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• Immune variation leads to diverse outcomes in human malaria (2020-01-15)

  Falciparum malaria is clinically heterogeneous and yet in most cases the risk of life-threatening disease dramatically declines after the first few infections of life because children rapidly acquire disease tolerance (resistance to severe malaria without improved control of parasite burden). Identifying the factors that determine clinical outcome in a malaria-naive host is therefore paramount to reduce malaria mortality. However, the relative contribution of disease-causing variants of the Plasmodium var gene family versus pathogenic inflammatory cytokine cascades remains fiercely debated - we sought to reconcile these conflicting arguments by studying their interaction in vivo. To this end, two human challenge models were used to reveal the parasite-host interactions that underpin variation in falciparum malaria. To capture the diversity of human immune responses, each individual was analysed independently by tracking dynamic changes in their whole blood transcriptome through time. And to uncover evidence of preferential expansion of disease-causing variants, var gene expression was tracked in vivo from the start to end of infection. In this way, we could show that group A var genes are always expressed upon liver egress but in a minority population that does not increase over 10-days of blood cycling; there is no selection of disease-causing variants in the naive host. In fact, parasites do not respond in any way to differences or changes in host environment. On the other hand, host-intrinsic variation determines the intensity of inflammation and progression to clinical malaria. And furthermore, regulation of the interferon signaling network controls host fate. These data emphasise the role of human immune decision-making in shaping course & outcome of infection. 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/ . This dataset contains all the data available for this study on 2020-01-15.

  Dataset EGAD00001005790

• The clinicopathologic spectrum and genomic landscape of de-/trans-differentiated melanoma

  De- and trans-differentiation is a rare and only poorly understood phenomenon in cutaneous melanoma. To study this disease more comprehensively we have retrieved 11 primary cutaneous melanomas from our pathology archives showing biphasic features characterized by a conventional melanoma and additional areas of de-/trans-differentiation as defined by a lack of immunohistochemical expression of all conventional melanocytic markers (S-100 protein, SOX10, Melan-A and HMB-45). The clinical, histologic and immunohistochemical findings were recorded and follow-up was obtained. The patients were mostly elderly (median: 81 years; range: 42-86 years) without significant gender predilection, and the sun-exposed skin of the head and neck area was most commonly affected. The tumors were deeply invasive with a mean tumor thickness of 7 mm (range: 4-80 mm). The dedifferentiated component showed atypical fibroxanthoma-like features in the majority (7), while additional rhabdomyosarcomatous and epithelial transdifferentiation was noted histologically and/or immunohistochemically in two tumors each. The background conventional melanoma component was of desmoplastic (4), superficial spreading (3), nodular (2), lentigo maligna (1) or spindle cell (1) types. For the 7 patients with available follow-up data (median follow-up period of 25 months; range: 8-36 months), 2 died from their disease and 3 developed metastases. Next-generation sequencing of the cohort revealed somatic mutation of established melanoma drivers including mainly NF1 mutations in the conventional component (5 cases), which were also detected in the corresponding de-/trans-differentiated components. In summary, the diagnosis of de-/trans-differentiated melanoma is challenging and depends on the morphologic identification of the conventional melanoma component. Molecular analysis is diagnostically helpful as the mutated gene profile is shared between the conventional and de-/trans-differentiated components. Importantly, de-/trans-differentiation does not appear to confer a more aggressive behavior.

  Dataset EGAD00001007033

• The clinicopathologic spectrum and genomic landscape of de-/trans-differentiated melanoma

  De- and trans-differentiation is a rare and only poorly understood phenomenon in cutaneous melanoma. To study this disease more comprehensively we have retrieved 11 primary cutaneous melanomas from our pathology archives showing biphasic features characterized by a conventional melanoma and additional areas of de-/trans-differentiation as defined by a lack of immunohistochemical expression of all conventional melanocytic markers (S-100 protein, SOX10, Melan-A and HMB-45). The clinical, histologic and immunohistochemical findings were recorded and follow-up was obtained. The patients were mostly elderly (median: 81 years; range: 42-86 years) without significant gender predilection, and the sun-exposed skin of the head and neck area was most commonly affected. The tumors were deeply invasive with a mean tumor thickness of 7 mm (range: 4-80 mm). The dedifferentiated component showed atypical fibroxanthoma-like features in the majority (7), while additional rhabdomyosarcomatous and epithelial transdifferentiation was noted histologically and/or immunohistochemically in two tumors each. The background conventional melanoma component was of desmoplastic (4), superficial spreading (3), nodular (2), lentigo maligna (1) or spindle cell (1) types. For the 7 patients with available follow-up data (median follow-up period of 25 months; range: 8-36 months), 2 died from their disease and 3 developed metastases. Next-generation sequencing of the cohort revealed somatic mutation of established melanoma drivers including mainly NF1 mutations in the conventional component (5 cases), which were also detected in the corresponding de-/trans-differentiated components. In summary, the diagnosis of de-/trans-differentiated melanoma is challenging and depends on the morphologic identification of the conventional melanoma component. Molecular analysis is diagnostically helpful as the mutated gene profile is shared between the conventional and de-/trans-differentiated components. Importantly, de-/trans-differentiation does not appear to confer a more aggressive behavior.

  Dataset EGAD00001007034

• Multi-Ethnic Study of Atherosclerosis (MESA) Cohort

  MESA The Multi-Ethnic Study of Atherosclerosis (MESA) is a study of the characteristics of subclinical cardiovascular disease (disease detected non-invasively before it has produced clinical signs and symptoms) and the risk factors that predict progression to clinically overt cardiovascular disease or progression of the subclinical disease. MESA researchers study a diverse, population-based sample of 6,814 asymptomatic men and women aged 45-84. Thirty-eight percent of the recruited participants are white, 28 percent African-American, 22 percent Hispanic, and 12 percent Asian, predominantly of Chinese descent. Participants were recruited from six field centers across the United States: Wake Forest University, Columbia University, Johns Hopkins University, University of Minnesota, Northwestern University and University of California - Los Angeles. Each participant received an extensive physical exam to determine coronary calcification, ventricular mass and function, flow-mediated endothelial vasodilation, carotid intimal-medial wall thickness and presence of echogenic lucencies in the carotid artery, lower extremity vascular insufficiency, arterial wave forms, electrocardiographic (ECG) measures, standard coronary risk factors, sociodemographic factors, lifestyle factors, and psychosocial factors. Selected repetition of subclinical disease measures and risk factors at follow-up visits allows study of the progression of disease. Blood samples have been assayed for putative biochemical risk factors and stored for case-control studies. DNA has been extracted and lymphocytes cryopreserved (for possible immortalization) for study of candidate genes and possibly, genome-wide scanning, expression, and other genetic techniques. Participants are being followed for identification and characterization of cardiovascular disease events, including acute myocardial infarction and other forms of coronary heart disease (CHD), stroke, and congestive heart failure; for cardiovascular disease interventions; and for mortality. In addition to the six Field Centers, MESA involves a Coordinating Center, a Central Laboratory, and Central Reading Centers for Computed Tomography (CT), Magnetic Resonance Imaging (MRI), Ultrasound, and Electrocardiography (ECG). Protocol development, staff training, and pilot testing were performed in the first 18 months of the study. The first examination took place over two years, from July 2000 - July 2002. It was followed by four examination periods that were 17-20 months in length. Participants have been contacted every 9 to 12 months throughout the study to assess clinical morbidity and mortality. MESA Family The general goal of the MESA Family Study, an ancillary study to MESA funded by a grant from NHLBI, is to apply modern genetic analysis and genotyping methodologies to delineate the genetic determinants of early atherosclerosis. This is being accomplished by utilizing all the current organizational structures of the Multi-Ethnic Study of Atherosclerosis (MESA) and Genetic Centers at Cedars-Sinai Medical Center and University of Virginia. In the MESA Family Study, the goal is to locate and identify genes contributing to the genetic risk for cardiovascular disease (CVD), by looking at the early changes of atherosclerosis within families (mainly siblings). 2128 individuals from 594 families, yielding 3,026 sibpairs divided between African Americans and Hispanic-Americans, were recruited by utilizing the existing framework of MESA. MESA Family studied siblings of index subjects from the MESA study and from new sibpair families (with the same demographic characteristics) and is determining the extent of genetic contribution to the variation in coronary calcium (obtained via CT Scan) and carotid artery wall thickness (B-mode ultrasound) in the two largest non-majority U.S. populations. In a small proportion of subjects, parents of MESA index subjects participating in MESA Family were studied but only to have blood drawn for genotyping. The MESA Family cohort was recruited from the six MESA Field Centers. MESA Family participants underwent the same examination as MESA participants during May 2004 - May 2007. DNA was extracted and lymphocytes immortalized for study of candidate genes, genome-wide linkage scanning, and analyzed for linkage with these subclinical cardiovascular traits. While linkage analysis is the primary approach being used, an additional aspect of the MESA Family Study takes advantage of the existing MESA study population for testing a variety of candidate genes for association with the same subclinical traits. Genotyping and data analysis will occur throughout the study. MESA Air The general goal of the Multi-Ethnic Study of Atherosclerosis and Air Pollution ('MESA Air') is to prospectively examine the relation between an individual level assessment of long-term ambient air pollution exposures (including PM2.5 and the progression of subclinical cardiovascular disease in a multi-city, multi-ethnic cohort. MESA Air will also prospectively examine the relationship between an individual level assessment of long-term ambient air pollution exposures and the incidence of cardiovascular disease, including myocardial infarction and cardiovascular death. MESA AIR is funded by a grant from the United States Environmental Protection Agency to the University of Washington and subcontracts from the UW to other participating institutions. MESA Air will assess if ambient air pollution is associated with changes over time in subclinical measures of atherosclerosis and plasma markers of inflammation, oxidative damage, and endothelial activation in a longitudinal data model, adjusting for age, race/ethnicity, socioeconomic status, and specific cardiovascular risk factors (such as diabetes, hypertension, smoking, and diet). The study will similarly assess if the incidence of cardiovascular events is associated with long-term exposure to ambient air pollution, using a proportional hazards model. The study includes refinement of statistical tools, and explores joint/independent effects of acute and long-term pollutant exposure in the occurrence of cardiovascular disease. The MESA Air study is built on the foundation of the ongoing MESA study. The parent MESA Study cohort is located in six geographic areas ('Field Centers') that capture tremendous exposure heterogeneity, comparable to or greater than the variability in locations of prior U.S. cohort studies. In addition to the six Field Centers, the study involves a Coordinating Center, a Central Laboratory, and Reading Centers for Computed Tomography (CT), ultrasound and air pollution data. The cohort for the MESA Air study currently includes 6226 subjects: 5479 enrolled in the parent MESA study; 257 recruited specifically for this study, and 490 recruited from the MESA Family study. The entire MESA Air cohort will be followed over a 10-year project period for the occurrence of cardiovascular disease events. On two occasions over the ten-year study period, 3600 subjects from the MESA Air cohort, residing in nine locales, will undergo computed tomography scanning to assess presence and extent of coronary artery calcification (CAC), and ultrasound of the carotid artery to determine intima-media thickness (IMT). We will also repeatedly assess plasma markers of inflammation, oxidative damage, and endothelial function in 720 subjects. MESA Air adds state-of-the-art air pollution exposure assessment information to the MESA cohort study, and introduces new subjects and outcome measures to achieve our aims. The study will assess long-term individual-level exposure to ambient air pollutants for each subject using community-scale monitoring, outdoor spatial variation, subject proximity to pollution sources, pollutants' infiltration efficiency, and personal time-activity information. The exposure models will be validated using detailed monitoring in a subset of subjects. The MESA Cohort is utilized in the following dbGaP substudies. To view genotypes, analysis, expression data, other molecular data, and derived variables collected in these substudies, please click on the following substudies below or in the "Substudies" box located on the right hand side of this top-level study page phs000209 MESA Cohort. phs000420 MESA SHARe phs000283 MESA CARe phs000403 MESA ESP Heart-GO

  Study phs000209

• Privacy Notice for the Account User

  Privacy Notice for EGA User Account This Privacy Notice explains what personal data is collected by the specific service you are requesting, for what purposes, how it is processed, and how we keep it secure. Note that this service collects personal data directly provided by the user, and also collects personal data from users that is provided by other organisations. 1. Who controls your personal data and how to contact us? European Genome- Phenome Archive - EGA offers a service for permanent archiving and sharing of all types of personally identifiable genetic and phenotypic data resulting from biomedical research projects, jointly managed by European Molecular Biology Laboratory – European Bioinformatics Institute (EMBL-EBI) and Fundació Centre de Regulació Genòmica - Centre for Genomic Regulation (CRG). EMBL-EBI and CRG represent joint Data Controllers’ of processing of your personal data. They and their Data protection officers may be contacted for data protection queries and for exercising your rights under Section 8. You may contact EMBL-EBI, represented by dr. Thomas Keane, by: email at: tk2@ebi.ac.uk or post at EMBL-EBI, Wellcome Genome Campus, CB10 1SD Hinxton, Cambridgeshire, UK. EMBL’s Data Protection Officer may be contacted by: telephone at +49 6221 387-8590, email at dpo@embl.org, or post at EMBL Heidelberg, Data protection officer, Meyerhofstraße 1, 69117 Heidelberg, Germany. You may contact CRG, whose EGA team is represented by dr. Jordi Rambla de Argila, by: email at jordi.rambla@crg.eu, or post at Fundació Centre de Regulació Genòmica - Centre for Genomic Regulation (CRG), Dr.Aiguader 88, PRBB Building, 08003 Barcelona, Spain. CRG Data protection officer may be contacted by: email at dpo@crg.eu post at Fundació Centre de Regulació Genòmica - Centre for Genomic Regulation (CRG), C/ Dr. Aiguader, 88, PRBB Building, 08003 Barcelona, Spain. 2. Which is the lawful basis for processing personal data? We process your personal data on the grounds of important public interest. For monitoring your activities on the website, we process your personal data on the grounds of important public interest. Such legal basis is found in Article 5(1)(a) of EMBL Internal Policy No 68 on General Data Protection (hereinafter IP 68), which is equivalent to Article 6 (1)(e) of the EU General Data Protection Regulation (hereinafter GDPR) and upon which personal data are processed for the achievement of the aims laid down in 1973 agreement establishing EMBL, such as the promotion of the cooperation in the fundamental research, in the development of advanced instrumentation and in advanced teaching in molecular biology and dissemination of information. 3. What personal data is collected from users of the service? How do we use this personal data? We collect the following personal data from you: Name Email address Title/Position Organisation Organisational affiliation Username and password (to authenticate access to the system) IP Address (for anonymous usage statistics) We process your personal data: to provide you with the authenticated access to the EGA service (opening and managing submission and distribution account), to publicly publish some aggregate data to facilitate scientific research (e.g. number of accounts, geographic distribution), to better understand the needs of the users and to guide future improvements of the service, to create anonymous usage statistics. If you do not provide us with your personal data we will not be able to open the user account and offer you our services or we will only provide you a subset of functionalities available within the service. 4. Who will have access to your personal data? The personal data will be disclosed to: Authorised staff in the data controller’s institutions acting on data controller`s behalf and instructions (for all user account data), Requested dataset Data access committee – DAC will have access to the name, email, organization, affiliation, title/position of the distribution user account, using it for their own purpose of granting access to their datasets. 5. Will your personal data be transferred to third countries (i.e. countries not part of EU/EEA) and/or international organisations? Distribution user account data are in the process of granting access disclosed to dataset(s) DAC, which might be a recipient in countries outside of the European Economic Area. Insofar as the second joint controller may be subject to GDPR, data transfer to and from the first joint controller (EMBL-EBI) is necessary for important reasons of public interest embedded in the aims of the EMBL and justified in the Article 9(4) of IP 68 (equivalent to Article 49(1)(d) of GDPR) read in conjunction with EMBL`s 1973 establishing agreement and Article 179(2) of the Treaty on the Functioning of the European Union. 6. How long do we keep your personal data? All data are stored for as long as you have the account open. Thereafter the storage is prolonged for as long as our service is live, even if you stop using our services. This prolongation is necessary for further scientific research, to ensure legal compliance and security and to facilitate internal and external audits it they arise. By contrast, the log files for the data categories related to anonymous usage statistics (raw web service logs) are processed only for 30 days and thereafter erased. 7. The joint Data Controllers provide these rights regarding your personal data You have the right to: Not be subject to decisions based solely on an automated processing of data (i.e. without human intervention) without you having your views taken into consideration. Request at reasonable intervals and without excessive delay or expense, information about the personal data processed about you. Under your request we will inform you in writing about, for example, the origin of the personal data or the preservation period. Request information to understand data processing activities when the results of these activities are applied to you. It must be clarified that rights under points 4 and 5 are only available whenever you need support whilst using our website. For other processing based on the grounds of important public interest you cannot exercise your rights to object, rectify or erase your personal data according to the Article 13(2)(a)(b) of IP 68 (equivalent to Article 17(3)(b)(d) and Article 21(6) of the GDPR). 8. Supervisory authority If you wish to complain against the processing of your personal data, you may do so by post at: EMBL Heidelberg, Data Protection Committee, Meyerhofstraße 1, 69117 Heidelberg, Germany, or Autoritat Catalana de Protecció de Dades (Catalan Data Protection Authority), C/Rosselló 214, Esc A, 1r 1a, Barcelona 08008, Spain. Published at: February 6, 2019

  Documentation data-protection/privacy-notice/ega-user-account

• Finding the way towards the eradication of therapy-related myeloid neoplasms

  Therapy-related neoplasms are directly caused by the drugs used to eradicate a previous cancer. It is well known that a subset of drugs designed to kill cancer cells through DNA-damage-induced apoptosis can intrinsically, as secondary effect, cause DNA-damage in other cells, thus inducing a neoplasm. Those neoplasms have especially bad prognosis. Why are these drugs still in use? Because for many diseases we do not have anything better, at the moment. Approximately 0.5-1% of the kids treated for various types of cancers develop a therapy-related myeloid neoplasm (tMN) as a result of the treatment. Despite having the same origin, their prognostic and molecular features are different from the adult ones, and a complete understanding of the pathogenesis of tMN in children is still missing. A total of 84 paediatrics neoplasms have been profiled by either Whole Genome or Whole Exome sequencing by Jason R. Schwartz and his colleagues, in a collaborative effort guided at the St. Jude Children's hospital, in Memphis. They identified a mean of 28 somatic mutations per patient, a number which is significantly bigger than the number of mutations found in paediatrics primary neoplasms, as depicted in the original paper's figure 1b, shown here. Their sequencing data identified that Ras/MAPK pathway mutations, alterations in RUNX1 or TP53, and KMT2A rearrangements as the most frequent drivers of the disease. Clonal evolution analysis (the comparative study of the behaviour of cells harbouring different mutations) highlighted that, unlike in adults’ tMN, there were not pre-existing leukemic clones, and virtually all mutated cells were found arising as a direct consequence of cytotoxic therapy. This represents yet another important difference between adult and paediatric tMN. This important study have been published in Nature communications in February 2021. The sequencing data have been deposited at EGA under the study number EGAS00001004850. Thanks to this, other researchers around the world could re-use it to uncover more information, integrate and validate their studies. Revealing the molecular features underlying the development of cancers is the only way towards the development of new generation targeted therapies, which will allow us to finally drop the cytotoxic drugs eliciting such unwanted and catastrophic secondary effects as tMN. It is not an overstatement to say that, while improving the treatment of primary tumours, we could entirely eradicate therapy-related neoplasms right from their origin. Looking forward.

  Blog eradication-of-therapy-related-myeloid-neoplasms

• The evolutionary steps from primary to metastatic prostate cancer are largely uncharted, and the ability to use DNA present in body fluids as correlates of aggregate metastatic status is under-examined. We reconstructed phylogenies in ten prostate cancer patients with fatal disease using deep targeted sequencing of the prostate, adjacent and distant organs, as well as plasma, serum, and cerebrospinal fluid at various time points. A total of 163 samples are studied.

  The evolutionary steps from primary tumor to metastasis in prostate cancer are largely uncharted, and the ability to use serum, plasma, and cerebrospinal fluid as a correlate of aggregate metastatic tumor genomic status has not been tested. We used deep targeted sequencing to reconstruct tumor evolution in ten prostate cancer patients with fatal disease encompassing examination of the prostate and adjacent and distant organs, as well as plasma, serum, and cerebrospinal fluid at various time points. We show that there is substantial evolution from a common ancestor within the prostate that results in branching to multiple lineages which form an intermixed multi-clonal primary tumor mass. After the occurrence of key driver aberrations, one of these lineages will metastasize to multiple sites in a sequential fashion. These metastatic sites are then susceptible to being populated by cells from other intra-prostatic lineages or from other metastases. Genomic representation of metastases in body fluids is not uniform. Cerebrospinal fluid analysis can detect lineages not detected in circulating DNA, suggesting possible clinical utility.

  Study EGAS00001003848

• Emergence of oncofetal plasticity is ubiquitous in early colorectal cancers

  Metastasis formation is classically considered a late-stage event in colorectal cancer (CRC) evolution. Yet, the time and patterning by which metastatic competence is acquired remain poorly understood. Here, we show that metastasis-associated oncofetal cell states already emerge at the earliest stages of CRC, concurrent with invasive front formation. However, while necessary for metastasis, we detect them ubiquitously among early non-metastatic cancers, highlighting additional bottlenecks like immune evasion. To understand how oncofetal cells first emerge, we generated multiregional organoid models that reflect successive tumor progression stages within individual early-stage CRCs. Whole-genome sequencing and growth factor-dependency assays exclude tumor cell-intrinsic acquired traits. In contrast, single-cell spatial atlases of the tumor-microenvironment before and after malignant transformation revealed stereotypic patterning of fibroblast subtypes resembling normal tissue architecture, resulting in distinct regional microenvironments. At the onset of malignant growth into the submucosa, the first cancer-associated fibroblasts (CAFs) to appear strongly resemble submucosal trophocytes and colocalize with oncofetal cell states at invasive fronts. Functionally, fibroblast-organoid co-cultures confirm that these trophocyte-like CAFs induce plastic transitioning to oncofetal states. Thus, interactions between tumor and submucosal fibroblasts directly following malignant transformation dictate the timing and location at which oncofetal plasticity first occurs during CRC progression.

  Study EGAS50000001532

• Recurrent intra-tumour heterogeneity is a hallmark of metastatic prostate cancer

  The evolution of cancers from low grade to metastatic disease is a major determinant of cancer mortality. Cancer evolution involves a complex interplay between cell intrinsic genetics and transcriptional alterations and the extrinsic microenvironment. To define the key mechanisms underpinning metastatic development, we focused on the most lethal form of prostate cancer, metastatic castration-resistant prostate cancer, and employed single-cell multi-omics and whole-genome sequencing to deeply profile 34 metastatic lesions from 9 patients obtained from rapid autopsy. We found that intra-tumour heterogeneity is an indicator of key evolutionary processes, characterised by recurrent tumour populations acting as critical functional components of the tumour ecosystem, irrespective of clonal and microenvironmental backgrounds. Unexpectedly, microenvironments across metastatic sites played a limited role while clonal evolution primarily promoted transcriptional noise. Intra-patient functional convergence of tumour ecosystems was observed across metastatic sites, pointing towards system-level selection pressures that drive the heterogeneity landscape of mCRPC. Our findings reveal functional evolutionary convergence of metastatic disease into units of intra-tumour heterogeneity identifying critical determinants of metastatic progression for therapeutic targeting. Note: matched WGS for some tumour single-cell experiments, as well as germline WGS for patients CA0027, CA0034, CA0035, CA0043, and CA0076, can be found in EGAS00001006598.

  Study EGAS50000001312

• ChIP-seq for G3-MB

  ChIP-seq for H3K27ac and NeuroD1 in Group 3 Medulloblastoma cell models. Input DNA for each sample and target is also included.

  Dataset EGAD50000002303