified for many common diseases. However, in most instances the implicated common variants identified so far explain only a modest fraction of the genetic risk. In parallel to our efforts to identify the causative variants in the known loci it is necessary to assess the full spectrum of sequence variants for disease risk and in particular low frequency and rare variants that have not been tested in a comprehensive way so far. To this end an international effort by investigators who have performed whole exome sequencing in circa 12,000 individuals have assembled a set of ~250,000 exonic variants of low frequency – defined as seen in at least two studies and a minimum of three individuals (non-sysnonymous) or two individuals for SNPs altering splice sites / stop codons. The SNP content from the exome studies was complemented with additional interesting SNP sets totalling 25,000 markers (GWA tag SNPs, grid of common variants, HLA, Mitochondrial, Y-chromosome etc) and were used to generate a custom iSELECT array, the exome chip. Adequately powered association studies to test low frequency variants for association to disease risk are still very expensive if conducted by whole exome sequencing. The exome chip provides a cost efficient way to undertake such an experiment and the Wellcome Trust Cases Control Consortium will be applying this approach to eight diseases, type 1 and type 2 diabetes, coronary artery disease, hypertension, multiple sclerosis, rheumatoid arthritis, bipolar, and ankylosing spondylitis. The first objective will be to generate a large set of at least 10,000 common UK controls as analysis of lower frequency variants will require large sample sizes. This includes ~6000 samples from the 1958 Birth Cohort.

  Study EGAS00001000584

• The molecular landscape of colorectal cancer （17 cases）

  We performed whole-exome sequencing of tumor samples and adjacent normal mucosae from 17 cases to characterize the genetic alterations in china.

  Study EGAS00001002174

• Genome-wide SNP genotyping of Central African rainforest hunter-gatherers and neighbouring agriculturalists

  The emergence of agriculture in West-Central Africa, ~5,000 years ago, profoundly modified the cultural landscape and mode of subsistence of most sub-Saharan populations. How this major innovation has impacted the genetic history of rainforest hunter-gatherers — historically referred to as “pygmies” — and agriculturalists, however, remains poorly understood. Here, we report genome-wide SNP data from eight of these populations located west-to-east of the equatorial rainforest. We find that hunter-gathering populations present up to 50% of farmer genomic ancestry, and that substantial admixture began only within the last 1,000 years. Furthermore, we show that the historical population sizes characterising these communities already differed before the introduction of agriculture. Our results suggest that the first socio-economic interactions between rainforest hunter-gatherers and farmers introduced by the spread of farming were not accompanied by immediate, extensive genetic exchanges and occurred on a backdrop of two groups already differentiated by their specialisation in two ecotopes with differing carrying capacities.

  Study EGAS00001000605

• JMML targeted sequencing (2013)

  Juvenile myelomonocytic leukemia (JMML) is a rare myelodysplastic myeloproliferative neoplasm of early childhood initiated by germline or somatic RAS-activating mutations (Chang, Dvorak et al. 2014). Clinical evolution is heterogeneous, with acute myeloid leukemia (AML) transformation in 1/3 of cases and frequent relapses after hematopoietic-stem-cell transplantation (HSCT), although some patients experience spontaneous remission (Locatelli, Nollke et al. 2005; Matsuda, Shimada et al. 2007; Takagi, Piao et al. 2013; Locatelli and Niemeyer 2015). The initiating lesion incompletely predicts outcome, suggesting the involvement of additional mutations. Genetic profiling of a large JMML cohort (n=118), including whole-exome sequencing (WES) in 30 cases, uncovered additional genetic abnormalities in 56 cases (47%). Somatic events were rare (0.38/case/Mb) and restricted to sporadic (47/78; 60%) or NF1-associated (8/8; 100%) JMML. Multiple concomitant genetic hits were identified targeting the RAS pathway in 13/78 (17%), RAC2D63V, which activates the PI3K/PDK1/AKT and the mTORC2 pathways, and a novel pathway for JMML, the polycomb repressive complex 2 (PRC2), in 26/78 (33%) of the sporadic JMML cases. Interestingly, PRC2 imbalance was recently shown to synergize with RAS activation (De Raedt, Beert et al. 2014). JMML outcome was associated to the mutational profile, suggesting a dose-dependent effect for RAS-pathway activation, distinguishing very aggressive JMML rapidly progressing to AML.

  Study EGAS00001001324

• Admixture histories of São Tomé e Príncipe.

  In this study, we aim to reconstruct the complex genetic admixture histories of the population of São Tomé e Príncipe, an archipelago in the Gulf of Guinea that experienced successive waves of forced and deliberate migration from Africa since the 15th century, during and after the Trans-Atlantic Slave Trade.

  Study EGAS50000000920

• Osteosarcoma_RNAseq

  We propose to definitively characterise the somatic genetics of Osteosarcoma cancer through generation of comprehensive catalogues of somatic mutations by high coverage genome and transcriptome sequencing.

  Study EGAS00001000615

• BLUEPRINT ChIP-seq data for cells in the haematopoietic lineages, from adult and cord blood samples.

  ChIP-seq data for cells in the haematopoietic lineages, from adult and cord blood samples.

  Study EGAS00001000326

• Long read whole genome sequencing data from brain postmortem tissue

  Chart genetic variation in the human brain in healthy controls and Parkinson’s disease (PD) patients.

  Study EGAS50000000921

• HG_Retroduplications_in_Neurodevelopmental_Disorders

  Mobile genetic Elements (MEs) are pieces of DNA which, through an RNA intermediate, can generate new copies of themselves elsewhere in the host genome. Additionally, MEs can facilitate the duplication of non-ME transcripts, typically genes, through the mechanism of retroduplication. In humans, several disorders have been directly attributed to ME-derived mutagenesis but not to retroduplication events. We propose to whole genome sequence the 7 individuals with putative de novo gene retroduplications in order to identify the site of insertion. This sequencing will serve two primary purposes: 1.) Identify the first documented case of a de novo retrogene insertion event causing a disease in humans 2.) provide additional whole genome sequencing of undiagnosed probands recruited into the DDD 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 EGAS00001002907

• Clonal Evolution and Transcriptional Plasticity Shape Metastatic Dissemination Routes in Prostate Cancer

  This study provides comprehensive insights into the genetic and transcriptomic landscape of prostate cancer, highlighting significant clonal heterogeneity, transcriptional plasticity, and metastatic spread patterns. We examined the clonal evolution and metastatic dissemination of prostate cancer by integrating single-nuclei RNA sequencing (snRNA-seq) and low-pass whole-genome sequencing (WGS) data from 43 spatially distinct tumour samples in five patients with locally advanced disease. By reconstructing the evolutionary trajectories of each tumour, we identified distinct patterns of tumour evolution, including both monophyletic and polyphyletic metastatic dissemination, as well as ongoing primary tumour clonal evolution after metastatic spread. We observed converging changes leading to metastatic potential, such as androgen receptor independence and increased activity in the estrogen, WNT, and JAK/STAT pathways in identified seeding areas. These findings enhance our understanding of the disease's progression and may inform future therapeutic strategies.

  Study EGAS50000000927

• Genome_Diversity_in_Africa_Project___GemCode_libraries

  Globally, human populations show structured genetic diversity as a result of geographical dispersion, selection and drift. Understanding this genetic variation can provide insights into the evolutionary processes that shape both human adaptation and variation in disease. Populations from Africa have the highest levels of genetic diversity. This characteristic, in addition to historical genetic admixture, can lead to complexities in the design of studies assessing the genetic determinants of disease and human variation. However, such studies of African populations are also likely to provide new opportunities to discover novel disease susceptibility loci and variants and refine gene–disease association signals. A systematic assessment of genetic diversity within Africa would facilitate genomic epidemiological studies in the region.The Genome Diversity in Africa Project (GDAP) will extend and expand the African Genome Variation (AGV) project, an international collaboration aimed to produce a comprehensive catalogue of human genetic variation in Sub-Saharan Africa (SSA). Using a sequencing-based approach, GDA project aims to capture human genetic variation in Africa, including single nucleotide polymorphisms (SNPs), structural variants, and haplotypes. This resource will make a substantial contribution to understanding patterns of genetic diversity within and among populations in Africa, as well as providing a global resource to help design, implement and interpret genomic studies in African populations and studies comprising globally diverse populations, complementing existing genomic resources. Specifically, we plan to carry out whole genome sequencing at high depth (30x) of up to 1000 individuals across Africa (25 individuals from each ethnolinguistic group). We have already completed sequencing from 5 ethno-linguistic groups and we are now adding others.Our scientific objectives are to: 1) develop a resource that provides a comprehensive catalogue of genetic variation in populations from Africa accessible to the global scientific community; 2) characterise population genetic diversity, structure, gene flow and admixture across Africa; 3) develop a cost-efficient, next-generation genotype array for diverse populations across Africa; and 4) facilitate whole genome-sequencing association studies of complex traits and diseases by developing a reference panel for imputation and resource for enhancing fine-mapping disease susceptibility loci. These scientific objectives will be supported by cross-cutting operational activities, including network and management of the consortium, research ethics, and research capacity building in statistical genetics and bioinformatics.

  Study EGAS00001001589

• H3Africa - An integrated approach to the identification of genetic determinants of susceptibility to trypanosomiasis

  The over-arching aim of this network is to improve the health of people living in some of the poorest countries in the world that carry a disproportionate burden of infectious diseases. Despite their importance, the study of many tropical diseases has lagged behind that of diseases of developed countries. This network will redress the balance by performing high quality research into two neglected tropical diseases, human African Trypanosomiasis (HAT) and schistosomiasis. Our aim is to investigate the genetic determinants of the human reservoirs of HAT and schistosomiasis, filling an important knowledge gap, while extending and strengthening the underpinning infrastructure to deliver these scientific objectives in particular by developing the next generation of African geneticists.

  Study EGAS00001007173

• Sequencing of heritable Bleeding and Platelet Disorders

  The BRIDGE-BPD study aims to discover new causal genes for Bleeding and Platelet Disorders (BPD) by high throughput sequencing using cluster analyses based on improved and standardized deep phenotyping of cases. BPD is one of the 13 Rare Disease projects under the NIHR BioResource Rare Diseases BRIDGE consortium, which is a collaboration aiming to discover the genetic sequence variants underlying unresolved inherited disorders and to improve identification of already identified high penetrance variants.

  Study EGAS00001001172

• Identification_of_rare_variants_associated_with_cardiovascular_traits_in_Cilento_isolates

  The aim of this project is to identify rare genetic variants of large effect implicated in complex diseases by focusing on the study of cardiovascular diseases and related quantitative traits in a well characterized isolated population in Cilento area, Italy.The reference panel has been selected carefully in order to maximize the imputation coverage and quality on the all population samples. The selected individuals should meet three criteria: selected individuals should be chip-genotyped and closely related to the maximum number of chip-genotyped individuals so as to maximize imputation coverage; relatedness between selected individuals should be minimal, so as to minimize redundancy in genetic information of the reference panel.We perform exome sequencing on samples from 250 individuals from the Campora and Gioi-Cardile populations.

  Study EGAS00001000620

• High-grade B-cell lymphoma, not otherwise specified: an LLMPP study

  Molecular characterization of high-grade B-cell lymphoma, not otherwise specified (HGBCL-NOS), is hindered by its rarity, evolving definition, and poor diagnostic reproducibility. To address this challenge, we analyzed 92 HGBCL-NOS tumors collected across Lymphoma/Leukemia Molecular Profiling Project sites. These tumors were profiled using whole-genome sequencing (WGS) or whole-exome sequencing (WES) to identify somatic mutations, WGS or low-pass WGS to detect copy number alterations, targeted capture sequencing to assess MYC and BCL2 structural variants, and RNA sequencing. The genetic features of HGBCL-NOS were compared to those of diffuse large B-cell lymphoma (DLBCL-NOS) and EBV-negative adult Burkitt lymphoma (BL). DLBCL-NOS tumors underwent targeted capture sequencing using a panel of 125 genes recurrently mutated in aggressive B-cell lymphomas. BL biopsies were drawn from the Burkitt Lymphoma Genome Sequencing Project and had available WGS (dbGaP Study Accession: phs000527.v18.p6).

  Study EGAS50000000932

• Illumina HumanCoreExome genotyping data from the British Society for Surgery of the Hand Genetics of Dupuytren’s Disease consortium (BSSH-GODD consortium) collection

  Dupuytren's Disease (DD - OMIM126900) is the most common heritable disorder of connective tissue. It is a fibroproliferative disorder of the palmer fascia, causing flexion contractures of affected digits. DD affects men more commonly than women. DD is an archetypal complex disease, with multiple genetic and environmental factors affecting the final expression of the disease phenotype. The incidence increases with age, and the prevalence of DD is therefore increasing as the UK population ages. Half of all patients present before age 60. DD causes significant functional impairment, and severe contractures can lead to permanent disability. The mainstay of current treatment is surgery, but recurrence and complications are both high. For severe contractures, the only suitable treatment option is amputation. The direct costs to the NHS are high, and underestimate the true economic costs to society. We collected salivary samples from adults in the UK who have had surgery for DD. We have genotyped these samples using the Illumina HumanCoreExome Beadchips. https://research.ndorms.ox.ac.uk/public/dupuytrens/what-is-dupuytrens-disease/

  Study EGAS00001001206

• Bacterial SNPs in the human gut microbiome associate with host BMI

  Genome-wide association studies (GWAS) have revolutionized the field of genetics, providing numerous associations between human SNPs and health traits. Likewise, metagenome-wide association studies (MWAS) between bacterial SNPs and human traits can suggest mechanistic links between the microbiota and its host. However, very few such studies have been done to date, in part due to the large number of samples required to address the variable coverage of bacteria across samples and the fact that most bacteria are present in only a subset of the population. Here, we devised an MWAS framework to detect SNPs and associate them with host phenotypes systematically. We recruited and obtained gut metagenomic samples from a cohort of 7,190 healthy individuals and discovered 1,358 statistically significant associations between a bacterial SNP and host body mass index (BMI). To address the possible effects of population structure and linkage disequilibrium, we applied a clumping procedure, and found 40 independent associations between SNPs and host BMI. We uncovered BMI-associated SNPs in the genomes of 27 bacterial species, even though the relative abundance of 12 of these species was not associated with the phenotype. We separated genome-wide sub-species variations from local associations in individual SNPs, and demonstrated how this framework can highlight specific bacterial functions of interest. Our results demonstrate the importance of considering nucleotide-level diversity in microbiome studies and pave the way toward a better understanding of interpersonal gut microbiome differences and their health implications.

  Study EGAS00001007204

• scD&D-seq of mobilized PBMC from a healthy individual having IDH2 R140Q CHIP

  Single-cell D&D-seq profiles from a mobilized CHIP (clonal hematopoiesis of indeterminate potential) PBMC sample (2 replicates) co-profiled with IDH2 R140Q GoT-ChA.

  Study EGAS50000001590

• Context-specific regulatory genetic variation in MTOR dampens neutrophil-T cell crosstalk in pneumonia-associated sepsis, modulating disease

  Sepsis is a heterogeneous clinical syndrome with a high mortality, requiring personalised stratification strategies. Here, we characterise genetic variation that modulates MTOR, a critical regulator of metabolism and immune responses in sepsis. The effects are highly context specific, involving a regulatory element that affects MTOR expression in activated T cells with opposite direction of effect in neutrophils. We show that the G-allele of the lead variant, rs4845987, associated with decreased risk of T2D, reduces MTOR expression in T cells and improves survival in sepsis due to pneumonia, with effects specific to sepsis endotype. Using ex vivo models, we demonstrate that activated T cells promote immunosuppressive sepsis neutrophils through released cytokines, a process dampened by hypoxia and the mTOR inhibitor rapamycin. Our work demonstrates a novel epigenetic mechanism that fine-tunes MTOR transcription and T cell activity via the variant-containing regulatory element, which further exhibits an allelic effect upon vitamin C treatment. These findings reveal how genetic variation interacts with disease state to modulate immune cell-cell communication, providing a patient stratification strategy to inform more effective sepsis treatment.

  Study EGAS50000000894

• bulk ATACseq: A Cultured Leukemia Stem Cell Model Enables Validation of CDK6 as a Stemness Target Against Acute Myeloid Leukemia

  Acute myeloid leukemia (AML) represents a group of aggressive hematological malignancies, the clinical management of which is made challenging due to the persistence of rare and therapy resistant leukemia stem cells (LSCs) which serve as a source of disease relapse and poor outcomes. There are currently a paucity of methods to reliably enrich and study LSCs, hindering the development of therapies that specifically target LSCs. In this study, we deeply characterize the OCI-AML8227 culture model, which maintains a functional stemness hierarchy originating from its highly primitive CD34⁺CD38⁻ cells, to elucidate LSC biology and uncover LSC-specific therapeutic vulnerabilities. We analyzed both bulk and single-cell proteomics, transcriptomics, and epigenomics to generate a LSC protein-protein interaction network, which was then integrated with an LSC-focused small molecule screen using this model. From these findings, CDK6 was discovered as a therapeutic vulnerability specific to LSCs, which was validated in findings from the BEAT-AML cohort and a patient-derived xenograft (PDX) panel of AML samples through palbociclib treatment. Taken together, our studies validate CDK6 as a druggable vulnerability in LSCs, and authenticate OCI-AML8227 cells as a LSC target discovery engine.

  Study EGAS50000000787

• scATAC: A Cultured Leukemia Stem Cell Model Enables Validation of CDK6 as a Stemness Target Against Acute Myeloid Leukemia

  Acute myeloid leukemia (AML) represents a group of aggressive hematological malignancies, the clinical management of which is made challenging due to the persistence of rare and therapy resistant leukemia stem cells (LSCs) which serve as a source of disease relapse and poor outcomes. There are currently a paucity of methods to reliably enrich and study LSCs, hindering the development of therapies that specifically target LSCs. In this study, we deeply characterize the OCI-AML8227 culture model, which maintains a functional stemness hierarchy originating from its highly primitive CD34⁺CD38⁻ cells, to elucidate LSC biology and uncover LSC-specific therapeutic vulnerabilities. We analyzed both bulk and single-cell proteomics, transcriptomics, and epigenomics to generate a LSC protein-protein interaction network, which was then integrated with an LSC-focused small molecule screen using this model. From these findings, CDK6 was discovered as a therapeutic vulnerability specific to LSCs, which was validated in findings from the BEAT-AML cohort and a patient-derived xenograft (PDX) panel of AML samples through palbociclib treatment. Taken together, our studies validate CDK6 as a druggable vulnerability in LSCs, and authenticate OCI-AML8227 cells as a LSC target discovery engine.

  Study EGAS50000000788

• 3D tissue engineered human skeletal muscle modelling Facioscapulohumeral Muscular Dystrophy

  acioscapulohumeral muscular dystrophy (FSHD) is caused by sporadic misexpression of the transcription factor double homeobox 4 (DUX4) in skeletal muscles. So far, monolayer cultures and animal models have been used to study the FSHD disease mechanism and for FSHD therapy development, but these models do not fully recapitulate the disease and there is a lack of knowledge on how DUX4 misexpression leads to skeletal muscle dysfunction. To overcome these barriers, we have developed a 3D tissue engineered skeletal muscle (3D-TESM) model by generating genetically matched myogenic progenitors (MPs) from human induced pluripotent stem cells of three mosaic FSHD patients. 3D-TESMs derived from genetically affected MPs recapitulate pathological features including DUX4 and DUX4 target gene expression, smaller myofiber diameters, and reduced absolute forces upon electrical stimulation. RNA sequencing data illustrates increased expression of DUX4 target genes in 3D-TESMs compared to 2D myotubes, and cellular differentiation was improved by 3D culture conditions. Treatment of 3D-TESMs with small molecules identified in drug development screens in 2D muscle culture showed no improvements in contractile force and sarcomere organization, highlighting the potential benefit of 3D-TESMs for preclinical drug potency screening by eliminating false-positive compounds for FSHD research and drug development.

  Study EGAS50000000502

• MED12L Gene Alterations Define Aggressive BRCA2-Mutant Prostate Cancers

  Germline mutation of BRCA2 increases the lifetime risk of developing prostate cancer (PCa) by over 700%. BRCA2-mutant PCa have poorer prognosis than sporadic PCa, with rapid development of metastatic, castrate-resistant prostate cancer (mCRPC) and 5-year cancer-specific survival rates of ~50-60%1-4. Despite this, unique genomic driver events that explain the aggressiveness of localized BRCA2-mutant PCa are lacking. We used whole-genome sequencing to fully characterize 14 BRCA2-mutant PCa and demonstrate that BRCA2-mutant PCa is associated with increased genetic instability and a mutually exclusive mutational burden when compared to sporadic PCa. Importantly, BRCA2-mutated cancers are defined by unique copy number gains and hypomethylation events, including alterations in the MED12L/MED12 axis, which are found solely in mCRPC and are enriched in PCa tumours harbouring aggressive intraductal carcinoma (IDC-P) pathologic sub-types. Our findings begin to explain the clinical entity of BRCA2-mutated PCa as these tumours have a unique and aggressive genotype de novo, associated with IDC-P and mCRPC, even in the hormone-naive setting.

  Study EGAS00001001615

• DUX4 activates novel intergenic transcripts and isoforms in a tissue-specific context

  DUX4, a transcription factor driving zygotic genome activation during the embryonic cleavage stage in mammals, regulates the expression of genic and non-genic elements and modulates chromatin accessibility. Its misexpression in skeletal muscle causes Facioscapulohumeral muscular dystrophy (FSHD). The sporadic expression of DUX4 in FSHD muscle and the limitations of short-read RNA sequencing challenge, however, a comprehensive grasp of its consequences on the muscle transcriptome. Here, leveraging full-length isoform RNA sequencing with short-read RNA sequencing on DUX4-inducible myoblasts, we elucidated DUX4-induced transcriptomic changes within a myogenic context. DUX4 yields a complex transcriptome featuring numerous unannotated isoforms from known and novel loci. Moreover, we observed distinct isoform usage of DUX4 target genes between myogenic and embryonic cleavage states highlighting the distinct differences between DUX4 transcription factor activity in skeletal muscle and during the cleavage stage. We also identified ~1,400 unannotated intergenic isoforms predominantly originating from repetitive elements such as LTRs, LINEs, and SINEs. Integration with available datasets delineates the transcriptional and epigenetic landscape of these loci across myogenic and embryonic backgrounds. Like the cell type-specific isoform production, the usage of DUX4 binding sites at these intergenic loci is in part cell type-specific. Collectively, these findings demonstrate substantial and context-specific transcriptomic alterations induced by DUX4 further enriching our understanding of DUX4-induced muscle pathology.

  Study EGAS50000000503

• Rare SNPs in receptor tyrosine kinases are negative outcome predictors in multiple myeloma

  Multiple myeloma (MM) is a plasma cell disorder that is characterized by a great genetic heterogeneity. Recent next generation sequencing studies revealed an accumulation of tumor-associated mutations in receptor tyrosine kinases (RTKs) which may also contribute to the activation of survival pathways in MM. To investigate the clinical role of RTK-mutations in MM, we deep-sequenced the coding DNA-sequence of EGFR, EPHA2, ERBB3, IGF1R, NTRK1 and NTRK2 which were previously found to be mutated in MM, in 75 uniformly treated MM patients of the "Deutsche Studiengruppe Multiples Myelom". Subsequently, we correlated the detected mutations with common cytogenetic alterations and clinical parameters. We identified 11 novel non-synonymous SNVs or rare patient-specific SNPs, not listed in the SNP databases 1000 genomes and dbSNP, in 10 primary MM cases. The mutations predominantly affected the tyrosine-kinase and ligand-binding domains and no correlation with cytogenetic parameters was found. Interestingly, however, patients with RTK-mutations, specifically those with rare patient-specific SNPs, showed a significant lower overall, event-free and progression-free survival. This indicates that RTK SNVs and rare patient-specific RTK SNPs are of prognostic relevance and suggests that MM patients with RTK-mutations could potentially profit from treatment with RTK-inhibitors.

  Study EGAS00001001665

• Emirati Genome Project subset of 43,608 WGS samples for population-scale variant discovery and allele frequency mapping.

  Here, we present a comprehensive genomic characterization of a cohort of 43,608 Emirati genomes sequenced as part of the Emirati Genome Program (EGP). This study identified more than 421 million single nucleotide variants and indels and more than 600 million copy number- and structural variants. Small variants had 756 million molecular effects annotated. Of the identified variants, 69.04% were observed with more than one allele. Of 7.7 million polymorphic variants having an allele frequency (AF) of more than 5% in EGP, 1,348 have a predicted deleterious effect on a protein. Characterization of global variation reveals that EGP represents a genetic continuum encompassing the range of African, Asian, and European populations. It is best described by two Arabian, an Eurasian, and an African component, with the predominant Arabian component linked to mitochondrial haplogroups J and T, which are commonly attributed to the Middle East. Various aneuploidies of sex chromosomes were detected in 93 individuals overall and of chromosome 21 in 41 individuals. The median inbreeding coefficient and cumulative runs of homozygosity (ROHs) lengths were increased due to extensive consanguinity, being largest in the groups with Arabian main ancestry components and higher than reported for Qatar. Families were identified based on genetic relatedness and classified into 264 families with unrelated parents and 247 families with third- and fourth-degree consanguineous parents. Representative consanguineous pedigrees of families in EGP were outlined. Cumulative ROHs were affected by the main ancestry component and significantly increased in offspring of consanguineous parents, with a pronounced difference between 3rd and 4th-degree relatedness. Investigation of cumulative AFs of variants causing Mendelian diseases highlighted genes related to alpha- and beta-thalassemia (HBB, HBA2). It showed a high burden of variants causing severe recessive diseases, metabolic and retinal disorders, and hearing loss. In summary, EGP represents a landmark effort in characterizing the genetic diversity of the Emirati population, leveraging the largest Middle Eastern cohort reported to date.

  Study EGAS50000001071

• Breast_Cancer_Matched_Pair_Cell_Line_Whole_Genomes

  We propose to definitively characterise the somatic genetics of matched pair breast cancer cell lines through generation of comprehensive catalogues of somatic mutations by high coverage genome sequencing coupled with integrated transcriptomic and methylation analyses.

  Study EGAS00001000166

• Adenoma to Carcinoma transition in Colorectal Cancer

  Although colorectal carcinoma development is well accepted as a step-wise and sequential process, it is commonly investigated using non-sequential adenoma and carcinoma samples. Here we compared molecular pathologies of the earliest carcinoma stages with those in their adenomatous precursors to unravel common and divergent genetic traits between matched neoplasms with a shared evolutionary history but different contemporary biology.

  Study EGAS00001003468

• BASIS_RNAseq

  We propose to definitively characterise the somatic genetics of ER+ve, HER2-ve breast cancer through generation of comprehensive catalogues of somatic mutations in 500 cases by high coverage genome sequencing coupled with integrated transcriptomic and methylation analyses.

  Study EGAS00001000707

• Illumina ExomeChip genotyping data from the Cretan Greek isolate collection HELIC MANOLIS

  Isolated populations can empower the identification of rare variation associated with complex traits through next generation association studies. Here we have genotyped individuals from a Greek population isolate on the Illumina HumanExome Beadchip. The HELIC (Hellenic Isolated Cohorts) MANOLIS (Minoan Isolates) collection focuses on Anogia and surrounding Mylopotamos villages. Recruitment of this population-based sample was primarily carried out at the village medical centres. All individuals were older than 17 years and had to have at least one parent from the Mylopotamos area. www.helic.org **The data may not be used for population genetics analyses.**

  Study EGAS00001000630

• Combination_therapies_for_personalized_cancer_medicine

  It is the ambition of the team formed by members of the Netherlands Cancer Institute (NKI) and the Cancer Genome Project at the Wellcome Trust Sanger Institute (WTSI) to unravel the genomic and phenotypic complexity of human cancers in order to identify optimal drug combinations for personalized cancer therapy. Our integrated approach will entail (i) deep sequencing of human tumours and cognate mouse tumours; (ii) drug screens in a 1000+ fully characterized tumour cell line panel; (iii) high-throughput in vitro and in vivo shRNA and cDNA drug resistance and enhancement screens; (iv) computational analysis of the acquired data, leading to significant response predictions; (v) rigorous validation of these predictions in genetically engineered mouse models and patient-derived xenografts. This integrated effort is expected to yield a number of combination therapies and companion-diagnostics biomarkers that will be further explored in our existing clinical trial networks.

  Study EGAS00001000655

• Fixation effects on variant-calling in a clinical resequencing panel

  Formalin fixation is the standard method for preservation of tissue for diagnostic purposes, including pathological review and molecular assays. However, this method is known to cause artifacts that can affect the accuracy of molecular genetic tests. We assessed the applicability of alternative fixatives to determine whether these perform significantly better on next-generation sequencing assays, and whether adequate morphology is retained for primary diagnosis, in a prospective study using a clinical-grade laboratory-developed targeted resequencing assay. We examined and quantified several parameters relating to sequencing quality and variant-calling from tumor and normal colon epithelial tissues. We identify one alterative fixative, Sakura Universal Molecular Fixative that suppresses many formalin-related artifacts while retaining adequate morphology for pathological review.

  Study EGAS00001003507

• PAGE: Prenatal Assessment of Genomes and Exomes

  The Prenatal Assessment of Genomes and Exomes (PAGE) study is a multicentre prospective trial, performing exome sequence analysis on samples from 1000 families with structural anomalies in prenatal ultrasound screening but normal aneuploidy results. The data will enable discovery of novel genetic disorders and increase the diagnostic yield. Where appropriate, results will be reported back to the families at the end of the pregnancy, after thorough clinical review. Ultimately, the translation of the acquired know-how into cost-effective prenatal diagnostic sequencing will improve genetics-derived prognoses and allow more informed parental counselling as well as management of pregnancy and childbirth.

  Study EGAS00001001713

• Exome sequencing of uterine leiomyosarcomas

  Uterine leiomyosarcomas (ULMSs) are aggressive smooth muscle tumors associated with poor clinical outcome. Despite previous cytogenetic and molecular studies, their molecular background has remained elusive. To examine somatic variation in ULMS, we performed exome sequencing on 19 tumors. Altogether 43 genes were mutated in at least two ULMSs. Most frequently mutated genes included tumor protein P53 (TP53; 6/19; 33%), alpha thalassemia/mental retardation syndrome X-linked (ATRX; 5/19; 26%), and mediator complex subunit 12 (MED12; 4/19; 21%). Unlike ATRX mutations, both TP53 and MED12 alterations have repeatedly been associated with ULMSs. All the observed ATRX alterations were either nonsense or frameshift mutations. ATRX protein levels were reliably analyzed by immunohistochemistry in altogether 44 ULMSs, and the majority of tumors (23/44; 52%) showed clearly reduced expression. Loss of ATRX expression has been associated with alternative lengthening of telomeres (ALT), and thus the telomere length was analyzed with telomere-specific fluorescence in situ hybridization. The ALT phenotype was confirmed in all ULMSs showing diminished ATRX expression. Exome data also revealed one nonsense mutation in death-domain associated protein (DAXX), another gene previously associated with ALT, and the tumor showed ALT positivity. Aberrant expression of both TP53 and ATRX were associated with poor overall survival. In conclusion, exome sequencing revealed that TP53, ATRX, and MED12 are frequently mutated in ULMSs. ALT phenotype was commonly seen in tumors, indicating that ATR inhibitors, which were recently suggested as possible new drugs for ATRX-deficient tumors, could provide a potential novel therapeutic option for ULMS.

  Study EGAS00001001612

• Biallelic DICER1 mutations in sporadic pleuropulmonary blastoma

  Pleuropulmonary blastoma (PPB) is an extremely rare pediatric malignancy in the lung, whose pathogenesis is poorly understood, except for recent reports of frequent germline heterozygous DICER1 mutations. To investigate the genetic basis of PPB, we performed whole-exome sequencing in 7 representative PPB cases, followed by targeted deep sequencing in 12 cases with PPB. DICER1 mutations were found in 11/12 cases. Biallelic DICER1 mutations were common in PPB, in which RNase IIIb domain mutations were found in all cases with or without nonsense/frameshift mutations and were somatic in all evaluable cases. A majority of cases had mutated DICER1 alleles in germline with or without an additional somatic mutation in the remaining allele, while other cases had exclusively somatic mutations involving the RNase IIIb domain. TP53 deletions/mutations were detected in 8/12 cases. Our results highlight a unique role of the RNase IIIb domain mutations and TP53 inactivation in PPB pathogenesis.

  Study EGAS00001000662

• ATAC-seq iPSC cells or smNPC cells for allelic imbalance

  In order to confirm the predicted impact of the PD-associated allele of rs144814361 on BAG3 promoter, we proceeded with genome editing of the TH-REP1 cell line by using prime editing to insert the “T” allele at the position chr10:119651405 in the BAG3 promoter. 3 replicates for each condition: 1) iPSC Wild Type 2) SNP-BAG3 variant in iPSC 3) SNP-BAG3 variant in smNPC. Allelic imbalance is further assessed using read counting at this specific position.

  Study EGAS50000001579

• Whole-Genome sequencing of hepatocellular carcinomas

  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 and whole exome sequencing together with CGH-SNP, methylome and transcriptomic profiling. For this purpose, a series of 500 liver tumors are collected through the French National Liver Collection and these samples will be analyzed using the different omics technologies. The data will be deposited in the ICGC and EGA database to be publically available for the scientific community. 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. The dataset will include 50 whole genome sequencing tumor/germline pairs, of which 6 are deposited in February 2014.

  Study EGAS00001000706

• Probabilistic modeling of personalized drug combinations from integrated chemical screen and molecular data in sarcoma

  Background: Cancer patients with advanced disease exhaust available clinical regimens and lack actionable genomic medicine results, leaving a large patient population without effective treatments options when their disease inevitably progresses. To address the unmet clinical need for evidence-based therapy assignment when standard clinical approaches have failed, we have developed a probabilistic computational modeling approach which integrates sequencing data with functional assay data to develop patient-specific combination cancer treatments. Methods: Tissue taken from a murine model of alveolar rhabdomyosarcoma was used to perform single agent drug screening and DNA/RNA sequencing experiments; results integrated via our computational modeling approach identified a synergistic personalized two-drug combination. Cells derived from the tumor were allografted into mouse models and used to validate the personalized two-drug combination. Computational modeling of single agent drug screening and RNA sequencing of multiple heterogenous sites from a single patient’s epithelioid sarcoma identified a personalized two-drug combination effective across all tumor regions. The heterogeneity-consensus combination was validated in a xenograft model derived from the patient’s primary tumor. Cell cultures derived from human and canine undifferentiated pleomorphic sarcoma were assayed by drug screen; computational modeling identified a resistance-abrogating two-drug combination common to both cell cultures. This combination was validated in vitro via a cell regrowth assay. Results Our computational modeling approach addresses three major challenges in personalized cancer therapy: synergistic drug combination predictions (validated in vitro and in vivo in a genetically engineered murine cancer model), identification of unifying therapeutic targets to overcome intra-tumor heterogeneity (validated in vivo in a human cancer xenograft), and mitigation of cancer cell resistance and rewiring mechanisms (validated in vitro in a human and canine cancer model). Conclusions These proof-of-concept studies support the use of an integrative functional approach to personalized combination therapy prediction for the population of high-risk cancer patients lacking viable clinical options and without actionable DNA sequencing-based therapy.

  Study EGAS00001003564

• Evolutionary origin and methylation status of human intronic CpG islands that are not present in mouse

  Imprinting of the human RB1 gene is due to the presence of a differentially methylated CpG island (CGI) in intron 2, which is part of a retrogene derived from the PPP1R26 gene on chromosome 9. The murine Rb1 gene does not have this retrogene and is not imprinted. We have investigated whether the RB1/Rb1 locus is unique with respect to these differences. For this we have compared the CGIs from human and mouse by in silico analyses and found out that there are at least 2033 human intronic CGIs that are not present in the mouse. Among these CGIs, 104 show sequences similarities elsewhere in the human genome, which suggests that they arose by retrotransposition. We could narrow down the time points when most of these CGIs appeared during evolution. Their methylation status was analysed in two monocyte methylome datasets from whole genome bisulfite sequencing and in 18 published methylomes. Five CGIs appear to be differentially methylated, which suggests that they are subject of genomic imprinting. They are located in introns of the following genes: RB1, ASRGL1, PARP11, PDXDC1 and MYO1D. Four of these CGIs are parts of retrogenes. Our study supports the notion that imprinting builds on host defence mechanisms by which the genome protects itself against retrotransposed and foreign DNA and that the epigenetic fate of the retrotransposed DNA depends on selective forces at the integration site.

  Study EGAS00001000719

• Assessment_of_epigenetic_variation_in_human_iPS_cells_Medip

  n order to progress human induced pluripotent stem cells (hiPSCs) towards the clinic, several outstanding questions must be addressed. It is possible to reprogram different somatic cell types into hiPSCs and from studies in the mouse, it appears that an epigenetic memory of the starting cell type is carried over to hiPSCs. However a comprehensive comparative study of the characteristics of these hiPSCs has been missing from the literature. Importantly studies which aimed to address these aspects of hiPSCs have used cells from different patients. In order to avoid this important confounding variable and to keep the genetic background constant, tissue samples were procured from the patients and reprogrammed to iPS cells. The methylation status of these iPS cells will be compared.Protocol:Primary cell cultures were generated and reprogrammed to iPS cells. DNA was extracted and immunoprecipitated using anti-methyl cytosine and anti-hydroxymethyl cytosine antibodies.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 EGAS00001000741

• Phylogenetic analysis of paired breast carcinomas identifies genetic events associated with clonal recurrence and invasive progression

  Development of ipsilateral breast carcinoma following diagnosis of breast ductal carcinoma in situ (DCIS) has been assumed to represent recurrence of the primary tumour. However, this may not be the case and it is important to know how often recurrences are new tumours. Ipsilateral primary-recurrence pairs (n=78) were sequenced to test their clonal relatedness. Shared genetic events were identified from whole exome sequencing (n=54 pairs) using haplotype-specific copy number and phylogenetic analysis. The remaining pairs were sequenced by a targeted panel or low-coverage whole genome sequencing. We included 32 non-recurrent DCIS to compare recurrent and non-recurrent disease. We found that 7% of DCIS recurrences were non-clonal by whole exome sequencing, indicative of a new breast carcinoma. Lower resolution methods detected a higher non-clonality rate (29%). Comparing primary DCIS with their recurrences found that evolution of DCIS to invasive disease was associated with increased ploidy and copy number events. TP53 mutations were enriched in DCIS with clonal recurrence compared with non-recurrent DCIS. Our results verify that de novo “recurrent tumours” of independent origin occur in patients who may be at high risk. (https://www.biorxiv.org/content/10.1101/2024.05.19.594731v2.full)

  Study EGAS50000001298

• Pangenomic classification of pituitary adenomas

  Pituitary neuroendocrine tumors (PitNETs) are common. They are classified in five main histological types: PitNETs of POU1F1 (Pit1) lineage -lactotroph, somatotroph and thyrotroph -, gonadotroph, and corticotroph PitNETs. Pituitary tumorigenesis is poorly understood. We report here a pangenomic characterization of 134 PitNETs from all types, based on exome, genome, transcriptome, miRnome and methylome. Pit1 lineage was associated with a specific epigenetic signature of diffuse DNA hypomethylation, and correlated with expression of Pit1 markers and chromosomal instability. 45% of somatotroph PitNETs showed GNAS mutations. GNAS-wild type somatotroph showed a distinct transcriptome profile, expressing gonadotroph transcription factor NR5A1 (SF1). Sparsely granulated somatotroph PitNETs was classified apart from somatotroph, owing to a thyrotroph transcriptome signature. 43% of corticotroph PitNETs showed USP8 mutations, sharing a low epithelial-mesenchimal transition (EMT) transcriptome signature. Silent corticotroph PitNETs showed a gonadotroph transcriptome signature evoking transdifferentiation, and lost somatostatin target SSTR5 expression.

  Study EGAS00001003642

• Ashkenazi Jewish Leukoencephalopathy

  Genetic leukoencephalopathies (gLEs) are a group of heterogeneous disorders with white matter abnormalities in the central nervous system (CNS). Patients affected with gLEs have brain white matter defects that can be seen in MRI and exhibit variable neurologic phenotypes including motor impairment, hypotonia, pyramidal dysfunction, dystonia and/or dyskinesias, ataxia, seizures, cortical blindness, optic atrophy, and impaired cognitive development. The exact causes in half of gLEs are unknown. We studied three unrelated families affected with an undiagnosed gLE and discovered a homozygous germline mutation c.2536T>G in VPS11 by whole exome sequencing, a gene involved in membrane trafficking and fusion of the lysosomes and endosomes, as a novel cause of a new gLE syndrome.

  Study EGAS00001001767

• Whole genome sequencing of six ethnic groups from Burkina Faso, Cameroon, and Tanzania

  We conducted low-coverage (~10x) sequencing of six ethnic groups from three malaria-endemic countries in sub-Saharan Africa, with the aim of characterising genetic diversity and improving imputation performance for genotyped samples in these populations. This data is part of a pre-publication release and is available under managed access. Please see https://www.malariagen.net/data/terms-use/human-gwas-data for more information on MalariaGEN data access policies. The purpose of the project was to support the discovery and understanding of genetic variants that influence human disease. Specifically defined goals were: a. the discovery of single nucleotide variants at frequencies of 1% or higher in diverse populations, b. even more comprehensive discovery (variants down to frequencies of 0.1 - 0.5%) in functional gene regions, and c. discovery of structural variants, such as copy number variants, other insertions and deletions, and inversions, including sequence-level understanding of breakpoints.

  Study EGAS00001003648

• Systems biology of Colorectal Cancer

  Colorectal cancer (CRC) is one of the most common cancers in both males and females, and it is perhaps the best understood of all epithelial tumors in terms of its molecular origin. Yet, despite large amount of work that has concentrated on understanding of colon tumorigenesis, we still do not know the full complement of molecular lesions that are individually necessary – and together sufficient – to cause colorectal cancer. Neither do we understand why some specific mutations that are relatively rare in other tumors (e.g. loss of the APC tumor suppressor) are extremely common in colorectal cancer. We propose here to use the tools of systems biology to develop a quantitative and comprehensive model of colorectal tumorigenesis. The model will include identification of cell-type specific and oncogenic pathways that contribute to colon tumorigenesis, and explain in molecular detail how a genotype of an individual CRC leads to activation of downstream genes that drive uncontrolled cell growth. This model will subsequently be used to find novel therapeutic targets, to guide genetic screening to identify individuals with elevated risk for developing CRC, and to classify patients into molecular subgroups to select the treatment combination that is optimal for each patient (personalized medicine). The specific objectives of the SYSCOL project are: 1. Identify genetic markers for individual risk using genotyping and sequencing of constitutional DNA from sporadic and familial CRC cases and controls 2. Identify genes and regulatory elements that contribute to colorectal cancer cell growth 3. Use data from Aims 1-2 to develop a quantitative model for colorectal tumorigenesis 4. Apply the model for identification of high-risk individuals, for molecular classification of the disease, and for identification of novel molecular treatment targets

  Study EGAS00001000854

• Succession Of Transiently Active Tumour-Initiating Cell Clones inHuman Pancreatic Cancer

  To elucidate whether newly acquired genetic alterations during serial transplantation of patient derived primary pancreatic cancer cultures contribute to the observed clonal dynamics in vivo, all coding genes of two patient derived primary cultures and derived genetically marked serial xenografts (1°/2°/3°) were sequenced.

  Study EGAS00001000882

• UAMS Smoldering Myeloma Timeline Cohort

  To better understand the pattern of genetic changes over time, we performed whole exome sequencing of sequential bone marrow samples from 9 patients taken overtime including some paired SMM/newly diagnosed MM/Relapse MM samples. Samples from 9 patients (9 controls and 53 tumors) underwent whole exome sequencing with an additional capture for the IGH, IHK, IGL, and MYC loci. DNA was obtained from either CD138+ cells from the bone marrow of smoldering myeloma patients through time (tumor) or from stem cell harvests or peripheral blood cells from the same patient (control). 100 ng of DNA was fragmented, end-repaired, and adapters ligated using NimbleGen's MedExome. After PCR amplification hybridized libraries underwent further amplification before being sequenced on a NextSeq500 (Illumina) using 75 bp paired end reads.

  Study EGAS00001003687