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

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

  Study EGAS00001000884

• Whole-genome plasma sequencing reveals focal amplifications as a driving force in metastatic prostate cancer

  Genomic alterations in metastatic prostate cancer remain incompletely characterized. Here we analyze 493 prostate cancer cases from the TCGA database and perform whole-genome plasma sequencing on 95 plasma samples derived from 43 patients with metastatic prostate cancer. From these samples, we identify established driver aberrations in a cancer-related gene in nearly all cases (97.7%), including driver gene fusions (TMPRSS2:ERG), driver focal deletions (PTEN, RYBP, SHQ1), and driver amplifications (AR, MYC). In serial plasma analyses, we observe changes in focal amplifications in 40% of cases. The mean time interval between new amplifications was 26.4 weeks (range: 5-52 weeks), suggesting that they represent rapid adaptations to selection pressure. An increase in neuron-specific enolase is accompanied by clonal pattern changes in the tumor genome, most consistent with subclonal diversification of the tumor. Our findings suggest a high plasticity of prostate cancer genomes with newly occurring focal amplifications as a driving force in progression

  Study EGAS00001001018

• Neuroblastoma relapse trio series from the AMC

  The majority of neuroblastoma patients have tumors that initially respond to chemotherapy, but a large proportion of patients will experience therapy-resistant relapses. The molecular basis of this aggressive phenotype is unknown. Whole genome sequencing of 23 paired diagnostic and relapsed neuroblastomas showed clonal evolution from the diagnostic tumor with a median of 29 somatic mutations unique to the relapse sample. Eighteen of the 23 relapse tumors (78%) showed RAS-MAPK pathway mutations. Seven events were detected only in the relapse tumor while the others showed clonal enrichment. In neuroblastoma cell lines we also detected a high frequency of activating mutations in the RAS-MAPK pathway (11/18, 61%) and these lesions predicted for sensitivity to MEK inhibition in vitro and in vivo. Our findings provide a rationale for genetic characterization of relapse neuroblastoma and show that RAS-MAPK pathway mutations may function as a biomarker for new therapeutic approaches to refractory disease.

  Study EGAS00001001183

• Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma

  Follicular lymphoma (FL) is an incurable B-cell malignancy characterized by the t(14;18) and mutations in one or more components of the epigenome. Whilst frequent gene mutations in signaling pathways, including JAK-STAT, NOTCH and NF-κB, have also been defined, the spectrum of these mutations typically overlap with the closely-related diffuse large B cell lymphoma (DLBCL). A combination of discovery exome and extended targeted sequencing revealed recurrent somatic mutations in RRAGC uniquely enriched in FL patients (17%). More than half of the mutations preferentially co-occurred with ATP6V1B2 and ATP6AP1 mutations, components of the vacuolar H+-adenosine triphosphate ATPase (v-ATPase) known to be necessary for amino acid-dependent mTORC1 activation. RagC mutants increased raptor binding whilst rendering mTORC1 signaling resistant to amino acid deprivation through nucleotide-independent mechanisms. Collectively, the activating nature of the RRAGC mutations, their existence within the dominant clone and stability during disease progression supports their potential as an excellent candidate to be therapeutically exploited.

  Study EGAS00001001190

• MutWP5__CRUK_Mutographs_of_Cancer__Breast__Reduction_Mammoplasty___Exome__Novaseq_

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

  Study EGAS00001003527

• Super enhancers define regulatory subtypes and cell identity in neuroblastoma - RNA-seq

  Half of the children diagnosed with neuroblastoma have high-risk disease, disproportionately contributing to overall childhood cancer-related deaths. In addition to recurrent gene mutations, there is increasing evidence supporting the role of epigenetic deregulation in disease pathogenesis. Yet, comprehensive cis-regulatory network descriptions from neuroblastoma tissues are lacking. Here, using genome-wide H3K27ac profiles across 60 neuroblastomas, covering the different clinical and molecular subtypes, we identified four major super enhancer-driven epigenetic subtypes and their underlying master regulatory networks. Three of these subtypes recapitulated known clinical groups, namely MYCN amplified, MYCN non-amplified high-risk and MYCN non-amplified low-risk neuroblastomas. The fourth subtype, exhibiting mesenchymal characteristics, shared features with multipotent Schwann cell precursors, was induced by RAS activation and enriched in relapsed disease. Notably, CCND1, a disease essential gene, was regulated by both mesenchymal and adrenergic regulatory networks converging on distinct super-enhancer modules. Together, this reveals subtype-specific super-enhancer regulation in neuroblastoma.

  Study EGAS00001004552

• Chromosomal copy number heterogeneity predicts survival rates across cancers

  Survival rates of cancer patients vary widely within and between malignancies. While genetic aberrations are at the root of all cancers, individual genomic features cannot explain these distinct disease outcomes. In contrast, intra-tumour heterogeneity (ITH) has the potential to elucidate pan-cancer survival rates and the biology that drives cancer prognosis1,2. Unfortunately, a comprehensive and effective framework to measure ITH across cancers is missing3. Here, we introduce a scalable measure of chromosomal copy number heterogeneity that predicts patient survival across cancers. We show that the level of ITH can be derived from a single-sample copy number profile. Using gene-expression data we demonstrate that ongoing chromosomal instability underlies the observed heterogeneity. Analysing 11,534 primary cancer samples from 35 different malignancies, we find that copy number heterogeneity can be accurately deduced and predicts cancer survival across tissues of origin and stages of disease. Our results provide a unifying molecular explanation for the different survival rates observed between cancer types.

  Study EGAS00001004702

• A comprehensive assessment of somatic mutation detection in cancer using whole genome sequencing

  As whole genome sequencing for cancer genome analysis becomes a clinical tool, a full understanding of the variables affecting sequencing analysis output is required. Using tumor-normal sample pairs from two different types of cancer, chronic lymphocytic leukemia and medulloblastoma, we conducted a benchmarking exercise within the context of the International Cancer Genome Consortium. We compare sequencing methods, analysis pipelines, and even validation methods. Here we show that using PCR-free methods and increasing sequencing depth to ~100x showed benefits, as long as the tumor:control coverage ratio remains balanced. We observe widely varying mutation call rates and low concordance among analysis pipelines, reflecting the artifact-prone nature of the raw data and lack of standards for dealing with the artifacts. However, armed with the benchmark mutation set we have created, we show that many issues are in fact easy to remedy and have an immediate positive impact on mutation detection accuracy.

  Study EGAS00001001539

• Super enhancers define regulatory subtypes and cell identity in neuroblastoma

  Half of the children diagnosed with neuroblastoma have high-risk disease, disproportionately contributing to overall childhood cancer-related deaths. In addition to recurrent gene mutations, there is increasing evidence supporting the role of epigenetic deregulation in disease pathogenesis. Yet, comprehensive cis-regulatory network descriptions from neuroblastoma tissues are lacking. Here, using genome-wide H3K27ac profiles across 60 neuroblastomas, covering the different clinical and molecular subtypes, we identified four major super enhancer-driven epigenetic subtypes and their underlying master regulatory networks. Three of these subtypes recapitulated known clinical groups, namely MYCN amplified, MYCN non-amplified high-risk and MYCN non-amplified low-risk neuroblastomas. The fourth subtype, exhibiting mesenchymal characteristics, shared features with multipotent Schwann cell precursors, was induced by RAS activation and enriched in relapsed disease. Notably, CCND1, a disease essential gene, was regulated by both mesenchymal and adrenergic regulatory networks converging on distinct super-enhancer modules. Together, this reveals subtype-specific super-enhancer regulation in neuroblastoma.

  Study EGAS00001004551

• RNA-seq from human embryonic tissues (additional samples 2018)

  How the genome activates or silences transcriptional programmes governs organ formation. Little is known about this in human post-implantation embryos undermining our ability to benchmark the fidelity of in vitro stem cell differentiation or cell programming, or interpret noncoding variation as potential causes of disease. Here, by studying histone modification we identified genome-wide open chromatin states and active repression across thirteen tissues during human organogenesis. We integrated the data with transcription to build the first view of how promoter states from nearly 20,000 genes differentially regulate alternative organ fates, arguing against bivalency during human organogenesis. The data illustrate tissue-specific as well as complex patterns of enhancer activity functional in zebrafish and impute master transcription factors. Overlaying 739 noncoding de novo mutations in patients allowed phenotypic correlation of developmental disorders to unanticipated target genes. Taken together, the data provide a comprehensive genomic framework for understanding normal and abnormal human development.

  Study EGAS00001003738

• whole-genome sequencing in 17 ESCC cases and whole-exome sequencing in 71 cases

  Esophageal cancer is one of the most aggressive cancers and the sixth leading cause of cancer death worldwide1. Approximately 70% of the global esophageal cancers occur in China and over 90% histopathological forms of this disease are esophageal squamous cell carcinoma (ESCC)2-3. Currently, there are limited clinical approaches for early diagnosis and treatment for ESCC, resulting in a 10% 5-year survival rate for the patients. Meanwhile, the full repertoire of genomic events leading to the pathogenesis of ESCC remains unclear. Here we show a comprehensive genomic analysis in 158 ESCC cases, as part of the International Cancer Genome Consortium (ICGC) Research Projects (http://icgc.org/icgc/cgp/72/371/1001734). We conducted whole-genome sequencing in 17 ESCC cases and whole-exome sequencing in 71 cases, of which 53 cases and additional 70 ESCC cases were subjected to array comparative genomic hybridization (a-CGH) analysis.

  Study EGAS00001000709

• Subtype specific progression from DCIS to invasive breast cancer

  Breast cancer consists of at least five main molecular “intrinsic” subtypes, which are reflected in both pre-invasive and invasive disease. Although previous studies have suggested that many of the molecular features of invasive breast cancer are established early, it is unclear what mechanisms drive progression, and whether the mechanisms of progression are dependent or independent of subtype. We have generated mRNA, miRNA and DNA copy number profiles from a total of 59 in situ lesions and 85 invasive tumors, in order to comprehensively identify those genes, signaling pathways, processes, and cell types that are involved in breast cancer progression. Our work provides evidence that there are molecular features associated with disease progression that are unique to the intrinsic subtypes. We additionally establish subtype-specific signatures that are able to identify a small proportion of pre-invasive tumors with expression profiles that resemble invasive carcinoma, indicating a higher likelihood of future disease progression.

  Study EGAS00001001866

• Longitudinal Single-Cell Profiling Reveals Molecular Heterogeneity and Tumor-Immune Evolution in Refractory Mantle Cell Lymphoma

  The mechanisms driving therapeutic resistance and poor outcomes of mantle cell lymphoma (MCL) are incompletely understood. We characterize the cellular and molecular heterogeneity within and across patients and delineate the dynamic evolution of tumor and immune cell compartments at single cell resolution in longitudinal specimens from ibrutinib-sensitive patients and non-responders. Temporal activation of multiple cancer hallmark pathways and acquisition of 17q are observed in a refractory MCL. Multi-platform validation is performed at genomic and cellular levels in PDX models and larger patient cohorts. We demonstrate that the molecular targeting of BIRC5/survivin, locates at 17q and upregulates in resistant MCL tumor cells, results in marked tumor inhibition in preclinical models. In addition, we discovere notable differences in the tumor microenvironment including progressive dampening of CD8+ T cells and aberrant cell-to-cell communication networks in refractory MCLs. This study reveales diverse and dynamic tumor and immune programs underlying therapy resistance in MCL.

  Study EGAS00001005019

• HSC_colony_many_years_post_allogeneic_bone_marrow_transplant_TGS

  This study looks at human donors and recipients of allogeneic blood & marrow marrow transplantation. Each transplant "pair" (donor & recipient) underwent the transplant procedure 10 -30 years prior to sampling - the majority for an underlying diagnosis of leukemia. We will perform whole-genome sequencing on tens to hundreds of single HSPC (haematopoietic stem and progenitor cell)-derived colonies per individual. We will infer the phylogeny of these cells (those from both donor & recipient within a pair) by analysing the somatically acquired mutations within each cell. The structure of the phylogeny will allow estimates of hitherto unknown parameters such as the number of HSCs that engraft long-term, the dynamics of the engraftment process on the HSC level, and the additional mutation burden acquired through the arduous transplant procedure. This TGS part of the study is used for assessing the contribution of clones to mature blood subsets, and better timing mutations relative to transplantation.

  Study EGAS00001005298

• 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

• Real-time response profiling through serial plasma analyses during FOLFOX treatment in patients with colorectal cancer

  Response evaluation of cancer therapeutics relies on the assessment of the change in tumor burden, which is performed in accordance with defined criteria every 8-12 weeks. However, predictive factors for response are not available for the majority of patients with advanced stage colorectal cancer. Here we show that measurement of circulating tumor DNA (ctDNA) levels during one of the most commonly administered drug regimens, i.e. FOLFOX, allows an early, real-time assessment of treatment response. During the 48-hour FOLFOX application, we serially assessed plasma DNA and observed that ctDNA levels initially decreased during the first 23 hours. In patients with stable disease or partial response, ctDNA levels remained low, whereas in patients with progressive disease, ctDNA levels increased at the end of the treatment cycle predicting clinical and radiologic response correctly. Hence, ctDNA monitoring during treatment may contribute to an early outcome prediction with significant implications for the management of patients.

  Study EGAS00001004213

• Molecular profiling of metastatic uveal melanoma

  Metastatic uveal melanoma is less well understood than its primary counterpart, has a distinct biology compared to skin melanoma and lacks effective treatments. Here we genomically profile metastatic tumors and infiltrating lymphocytes. BAP1 alterations were overrepresented and occurred in 29/32 of cases. An outlier tumor had high mutational burden associated with UV-damage. CDKN2A deletions also occurred, which are rarely present in primaries. We profiled recurrent copy number alterations associated with metastasis and performed a focused knockdown screen on overexpressed targets. We investigated the role of BAP1 by reintroducing a functional allele into a deficient patient-derived cell line, revealing a broad shift towards a transcriptomic subtype associated with better prognosis. Tumor-infiltrating lymphocytes were in several cases tumor-reactive, but expression of the immune checkpoint receptors TIM-3, TIGIT and LAG3 was abundant. This study represents the largest whole-genome analysis of uveal melanoma to date and presents an updated view of the metastatic disease.

  Study EGAS00001004296

• Colorectal adenomas, NKI-AvL TGO series Stool-Proteomics

  Colorectal cancer (CRC) develops from normal epithelium, through a benign precursor lesion called adenoma, by accumulation of genetic alterations affecting oncogenes and tumour suppressor genes. About 5% of colorectal adenomas are estimated to progress to CRC. However, it is important to identify which adenomas actually are at high-risk of progression, because these should serve as intermediate endpoints for e.g. CRC screening programs. In clinical practice, adenomas with a size of ≥10 mm, villous component and/or high-grade dysplasia, called advanced adenomas, are considered high-risk, although this classification lacks solid evidence. Specific DNA copy number changes are associated with adenoma-to-carcinoma progression.For this tissue dataset, we applied low-pass whole genome sequencing to 98 non-advanced and advanced adenomas. These adenomas were classified as lesions with low-risk or high-risk of progression, according to the presence of specific DNA copy number changes (Carvalho et al, CancerPrevRes, 2018).

  Study EGAS00001002953

• Interethnic comparability in blood pressure GWAS

  We carried out a genome-wide association and replication study for blood pressure in a two-stage approach (max N = 289,038) with a discovery stage sample of 130,777 East Asian individuals, identifying 19 new genetic loci. We found a significant genetic heterogeneity between East Asian and European-descent populations at several blood pressure loci, conforming to “a common ancestry-specific variant association model”. At 6 unique loci, distinct non-rare (or common) ancestry-specific variants co-localized within the same linkage disequilibrium block despite the significantly discordant direction of effects for the proxy shared variants between the ethnic groups. The genome-wide transethnic correlation of causal-variant effect sizes is 0.898 and 0.851 for systolic and diastolic blood pressure, respectively. Some of the ancestry-specific association signals were also influenced by a selective sweep. Our results provide new evidence for the role of common ancestry-specific variants and natural selection in the occurrence of ethnic differences in complex traits such as blood pressure.

  Study EGAS00001002991

• Integrative molecular analysis of pediatric Anaplastic large cell lymphoma reveals subtypes with distinct immune suppression signatures.

  Anaplastic large cell lymphoma (ALCL) is a peripheral T-cell lymphoma accounting for 10–15% of all childhood lymphomas. While more than 90% of the ALCL cases contain ALK-rearrangement, these tumors possess significant inter-tumor molecular heterogeneity that contributes to distinct morphologic differences and clinical impact. To gain insight into the molecular heterogeneity within ALK+ ALCL, we performed whole-exome sequencing, RNA-sequencing, and methylome analysis of 42 primary pediatric ALK+ ALCL patients. Our data showed that ALK+ALCLs was subclassified into two subtypes based on ALK gene expression, methylation profiles, and somatic mutation patterns. ALK-low samples had more highly methylated gene regions while enriched with immune infiltration. ALK-high samples were enriched with somatic copy number alteration and high expression of MYC and PD-L1. These data indicate that ALK expression, somatic mutations, and aneuploidy status are negatively associated with immune infiltration, stipulating that ALK expression status might be associated with resistance to immune checkpoint inhibitors.

  Study EGAS00001004189

• Single-cell RNA-seq of bronchoalveolar lavage (BAL) fluid of late stage severe COVID-19 patients

  COVID-19-induced ‘acute respiratory distress syndrome’ (ARDS) is associated with prolonged respiratory failure and high mortality, but the mechanistic basis of lung injury remains incompletely understood. Here, we analyzed pulmonary immune responses and lung pathology in two cohorts of patients with COVID-19 ARDS using functional single cell genomics, immunohistology and electron microscopy. We describe an accumulation of CD163-expressing monocyte-derived macrophages, that acquired a profibrotic transcriptional phenotype during COVID-19 ARDS. Gene set enrichment and computational data integration revealed a significant similarity between COVID-19-associated macrophages and profibrotic macrophage populations identified in idiopathic pulmonary fibrosis. COVID-19 ARDS was associated with clinical, radiographic, histopathological, and ultrastructural hallmarks of pulmonary fibrosis. Exposure of human monocytes to SARS-CoV-2, but not Influenza A virus or viral RNA analogs, was sufficient to induce a similar profibrotic phenotype in vitro. In conclusion, we demonstrate that SARS-CoV-2 triggers profibrotic macrophage responses and pronounced fibroproliferative ARDS.

  Study EGAS00001005634

• A molecular signature for IL-10-producing Th1 cells in protozoan parasitic diseases

  Control of the intracellular parasites that cause malaria and visceral leishmaniasis (VL) is dependent on the generation of pro-inflammatory, IFNγ+ Tbet+ CD4+ T (Th1) cells by infected hosts. Immunoregulatory IL-10 produced by Th1 cells serves to mitigate subsequent inflammation and related disease pathology. However, these IL-10-producing Th1 (Tr1) cells can also not only promote parasite persistence, but may impair immunity to re-infection and potential vaccine efficacy. Here, we identify molecular and phenotypic signatures that distinguish Th1 cells from Tr1 cells in both experimental VL, caused by infection of C57BL/6 mice with the human parasite Leishmania donovani, and in Plasmodium falciparum-infected humans participating in controlled human malaria infection (CHMI) studies. Such characterisations allow for the better understanding of Tr1 cell development and function in the context of these parasitic diseases, and for the identification of targets for immune modulation to improve anti-parasitic immunity.

  Study EGAS00001004454

• The evolution of hematopoietic cells under cancer therapy

  Chemotherapies may increase mutagenesis of healthy cells and change the selective pressures in tissues thus influencing their evolution. However, their contributions to the mutation burden and clonal expansions of healthy somatic tissues are not clear. Here, exploiting the mutational footprint of some chemotherapies, we explore their influence on the evolution of hematopoietic cells. Cells of Acute Myeloid Leukemia (AML) secondary to treatment with platinum-based drugs showed the mutational footprint of these drugs, indicating that non-malignant blood cells received chemotherapy mutations. No trace of 5-fluorouracil (5FU) mutational signature was found in AML secondary to exposure to 5FU, suggesting that cells establishing the AML were quiescent during treatment. Using the platinum-based mutational signature as a barcode, we determined that secondary AMLs began their clonal expansion after the start of the cytotoxic treatment. Its absence in clonal hematopoiesis cases is consistent with a clonal expansion that predates the exposure to the cytotoxic agent.

  Study EGAS00001005234

• Ductal keratin 15+ luminal progenitors in normal breast exhibit a basal-like breast cancer transcriptomic signature

  Normal breast luminal epithelial progenitors have been implicated as cell of origin in basal-like breast cancer, but their anatomical localization remains understudied. Here, we combine micro-collection of uncultured organoids and single cell mRNA sequencing (scRNA-seq) of FACS-sorted luminal epithelial cells with multicolor imaging to profile ducts and terminal ductal lobular units (TDLUs) and compare them with breast cancer subtypes. Unsupervised clustering reveals eleven distinct clusters and a differentiation trajectory starting with keratin 15+ (K15+) progenitors enriched in ducts. Spatial mapping of luminal progenitors is confirmed at the protein level by staining with critical duct markers. Comparison of the gene expression profiles of normal luminal cells with those of breast cancer subtypes reveals a strong correlation between normal breast K15+ ductal progenitors and basal-like breast cancer. We propose that K15+ basal-like breast cancers originate in ductal progenitors, which emphasizes the importance of not only lineages but also cellular position within the ductal-lobular tree.

  Study EGAS00001005963

• Gain of function DNMT3A mutations cause microcephalic dwarfism and hypermethylation of Polycomb-regulated regions

  DNA methylation and Polycomb are key factors in the establishment of vertebrate cellular identity and fate. Here we report de novo missense mutations in DNMT3A, encoding the DNA methyltransferase DNMT3A, that cause microcephalic dwarfism, a hypocellular disorder of extreme global growth failure. Substitutions in the PWWP domain abrogate binding to the histone modifications H3K36me2/3, and alter DNA methylation in patient cells. Polycomb-associated DNA methylation canyons/valleys, hypomethylated domains encompassing developmental genes, become methylated with concomitant depletion of H3K27me3 and H3K4me3 bivalent marks. Such de novo DNA methylation occurs during differentiation of Dnmt3aW326R pluripotent cells in vitro, and is also evident in Dnmt3aW326R/+ dwarf mice. We therefore propose that the interaction of the DNMT3A PWWP domain with H3K36me2/3 normally limits DNA methylation of polycomb-marked regions. Our findings implicate the interplay between DNA methylation and polycomb at key developmental regulators as a determinant of organism size in mammals.

  Study EGAS00001003232

• Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer

  Triple negative breast cancer (TNBC) encompasses molecularly different subgroups, with a subgroup harboring evidence of defective homologous recombination (HR) DNA repair. Within a phase 2 window clinical trial, RIO trial (EudraCT 2014-003319-12), we investigate the activity of PARP inhibitors in 43 patients with untreated TNBC. The primary endpoint, decreased Ki67, occurs in 12% of TNBC. Multiple different approaches identify HR deficiency in the majority of TNBC, 69% with the mutational-signature-based HRDetect assay. Cancers with mutational signatures of HR deficiency have a functional defect in HR. Following rucaparib treatment there is no association of Ki67 change with HR deficiency. In contrast, early circulating tumor DNA dynamics identify activity of rucaparib in cancers with mutation-signatures of HR deficiency, with rucaparib inducing expression of interferon response genes in HR deficient cancers. The majority of TNBCs have a defect in DNA repair, identifiable by mutational signature analysis, that may be targetable with PARP inhibitors.

  Study EGAS00001004405

• Somatic_mutation_profiling_of_intestinal_crypts_from_IBD_Full_STDY

  Following on from our pilot study we will investigate further the role that somatic mutations in intestinal stem cells play in IBD. We will use laser capture microdissection to ascertain epithelial cells from an individual crypts/vilus. We will extract DNA from these and use a new low-input material library prep methods to make accurate libraries for sequencing. We will perform 15X whole-genome sequencing of crypts biopsied from patients. Biopsies have been taken from inflammed and noninflammed patches to compare mutation rates and mutational signatures. We will also test if crypts from inflammed patches of a single patient are clonal (either within a given inflammed patch or across inflammed patches). We will quantify the rate of cancer driver mutations in inflammed and non-inflammed crypts. 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 EGAS00001003249

• CCL22 chemokine mutations drive natural killer cell lymphoproliferative disease by biasing GPCR signaling

  Chronic lymphoproliferative disorder of natural killer cells (CLPD-NK) is characterized by clonal expansion of NK cells of incompletely understood genomic basis. Here, we report somatic mutations in the chemokine gene CCL22 as the hallmark of a distinct subset of CLPD-NK. CCL22 mutations were enriched at highly conserved residues, were mutually exclusive of STAT3 mutations, and were associated with gene expression similar to normal CD16dim/CD56bright NK cells. Mechanistically, the mutations resulted in ligand-biased chemokine receptor signaling, with decreased internalization of the G-protein-coupled receptor for CCL22, CCR4, via impaired β-arrestin recruitment. This resulted in increased cell chemotaxis in vitro, bidirectional crosstalk with the hematopoietic microenvironment, and enhanced NK cell proliferation in vivo in transgenic human IL-15 mice. Somatic CCL22 mutations illustrate a novel mechanism of tumor formation in which gain-of-function chemokine mutations promote tumorigenesis by biased G-protein-coupled receptor signaling and dysregulation of microenvironmental crosstalk.

  Study EGAS00001006009

• Germline TP53 mutations undergo copy number gain years prior to tumor diagnosis

  Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome associated with germline TP53 mutations. We performed whole-genome sequence (WGS) analysis of tumors from 22 TP53 mutation carriers. We observed somatic mutations affecting Wnt, PI3K/AKT signaling, epigenetic modifiers and homologous recombination genes as well as mutational signatures associated with prior chemotherapy. We identified near-ubiquitous early loss of heterozygosity of TP53, with gain of the mutant allele. This occurred earlier in these tumors compared to tumors with somatic TP53 mutations, suggesting the timing of this mark may distinguish germline from somatic TP53 mutations. Phylogenetic trees of tumor evolution, reconstructed from bulk and multi-region WGS, revealed that LFS tumors exhibit comparatively limited heterogeneity. Overall, our study delineates early copy number gains of mutant TP53 as a characteristic mutational process in LFS tumorigenesis, likely arising very early in life or in utero.years prior to tumor diagnosis.

  Study EGAS00001005982

• HSC_colony_many_years_post_allogeneic_bone_marrow_transplant___Bait_set_2

  This study looks at human donors and recipients of allogeneic blood & marrow marrow transplantation. Each transplant "pair" (donor & recipient) underwent the transplant procedure 10 -30 years prior to sampling - the majority for an underlying diagnosis of leukemia. We will perform whole-genome sequencing on tens to hundreds of single HSPC (haematopoietic stem and progenitor cell)-derived colonies per individual. We will infer the phylogeny of these cells (those from both donor & recipient within a pair) by analysing the somatically acquired mutations within each cell. The structure of the phylogeny will allow estimates of hitherto unknown parameters such as the number of HSCs that engraft long-term, the dynamics of the engraftment process on the HSC level, and the additional mutation burden acquired through the arduous transplant procedure. This TGS part of the study is used for assessing the contribution of clones to mature blood subsets, and better timing mutations relative to transplantation.

  Study EGAS00001005534

• A comprehensive characterization of the cell-free transcriptome reveals tissue- and subtype-specific biomarkers for cancer detection

  Cell-free RNA (cfRNA) is a promising analyte for cancer detection. However, a comprehensive assessment of cfRNA in individuals with and without cancer has not been conducted. We performed the first transcriptome-wide characterization of cfRNA in cancer (stage III breast [n=46], lung [n=30]) and non-cancer (n=89) participants from the Circulating Cell-free Genome Atlas (NCT02889978). Of 57,820 annotated genes, 39,564 (68%) were not detected in cfRNA from non-cancer individuals. Within these low-noise regions, we identified tissue- and cancer-specific genes, defined as "dark channel biomarker" (DCB) genes, that were recurrently detected in individuals with cancer. DCB levels in plasma were correlated with tumor shedding rate and RNA expression in matched tissue, suggesting that DCBs with high expression in tumor tissue could enhance cancer detection in patients with low levels of circulating tumor DNA. Overall, cfRNA provides a unique opportunity to detect cancer, predict the tumor tissue of origin, and determine the cancer subtype.

  Study EGAS00001004704

• Whole genome sequencing of EBV Associated Nasopharyngeal Carcinoma

  Interplay between EBV infection and acquired genetic alterations during nasopharyngeal carcinoma (NPC) development remains vague. Here we report a comprehensive genomic analysis of 70 NPCs, combining whole-genome sequencing (WGS) of microdissected tumor cells with EBV oncogene expression to reveal multiple aspects of cellular-viral co-operation in tumorigenesis. Genomic aberrations along with EBV-encoded LMP1 expression underpin constitutive NF-κB activation in 90% of NPCs. A similar spectrum of somatic aberrations and viral gene expression undermine innate immunity in 79% of cases and adaptive immunity in 47% of cases; mechanisms by which NPC may evade immune surveillance despite its pro inflammatory phenotype. Additionally, genomic changes impairing TGFBR2 promote oncogenesis and stabilize EBV infection in tumor cells. Fine-mapping of CDKN2A/CDKN2B deletion breakpoints reveals homozygous MTAP deletions in 32-34% of NPCs that confer marked sensitivity to MAT2A inhibition. Our work concludes that NPC is a homogeneously NF-κB-driven and immune-protected, yet potentially druggable, cancer.

  Study EGAS00001004705

• The European MAPPYACTS trial: Precision Medicine Program in Pediatric and Adolescent Patients with Recurrent Malignancies

  MAPPYACTS (NCT02613962) is an international prospective precision medicine trial aiming to define tumor molecular profiles in pediatric patients with recurrent/refractory malignancies, in order to suggest the most adapted salvage treatment. From February 2016 to July 2020, 787 patients were included in France, Italy, Ireland and Spain. At least one genetic alteration leading to targeted treatment suggestion was identified in 436 patients (69%) with successful sequencing; 10% of these were considered "ready for routine use". Of 356 patients with follow-up beyond 12 months, 107 (30%) received one or more matched targeted therapies, 56% of them within early clinical trials, mainly in the AcSé-ESMART platform trial (NCT02813135). Overall, matched treatment resulted in a 17% objective response rate, those of patients with "ready for routine use" alterations was 38%. In patients with extra-cerebral tumors, 76% of actionable alterations detected in tumor tissue were also identified in circulating cell free DNA (cfDNA).

  Study EGAS00001005935

• Comprehensive epigenomic profiling reveals the extent of disease-specific chromatin states and informs drug target discovery in ankylosing spondylitis

  Ankylosing spondylitis (AS) is a common, highly heritable inflammatory arthritis characterised by enthesitis of the spine and sacroiliac joints. Genome-wide association studies have revealed >100 genetic associations but their functional effects remain largely unresolved. Here, we present a comprehensive transcriptomic and epigenomic map of disease-relevant blood immune cell subsets from AS patients and healthy controls. We report differential disease signatures for specific genomic regions from individual -omic modalities and multi-omic integration, showing enrichment at genetically associated loci and evidence for altered monocyte function in AS. We link putative functional SNPs with cognate genes using high-resolution Capture-C at 10 loci, including PTGER4 and ETS1. We also show how disease-specific functional genomic data can be integrated with GWAS evidence to enhance therapeutic target discovery. This study combines multiple epigenetic and transcriptional analysis with GWAS to identify cell types, candidate drug target genes and transcriptional regulation of likely pathogenic relevance.

  Study EGAS00001006233

• Human genome-wide variations in the Massim region

  The Massim, a cultural region encompassing the southeastern tip of mainland Papua New Guinea (PNG) and nearby islands, is famous for the Kula trading network, in which different valuables circulate in different directions among the islands. To explore Massim genetic history, we generated genome-wide data from across the region and found variable levels of Papuan-related (indigenous) ancestry, including a novel ancestry associated with Rossel Island, and Austronesian-related ancestry that arrived later. We find genetic evidence for different patterns of contact across PNG, the Massim, and the Bismarck and Solomon Archipelagoes for Austronesian-related vs. Papuan-related ancestry, with more geographic restriction for the latter. Moreover, Kula-practicing groups share more genetic similarity than do other groups, and this likely predates the origin of Kula, suggesting that high between-group contact facilitated the formation of Kula. Our study provides the first comprehensive genome-wide assessment of Massim inhabitants and new insights into the fascinating Kula system.

  Study EGAS00001006010

• Atypical teratoid/rhabdoid tumoroids reveal subgroup-specific drug vulnerabilities

  Atypical teratoid/rhabdoid tumors (ATRTs) represent a rare, but aggressive pediatric brain tumor entity. They are genetically defined by mutations in SWI/SNF chromatin remodeling complex members SMARCB1 or SMARCA4. ATRTs can be subdivided in different molecular subgroups based on their epigenetic profiles. Although recent studies suggest that the different subgroups have distinct clinical features, subgroup-specific treatment regimens have not been developed thus far. This is hampered by the lack of pre-clinical in vitro models representative of the different molecular subgroups. Here, we describe the establishment of ATRT tumoroid models from the ATRT-MYC and ATRT-SHH subgroups. We demonstrate that ATRT tumoroids retain subtype-specific epigenetic and gene expression profiles. High throughput drug screens on our ATRT tumoroids revealed distinct drug sensitivities between and within ATRT subgroups. Our ATRT tumoroids represent the first pediatric brain tumor organoid model, providing representative pre-clinical models allowing for the development of subtype-specific therapies.

  Study EGAS00001006422

• MutWP5__CRUK_Mutographs_of_Cancer__Cancer_Mastectomy__Exome__Novaseq_

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

  Study EGAS00001003528

• Arriba: accurate and efficient detection of gene fusions from RNA-Seq (H021)

  The identification of gene fusions from RNA sequencing data is a routine task in cancer research and precision oncology. However, despite the availability of many computational tools, fusion detection remains challenging. Existing methods suffer from poor prediction accuracy and are computationally demanding. We developed Arriba, a novel fusion detection algorithm with high sensitivity and short runtime. When applied to a large collection of published pancreatic cancer samples (n=803), Arriba identified a variety of driver fusions, many of which affected druggable proteins, including ALK, BRAF, FGFR2, NRG1, NTRK1, NTRK3, RET, and ROS1. The fusions were significantly associated with KRAS wild-type tumors and involved proteins stimulating the MAPK signaling pathway, suggesting that they substitute for activating mutations in KRAS. In addition, we confirmed the transforming potential of two novel fusions, RRBP1-RAF1 and RASGRP1-ATP1A1, in cellular assays. These results demonstrate Arriba’s utility in both basic cancer research and clinical translation.

  Study EGAS00001003554

• Exome & MiSeq sequencing of individuals with Huntington's disease

  The age at onset of motor symptoms in Huntington's disease (HD) is driven by HTT CAG repeat length but modified by other genes. In this study, we used exome sequencing of 683 patients with HD with extremes of onset or phenotype relative to CAG length to identify rare variants associated with clinical effect. We discovered damaging coding variants in candidate modifier genes identified in previous genome-wide association studies associated with altered HD onset or severity. Variants in FAN1 clustered in its DNA-binding and nuclease domains and were associated predominantly with earlier-onset HD. Nuclease activities of purified variants in vitro correlated with residual age at motor onset of HD. Mutating endogenous FAN1 to a nuclease-inactive form in an induced pluripotent stem cell model of HD led to rates of CAG expansion similar to those observed with complete FAN1 knockout. Together, these data implicate FAN1 nuclease activity in slowing somatic repeat expansion and hence onset of HD.

  Study EGAS00001006383

• Resolving the immune landscape of human prostate at a single cell level in health and cancer

  The prostate gland produces prostatic fluid, high in zinc and citrate and essential for the maintenance of spermatozoa. Prostate cancer is a common condition with limited treatment efficacy in castration-resistant metastatic disease, including with immune checkpoint inhibitors. We used single-cell RNA-sequencing to perform an unbiased assessment of the cellular landscape of human prostate and identified a previously unappreciated subset of tumour-enriched androgen receptor-negative luminal epithelial cells, with increased expression of cancer-associated genes. We also found a variety of innate and adaptive immune cells in normal prostate that were transcriptionally perturbed in prostate cancer. An exception was a unique, prostate-specific, zinc transporter-expressing macrophage population (MAC-MT), that contributed to tissue zinc accumulation in homeostasis, but showed enhanced inflammatory gene expression in tumours, including T cell-recruiting chemokines. Remarkably, enrichment of the MAC-MT signature in cancer biopsies was associated with improved disease-free survival, suggesting beneficial anti-tumour functions.

  Study EGAS00001005787

• Molecular Profiling Reveals Unique Immune and Metabolic Features of Melanoma Brain Metastases

  There is a critical need to improve our understanding of the pathogenesis of -melanoma brain metastases (MBM). Thus, we performed RNA sequencing on 88 resected MBMs and 42 patient-matched extracranial metastases; tumors with sufficient tissue also underwent whole-exome sequencing, T-cell receptor sequencing, and IHC. MBMs demonstrated heterogeneity of immune infiltrates that correlated with prior radiation and post-craniotomy survival. Comparison with patient-matched extracranial metastases identified significant immunosuppression and enrichment of oxidative phosphorylation (OXPHOS) in MBMs. Gene-expression analysis of intracranial and subcutaneous xenografts, and a spontaneous MBM model, confirmed increased OXPHOS gene expression in MBMs, which was also detected by direct metabolite profiling and [U-13C]-glucose tracing in vivo IACS-010759, an OXPHOS inhibitor currently in early-phase clinical trials, improved survival of mice bearing MAPK inhibitor-resistant intracranial melanoma xenografts and inhibited MBM formation in the spontaneous MBM model. The results provide new insights into the pathogenesis and therapeutic resistance of MBMs.

  Study EGAS00001003672

• HSC_colony_many_years_post_allogeneic_bone_marrow_transplant___Bait_set_3

  This study looks at human donors and recipients of allogeneic blood & marrow marrow transplantation. Each transplant "pair" (donor & recipient) underwent the transplant procedure 10 -30 years prior to sampling - the majority for an underlying diagnosis of leukemia. We will perform whole-genome sequencing on tens to hundreds of single HSPC (haematopoietic stem and progenitor cell)-derived colonies per individual. We will infer the phylogeny of these cells (those from both donor & recipient within a pair) by analysing the somatically acquired mutations within each cell. The structure of the phylogeny will allow estimates of hitherto unknown parameters such as the number of HSCs that engraft long-term, the dynamics of the engraftment process on the HSC level, and the additional mutation burden acquired through the arduous transplant procedure. This TGS part of the study is used for assessing the contribution of clones to mature blood subsets, and better timing mutations relative to transplantation.

  Study EGAS00001006572

• Tocilizumab treatment leads to early resolution of myeloid dysfunction and lymphopenia in patients hospitalized with COVID-19

  Tocilizumab, an anti-interleukin-6 receptor inhibitor, is recommended in global treatment guidelines for patients hospitalized with severe COVID-19. Using proteomic and transcriptomic analysis, we characterized the immune profile and identified cellular and molecular pathways directly modified by tocilizumab in peripheral blood samples collected from patients enrolled in the COVACTA study, a phase 3, randomized, double-blind, placebo-controlled trial, to assess the efficacy and safety of tocilizumab in hospitalized patients with severe COVID-19 pneumonia. We identified factors predicting disease severity and clinical outcomes, including markers of inflammation, lymphopenia, myeloid dysfunction, and organ injury. Proteomic analysis confirmed a pharmacodynamic effect for tocilizumab. Transcriptomic analysis revealed that tocilizumab treatment leads to faster resolution of lymphopenia and myeloid dysfunction associated with severe COVID-19 thus supporting an underlying anti-inflammatory mechanism of action for the beneficial effects of tocilizumab in patients hospitalized with COVID-19.

  Study EGAS00001006688

• Malignant progression of an ancestral bone marrow clone harboring a CIC-NUTM2A fusion in isolated myeloid sarcoma

  Myeloid sarcoma is a rare condition consisting of extramedullary myeloid blasts found in association with acute myeloid leukemia (AML) or, in the absence of bone marrow involvement. We identified an infant with isolated myeloid sarcoma whose bone marrow was negative for involvement by flow cytometry. Sequencing revealed the fusion oncogene CIC-NUTM2A and identified the sarcoma to be clonally evolved from the bone marrow which carried the fusion despite the absence of pathology. Murine modeling confirmed the ability of the fusion to transform hematopoietic cells and identified receptor tyrosine kinase signaling activation consistent with disruption of the CIC transcriptional repressor. These findings extend the definition of CIC-rearranged malignancies to include hematologic disease, provide insight into the mechanism of oncogenesis, and demonstrate the importance of molecular analysis and tracking of bone marrow involvement over the course of treatment in myeloid sarcoma, including patients that lack flow cytometric evidence of leukemia at diagnosis.

  Study EGAS00001006833

• Comprehensive epigenomic profiling reveals the extent of disease-specific chromatin states and informs drug target discovery in ankylosing spondylitis

  Ankylosing spondylitis (AS) is a common, highly heritable inflammatory arthritis characterised by enthesitis of the spine and sacroiliac joints. Genome-wide association studies have revealed >100 genetic associations but their functional effects remain largely unresolved. Here, we present a comprehensive transcriptomic and epigenomic map of disease-relevant blood immune cell subsets from AS patients and healthy controls. We report differential disease signatures for specific genomic regions from individual -omic modalities and multi-omic integration, showing enrichment at genetically associated loci and evidence for altered monocyte function in AS. We link putative functional SNPs with cognate genes using high-resolution Capture-C at 10 loci, including PTGER4 and ETS1. We also show how disease-specific functional genomic data can be integrated with GWAS evidence to enhance therapeutic target discovery. This study combines multiple epigenetic and transcriptional analysis with GWAS to identify cell types, candidate drug target genes and transcriptional regulation of likely pathogenic relevance.

  Study EGAS00001006945

• Data Use Ontology (DUO) at EGA

  For those of you that follow the updates of GA4GH you will have seen the unanimous approval of the steering committee for DUO to be included in its suite of technical standards for the sharing of genomic and health related data. DUO has three main features: Each term has been generated by the community and includes a human readable definition that can be expanded where necessary. It is a machine-readable file that encodes how that data can be used and how a researcher intends to use the data. Can be implemented alongside an advanced search algorithm which would allow authenticated users to query and gain access to datasets pertaining to their research. e.g., an industry researcher working on cancer could potentially be matched to any dataset that is allowed for commercial use and for cancer research and offered the opportunity to fetch them automatically. So, what does this mean for EGA? EGA as a driver project has adopted this standard and will be utilizing it for two main purposes in the first instance. i) It will allow EGA users to instantly identify what terms they will need to agree to as part of any Data Access Agreements. This will save valuable time for both applicants and Data Access Committees alike - as you will be able to see if you are likely to be able to access the data based on your research intentions and working background. ii) In the future it will allow users to be able to search for data based on Data Use Ontology terms e.g., you could search for all data that can be used for General Research Use (GRU). As EGA moves forwards submitters will be asked to align their data access policies with DUO so that their dataset(s) can be tagged appropriately on our web pages. If you would like to add DUO to any of your existing datasets, or to any future datasets, do please just let us know.

  Blog data-use-ontology

• pancreatic ductal adenocarcinoma exomes in study: Pro-immunogenic Impact of MEK inhibition combined with an anti-CD40 immunostimulatory antibody

  This dataset contains 3 pairs of exomes, germline (from whole blood) and patient-derived xenograft (PDX), from human pancreatic durctal adenocarcinoma patients. The data is referred to in the publication: "Pro-immunogenic impact of MEK inhibition synergizes with agonist anti-CD40 immunostimulatory antibodies in tumor therapy" (Nature Communications, 2020) Abstract: Cancer types with lower mutational load and a non-permissive tumor microenvironment are intrinsically resistant to immune checkpoint blockade. While the combination of cytostatic drugs and immunostimulatory antibodies constitutes an attractive concept for overcoming this refractoriness, suppression of immune cell function by cytostatic drugs may limit therapeutic efficacy. Here we show that targeted inhibition of mitogen-activated protein kinase (MAPK) kinase (MEK) does not impair dendritic cell-mediated T-cell priming and activation. Accordingly, combining MEK inhibitors (MEKi) with agonist antibodies (Abs) targeting the immunostimulatory CD40 receptor resulted in potent synergistic anti-tumor efficacy. Detailed analysis of the mechanism of action of MEKi GDC-0623 by means of flow cytometric analysis of the tumor immune infiltrate and whole tumor transcriptomics showed that, in addition to its cytostatic impact on tumor cells, this drug exerts multiple pro-immunogenic effects, including the suppression of M2-type macrophages, myeloid derived suppressor cells and CD4+ T-regulatory cells. In addition, MEKi was found to induce tumor-cell intrinsic interferon signaling, which contributed to antigen presentation by tumor cells. Finally, the tumoridical impact of MEKi involves the activation of multiple pro-inflammatory pathways involved in immune cell effector function in the tumor microenvironment. Our data therefore indicate that the combination of MEK inhibition with agonist anti-CD40 Ab is a promising therapeutic concept, especially for the treatment of mutant Kras-driven tumors such as pancreatic ductal adenocarcinoma.

  Dataset EGAD00001005938

• Natural history of clonal haematopoiesis (2017-09-04)

  The incidence of acute myeloid leukemia (AML) increases with age and mortality exceeds 90% when diagnosed after age 60. Only 10-15% of cases evolve from a pre-existing myeloproliferative or myelodysplastic disorder; the remaining cases arise de novo without a detectable prodrome and are diagnosed upon development of bone marrow failure. Analysis of diagnostic blood samples has demonstrated that de novo AML is preceded by the accumulation of somatic mutations in pre-leukemic hematopoietic stem and progenitor cells (preL-HSPCs) that subsequently undergo clonal expansion. If individuals in this pre-leukemic phase could be identified, methods for determination of risk and monitoring for progression to overt AML could be developed. However recurrent AML mutations also accumulate during aging in healthy individuals who never develop AML, referred to as age related clonal hematopoiesis (ARCH). To distinguish individuals with preL-HSPCs at high risk of developing AML from those with ARCH, we undertook deep targeted sequencing of genes recurrently mutated in AML in blood samples from 133 individuals in the European Prospective Investigation into Cancer and Nutrition (EPIC) study taken on average 6 years before they developed AML (pre-AML group), together with 683 matched healthy individuals (Control group). Pre-AML cases displayed accelerated age-correlated accumulation of somatic mutations.The identity, number and variant allele frequency (VAF) of mutations differed between the two groups, and were incorporated into a computational model of AML risk prediction that accurately distinguished pre-AML cases from controls on average 7 years prior to AML development. Our findings provide proof of concept that early prediction of AML development is feasible in high-risk populations, paving the way for early disease detection, monitoring, and potentially prevention.

  Dataset EGAD00001003703

• Single-cell RNA-seq of cervix and placenta

  Placental trophoblasts have been detected in cervical smears early in gestation, creating opportunities for non-invasive prenatal diagnosis. However, trophoblast isolation is limited by the lack of a cell catalogue and molecular profile of cervical smears. To establish an atlas and to explore the potential of single-cell RNA-sequencing to detect cervical trophoblasts, 10,539 single-cell transcriptomes from 12 non-invasive exocervical smears from pregnant women were profiled. In addition, we characterized 34,565 cells from six placental biopsies. We uncovered a novel extravillous trophoblast cell subtype characterized by epithelial marker genes and reduced HLA-G expression. Integration of both cell atlases demonstrated surprisingly similar expression profiles between maternal epithelial cells and placental extravillous trophoblasts, indicating that these trophoblasts retained epithelial properties without an invasive mesenchymal phenotype. Additionally, differential expression analysis identified novel markers discriminating cervical and placental cell types. Those analyses may contribute to trophoblast discovery and isolation from cervical smears.

  Study EGAS00001007044

• Early evolutionary branching across spatial domains predisposes to clonal replacement under chemotherapy in neuroblastoma

  Neuroblastoma (NB) is one of the most lethal childhood cancers due its propensity to treatment resistance. By spatial mapping of subclone geographies before and after chemotherapy across 89 tumor regions from 12 NBs, we find that densely packed territories of closely related subclones present at diagnosis are replaced under effective treatment by islands of distantly related survivor subclones, originating from a different most recent ancestor compared to lineages dominating before treatment. Conversely, in tumors that progressed under treatment, ancestors of subclones dominating later in disease are present already at diagnosis. Chemotherapy treated xenografts and cell culture models replicates these two contrasting scenarios and shows branching evolution to be a constant feature of proliferating NB cells. Phylogenies based on whole genome sequencing of 505 individual NB cells indicate that a rich repertoire of parallel subclones, emerges already with the first oncogenic mutations and lays the foundation for clonal replacement under treatment.

  Study EGAS00001007650

• Whole genome sequencing of patients with or at risk for HCC

  Liver cancer is a major cause of cancer mortality worldwide. Screening individuals at high risk, including those with cirrhosis and viral hepatitis, provides an avenue for improved survival, but current screening methods are inadequate. In this study, we used whole-genome cell-free DNA (cfDNA) fragmentome analyses to evaluate 724 individuals from the United States, the European Union, or Hong Kong with hepatocellular carcinoma (HCC) or who were at average or high-risk for HCC. Using a machine learning model that incorporated multifeature fragmentome data, the sensitivity for detecting cancer was 88% in an average-risk population at 98% specificity and 85% among high-risk individuals at 80% specificity. We validated these results in an independent population. cfDNA fragmentation changes reflected genomic and chromatin changes in liver cancer, including from transcription factor binding sites. These findings provide a biological basis for changes in cfDNA fragmentation in patients with liver cancer and provide an accessible approach for noninvasive cancer detection.

  Study EGAS00001007249

• Mutational Mechanisms in Multiply Relapsed Pediatric Acute Lymphoblastic Leukemia

  Pediatric acute lymphoblastic leukemia (ALL) is marked by low mutational load at initial diagnosis, which increases at relapse. To determine which processes are active in (relapsed) ALL and how they behave during disease progression before and after therapy, we performed whole genome sequencing on tumor samples of 29 multiply relapsed ALL patients. Mutational load increased upon relapse in 28 patients and every subsequent relapse in 22 patients, with UV-like damage, APOBEC activity, reactive oxygen species, thiopurine-associated damage and an unknown therapy component driving mutagenesis. Thiopurines were the most prominent source of new mutations in relapse, affecting over half of the studied patients and causing potential relapse-driving mutations in multiple patients. Mutational processes often affected patients over longer time periods, but could also occur in isolated events, suggesting the requirement of additional triggers. Our data pose mutational processes as prominent secondary drivers with an important role in ALL development and progression.

  Study EGAS00001007900

• Mapping the human hematopoietic stem and progenitor cell hierarchy through integrated single-cell proteomics and transcriptomics

  Single-cell transcriptomics (scRNA-seq) has enabled the characterization of cell state heterogeneity and recapitulation of differentiation trajectories. However, since proteins are the main functional entities in cells, the exclusive use of mRNA measurements comes at the risk of missing important biological information. Here we leverage recent technological advances in single-cell proteomics by Mass Spectrometry (scp-MS) to generate the first scp-MS dataset of an in vivo differentiation hierarchy encompassing over 2,500 human CD34+ hematopoietic stem and progenitor cells. Through integration with scRNA-seq, we identify proteins that are important for stem cell quiescence, which were not indicated by their mRNA transcripts, and demonstrate functional expression covariance during differentiation that is only detectable on protein level. Finally, we show that modeling translation dynamics can infer cell progression during differentiation and explain 45% more protein variation from mRNA than linear correlation. Our work serves as a framework for future single-cell multi-omics studies across biological systems.

  Study EGAS00001007930

• Novel paediatric case of a spinal high-grade astrocytoma with piloid features in a patient with Noonan Syndrome

  Noonan Syndrome (NS) is associated with an increased risk of low-grade central nervous system tumours in children but only very rarely associated with high-grade gliomas. Here we describe the first reported case of a spinal high-grade astrocytoma with piloid features (HGAP) in a child with NS. This case was a diagnostic and treatment dilemma, prior to whole-genome germline and tumour sequencing, tumour transcriptome sequencing and DNA methylation analysis. The methylation profile matched strongly with HGAP and sequencing identified somatic FGFR1 and NF1 variants and a PTPN11 germline pathogenic variant. Therapeutic targets were identified but also alterations novel to HGAP such as differential expression of VEGFA and PD-L1. The germline PTPN11 finding has not been previously described in individuals with HGAP.  This case underscores the power of precision medicine from a diagnostic, therapeutic and clinical management perspective, and describes an association between HGAP and NS which has not previously been reported.

  Study EGAS00001007937

• The genetic history of the southern Andes from present-day Mapuche ancestry

  We generate genome-wide data from 64 participants from three Mapuche populations in Southern Chile: Pehuenche, Lafkenche, and Huilliche. Broadly, we describe three main ancestry blocks with a common origin, which characterize the Southern Cone, the Central Andes, and Amazonia. Within the Southern Cone, ancestors of the Mapuche lineages differentiated from those of the Far South during the Middle Holocene, and did not experience further migration waves from the north. We find that the deep genetic split between the Central and Southern Andes is followed by instances of gene flow, which may have accompanied the southward spread of cultural traits from the Central Andes, including crops and loanwords from Quechua into Mapudungun (the language of the Mapuche). Our findings add new perspectives on the genetic (pre)history of South America, from first settlement through to the present-day indigenous presence. Follow-up fieldwork took these results back to the indigenous communities to contextualize the genetic narrative alongside indigenous knowledge and perspectives.

  Study EGAS00001007200

• A longitudinal single-cell atlas of treatment response in pediatric AML

  Pediatric acute myeloid leukemia (pAML) is a disease characterized by heterogeneous cellular composition, driver alterations and prognosis. Characterization of this heterogeneity and how it affects treatment response remains relatively understudied in pediatric patients. We therefore used single-cell RNA sequencing and single-cell ATAC sequencing to profile 684,031 diagnosis, remission and relapse cells from 28 patients representing different pAML subtypes. Analysis revealed that at diagnosis, cellular compositions differed between distinct subgroups. Upon relapse, cellular hierarchies transitioned towards a more primitive state regardless of subtype. These primitive cells were distinct compared to cells at diagnosis, having underrepresentation of transcriptional programs involved in myeloid differentiation while programs commonly found in other lineages were overrepresented. In a subset of patients, this appeared to accompany the appearance of a B-lymphoid-like hierarchy. Together, our data reveal the emergence of apparent subtype-specific plasticity upon treatment and inform on potential novel therapeutic angles to target these cell populations.

  Study EGAS00001007323

• A clinically applicable connectivity signature for glioblastoma includes the tumor network driver CHI3L1

  Tumor microtubes (TMs) connect glioma cells to a network with considerable relevance for tumor progression and therapy resistance. The determination of TM-interconnectivity in individual tumors has been challenging and the impact on patient survival unresolved. Here, a connectivity signature from single-cell RNA-sequenced (scRNA-Seq) xenografted primary glioblastoma (GB) cells has been established using a dye uptake methodology, confirmed with recording of cellular calcium epochs and validated with clinical correlations. Astrocyte-like and mesenchymal-like GB cells have the highest connectivity signature scores in scRNA-sequenced patient-derived xenografts and patient samples. In large GB cohorts, network connectivity correlated with the mesenchymal subtype and dismal patient survival. CHI3L1 has been identified and validated as a robust molecular marker of connectivity with functional relevance. The connectivity signature allows novel insights into brain tumor biology, provides a proof-of-principle that tumor cell TM-connectivity is relevant for patients’ prognosis, and serves as a robust prognostic biomarker.

  Study EGAS00001007611

• Unraveling mutagenic processes influencing the tumor mutational patterns of individuals with Constitutional Mismatch Repair Deficiency

  Constitutional mismatch repair deficiency (CMMRD), caused by bi-allelic germline variants in one of the mismatch repair (MMR) genes, is a childhood cancer predisposition syndrome that often results in the development of multiple tumors early in life. A better understanding of mutational processes driving subsequent CMMRD tumors could advance optimal treatment. Therefore, we performed a genomic characterization of 41 tumors from 17 individuals with CMMRD. Mutational patterns in these tumors were found to be influenced by multiple factors, including the affected MMR genes, tumor types and somatic polymerase proofreading mutations. Temozolomide treatment left prominent mutational signatures in two second primary hematologic malignancies. Furthermore, a novel indel signature was found in 54% of the tumors, characterized by one base pair cytosine insertions in cytosine homopolymers. In conclusion, the analysis of sequential tumors in individuals with CMMRD reveals diverse mutational patterns influenced by the underlying mutated MMR gene, tumor type and treatment history.

  Study EGAS00001007660

• Cross-species Comparison Reveals Therapeutic Vulnerabilities Halting Glioblastoma Progression

  The growth of a tumor is tightly linked to the distribution of its cells along a continuum of activation states. Here, we systematically decode the activation state architecture (ASA) in a glioblastoma (GBM) patient cohort through comparison to adult murine neural stem cells. Modelling of these data forecast how tumor cells organize to sustain growth and identifies rate of activation as the main predictor of growth. Accordingly, patients with a higher quiescence fraction exhibit improved outcomes. Further, DNA methylation arrays enable ASA- related patient stratification. Comparison of healthy and malignant gene expression dynamics reveals dysregulation of the Wnt- antagonist SFRP1 at the quiescence to activation transition. SFRP1 overexpression renders GBM quiescent and increases overall survival of tumor-bearing mice. Surprisingly, it does so through reprogramming the tumor’s stem-like methylome into an astrocyte- like one. Our findings offer a framework for patient stratification with prognostic value, biomarker identification, and therapeutic avenues to halt GBM progression.

  Study EGAS00001008155

• Genome-wide Rare Variant Score Associates With Morphological Subtypes of Autism Spectrum Disorder

  Defining different genetic subtypes of Autism Spectrum Disorder (ASD) can help predict developmental outcomes. Based on minor physical and major congenital anomalies, we categorized 325 Canadian children with ASD into dysmorphic and non-dysmorphic subgroupings. We developed a method to calculate a genome-wide rare variant score (GRVS) from whole-genome sequencing (WGS) data for each ASD proband. GRVS is a sum of the number of variants in morphology-associated coding and non-coding regions, weighted by their effect sizes. Probands with dysmorphic ASD had a significantly higher GRVS compared to those with non-dysmorphic ASD (P= 0.027). Using the polygenic transmission disequilibrium test, we observed an over-transmission of ASD-associated common variants in non-dysmorphic ASD probands (P= 2.9×10-3). We replicated our findings using 442 ASD probands that had accompanying morphology data in the Simons Simplex Collection. Our findings provide support for an alternative genomic classification of ASD subgroups using morphology data, which may inform intervention protocols.

  Study EGAS00001005753

• Add Health: Longitudinal Study of a Nationally Representative Sample of Adolescents in Grades 7-12 in the United States during the 1994-95 School Year, Followed into Adulthood with Five Interviews/Surveys in 1995, 1996, 2001-02, 2008, and 2016-18

  The National Longitudinal Study of Adolescent to Adult Health [Add Health] is an ongoing longitudinal study of a nationally representative U.S. cohort of more than 20,000 adolescents in grades 7-12 (aged 12-19 years) in 1994 followed into adulthood with five interviews/surveys in 1995, 1996, 2001-02, 2008, and 2016-18. Add Health was designed to understand how social environments and behaviors in adolescence are linked to health and achievement outcomes in young adulthood. Add Health contains unprecedented environmental, behavioral, psychosocial, biological, and genetic data from early adolescence and into adulthood on a large, nationally representative cohort with unprecedented racial, ethnic, socioeconomic, and geographic diversity. Add Health has a large, multidisciplinary user base of over 50,000 researchers around the world who have published over 3,400 research articles. Add Health is housed at the Carolina Population Center of the University of North Carolina at Chapel Hill. Add Health datasets are distributed according to a tiered data disclosure plan designed to protect the data from the risk of direct and indirect disclosure of respondent identity. Add Health's large sample size, population diversity and rich longitudinal database of psychosocial, physical, and contextual data will permit investigation of an exceptionally broad range of phenotypes with known genetic variation. Prospective longitudinal measures are available to document change over time in each of these phenotypes, as well as change in the social environment and life experiences, making the Add Health sample ideal for understanding genetic linkages with health and behavior across the life course. The original design of Add Health included important features for understanding biological processes in health and developmental trajectories across the life course of young people, including an embedded genetic sample with more than 3,000 pairs of adolescents with varying biological resemblance (e.g., twins, full sibs, half sibs, and adolescents who grew up in the same household but have no biological relationship), testing of saliva and urine for sexually transmitted infections and HIV, and biomarkers of cardiovascular health, metabolic processes, immune function, renal function, and inflammation. Add Health therefore has critical objective indicators of health status and disease markers in young adulthood, well before chronic illness or its complications emerge in later adulthood. Because DNA has been collected on the full sample at Wave IV, it is possible to link genetic profiles with social, behavioral, and biological measures over time from adolescence into adulthood. Add Health sampled the multiple environments in which young people live their lives, including the family, peers, school, neighborhood, community, and relationship dyads, and provides independent and direct measurement of these environments over time. Add Health contains extensive longitudinal information on health-related behavior, including life histories of physical activity, involvement in risk behavior, substance use, sexual behavior, civic engagement, education, and multiple indicators of health status based on self-report (e.g., general health, chronic illness), direct measurement (e.g., overweight status and obesity), and biomarkers. No other data resource with this expanse of genotype and phenotype data on a large nationally representative longitudinal sample with race, ethnic, socioeconomic, and geographic diversity exists. A complete reference guide on study design and accomplishments can be found on the Add Health website: https://cdr.lib.unc.edu/concern/articles/6t053j27s.

  Study phs001367

• Integration of T Cell Repertoire, CyTOF, genotyping and symptomatology data reveals subphenotypic variability in COVID-19 Patients

  A total of 61 patients (33 mild and 28 severe) with a median age of 51 years who recovered from COVID-19 were included in this study (Table 1). All collected samples were confirmed in diagnosis of COVID-19 by RT-PCR and positive IgG serolog. For the 61 patients, TCR-seq, CyTOF, and genotyping data were generated and analyzed in separate studies, as part of larger cohorts. In total, there are 143 variables, with 129 being quantitative (TCRseq and CyTOF metrics) and 13 being qualitative (symptomatology and genotyping). For more information about cohort characteristics, data adquisition an pre-processing, please visit PMID: 39227859, 36969980 and 37287057.

  Dataset EGAD50000000840

• Targeted long-read snIso-Seq of the human brain in neurodegenerative diseases

  Nuclei were extracted from postmortem human brain, and cDNA libraries were generated using the 10X Genomics 3' v3.1 kit. Prior to fragmentation, 75% of the library was reserved for long-read sequencing. This unfragmented library was used for target enrichment with a custom 50 gene probe panel from Twist Biosciences. The resulting amplified cDNA libraries were sequenced on a Sequel II. The files provided have undergone CCS generation, and we recommend following the guidelines in https://isoseq.how/ for further analysis starting with removal of primers using lima. The primer sequences that should be supplied are the Read 1 and TSO primers from the 10X Genomics kit.

  Dataset EGAD50000000179

• 1. Identidication of molecular biological mechanism associated with the development and prognosis of uterine cancer, uterine sarcoma, and endometrial hyperplasia / 2. Identification of molecular biological mechanism associated with the development of endometriosis and malignant transformation, ovarian cancer, fallopian tubal cancer, peritoneal cancer, and other malignant tumors in gynecological organs

  To identify molecular subtypes and carcinogenesis in clear cell ovarian carcinomas by whole-exome sequencing, RNA-sequencing, and methylation array, and to characterize high-grade serous carcinomas by NGS-based, integrative genomic analyses, with focus on homologous recombination deficiency, molecular subtypes and prognositic factors.

  Study JGAS000560

• GeoMx DSP of NGS mRNA expression in pre-treatment biopsies from patients with metastatic triple-negative breast cancer treated with PARP inhibitors.

  This dataset contains GeoMx digital spatial profiling (DSP) data from 12 FFPE pre-treatment biopsies of metastatic HR-altered breast cancer patients subsequently treated with PARP inhibitors (Olaparib or Talazoparib). Samples were collected from primary breast tumors (n=7) and metastatic sites including lymph nodes (n=2), bone (n=2), and brain (n=1). Tissue sections were stained for pan-cytokeratin (PANCK) to selectively profile tumor cells, with NGS-based transcriptome data generated for both PANCK+ and PANCK- regions. The dataset includes raw data files (176 fastq files) along with clinical annotations.

  Dataset EGAD50000001932

• RoCK and ROI single-cell transcriptome of one acute lymphoblastic leukemia patient

  Whole-transcriptome single-cell RNA sequencing (scRNA-seq) was performed following the manufacturer’s protocol (BD Rhapsody, BD Biosciences). Targeted enrichment of BCR::ABL1 transcripts was conducted using the RoCK and ROI-seq approach, based on the barcoded bead technology of the BD Rhapsody platform. In the RoCK and ROI-seq workflow, the template-switch oligonucleotides (TSOs) attached to BD Rhapsody beads were modified with one or multiple capture sequences specific to transcripts of interest, enabling targeted transcript capture during reverse transcription. ROI primers that are added during library preparation to direct amplification and sequencing toward these defined regions of interest (ROIs). Resulting libraries were sequenced on an Illumina sequencer.

  Dataset EGAD50000001976

• Gremlin 1 + fibroblastic niche maintains dendritic cell homeostasis in lymphoid tissues

  Although cross-species transcriptional analysis has been generated for DCs37, transcriptomic conservation between mouse and human FRCs at single-cell resolution has been unclear. To test whether GREM1+ FRCs might also play a role in DC homeostasis in humans, we performed scRNA-seq of CD45–PDPN+ stromal cells, as well as CD45+CD11c+ immune cells from healthy human LNs of three donors.

  Study EGAS00001006211

• HV31 - Read identifier list for local CCS, CLR, ONT and MGI reads

  This file contains read identifiers for local CCS, CLR, ONT and MGI reads for each of the eight selected genomic regions (HLA, KIR, IGH, IGK, IGL, TRA, TRD, andTRG). We extracted these reads by aligning whole-genome sequencing data to a draft whole-genome de novo assembly, and selecting reads that map to contigs representing each region. These reads were involved in the polishing and validation of the HV31 assembly. Please refer to the relevant manuscript (https://doi.org/10.1101/2021.02.03.429586) for additional details. Read identifiers are stored in JSON format. Along with the full FASTQ files, this file enables convenient re-analysis of the HV31 sequencing data in the eight selected regions.

  Dataset EGAD00001007761

• Detection of cancer cell transcriptomes

  Single cell transcriptomes, generated using chromium 10X 3' sequencing, for two tumour types (AT/RT, and Ewing's sarcoma). For each individual, tumour and normal whole genome sequencing was also obtained using Illumina short read sequencing to an average depth of 30X. These data were used to validate the accuracy of a method for identifying cancer cell transcriptomes based on the allelic shift produced by copy number changes.

  Dataset EGAD00001009005

• The BEACCON study: tumour sequencing

  This dataset consists of paired-end DNA sequencing (whole exome and targeted-capture) of tumours for the BEACCON study. There are 240 unique samples consisting of 92 matched tumour-germline pairs and 56 unmatched tumours totalling 148 patients. There are 33 paired and 6 unpaired tumours sequenced using the Agilent SureSelect All Human Exon v6 libraries, 1 paired and 8 unpaired tumours sequenced using Agilent SureSelect All Human Exon v7 libraries and 48 paired and 3 unpaired tumours sequenced using Twist Bioscience Comprehensive Human Exome v1 libraries totalling 176 whole exome samples. There are 3 paired and 58 unpaired tumours sequenced using a custom Agilent SureSelectXT library totalling 64 targeted capture samples.

  Dataset EGAD00001009299

• MPM cell lines

  RNA-sequencing data for 12 MPM cell lines treated with 0.1% DMSO or 1 µM palbociclib for 9-10 days. Experiment was performed in duplicates for sensitive cells (MPM08, MPM21, MPM38, MPM57, MPM59, Meso11, Meso13, Meso34 and Meso56) and only once for resistant cells (MPM31, MPM34 and MPM36) except for Meso11 which was done in triplicates. For Meso11, Meso13, Meso34 and Meso56, a drug washout of 48 hours was also performed. 4 MPM cell lines (MPM31, MPM34, MPM59 and MPM66) were also analyzed in untreated condition. 2 FASTQ files for each sample (n=56) (paired)

  Dataset EGAD00001008741

• Dataset for Sarcoma-WES linked from study EGAS00001004813

  Sequencing data of 144 sarcoma tumor and control runs, which were uploaded to EGAS00001004813. The sequencing was always paired.

  Dataset EGAD00001010258

• Multi-region targeted Sequencing data of 10 neuroblastoma cases

  To investigate intratumour heterogeneity and to better understand tumour evolution in neuroblastoma, we have performed a multi-region targeted re-sequencing on a total of 140 samples from 9 primary neuroblastomas (2 low-risk, 1 intermediate-risk and 6 high-risk) and 2 relapsed neuroblastoma.

  Dataset EGAD00001008156

• Whole genome sequencing of multiple myeloma patient samples.

  Tumor (CD138+ plasma cells) and non-tumor (peripheral blood white cells or stem cell harvest) DNA from patients with a plasma cell dyscrasias were sequenced. Whole genome sequencing using high molecular weight DNA was performed using the 10X Genomics Chromium platform on either a HiSeq4000 or NovaSeq (Illumina) using 100 to 150 bp paired-end reads. The dataset consists of 111 patients, and 223 samples in total (matched tumor and control per patient; one patient had 2 tumor samples sequenced). Diseases consisted of 2 MGUS patients, 8 SMM patients, 91 newly diagnosed myeloma patients, 1 previously treated patient, 4 relapsed MM patients, and 5 PCL patients. Paired RNA-seq data are available for 81 of the samples under study EGAS00001003411.

  Dataset EGAD00001004452

• A Tumour Organoid Biobank for Mapping Cancer Cell Vulnerabilities - RNA

  RNA sequencing data from cancer patient-derived organoids. Part of a study to include genomic and transcriptomic sequencing data, along with CRISPR screening data from cancer patient-derived organoids and matched tumour tissues. Some organoids were developed as part of the Human Cancer Models Initiative (HCMI) in collaboration with Cancer Research UK (CRUK). The study includes organoids derived from colorectal, oesophageal, ovarian, pancreatic, and stomach cancer samples.

  Dataset EGAD00001015470

• Chromatin accessibility (ATAC-seq) and transcriptome (RNA-seq) data from immune cells for healthy young and healthy old subjects

  Dataset consisting of: (1) N=234 genome-wide chromatin accessibility (ATAC-seq) profiles for distinct N=21 healthy old and N=28 healthy young subjects. ATAC-seq biological samples provided for the following tissues: PBMC (N=24), CD14+ monocytes (N=18), CD8+ memory T cells (N=7), CD8+ naive T cells (N=7), CD4+ memory T cells (N=7), CD4+ naive T cells (N=7), and naive B cells (N=7). (2) N=39 genome-wide transcription (RNA-seq) data for distinct N=15 healthy old and N=24 healthy young subjects' PBMCs.

  Dataset EGAD00001003602

• Organoid Derivation Project - WGS (2024-10-14)

  Sequencing of tissue samples and their derived organoids. This dataset contains a subset of colorectal and colorectal liver metastasis samples.

  Dataset EGAD00001015424

• Complex structural variation patterns in pediatric solid tumors WGS

  Paired tumor-normal whole genome sequencing data from primary tumors of patients diagnosed with neuroblastoma, Ewing sarcoma, Wilms tumor, hepatoblastoma and rhabdomyosarcoma

  Dataset EGAD00001011378

• The G2 gene expression signature and MYC overexpression are independent poor prognostic factors in childhood high-grade osteosarcoma

  Key objective Are the prognostic transcriptomic G1/G2 gene expression signature, MYC overexpression, and MYC amplification replicable stratifying biomarkers for future clinical trials in high-grade osteosarcoma? Knowledge gathered In an unselected cohort, the G2 gene expression signature and MYC overexpression, but not MYC amplification, were independently associated with poor event-free and overall survival. Relevance Transcriptomic biomarkers may serve as stratifying factors that guide the management of patients with high-grade osteosarcoma. Current data underlines the importance of prospective validation of the G1/G2 signature and MYC overexpression in an international, multicenter, study.

  Dataset EGAD00001015503

• Lipomatous tumors with 12q amplification

  The project concerns whole genome sequencing (short-read and long-read) and RNA-sequencing of lipomatous tumors with 12q-amplification. A subset of lipomatous tumors is driven by amplification of genes mapping to chromosome arm 12q, including the MDM2 gene. The goals of the study were to compare expression levels of genes mapping to 12q in tumors with amplification in rod-shaped or circularized chromosomes as well as to assess and compare the structural variants in those tumors. In total, 20 samples were analyzed, and the data were correlated with genomic data on bulk and single cell DNA from the same tumors. The fastq files from the tumors were uploaded to EGA.

  Dataset EGAD50000000087

• Synergy study: "Tissue resident CD8+ T cell clonal expansion in advanced triple negative breast cancer is associated with response to chemoimmunotherapy"

  Dataset of 10x Genomics 5'prime single-cell RNA sequencing of 40 tumor biopsy samples or triple negative breast cancer. Samples are taken before and after immuno checkpoint blockade treatment. Processed according the 10X genomics protocol, sequenced on Immumina NovaSeq6000. Raw sequencing reads are further processed with Cellranger 3.0 to get gene-expression matrices.

  Study EGAS50000000527

• Low T cell diversity is associated with poor outcome in bladder cancer - Total RNAseq data

  T cells are crucial effector cells in the endogenous defense against cancer, yet the clinical impact of their quantity, diversity, and dynamics remains underexplored. In this study we performed total RNAseq on blood samples from 8 patients with muscle invasive bladder cancer. The goal was to compare blood T cell subtype composition between patients with low and high TCR diversity.

  Study EGAS50000000939

• Transcriptomic profiling of T cells following ABHD11 inhibition

  This dataset contains paired-end RNA sequencing data from human T cells treated with ML226, a selective ABHD11 inhibitor, and matched vehicle controls. The experiment was designed to investigate the role of ABHD11 in sterol metabolism and its impact on T cell effector function and autoimmunity. Samples were collected across biological replicates following 24-hour treatment, and RNA was extracted for high-throughput sequencing. Sequencing was performed using an Illumina platform. The dataset supports analysis of differentially expressed genes, alternative transcript usage, and pathway-level effects of ABHD11 inhibition. This dataset is part of the study titled "ABHD11 inhibition drives sterol metabolism to modulate T cell effector function and alleviate autoimmunity".

  Dataset EGAD50000001845

• SCANDARE HNSCC 3' Tag RNA-seq

  SCANDARE (NCT03017573) is a multicentric biobanking study, enrolling adult patients with newly diagnosed head and neck squamous cell carcinoma (HNSCC), triple negative breast cancer (TNBC), ovarian and cervical cancer. Tumor tissue and blood samples are collected at several time points during patient's journey, including at diagnosis, post-neoadjuvant chemotherapy in case of neoadjuvant treatment, at surgery, at recurrence and at disease progression following treatment initiated at recurrence. Since its launch in 2017 at Institut Curie, SCANDARE has enabled the longitudinal collection and preservation of samples for in-depth analyses. Here, we describe molecular alterations in 264 FFPE samples at baseline from 90 HNSCC patients using 3'-tag RNA-seq technology, with FASTQ files deposited in the dataset.

  Dataset EGAD50000001655

• SCANDARE TNBC WES data

  SCANDARE (NCT03017573) is a multicentric biobanking study, enrolling adult patients with newly diagnosed head and neck squamous cell carcinoma (HNSCC), triple negative breast cancer (TNBC), ovarian and cervical cancer. Tumor tissue and blood samples are collected at several time points during patient's journey, including at diagnosis, post-neoadjuvant chemotherapy in case of neoadjuvant treatment, at surgery, at recurrence and at disease progression following treatment initiated at recurrence. Since its launch in 2017 at Institut Curie, SCANDARE has enabled the longitudinal collection and preservation of samples for in-depth analyses. Here, we describe molecular alterations in 247 frozen samples at baseline and 138 germline DNA from 139 TNBC patients using WES technology, with FASTQ files deposited in the dataset.

  Dataset EGAD50000001661

• SCANDARE TNBC WGS data

  SCANDARE (NCT03017573) is a multicentric biobanking study, enrolling adult patients with newly diagnosed head and neck squamous cell carcinoma (HNSCC), triple negative breast cancer (TNBC), ovarian and cervical cancer. Tumor tissue and blood samples are collected at several time points during patient's journey, including at diagnosis, post-neoadjuvant chemotherapy in case of neoadjuvant treatment, at surgery, at recurrence and at disease progression following treatment initiated at recurrence. Since its launch in 2017 at Institut Curie, SCANDARE has enabled the longitudinal collection and preservation of samples for in-depth analyses. Here, we describe molecular alterations in 108 FFPE samples at baseline and 108 germline DNA from 108 TNBC patients using WGS technology, with FASTQ files deposited in the dataset.

  Dataset EGAD50000001662

• Summarized somatic variant calls from CMMRD-associated high-grade gliomas

  This dataset contains summarized somatic variant call data derived from paired tumor–blood whole-exome sequencing of human samples. Access to the dataset is controlled and granted only upon submission and approval of a formal data access request. Requests are reviewed by the Data Access Committee led by the Principal Investigator to ensure compliance with applicable legal, ethical, and data protection requirements. Users must not attempt to re-identify study participants and must comply with all relevant confidentiality and data protection regulations. In accordance with local legal and ethical requirements, individual-level raw sequencing data are not shared.

  Dataset EGAD50000002180

• SCANDARE TNBC shallow WGS data

  SCANDARE (NCT03017573) is a multicentric biobanking study, enrolling adult patients with newly diagnosed head and neck squamous cell carcinoma (HNSCC), triple negative breast cancer (TNBC), ovarian and cervical cancer. Tumor tissue and blood samples are collected at several time points during patient's journey, including at diagnosis, post-neoadjuvant chemotherapy in case of neoadjuvant treatment, at surgery, at recurrence and at disease progression following treatment initiated at recurrence. Since its launch in 2017 at Institut Curie, SCANDARE has enabled the longitudinal collection and preservation of samples for in-depth analyses. Here, we describe molecular alterations in 251 frozen samples at baseline from 143 TNBC patients using shallow WGS technology, with FASTQ files deposited in the dataset.

  Dataset EGAD50000001849

• Understand Paratyphoid Disease - host responses to human challenge with S. Paratyphi A (2019-08-28)

  This project aims to evaluate the transcriptional response to disease measured in whole blood of participants who developed enteric fever after challenge and, importantly, those who were challenged but stayed well throughout the challenge period. This data will provide unique coverage of the transcriptome and will yield invaluable insight after integration with a wealth of clinical data collected during this trial. 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 2019-08-28.

  Dataset EGAD00001005298

• RNA-seq of iPSC-derived oligodendrocytes of individuals with and without t(1;11) translocation

  This dataset contains high-throughput RNA-sequencing of 14 samples, each sample comprising oligodendrocytes derived from human induced pluripotent stem cells, from individuals with and without a balanced t(1;11) translocation which substantially increases risk of major mental illness. 5 samples derive from 2 control individuals, and 9 samples from 3 individuals carrying the translocation. Libraries were prepared from each total-RNA sample using the TruSeq Stranded Total RNA with Ribo-Zero kit. Libraries were then sequenced using the NextSeq 500/550 High-Output v2 (150 cycle) Kit on the NextSeq 550 platform. Raw paired-end sequencing data is stored in two FASTQ files per sample.

  Dataset EGAD00001006341

• ATAC-seq dataset of Single cell RNA sequencing reveals induced bifurcated differentiation after RUNX1::RUNX1T1 depletion in patient-derived leukemic blasts

  In this study, we demonstrate that primary AML cells harboring the chromosomal translocation t(8;21) are critically dependent on the corresponding fusion gene, RUNX1::RUNX1T1, to suppress differentiation and maintain stemness. Silencing RUNX1::RUNX1T1 expression using siRNA-loaded lipid nanoparticles induces significant changes in chromatin accessibility, redirecting the leukemia-associated transcriptional network towards a myeloid differentiation program. Single-cell analyses reveal that this transcriptional reprogramming is associated with the depletion of immature stem and progenitor-like cell populations, accompanied by an expansion of granulocytic and eosinophilic/mast cell-like populations with impaired self-renewal capacity.

  Dataset EGAD00001015509

• scRNA-seq dataset of Single cell RNA sequencing reveals induced bifurcated differentiation after RUNX1::RUNX1T1 depletion in patient-derived leukemic blasts

  In this study, we demonstrate that primary AML cells harboring the chromosomal translocation t(8;21) are critically dependent on the corresponding fusion gene, RUNX1::RUNX1T1, to suppress differentiation and maintain stemness. Silencing RUNX1::RUNX1T1 expression using siRNA-loaded lipid nanoparticles induces significant changes in chromatin accessibility, redirecting the leukemia-associated transcriptional network towards a myeloid differentiation program. Single-cell analyses reveal that this transcriptional reprogramming is associated with the depletion of immature stem and progenitor-like cell populations, accompanied by an expansion of granulocytic and eosinophilic/mast cell-like populations with impaired self-renewal capacity.

  Dataset EGAD00001015510

• sWGS on cfDNA and matching tumor DNA in pediatric cancer

  This dataset contains shallow whole genome sequencing data from paired cfDNA - tumor DNA samples of various pediatric cancer entities (total 215 samples). Files are provided in fastq format. Samples were sequenced on an Ion Proton sequencer (Thermo Fisher Scientific) or a Hiseq3000 (Illumina). Data analysis is available at https://github.com/rmvpaeme/sWGS_pediatric_cancer.

  Dataset EGAD00001007508

• WGBS Discovery Samples

  The dataset contains valuable genomic data from a discovery cohort consisting of 29 individuals. This cohort is comprised of 8 healthy individuals (control), 8 patients with ST-segment elevation myocardial infarction (STEMI), 7 patients with non-ST-segment elevation myocardial infarction (NSTEMI), and 6 patients with unstable angina (UA). The genomic data was obtained by isolating cell-free circulating DNA (ccfDNA) and subjecting it to bisulfite conversion using a low-input BS-seq (PBAT) protocol. Sequencing was done on the Novaseq 6000 platform.

  Dataset EGAD00001010935

• Tumor-derived cell lines as pharmacogenomic models to predict therapeutic vulnerabilities in hepatocellular carcinoma

  Hepatocellular carcinoma (HCC) is a heterogeneous aggressive malignancy with low efficacy of current therapies at advanced stages. We integrated molecular and pharmacological profiling of a large panel of liver cancer cell lines (LCCL) to assess their clinical relevance as HCC preclinical models and identify new effective therapies and biomarkers of response. Here, we performed multi-omic analysis including whole-exome, RNA and microRNA sequencing in a series 34 LCCL. Molecular profiles of LCCL and primary HCC were compared and we searched for molecular features associated with drug response. Our panel of LCCL faithfully recapitulated the most aggressive molecular “proliferation class” of HCC.

  Dataset EGAD00001004938

• DPY30 ChIP-seq

  H9 human embryonic stem cells (hESCs) were cultured in feeder-free chemically-defined conditions in medium containing 10ng/ml Activin A and 12ng/ml FGF2 (Vallier L. 2011, Methods in Molecular Biology, 690: 57-66). Chromatin immunoprecipitation was performed as described in Brown S. et al. 2011. Stem Cells 29: 1176-85 by using 5ug of anti-DPY30 antibody (Sigma, cat. number HPA043761). This protocol was performed in control hESCs (expressing a scrambled shRNA) and in hESCs stably expressing an shRNA against DPY30 (Sigma, clone n. TRCN0000131112).This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Dataset EGAD00001001268

• Genomic Evolution of Breast Cancer Metastasis and Relapse

  Recurrent breast cancer is almost universally fatal. We characterize 170 patients locally relapsed or distant metastatic cancers using massively parallel sequencing. We identify that the relapse-seeding clone disseminates late from the primary tumor. TP53 and AKT1 appear to be enriched in ER-positive cancers predisposed to relapse. Mutation acquisition continues at relapse as the same mutation signatures continue to operate and new signatures, such as that caused by radiotherapy appear de novo. In 49% of cases we identify drivers mutations private to the relapse and these are sampled from a wider range of cancer genes, including SWI-SNF complex and JAK-STAT signaling.

  Dataset EGAD00001002698

• Genome-Wide Association Study of Anorexia Nervosa (Price Foundation, Klarman Family Foundation, Center for Applied Genomics at the Children's Hospital of Philadelphia, Scripps Translational Sciences Institute Clinical Translational Science Award)

  Twin studies are consistent with substantial heritability in anorexia nervosa (AN), although detecting and confirming individual risk alleles has been difficult, due to small effects of single alleles and limited samples in prior studies. Methods: 1105 AN DNA samples obtained in a multisite study and 3733 pediatric patients of normal body weight were genotyped using the Illumina 610Q chip at The Center for Applied Genomics at The Children's Hospital of Philadelphia. Cases and controls were of European ancestry. Single nucleotide polymorphism (SNP) genotypes were subjected to quality control procedures, including elimination of SNPs with: call rates < 95%, minor allele frequency < 5%, and if Hardy-Weinberg equilibrium testing yielded p < 0.0001. Samples were removed if not of European ancestry or if showing cryptic relatedness. Eight AN DNA samples were deleted for low call rate, and 51 AN samples were deleted for cryptic relatedness. The statistical program, PLINK, was used to calculate a P value for each SNP passing quality control using the Cochran-Armitage trend test. The PennCNV program was used to define copy number variation (CNV). Results: We performed a genome-wide association study (GWAS) using with 1033 AN cases and 3733 controls (genomic inflation factor = 1.08). There were 11 SNPs with P<1X10-5 [(rsID, chromosome location, nearest gene, distance to nearest gene (base-pair), P value) rs6959888, 7q21.13, ZNF804B, 0, 1.63E-06; rs17725255, 20p11.23, CSRP2BP, 39396, 1.72E-06; rs10494067, 1p13.3, NTNG1, 0, 5.83E-06; rs2383378, 14q12, AKAP6, 0, 6.41E-06; rs410644, 5q14.1, SSBP2, 40462, 6.74E-06; rs4479806, 5p14.1, CDH9, 156926, 7.79E-06; rs957788, 13q33.3, FAM155A, 0, 8.11E-06; rs830998, 2q31.1, LRP2, 0, 8.68E-06; rs6782029, 3p25.3, VGLL4, 0, 9.04E-06; rs512089, 9p21.3, ELAVL2, 47984, 9.85E-06; rs3808986, 11q24.3, APLP2, 29217, 9.92E-6]. CNV analyses were performed on 1015 AN cases and 3532 controls. Overall frequencies of common or rare CNVs were similar between cases and controls. Specific rare and large (>500 kb, <1%) CNVs of interest included deletion of a large (~1.4Mbp) region of chr13q12 found in 2 AN samples and at a 10 fold lower frequency in a large sample (72,918) of subjects containing the genes SGCG, SACS, TNFRSF19, MIPEP, PCOTH, C1QTNF9B, SPATA13, MIR2276, and C1QTNF9, and an overlapping deletion and a duplication observed in 3 AN samples overlapping the CNTN6 and CNTN4 genes. Partially overlapping ~ 30 kb duplications were seen in 12 AN cases and in 1 control at the CDC5L gene on chromosome 6. Partially overlapping deletion of the 3' half of the PSTPIP1 gene was seen in 5 AN cases and no controls. Finally, a ~ 60 kb deletion of the PLEC1 gene was observed in 5 AN cases and in none of 3532 controls. Discussion: This is the first GWAS of AN. These preliminary results are consistent with absence of a major gene effect in AN. These results are consistent with genetic risk conveyed by multiple common alleles of small effect, as well as some uncommon CNVs of potentially larger effect. None of the implicated genes has a clear role in eating behavior. It must be emphasized that these results are preliminary and an additional ~ 400 AN cases will be analyzed as time and resources permit. These results require confirmation through study of independent populations of AN women.

  Study phs000679

• Women's Health Initiative Clinical Trial and Observational Study

  The Women's Health Initiative (WHI) is a long-term national health study that has focused on strategies for preventing heart disease, breast and colorectal cancer, and osteoporotic fractures in postmenopausal women. The original WHI study included 161,808 postmenopausal women enrolled between 1993 and 1998. The Fred Hutchinson Cancer Research Center in Seattle, WA serves as the WHI Clinical Coordinating Center for data collection, management, and analysis of the WHI. The WHI has two major parts: a partial factorial randomized Clinical Trial (CT) and an Observational Study (OS); both were conducted at 40 Clinical Centers nationwide. The CT enrolled 68,132 postmenopausal women between the ages of 50-79 into trials testing three prevention strategies. If eligible, women could choose to enroll in one, two, or all three of the trial components. The components are: Hormone Therapy Trials (HT): This double-blind component examined the effects of combined hormones or estrogen alone on the prevention of coronary heart disease and osteoporotic fractures, and associated risk for breast cancer. Women participating in this component with an intact uterus were randomized to estrogen plus progestin (conjugated equine estrogens [CEE], 0.625 mg/d plus medroxyprogesterone acetate [MPA] 2.5 mg/d] or a matching placebo. Women with prior hysterectomy were randomized to CEE or placebo. Both trials were stopped early, in July 2002 and March 2004, respectively, based on adverse effects. All HT participants continued to be followed without intervention until close-out. Dietary Modification Trial (DM): The Dietary Modification component evaluated the effect of a low-fat and high fruit, vegetable and grain diet on the prevention of breast and colorectal cancers and coronary heart disease. Study participants were randomized to either their usual eating pattern or a low-fat dietary pattern. Calcium/Vitamin D Trial (CaD): This double-blind component began 1 to 2 years after a woman joined one or both of the other clinical trial components. It evaluated the effect of calcium and vitamin D supplementation on the prevention of osteoporotic fractures and colorectal cancer. Women in this component were randomized to calcium (1000 mg/d) and vitamin D (400 IU/d) supplements or a matching placebo. The Observational Study (OS) examines the relationship between lifestyle, environmental, medical and molecular risk factors and specific measures of health or disease outcomes. This component involves tracking the medical history and health habits of 93,676 women not participating in the CT. Recruitment for the observational study was completed in 1998 and participants were followed annually for 8 to 12 years. Extension Studies: The original protocol allowed for follow-up until March 2005, after which participants were invited to enroll in the first WHI Extension Study for follow-up through 2010. Participants were invited again to participate in the second WHI Extension Study with continued follow up from 2010 to at least 2015. As of March 31, 2011 there were 93,122 women enrolled in the second extension. In Extension Study 2, the overall WHI study population was divided into two new subsamples, the Medical Records Cohort (MRC) and the Self-Report Cohort (SRC). The MRC consists of all former hormone trial participants and all African American and Hispanic participants from all study components. The SRC consists of the remaining participants. The extent of outcome information collected differs between the two cohorts, with more extensive outcomes information collection on the MRC. As part of Extension Study 2, selected older WHI participants were invited to participate in an In Person Visit (a.k.a., Long Life Study) at their homes during which additional blood samples were collected and various measurements were taken (such as blood pressure, height, weight, waist circumference, grip strength, etc.). In October 2015, Extension Study 2 was renewed with continued follow-up planned through October 2020, pending annual contract review and renewal. Additional Information: The WHI website, https://www.whi.org/about/SitePages/About%20WHI.aspx has much more information about the study. For WHI data collection forms used over the years, please see https://www.whi.org/researchers/studydoc/SitePages/Forms.aspx. For additional dataset documentation, see https://www.whi.org/researchers/data/Pages/Available%20Data.aspx. For data preparation and use, please refer to 'WHI dbGaP Cohort Data Release Data Preparation Guide May 2018' for additional details about the WHI data. The WHI 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 phs000200 WHI Cohort. phs000386 WHI SHARe phs000281 GO-ESP WHISP phs000315 WHI GARNET phs000503 WHISE phs000227 PAGE WHI phs000675 WHIMS+ phs000746 WHI Harmonized and Imputed GWAS phs001334 WHI Metabolomics of CHD phs001335 WHI BA23 phs001614 WHI LLS Phase III GWAS

  Study phs000200

• Olink Explore Protein Expression

  Serum samples (DC, CRSsNP, CRSwNP, N-ERD, n=20 each) were subjected to the Olink Explore 3072 analysis including the following panels: Olink Explore 384 Cardiometabolic and Cardiometabolic II, Olink Explore 384 Inflammation and Inflammation II, Olink Explore 384 Neurology and Neurology II, Olink Explore Oncology and Oncology II. The latter had 4 failed samples. From the originally 2925 unique proteins determined, 84 proteins had missing values in all samples and were removed. Further 164 proteins had >50% of values below LOD across all four groups and were removed with remaining values below threshold adjusted to LOD. This data cleaning left 2695 unique assays (2677 unique proteins) in serum to be analysed. Additionally, six assays (LMOD1, IDO1, SCRIB, CXCL8, IL6, TNF) were measured four times each in different panel.

  Dataset EGAD50000001327