16624 results for "sec+and+unspecified+malignant+neoplasm"

in 43.27 milliseconds.

• Single-cell transcriptional mapping reveals genetic and hierarchy-based determinants of aberrant differentiation in AML

  Therapeutic targeting of acute myeloid leukemia (AML) has in part been hampered by profound cell state heterogeneity among leukemia cells. To develop a more precise understanding of leukemia cell states in AML, we constructed a reference atlas of human hematopoiesis from 263,519 single cell transcriptomes spanning 55 cellular states. Using this atlas, we mapped over 1.2 million single-cell transcriptomes spanning 318 myeloid leukemia samples. This uncovered twelve recurrent patterns of aberrant differentiation in AML and additional leukemia cell states involving lymphoid and erythroid progenitors. Systematic mapping of genotype-to-phenotype associations revealed specific differentiation landscapes associated with >45 genetic drivers. Importantly, AML samples sharing common genetic driver alterations can have distinct cellular origins which inform the cellular identity of their disease-sustaining leukemia stem cell (LSC). Further, distinct LSC-driven hierarchies can co-exist within individual patients. Thus, precise mapping of malignant cell states provides insights into leukemogenesis, refines disease classification, and informs therapy development.

  Study EGAS50000000918

• ScRNA sequencing and snp-array genotyping of peripheral immune cells in Type 1 diabetes mellitus (T1DM)

  Type 1 diabetes mellitus (T1DM) is a prototypic endocrine autoimmune disease resulting from an immune-mediated destruction of pancreatic insulin-secreting beta-cells. A comprehensive immune cell phenotype evaluation in T1DM has not been performed thus far at the single. In this cross-sectional analysis, we generated a single-cell transcriptomic dataset of peripheral blood mononuclear cells (PBMCs) from 46 manifest T1DM (Stage 3) cases and 31 matched controls.Our study reveals a surprisingly strong systemic dimension at the level of immune cell network in T1DM, defines disease-relevant molecular subtypes and has the potential to guide non-invasive test development and patient stratification.

  Dataset EGAD50000000345

• GEX CITE-Seq performance dataset

  To understand the impact of enzymatic treatments on gene expression and epitope preservation on major immune cell populations, skin dissociation (SkinD) and solid soft tumor dissociation (TumorD) were tested on three healthy PBMC samples in triplicate (D1, D2, D3), against an untreated control. CITE-seq performance was assessed on a solid biopsy cohort of 11 samples (5 healthy skin samples, 3 primary melanoma samples, 3 melanoma metastasis samples) as well as on a liquid biopsy PBMC cohort consisting of three healthy donors and three immunotherapy-treated melanoma patients. This dataset contains the GEX data for each sample. Data is provided in the form of pooled BAM files. Linkage between samples, BAM files and hashtags is provided in a separate linkage file.

  Dataset EGAD00001008418

• ADT/SPEX CITE-Seq performance dataset

  To understand the impact of enzymatic treatments on gene expression and epitope preservation on major immune cell populations, skin dissociation (SkinD) and solid soft tumor dissociation (TumorD) were tested on three healthy PBMC samples in triplicate (D1, D2, D3), against an untreated control. CITE-seq performance was assessed on a solid biopsy cohort of 11 samples (5 healthy skin samples, 3 primary melanoma samples, 3 melanoma metastasis samples) as well as on a liquid biopsy PBMC cohort consisting of three healthy donors and three immunotherapy-treated melanoma patients. This dataset contains the ADT/SPEX data for each sample. Data is provided in the form of pooled BAM files. Linkage between samples, BAM files and hashtags is provided in a separate linkage file.

  Dataset EGAD00001008419

• SUM-seq data for Primary T-cells differentiated to helper subtypes

  Briefly, naive CD4+ T cells were isolated from PBMCs obtained from buffy coats from three healthy human donors, and differentiated into Th0, iTreg, Th2, Th1, Th17, and IFN-β-activated subsets. This allowed us to study the differentiation of naive CD4+ T cells into distinct helper subsets under the influence of a specific cytokine environment. Following 5 days of differentiation, T cells were left unstimulated or re-stimulated with phorbol 12-myristate 13-acetate (PMA) and ionomycin to assess their functional responses. Thus, this SUM-seq experiment consisted of 36 multiplexed conditions (3 donors x 6 stimulations x with/without re-stimulation). Single-cell chromatin accessibility and gene expression data is provided as demultiplexed fastq files.

  Dataset EGAD50000001204

• WES

  Exome Sequencing. 3 ug of genomic DNA from each lymph node sample were sheared and used for the construction of a paired-end sequencing library as described in the paired-end sequencing sample preparation protocol provided by Illumina. Enrichment of exonic sequences was then performed for each library using either the Sure Select Human All Exon 50 Mb or All Exon+UTRs v4 kits following the manufacturer’s instructions (Agilent Technologies). Exon-enriched DNA was pulled down by magnetic beads coated with streptavidin (Invitrogen), followed by washing, elution and 18 additional cycles of amplification of the captured library. Enriched libraries were sequenced in one lane of an Illumina GAIIx sequencer or in two lanes of a HiSeq2000 when using pools of eight samples.

  Dataset EGAD00001005424

• Sequencing data from a phase II study of nivolumab and ipilimumab in recurrent or refractory cancer of unknown primary (CheCUP trial)

  Sequencing data from a phase II study of nivolumab and ipilimumab in recurrent or refractory cancer of unknown primary (CheCUP trial). Panel sequencing data from baseline FFPE biopsies were used to perform a comprehensive genomic profiling of CUP metastases. Combined targeted next-generation sequencing of patient-specific hotsport mutations and shallow whole genome sequencing of baseline and follow-up liquid biopsy samples were used to analyze ctDNA and to evaluate response to immunei checkpoint inhibitor treatment. In some cases, whole exome sequencing of peripheral blood mononuclear cells was performed to screen for potential CHIP and germline mutations.

  Dataset EGAD00001011130

• 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

• Combined clinical and gene expression score identifies high-risk individuals among follicular lymphoma patients on immunotherapy

  Follicular lymphoma (FL) is usually an indolent malignant B-cell lymphoma, but at least 30% of the patients experience transformation to Diffuse Large B-cell Lymphoma (DLBCL) with inferior survival. Early identification of patients with poor prognosis is essential for tailoring treatment. Here, we describe a network-based integrative analysis of 168 FL-biopsies from 127 patients with long clinical follow-up and transformation status. A distinct shift in expression towards a DLBCL expression phenotype is observed in BTK associated genes in cases with transformation. This shift is present years prior to transformation. An integrated score combining the BTK score and a clinical index is proposed, termed the BTK-FLIPI score. It identifies patients (16%) with very poor prognosis, with median time to progression 21.7 months (95% CI: 14.3-42.6) versus 70.9 months (95% CI: 41.5-95.0) for the remainder. The results suggest BTK as a potential target for treatment of high-risk FL-patients.

  Study EGAS00001002566

• McGill EMC Community projects Release 7 for cell line "lung epithelial"

  Complete reference epigenome (as defined by IHEC) of a lung epithelial cell line with non-small Cell Lung Adenocarcinoma

  Dataset EGAD00001007679

• McGill EMC Community projects Release 7 for cell line "hTERT RPE1"

  Complete reference epigenome (as defined by IHEC) of normal hTERT RPE1 cell line as well as hTERT RPE1 cell lines engineered to express EPC1-PHF1 and JAZF1-SUZ12 fusion proteins, found in Endometrial Stromal Sarcoma.

  Dataset EGAD00001007680

• Influence of culture media on airway differentiation at the Air-Liquid Interface

  Single-cell dataset of human airways after in vitro regeneration at the Air-Liquid Interface. Samples from 2 donors were used for the establishment of Human Bronchial Epithelial Cell cultures (HBECs) and were analyzed during proliferation, at the onset of differentiation (ALI0) and after full differentiation (ALI28), in 4 distinct culture media. Single-cell RNAseq was performed with 10x Genomics 3’ v2 RNA-seq using hashtag antibodies for multiplexing, and sequenced on a NextSeq 500. Samples from 3 additional donors were used for the establishment of Human Nasal Epithelial Cell cultures (HNECs) and were analyzed during proliferation in three distinct culture media. Single-cell RNAseq was performed with 10x Genomics 3’ v3 RNA-seq without multiplexing, and sequenced on a NextSeq 2000.

  Dataset EGAD00001011362

• Molecular analyses of stage IIIa NSCLC patients treated with neoadjuvant chemmoimmuntherapy

  This dataset comprises molecular and immunogenomic profiles from 60 individual NSCLC patients (30 male, 30 female), with samples collected at multiple timepoints including initial biopsies (IB), resections (RES), and peripheral blood mononuclear cells (PBMC) at different timepoints during treatment. It includes 32 FFPE tumor samples sequenced on Illumina with the FoundationOne panel, 20 FFPE samples sequenced on IonTorrent with the Oncomine Comphrehensive Assay Plus, and 41 samples assessed with IonTorrent via Oncomine Immune Response Research Assay panel for targeted gene expression. T-cell receptor (TCR) repertoire profiling was performed on 62 tumor samples (initial biopsies and resections, Oncomine TCR Beta-SR Assay), and 155 blood-derived samples were sequenced with Oncomine TCR Beta-LR Assay. Data files include processed sequencing results in bam format.

  Dataset EGAD50000001630

• 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

• The Mutational Landscape of CTCL and Sezary Syndrome

  Sezary syndrome is a leukemic and aggressive form of cutaneous T-cell lymphoma (CTCL) resulting from the malignant transformation of skin-homing central memory CD4+ T cells. To identify new genetic alterations involved in Sezary syndrome and CTCL transformation we performed whole-exome sequencing of tumor-normal sample pairs from 26 Sezary syndrome and 16 CTCL patients. These analyses revealed a distinctive pattern of somatic copy number alterations in Sezary syndrome including highly prevalent recurrent chromosomal deletions involving the TP53, RB1, PTEN, DNMT3A, and CDKN1B tumor suppressor genes. Mutation analysis identified a broad spectrum of somatic mutations involving key genes involved in epigenetic regulation (TET2, CREBBP, MLL3, BRD9, SMARCA4 and CHD3) and signaling, including mutations in MAPK1, BRAF, CARD11 and PRKG1 driving increased MAPK, NFKB and NFAT activity upon T-cell receptor stimulation. Collectively, our findings provide new insights into the genetics of Sezary syndrome and CTCL and support the development of personalized therapies targeting key oncogenically activated signaling pathways for the treatment of these diseases.

  Study phs000994

• Health Information National Trends Survey-SEER (HINTS-SEER)

  HINTS-SEER is a cross-sectional survey that sampled cancer survivors from three different SEER cancer registries. Sampling frames of survivors from each registry were stratified by time since diagnosis and race/ethnicity, with non-malignant tumors and non-melanoma skin cancers excluded. Respondents who consented completed a self-administered questionnaire sent through the mail and resulted in a total sample of 1,234 respondents. The goal of HINTS-SEER was to better understand the communication needs and practices, information preferences, risk behaviors and cancer knowledge of cancer survivors using a modified version of the Health Information National Trends Survey (HINTS) specifically designed for cancers survivors. Demographic information on the survivors showed that over 60% of the sample was 10 or more years since diagnosis with the most common cancers being male reproductive (24.6%), female breast (23%) and melanoma (9.6%) and gastrointestinal (8.6%). De-identified data is available in SAS, SPSS, and STATA formats, as part of a data package that also includes a history document, methodology report, data analysis recommendations, and a codebook.

  Study phs004065

• Ovarian cancer organoid biobank

  Ovarian cancer (OC) is a heterogeneous disease usually diagnosed at a late stage. Experimental in vitro models that faithfully capture the hallmarks and tumor heterogeneity of OC are limited and hard to establish. We present a novel protocol that enables efficient derivation and long-term expansion of OC organoids. Utilizing this protocol, we have established 56 organoid lines from 32 patients, representing the spectrum of ovarian neoplasms, including non-malignant borderline tumors, as well as mucinous, clear-cell, endometrioid, low- and high-grade serous carcinomas. OC organoids recapitulate histological and genomic features of the pertinent lesion from which they were derived, illustrating intra- and inter-patient heterogeneity, and can be genetically modified. We show that OC organoids can be used for drug screening assays and capture different tumor subtype responses to the gold standard platinum-based chemotherapy, including acquisition of chemoresistance in recurrent disease. Finally, OC organoids can be xenografted, enabling in vivo drug sensitivity assays. Taken together, this demonstrates their potential application for research and personalized medicine.

  Study EGAS00001003073

• 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

• Mesenchymal inflammation drives genotoxic stress in hematopoietic stem cells and predicts disease evolution in human pre-leukemia

  Mesenchymal niche cells may drive tissue failure and malignant transformation in the hematopoietic system but the molecular mechanisms and their relevance to human disease remain poorly defined. We demonstrated that perturbation of mesenchymal cells in a mouse model of the preleukemic disorder Shwachman-Diamond syndrome induces mitochondrial dysfunction, oxidative stress and activation of DNA damage responses in hematopoietic stem and progenitor cells. In this study we demonstrate, through massive parallel RNA sequencing of highly purified mesenchymal cells in a range of human preleukemic syndromes, TP53-S100A8/9-TLR4 inflammatory signaling as a common driving mechanism of genotoxic stress, which could be attenuated by TLR4 blockade. S100A8/9 expression in mesenchymal cells predicted outcome in myelodysplastic syndromes, the principal human preleukemic condition, independent of known prognostic variables. Collectively, findings reveal a concept of mesenchymal niche-induced genotoxic stress in heterotypic stem and progenitor cells through inflammatory signaling as an actionable determinant of disease outcome in human preleukemia. The data further provide novel conceptual and mechanistic insights into the intimate link between inflammation and cancer.

  Study EGAS00001001926

• Spatial transcriptomics reveal topological immune landscapes of Asian head and neck angiosarcoma

  Angiosarcomas are rare malignant tumors of the endothelium, arising commonly from the head and neck region (AS-HN) and recently associated with ultraviolet (UV) exposure and human herpesvirus-7 (HHV-7) infection. We examined 81 cases of angiosarcomas, including 47 cases of AS-HN, integrating information from whole genome sequencing, gene expression profiling and spatial transcriptomics (10X Visium). In the AS-HN cohort, we observed recurrent somatic mutations in CSMD3 (18%), LRP1B (18%), MUC16 (18%), POT1 (16%) and TP53 (16%). UV-positive AS-HN harbored significantly higher tumor mutation burden (TMB) than UV-negative cases (p=0.0294). NanoString profiling identified three clusters with distinct tumor inflammation signature (TIS) scores (p<0.001). Spatial transcriptomics revealed topological profiles of the tumor microenvironment, identifying dominant but tumor-excluded inflammatory signals in “immune-hot” cases and immune foci even in otherwise “cold” cases. In conclusion, spatial transcriptomics reveal the tumor immune landscape of angiosarcoma, and in combination with multi-omic information, may improve implementation of treatment strategies.

  Study EGAS00001007083

• Evolutionary trajectories of IDH-mutant astrocytoma identify molecular grading markers related to cell cycling

  To study the evolutionary processes that drive malignant transformation in IDH-mutant astrocytomas, we performed multi-omics on a large cohort of matched initial and recurrent tumor samples. We find that genome-wide DNA-methylation levels decreased over time, mainly in patients with high-grade recurrences. DNA-demethylation was lifted from specific loci associated with DNA replication, and was associated with upregulation of cell cycling associated genes. Upregulation of cell cycling genes occurred predominantly in proliferating tumor cells, and was associated with tumor grade. Temporal DNA-demethylation and upregulation of cell cycling were hardly affected by chemo- and/or radiotherapy, indicating treatment does not affect the course of disease. Further, we defined a DNA-methylation based signature associated with tumor grade and poor prognostic genetic events, with a prognostic power stronger than CDKN2A/B deletion. We validated its prognostic power on primary tumor samples of patients included in the CATNON randomized phase 3 clinical trial. Therefore this model can serve as a molecular grading marker for IDH-mutant astrocytomas.

  Study EGAS00001007527

• 16S V3-V4 sequencing of lung microbiota from 17 NSCLC patients eligible for surgery without neoadjuvant treatment

  This dataset is composed of 86 samples: 15 samples of bronchoalveolar lavage fluid (BAL), 17 samples of non-malignant lung tissue, 14 samples of peritumoural tissue, 16 tumour tissues, 8 negative DNA extraction controls, 16 negative sampling controls for BAL. Samples were obtained from 17 NSCLC patients (average age 68 years). Sequenced region was 16S V3-V4. Fastq files are provided.

  Dataset EGAD00001006567

• RNA-seq data from the MESOMICS project (French project of molecular characterization of malignant pleural mesothelioma)

  The dataset includes fastq files from 109 tumor samples as well as RNA-seq gene expression R data, RNA-seq transcript expression R data, RNA-seq gene counts matrix, RNA-seq transcript counts matrix, RNA-seq gene FPKM matrix RNA-seq transcript FPKM matrix for the 109 samples. The sequencing was done with HiSeq 2000 instrument.

  Dataset EGAD00001007024

• Gene expression adaptation of metastases to their host tissue

  The adaptation of metastatic cells to their host tissue critically determines the pathogenicity of a cancer and therefore patient survival. Yet, it remains elusive to what extent the host environment drives gene expression programs in metastatic cells. Here we identify adaptive mechanisms that enable metastases to establish themselves in a novel tissue context. We performed single-cell RNA-sequencing on malignant and benign tissue samples from untreated donors with colorectal adenocarcinoma and liver metastasis to deduce tissue adaptive expression patterns. A novel computational approach identified genes and pathways that consistently adapted to the host tissue at the transition from the primary tumor to the paired metastasis across donors. This analysis revealed that the majority of expression changes in the metastasis reflect an expression signature reminiscent of benign liver epithelial cells. Cellular processes adapting to the liver environment include basic cellular functions such as energy metabolism, as well as tissue-specific pathways such as the regulation of lipid metabolism by PPAR-α. These adaptations potentially increase the pathogenicity of the metastatic cells and may provide new therapeutic strategies.

  Study EGAS50000000817

• Population_dynamics_in_abnormal_haematopoiesis

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

  Study EGAS00001003181

• Evaluating gene expression in aggressive B-cell lymphoma using a quantitative nuclease protection assay

  Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL), comprising 25-30% of all NHL in developed countries with an annual incidence in the USA of 7 cases/100000 persons/year. Collectively, DLBCL is classified based on a common morphological appearance of diffuse growth of large transformed B-cells, immunophenotype, high proliferation rate and aggressive behaviour. Despite these similarities, DLBCLs are a heterogeneous collection of malignancies with distinct clinical and molecular characteristics that do not always correlate with immunohistological features. This gene expression dataset includes transcriptomes of ABC-DLBCLs and of GCB-DLBCLs where cell of origin is determined by the HTG-EdgeSeq quantitative nuclease protection assay. Also included are clonality results from BCR profiling from high-grade B-cell lymphomas sequenced using a NOVA sequencer

  Dataset EGAD00001011309

• Genetic analysis of HLA and immune escape genes in Diffuse Large B-cell Lymphoma

  We performed genetic analysis of HLA and immune escape genes in samples from 44 patients sequenced by whole exome sequencing (34 tumor samples, 32 normal samples) and whole genome sequencing (10 tumor samples, 12 normal samples). We also performed HLA targeted sequencing in 26/44 patients (26 tumor samples, 26 normal samples).

  Dataset EGAD00001007565

• Low-coverage whole genome sequencing for a highly selective cohort of severe COVID-19 patients

  We generated a dataset consisting of 79 VCF files, and respective FASTQ and CRAM files, methodically generated using the GLIMPSE1 imputation algorithm leveraging the 1000 Genomes Project Phase 3 dataset as the reference panel of haplotypes. In total this dataset is composed of approximately 325 GB of FASTQ data, 156 GB of CRAM data, and 6 GB of VCF data. Our samples were specifically derived from sequenced DNA from a highly selective cohort of patients, mostly comprised of Iberian Populations in Spain (IBS) individuals but also containing some individuals with other genetic backgrounds, who presented severe COVID-19 symptoms during the initial wave of the SARS-CoV-2 pandemic in Madrid, Spain. On average, each VCF file in this rich dataset contains 9.49 million high-confidence single nucleotide variants [95%CI: 9.37 million - 9.61 million].

  Dataset EGAD00001011363

• EstMB cohort participants sequenced with MGISEQ-2000 platform

  Participants collected a fresh stool sample immediately after defecation using a sterile Pasteur pipette and placed it in a 15 mL conical polypropylene tube. They were instructed to collect the sample as close as possible to their study center visit. Samples were transported and stored at −80 °C until DNA extraction. Microbial DNA was extracted from 200 mg of stool using a QIAamp DNA Stool Mini Kit (Qiagen), following manufacturer's instructions, after all samples were collected. DNA was quantified using a Qubit 2.0 Fluorometer with a dsDNA Assay Kit (Thermo Fisher Scientific). Library preparation and circularization of equimolarly pooled libraries were done with MGIEasy FS DNA Library Prep Set (MGI Tech Co, Ltd, Shenzhen, China) according to the standard protocol. The sequencing was performed with MGISEQ-2000 High-throughput Sequencing Set (FCL PE150) according to the manufacturer’s instructions (MGI Tech, Shenzhen, China)

  Dataset EGAD50000002213

• Analysis of DNA methylation in normal B cells and chronic lymphocytic leukemia

  Charting differences between tumors and normal tissue is a mainstay of cancer research. However, clonal tumor expansion from complex normal tissue architectures potentially obscures cancer-specific events, including divergent epigenetic patterns. Using whole-genome bisulfite sequencing of normal B cell subsets, we observed broad epigenetic programming of selective transcription factor binding sites coincident with the degree of B cell maturation. By comparing normal B cells to malignant B cells from 268 patients with chronic lymphocytic leukemia (CLL), we showed that tumors derive largely from a continuum of maturation states reflected in normal developmental stages. Epigenetic maturation in CLL was associated with an indolent gene expression pattern and increasingly favorable clinical outcomes.As second study using these samples focued on evolution and resulting intra-tumor heterogeneity in CLL. We used 450k bead-chip arrays to study DNA methylomes in 68 chronic lymphocytic leukemia (CLL) cases, including 28 serial cases. The result establishs linked evolution of epigenetic and genetic alterations in progressive disease, revealing an important aspect of the biology of epigenetics in cancer.

  Study EGAS00001000534

• Exploring the driver events of eccrine poromas and porocarcinomas: A retrospective, cross-institutional study of 90 cases

  Eccrine poroma (EP) and porocarcinoma (EPC) are rare benign and malignant adnexal neoplasms of the terminal sweat gland duct, respectively. Both can arise de novo, however, EPCs can also arise from a pre-existing EP. To-date, genetic investigation of these tumors has involved studies with small sample sizes and/or limited analyses. To comprehensively compare the driver events and mutational landscape of these tumors, we performed a retrospective multi-institutional whole-exome sequencing and RNA sequencing study on the largest cohort of EPs and EPCs to-date (n=90). We uncovered novel events and delineated different pathways of tumorigenesis underlying these tumors, with EPs driven largely by fusion genes, and EPCs driven largely by somatic mutations, with rare YAP1 and frequent PAK gene novel fusions.

  Dataset EGAD00001015378

• Exploring the driver events of eccrine poromas and porocarcinomas: A retrospective, cross-institutional study of 90 cases

  Eccrine poroma (EP) and porocarcinoma (EPC) are rare benign and malignant adnexal neoplasms of the terminal sweat gland duct, respectively. Both can arise de novo, however, EPCs can also arise from a pre-existing EP. To-date, genetic investigation of these tumors has involved studies with small sample sizes and/or limited analyses. To comprehensively compare the driver events and mutational landscape of these tumors, we performed a retrospective multi-institutional whole-exome sequencing and RNA sequencing study on the largest cohort of EPs and EPCs to-date (n=90). We uncovered novel events and delineated different pathways of tumorigenesis underlying these tumors, with EPs driven largely by fusion genes, and EPCs driven largely by somatic mutations, with rare YAP1 and frequent PAK gene novel fusions.

  Dataset EGAD00001015376

• Exploring the driver events of eccrine poromas and porocarcinomas: A retrospective, cross-institutional study of 90 cases

  Eccrine poroma (EP) and porocarcinoma (EPC) are rare benign and malignant adnexal neoplasms of the terminal sweat gland duct, respectively. Both can arise de novo, however, EPCs can also arise from a pre-existing EP. To-date, genetic investigation of these tumors has involved studies with small sample sizes and/or limited analyses. To comprehensively compare the driver events and mutational landscape of these tumors, we performed a retrospective multi-institutional whole-exome sequencing and RNA sequencing study on the largest cohort of EPs and EPCs to-date (n=90). We uncovered novel events and delineated different pathways of tumorigenesis underlying these tumors, with EPs driven largely by fusion genes, and EPCs driven largely by somatic mutations, with rare YAP1 and frequent PAK gene novel fusions.

  Dataset EGAD00001015377

• Exploring the driver events of eccrine poromas and porocarcinomas: A retrospective, cross-institutional study of 90 cases

  Eccrine poroma (EP) and porocarcinoma (EPC) are rare benign and malignant adnexal neoplasms of the terminal sweat gland duct, respectively. Both can arise de novo, however, EPCs can also arise from a pre-existing EP. To-date, genetic investigation of these tumors has involved studies with small sample sizes and/or limited analyses. To comprehensively compare the driver events and mutational landscape of these tumors, we performed a retrospective multi-institutional whole-exome sequencing and RNA sequencing study on the largest cohort of EPs and EPCs to-date (n=90). We uncovered novel events and delineated different pathways of tumorigenesis underlying these tumors, with EPs driven largely by fusion genes, and EPCs driven largely by somatic mutations, with rare YAP1 and frequent PAK gene novel fusions.

  Dataset EGAD00001015379

• November 2020 data update (fastq) for reference epigenomes generated at Centre for Epigenome Mapping Technologies, Genome Sciences Center, B.C. Cancer Agency as part of the International Human Epigenome Consortium.

  November 2020 data update (fastq) for reference epigenomes generated at Centre for Epigenome Mapping Technologies (Canadian Epigenetics, Environment and Health Research Consortium), Genome Sciences Center, B.C. Cancer Agency, Vancouver, Canada as part of the International Human Epigenome Consortium.

  Dataset EGAD00001007529

• BLUEPRINT release August 2016, ChIP-Seq for monocyte - RPMI_T=24hrs, on genome GRCh38

  ChIP-Seq data for 3 monocyte - RPMI_T=24hrs sample(s). 7 run(s), 7 experiment(s), 7 analysis(s) on human genome GRCh38. Part of BLUEPRINT release August 2016. Analysis documentation available at http://ftp.ebi.ac.uk/pub/databases/blueprint/releases/20160816/homo_sapiens/README_chipseq_analysis_ebi_20160816

  Dataset EGAD00001002474

• BLUEPRINT release August 2016, ChIP-Seq for monocyte - RPMI_LPS_T=24hrs, on genome GRCh38

  ChIP-Seq data for 3 monocyte - RPMI_LPS_T=24hrs sample(s). 8 run(s), 8 experiment(s), 8 analysis(s) on human genome GRCh38. Part of BLUEPRINT release August 2016. Analysis documentation available at http://ftp.ebi.ac.uk/pub/databases/blueprint/releases/20160816/homo_sapiens/README_chipseq_analysis_ebi_20160816

  Dataset EGAD00001002388

• BLUEPRINT release August 2016, ChIP-Seq for monocyte - Attached_T=1hr, on genome GRCh38

  ChIP-Seq data for 3 monocyte - Attached_T=1hr sample(s). 8 run(s), 7 experiment(s), 7 analysis(s) on human genome GRCh38. Part of BLUEPRINT release August 2016. Analysis documentation available at http://ftp.ebi.ac.uk/pub/databases/blueprint/releases/20160816/homo_sapiens/README_chipseq_analysis_ebi_20160816

  Dataset EGAD00001002415

• BLUEPRINT release August 2016, ChIP-Seq for monocyte - RPMI_BG_T=1hr, on genome GRCh38

  ChIP-Seq data for 2 monocyte - RPMI_BG_T=1hr sample(s). 6 run(s), 6 experiment(s), 6 analysis(s) on human genome GRCh38. Part of BLUEPRINT release August 2016. Analysis documentation available at http://ftp.ebi.ac.uk/pub/databases/blueprint/releases/20160816/homo_sapiens/README_chipseq_analysis_ebi_20160816

  Dataset EGAD00001002297

• BLUEPRINT release August 2016, ChIP-Seq for monocyte - RPMI_T=1hr, on genome GRCh38

  ChIP-Seq data for 2 monocyte - RPMI_T=1hr sample(s). 4 run(s), 4 experiment(s), 4 analysis(s) on human genome GRCh38. Part of BLUEPRINT release August 2016. Analysis documentation available at http://ftp.ebi.ac.uk/pub/databases/blueprint/releases/20160816/homo_sapiens/README_chipseq_analysis_ebi_20160816

  Dataset EGAD00001002453

• Whole genome sequencing data of high-grade serous ovarian cancer samples (set 7b)

  Whole genome sequencing data of 21 high-grade serous carcinoma (HGSC) patients (59 samples) sequenced with MGISEQ-2000.

  Dataset EGAD00001011086

• BLUEPRINT release August 2016, ChIP-Seq for monocyte - RPMI_LPS_T=1hr, on genome GRCh38

  ChIP-Seq data for 2 monocyte - RPMI_LPS_T=1hr sample(s). 8 run(s), 6 experiment(s), 6 analysis(s) on human genome GRCh38. Part of BLUEPRINT release August 2016. Analysis documentation available at http://ftp.ebi.ac.uk/pub/databases/blueprint/releases/20160816/homo_sapiens/README_chipseq_analysis_ebi_20160816

  Dataset EGAD00001002376

• BLUEPRINT release August 2016, ChIP-Seq for monocyte - RPMI_BG_T=4hrs, on genome GRCh38

  ChIP-Seq data for 3 monocyte - RPMI_BG_T=4hrs sample(s). 8 run(s), 8 experiment(s), 8 analysis(s) on human genome GRCh38. Part of BLUEPRINT release August 2016. Analysis documentation available at http://ftp.ebi.ac.uk/pub/databases/blueprint/releases/20160816/homo_sapiens/README_chipseq_analysis_ebi_20160816

  Dataset EGAD00001002368

• Single-Cell RNA-Sequencing of Human Prostatectomy Tissue

  The tissue microenvironment in prostate cancer is profoundly altered. How prostate cancer cells and their precursors mediate those changes is unclear, in part due to the inability to longitudinally study the disease evolution in human tissues. To overcome this limitation, we performed extensive single-cell RNA-sequencing (scRNA-seq) to assess the transcriptional profiles of the tissue microenvironment in prostate tissues from prostatectomies from men diagnosed with prostate cancer. For each subject, benign-enriched and tumor-enriched tissues were collected from the peripheral zone of the prostate. Our studies of human tissues revealed that cancer cell-intrinsic activation of MYC signaling was the top up-regulated pathway in human cancers, representing a common denominator across the well-known molecular and pathological heterogeneity of human prostate cancer. Numerous non-malignant cell states in the tumor microenvironment (TME), including non-cancerous epithelial, immune, and fibroblast cell compartments, were conserved across individuals, suggesting that these cell types may be a sequelae of the convergent MYC activation in the cancer cells.

  Study phs003480

• Targeting Heterochromatin Eliminates Malignant Stem Cells in Chronic Myelomonocytic Leukemia Through Reactivation of Retroelements and Innate Immune pathways

  Hematopoietic stem cell (HSC) aging involves heterochromatin reorganization. These repressive marks together with DNA methylation are essential for suppressing transposable elements (TEs). In this study we analyze heterochromatin and transcriptomic changes occurring at genes and TEs in HSCs from chronic myelomonocytic leukemia, a severe myeloid malignancy affecting the elderly, compared to age-matched cells, and in the presence or absence of a combination of epidrugs.

  Study EGAS50000000688

• Targeting Heterochromatin Eliminates Malignant Stem Cells in Chronic Myelomonocytic Leukemia Through Reactivation of Retroelements and Innate Immune pathways

  Hematopoietic stem cell (HSC) aging involves heterochromatin reorganization. These repressive marks together with DNA methylation are essential for suppressing transposable elements (TEs). In this study we analyze heterochromatin and transcriptomic changes occurring at genes and TEs in HSCs from chronic myelomonocytic leukemia, a severe myeloid malignancy affecting the elderly, compared to age-matched cells, and in the presence or absence of a combination of epidrugs.

  Study EGAS50000000367

• DAC for a single-cell multi-omic atlas of nodal B-cell non-Hodgkin lymphomas

  Nodal B-cell non-Hodgkin lymphomas (B-NHL) are a clinically diverse set of cancers thought to originate from distinct stages of B-cell maturation. To characterize intratumor heterogeneity across B-NHL entities, we performed CITE-Seq (cellular indexing of transcriptomes and epitopes) on 51 lymph node samples including mantle cell lymphoma (MCL, n = 8), follicular lymphoma (FL, n = 12), germinal center (GCB, n = 5) or activated B-cell (non-GCB/ABC, n = 7) diffuse large B-cell lymphoma (DLBCL) and marginal zone lymphoma (MZL, n = 11) tumors, in addition to non-malignant reactive lymph nodes (rLN, n = 8). We also performed 5 prime scRNA-seq with immune receptor profiling for 11 of these samples (2 rLN, 2 MCL, 3 FL, 2 DLBCL, and 2 MZL).

  Dac EGAC50000000226

• Immune profiling reveals enrichment of distinct immune signatures in oral epithelial dysplasia

  The dataset contains transcriptomic information of 36 oral potentially malignant disorders (OPMD), 14 fibroepithelial polyps (FEP), and 6 early stage oral squamous cell carcinoma (OSCC) from the Asian population. Total RNA was extracted from formalin-fixed paraffin embedded (FFPE) tissue sections. RNA libraries were prepared using the NEB NextUltra RNA kit with Illumina Ribo-Zero rRNA removal as per manufacturer’s instructions. RNA sequencing was performed on the HiSeq2500 platform to generate paired-end 150 nucleotides reads and with a coverage of 50 million reads per sample. Uploaded bam files have been mapped to the GRCh38 human genome using TopHat2. Clinical and demographic data for these patients are available from the associated publications or by request.

  Dataset EGAD00001007970

• Single-Cell Mitochondrial Mutation Lineage Tracing of Non-Dysplastic and Dysplastic Barrett's Esophagus

  This study addresses a critical knowledge gap in understanding Barrett's esophagus (BE), a common metaplastic condition and precursor to esophageal adenocarcinoma, by identifying lineage connections and cell states underlying its development and malignant transformation. We collected biopsies from 13 Barrett's esophagus patients undergoing routine surveillance endoscopy, sampling metaplastic tissue alongside normal squamous esophagus and gastric cardia tissues when clinically appropriate. Our novel approach integrated single-cell RNA sequencing of nearly 180,000 cells with mitochondrial DNA mutation analysis for lineage tracing, coupled with spatial transcriptomics and comprehensive whole-exome sequencing. For one patient with high-grade dysplasia, we performed detailed whole-exome sequencing analysis at 100x coverage on dissociated Barrett's esophagus cells alongside matched normal esophagus and gastric cardia tissues. This genomic profiling revealed critical genetic drivers of malignant transformation, including a truncating mutation in the mutation cluster region of APC (a negative WNT regulator), mutations in the tumor suppressor genes CDKN2A and TP53, and significant copy number alterations including loss of CDKN2A on chromosome 9. These genetic alterations corresponded with the transcriptional changes observed in our single-cell data, particularly WNT pathway dysregulation and the expansion of LGR5-expressing stem cells, providing molecular evidence for how single clones can initiate the dysplastic transformation. Data deposited in dbGaP consist specifically of the whole-exome sequencing raw files, processed variant calls, and copy number analyses from the single patient with high-grade dysplasia and matched normal esophagus and stomach control tissue. Whole exome sequencing was performed on an Illumina NovaSeq 6000. Sequencing data was preprocessed following the Genome Analysis Toolkit's (GATK) Best Practices. Sequencing data was analyzed with Mutect2 (GATK, v4.2.5.0) to identify short somatic mutations including single-nucleotide polymorphisms and insertions and deletions. The Barrett's esophagus sample was run with the two matched normals, as well as the publicly available germline resource somatic-hg38_af-only-gnomad.hg38.vcf.gz (GATK). Somatic variant calls were filtered using FilterMutectCalls (GATK) and loaded into the Integrative Genomics Viewer (v2.12.3) for identification of high-quality variants in known esophageal adenocarcinoma regulators. Copy number alterations in the Barrett's esophagus sample were estimated using CNVkit (v0.9.9). CNV, Mutect2, and SVC analyses will be made available through dbGAP. Copy number alterations in the Barrett's esophagus sample were estimated using CNVkit (v0.9.9) with the default run settings; a pooled reference was generated from the normal esophagus and stomach samples. Copy number results were plotted directly within CNVkit using the function scatter.

  Study phs003949

• EOSC4Cancer Longitudinal Synthetic Colorectal Cancer Genomic data developed at BSC

  The synthetic genomes have been created trying to mimic real cancer data of 4 patients (Named 185,186,187 and 188). Mutations are based on real CRC patients from the PCAWG dataset. For each patient, two tumor samples at different time points and one healthy sample have been simulated. The cancer intra-tumor heterogeneity and evolution in the patients is depicted by simulating reads from tumor subclones separately and then mixing them according to their clonal proportions in each sample. For rapid use and transfer only selected chromosomes have been generated for each patient. Chromosomes per patient: -185: chr4, chr5, chr7, chr17 -186: chr1, chr7, chr12, chr17 -187: chr1, chr2, chr5, chr12, chr17 -188: chr2, chr5, chr12, chr13, chr17 Worflows used to create BAM/BAI, VCF and MAF files from FASTQ (Alignment with GRCh38): - https://usegalaxy.eu/published/workflow?id=2c3d05023c02113e - https://usegalaxy.eu/published/workflow?id=1da86d74f8535f4e

  Dataset EGAD50000000276

• Sarcopenia related to Head and Neck squamous cell carcinomas: transcriptome modifications of muscle cells induced by distant malignant cells

  The biological mechanisms of sarcopenia are still very poorly understood, particularly in the case of Head and Neck Squamous Cell Carcinomas (HNSCC). However, there is good reason to believe that diffusible factors originating from tumor cells exert a distant deleterious effect on muscle cells. To test this hypothesis we implemented a dual approach based both on experiments carried out in vitro and on the study of muscle fragments from patients.

  Study EGAS50000000669

• Spatial genomic heterogeneity in multiple myeloma revealed by multi- region sequencing

  The bone-marrow (BM) containing skeletal system is the reservoir of Multiple Myeloma (MM), the malignant counterpart of antibody-secreting plasma cells. To gain insight into its spatial clonal architecture, we performed multi-region whole-exome sequencing of radiology-guided fine-needle aspirates from 51 MM patients. We found spatial genomic heterogeneity in a substantial proportion of cases including bi-allelic inactivation of tumor suppressors and mutations affecting cancer genes. The amount of heterogeneous mutations associated with the size of focal tumor lesions in whole body imaging consistent with focal outgrowth of highly advanced clones. In conclusion, our results support the regional initiation of transformation processes leading to high-risk disease as well as the pre-existence of key driver events in restricted areas. As such, our study does not only provide new insights in the underlying biology of MM progression but also has considerable implications for standard diagnostic approaches in the clinic.

  Study EGAS00001002111

• RNAseq of 704 patients with soft tissue tumors

  The dataset contains transcriptome sequencing (RNA-seq) data of 704 soft tissue tumors (STT) from 704 patients. The sequencing data comes in FASTQ format and contains 1408 files. A total of 56 different STT types were included in the present study and each tumor type was represented by >2 samples. The vast majority of the patients had been diagnosed and treated at the sarcoma centers in Lund (Sweden) or Stockholm (Sweden) during the period 1988-2020, but also a few samples from other centers, obtained through previous collaborative projects, were included. RNA was extracted from fresh frozen tumor material and samples were primary lesions unless otherwise indicated. The sequencing was performed using 2x150 bp paired-end chemistry on a series of Illumina instruments at various facilities during the period 2013-2023.Samples were obtained after informed consent from the patients and the study was approved by the regional ethics committee (Etikprövningsmyndigheten, Uppsala, dnr 2023-01550-01, dnr 2025-02997-02).

  Dataset EGAD50000002120

• Variant calling dataset from the whole-exome study of familial pulmonary fibrosis in the Canary Islands-VCF files

  Sequence reads were obtained from a set of 13 families with familial pulmonary fibrosis in the Canary Islands, Spain, using Illumina paired-end reads, respectively, at the Institute of Technology and Renewable Energy (ITER). Briefly, we used bcl2fastq v2.18 to perform sample demultiplexing and BWA-MEM v0.7.15 (https://github.com/lh3/bwa) to align reads to GRCh37/hg19 reference. Resulting BAM files were assessed with SAMtools v1.3 (http://www.htslib.org) and Picard v2.10.10 (https://broadinstitute.github.io/picard/) for quality control steps. Small insertions/deletions (< 50 bp) and single nucleotide variants (SNVs) were identified using an in-house bioinformatics pipeline based on GATK HaplotypeCaller v3.8 (https://gatk.broadinstitute.org/hc/en-us/articles/360037225632-HaplotypeCaller). This pipeline follows the Best Practices recommendations for germline variant calling and its description is publicly available (https://github.com/genomicsITER/benchmarking/tree/master/WES).

  Dataset EGAD50000001152

• The genomic basis of childhood T-lineage acute lymphoblastic leukemia

  T-lineage acute lymphoblastic leukemia (T-ALL) is a high-risk tumor that has eluded comprehensive genomic characterization, in part due to the high frequency of non-coding genomic alterations resulting in oncogenic dysregulation. Here we report integrated genome and transcriptome sequencing of T-ALL tumor and remission samples obtained from over 1300 uniformly treated children with T-ALL, coupled with epigenomic and single cell analysis of malignant and normal T cell precursors. Integrated analysis identified 15 subtypes with distinct genomic drivers, gene expression, developmental state and outcome. Integration with chromatin topology analyses enabled elucidation of multiple mechanisms of enhancer deregulation that involve enhancers and genes in a subtype-specific fashion. We show that the immunophenotypically-described, high-risk entity of early T-cell precursor ALL is superseded by a broader category of leukemias of variable immunophenotype with diverse genomic alterations of a core set of genes encoding regulators of hematopoietic stem cell development. Numerous genetic alterations and disease subtypes emerged as independent predictors of survival and treatment failure in univariable and multivariable outcome models. These findings provide a roadmap for the classification, risk stratification and mechanistic understanding of this disease.

  Study EGAS50000000016

• Frequent mutation of the major cartilage collagen gene, COL2A1, in chondrosarcoma

  Chondrosarcoma (CHS) is a heterogeneous collection of malignant bone tumours and is the second most common primary malignancy of bone after osteosarcoma. Recent work has identified frequent, recurrent mutations in IDH1/2 in nearly half of central CHS. However, there has been little systematic genomic analysis of this tumour type and thus the contribution of other genes is unclear. Here we report comprehensive genomic analyses of 49 cases of CHS. We identified hypermutability of the major cartilage collagen COL2A1 with insertions, deletions and rearrangements identified in 37% of cases. The patterns of mutation were consistent with selection for variants likely to impair normal collagen biosynthesis. In addition we identified mutations in IDH1/2 (59%), TP53 (20%), the RB1 pathway (27%) and hedgehog signaling (22%).

  Dataset EGAD00001000358

• Single-cell profiling of co-cultures of GSCCs and macrophages

  Glioblastoma (GBM) remains the most malignant primary brain tumor, with a median survival rarely exceeding 2 years. Tumor heterogeneity and an immunosuppressive microenvironment are key factors contributing to the poor response rates of current therapeutic approaches. GBM-associated macrophages (GAMs) often exhibit immunosuppressive features that promote tumor progression. However, their dynamic interactions with GBM tumor cells remain poorly understood. Here, we used patient-derived GBM stem cell cultures and combined single-cell RNA sequencing of GAM-GBM co-cultures and real-time in vivo monitoring of GAM-GBM interactions in orthotopic zebrafish xenograft models to provide insight into the cellular, molecular, and spatial heterogeneity. Our analyses revealed substantial heterogeneity across GBM patients in GBM-induced GAM polarization and the ability to attract and activate GAMs – features that correlated with patient survival. Differential gene expression analysis, immunohistochemistry on original tumor samples, and knock-out experiments in zebrafish subsequently identified LGALS1 as a primary regulator of immunosuppression. Overall, our work highlights that GAM-GBM interactions can be studied in a clinically relevant way using co-cultures and avatar models, while offering new opportunities to identify promising immune-modulating targets.

  Study EGAS00001007482

• Oncoprint GSCCs

  Glioblastoma (GBM) remains the most malignant primary brain tumor, with a median survival rarely exceeding 2 years. Tumor heterogeneity and an immunosuppressive microenvironment are key factors contributing to the poor response rates of current therapeutic approaches. GBM-associated macrophages (GAMs) often exhibit immunosuppressive features that promote tumor progression. However, their dynamic interactions with GBM tumor cells remain poorly understood. Here, we used patient-derived GBM stem cell cultures and combined single-cell RNA sequencing of GAM-GBM co-cultures and real-time in vivo monitoring of GAM-GBM interactions in orthotopic zebrafish xenograft models to provide insight into the cellular, molecular, and spatial heterogeneity. Our analyses revealed substantial heterogeneity across GBM patients in GBM-induced GAM polarization and the ability to attract and activate GAMs – features that correlated with patient survival. Differential gene expression analysis, immunohistochemistry on original tumor samples, and knock-out experiments in zebrafish subsequently identified LGALS1 as a primary regulator of immunosuppression. Overall, our work highlights that GAM-GBM interactions can be studied in a clinically relevant way using co-cultures and avatar models, while offering new opportunities to identify promising immune-modulating targets.

  Study EGAS00001007481

• Comprehensive molecular profiling identifies novel genetic drivers and subtypes underlying medulloblastoma

  Current therapies for medulloblastoma (MB), a highly malignant childhood brain tumor, impose debilitating effects on the developing child, warranting the development of molecularly targeted treatments with reduced toxicities. Prior studies have failed to disclose the full spectrum of driver genes and molecular processes operative in MB or adequately explain heterogeneity among molecular subgroups. Herein, we detail the somatic landscape across 491 sequenced MBs and molecular heterogeneity amongst 1,256 epigenetically analyzed cases, identifying subgroup-specific mutational signatures, driver genes, and pathway alterations including previously unappreciated actionable therapeutic targets. Integrative approaches for assigning driver genes to subgroups explained &gt;65-70% of Group 3 and Group 4, doubling previous knowledge. Novel subtypes underlying Group 3 and Group 4 were differentially enriched for specific driver events, including hotspot in-frame indels targeting KBTBD4 and ‘enhancer hijacking’ driving activation of PRDM6. Thus, application of integrative genomics to an unprecedented cohort of clinical samples derived from a single childhood cancer entity has disclosed a series of new cancer genes and biologically relevant subtype diversity that represent attractive therapeutic targets for treating MB.

  Study EGAS00001001953

• 12 Pediatric B-cell precursor acute lymphoblastic leukemia samples with very early relapse

  Sequencing data (BAM/CRAM) of diagnosis-relapse pairs of 12 children who relapsed very early, followed by a deep-sequencing validation of all identified mutations.

  Dataset EGAD00001008309

• Brazilian Thyroid WES

  Medullary thyroid cancer (MTC) is a rare malignant tumor that arises from parafollicular cells. Approximately 8% of thyroid cancer cases are MTC, and about 25% of these have a hereditary component. Incorporating molecular parameters into tumor classification is important. Besides, the presence of pathogenic germline variants can impact directly on cancer prevention. Thus, the aim of this study was to perform whole exome sequencing (WES) on a consecutive series of hereditary RET wild-type MTC patients to identify genetic variants that may be involved in the carcinogenesis of this tumor. WES was performed on 28 patients negative for germline RET pathogenic variants using the NovaSeq 6000 platform. Variant classification followed American College of Medical Genetics and Genomics guidelines.Our study represents a significant advancement in gene discovery for MTC genetics.

  Dataset EGAD50000000086

• Whole genome sequence and RNA-seq data from paired tumour and germline samples from mesothelioma patients.

  Malignant pleural mesothelioma (MPM) has a poor overall survival with few treatment options. Whole genome sequencing (WGS) combined with RNA sequencing (RNA-seq) analysis of the immune features of MPM offers the prospect of identifying changes that could inform future clinical trials. We analysed somatic mutation and RNA-seq data from 229 MPM samples, including 58 MPM samples that had undergone WGS from our own institutions, together with other published data. This combined analysis identified somatic driver genes, including newly identified candidate genes. Whole genome doubling was a frequent event that correlated with shorter survival. Mutational signature analysis revealed dominant signatures and showed that defects in homologous recombination repair were infrequent in our cohort. Within the tumour immune environment we identified high M2 macrophage infiltrate linked with MMP2, MMP14, TGFB1 and CCL2 expression, representing an immunosuppressive environment. A small subset of samples had a higher proportion of CD8 T cells and a high cytolytic score, suggesting a ‘hot’ immune environment which is independent of the somatic mutations. We propose that our findings on genomic changes and subtypes of immune microenvironments may influence therapeutic planning in the future.

  Study EGAS00001005196

• Genomic and transcriptomic landscape of T-cell lymphoblastic lymphoma compared to T-cell acute lymphoblastic leukemia: similar subtypes and different fusions

  Due to the lower incidence of T-LBL and difficulties in obtaining diagnostic T-LBL material, extensive research on T-LBL has been hampered whereas genetic aberrations in T-ALL are thoroughly characterized. Given the similarities and differences between T-LBL and T-ALL, the question has been raised whether T-LBL and T-ALL represent two different diseases or different manifestations of the same disease. This study aims to identify the genomic and transcriptomic landscape of T-LBL and compare the findings to what is found T-ALL. Comparison of the molecular aberrations between T-LBL and T-ALL can provide insights into the overlap and differences in malignant development between the two entities, which could lead to improved risk stratification in T-LBL in order to eventually adapt T-LBL treatment protocols based on molecular-genetic prognostic factors.

  Dataset EGAD00001015357

• Chronic lymphocytic leukemia driven by paradoxical ERK activation during BRAF inhibitor treatment

  Whole-exome sequencing of a chronic lymphocytic leukemia (CLL) developed during vemurafenib treatment of a patient with malignant melanoma. Peripheral blood mononuclear cells were separated by Ficoll gradient centrifugation. DNA was extracted from highly purified (&gt;97%) CD19+CD5+ cells obtained from the patient while being under BRAF inhibition versus CD14+ germline control cells (&gt;90% purity). No alterations that could be linked to aberrant RAS activity or paradoxical RAF/MEK/ERK signaling could be identified in the CLL, which shows characteristic copy number alterations.

  Dataset EGAD00001000997

• Synthetic - FEGA Sweden Heilsa synthetic dataset December 2023

  Synthetic - This submission contains a subset of a synthetic dataset derived from the project Heilsa Tryggvedottir - a Nordic collaboration on sharing sensitive human data. Heilsa Tryggvedottir is funded by the Nordic e-Infrastructure Collaboration (NeIC), the ELIXIR nodes of Finland, Norway, and Sweden, Computerome in Denmark, and the Estonian Scientific Computing Infrastructure (ETAIS). In the synthetic data creation process, it was attempted to strike a fine balance between the usability of the datasets (e.g. technical FEGA development, testing, user training, and basic bioinformatics) and compliance with GDPR. File names and file content (e.g. headers in fastq) are anonymized. Moreover, the X, Y, and mitochondrial sequences have been discarded from the original data since these data can be used for maternal, paternal, or ethnic origin tracing. The dataset does not follow natural haplotype distribution (inherent to imputation panels). The only inputs derived from real sequence data are variant distribution density per chromosome and learning sequencing error models. The synthetic dataset consists of two fastq files, a cram file, a vcf file, and two index files.

  Dataset EGAD50000000119

• SPECIAL: scRNA-seq

  Tumour biopsies were collected from twenty-three patients (46 samples) (of which 20 were matched) with locally advanced or metastatic melanoma (stage IIIB – stage IV). Library construction was done either with the Chromium Single Cell 3ʹ GEM, Library &amp; Gel Bead Kit v3 (n = 16; 10x genomics, Cat#1000092) or the Chromium Single Cell A Chip Kit and 5’ Library &amp; Gel Bead Kit (10x genomics, Cat#1000014). All libraries were sequenced on Illumina NextSeq, HiSeq4000 or NovaSeq6000 until sufficient saturation was reached (60% on average). The reference genome used in this study was GRCh38.

  Dataset EGAD00001009291

• Multi-Modal Single-Cell, Spatial, and Genomic Analyses of Human Non-Small Cell Lung Cancer Brain Metastases

  We performed single nuclei RNA-sequencing (snRNA-seq) with matched T cell receptor sequencing (TCR-seq), and pool matched low pass whole genome sequencing (WGS) of 12 treatment-naive non-small cell lung cancer (NSCLC) primary tumors (PTs) and 31 treatment-naive NSCLC brain metastases (BMs). In total, we recovered 277,206 cell transcriptomes in 43 samples. Single-nuclei suspension from frozen NSCLC metastases were generated using methods published in Slyper et al. (Nature Medicine, 2020, PMID:32405060) with modifications. The tissue was first cut in 20 &#181;m sections using a cryostat and stored on dry ice until the next step. Then the tissue was put on wet ice and washed once with 5 ml PBS to remove OCT. After this step nuclei were extracted by vigorous pipetting in salt-tris buffer with Tween-20 (TST) followed by a high-volume wash in salt-tris buffer (ST). Nuclei were counted and 10,000-14,000 and were loaded using a Chromium controller (10X genomics) and Chromium Single Cell 5' Reagents (V1.1 and V2). Complementary DNA libraries were generated according to manufacturer's instructions, with the modification of one additional cycle of amplification. Matched single nuclei T cell receptor (snTCR) sequencing libraries were prepared from amplified cDNA libraries using either Chromium Single Cell V(D)J Enrichment Kit for human T cells Reagent Kit, v1.1, or single cell human TCR amplification kit. Final snTCR sequencing libraries were prepared using Single Index Kit T Set A for V1.1 libraries or Library construction kit and Dual Index Kit TT set A for V2 libraries. Sequencing libraries were quantified using Tapestation D5000 reagents and a 2200 TapeStation and pooled for sequencing. Pool matched low pass whole-genome sequencing (lp-WGS) was performed in addition to snRNA-seq to improve the identification of the malignant and non-malignant cell compartments. Nuclei from snRNA-seq sample preparations were collected by centrifugation (500g, 5 min), snap frozen after removing excess ST buffer, and stored at -200C until further processing. If insufficient nuclei (0C for 9 minutes. Adapters were not diluted, and the optional PCR (5 cycles) and cleanup were performed. After library cleanup with AMPure beads (Beckman Coulter, Brea, CA), libraries were quantified with Tapestation D5000 HS tapes (Agilent) and stored at -200C until sequencing.Using multiplexed immunofluorescence in an independent cohort of treatment-na&#239;ve pairs of primary tumors and brain metastases from the same patients with NSCLC, we validated genomic and tumor-microenvironmental findings and identified a cancer cell population characterized by neural features that strongly enriched in brain metastases. This comprehensive analysis provides insights into human NSCLC brain metastasis biology and serves as an important resource for additional discovery.

  Study phs003865

• Patient-derived pediatric brain tumor organoids faithfully recapitulate primary tumors

  Extensive molecular analysis by many groups has revealed a heterogeneous landscape of embryonal brain tumors, including medulloblastoma (MB) and atypical teratoid/rhabdoid tumor (ATRT). MB, the most common malignant pediatric brain tumor, is comprised of four molecularly distinct subgroups: Wingless (WNT), Sonic Hedgehog (SHH), Group 3 (G3), and Group 4 (G4). Among these, MB-SHH harboring MYCN amplification and TP53 mutation and MB-G3 with MYC overexpression or amplification constitute the most aggressive tumors, have the poorest clinical outcomes, and lack effective therapeutic options for recurrent disease. Here we describe the establishment of tumor organoid (TO) models from patient-derived orthotopic xenografts (PDOX) of MYCN-amplified and TP53-mutant MB-SHH, MYC-amplified MB-G3 and two ATRT which all grew in mice when reimplanted into the cortices of naïve recipient animals (TOX). Methylation, bulk and single-cell RNA sequencing, and whole genome sequencing demonstrated that TOs and TOXs faithfully recapitulated the molecular landscape and heterogeneity of PDOXs and primary patient tumors compared to established cell lines. The development of TOs will facilitate in vitro high-throughput drug or CRISPR screens without the need for use tumor-bearing mice. This will also accelerate the identification and validation of new vulnerabilities and in vivo preclinical testing toward clinical trials.

  Study EGAS00001008305

• CCMA-WGSraw

  This dataset has the mapped bam files from WGS for the cancer models in CCMA.

  Dataset EGAD00001010035

• Targeted panel DNA sequencing of melanomas, nevi and melanocytic tumors

  This dataset was derived from 360 formalin-fixed paraffin-embedded (FFPE) samples distributed across (i) 118 primary melanomas, (ii) 132 nevi and (iii) 110 melanocytic tumors. Next generation sequencing (NGS) libraries were prepared following the FFPE DNA Archer VariantPlex Somatic Protocol for Illumina. Input DNA was determined by the PreSeq DNA QC assay, with 100 ng of DNA used for samples with high quality scores, 200 ng for low quality scores and 300 ng for samples with bad quality scores as defined by the PreSeq DNA QC assay. NGS libraries were quantified using the KAPA Library Quantification Kit for Illumina (KK4824) and sequencing performed on the Nextseq 500/2000 without custom primers using paired-end sequencing (151bp for Read 1 and Read 2) with index reads (8bp for Index Read 1 and Index Read 2). For each sample, resulting paired-end fastq files are available as part of this dataset. Prefix for each sample name is associated with the the type of sample: NAE: nevi samples. MEL: Melanoma samples. BL: melanocytic tumor.

  Dataset EGAD50000001297

• SUM-seq data for spontaneously differentiated iPSCs to EBs

  Clonal CRISPRi/a hiPS cell lines were plated to induce spontaneous differentiation in KSR medium (KSR medium: knockout DMEM/F12 (Gibco, 12660012), 2 mM GlutaMAX, 1× NEAAs, 20% knockout serum replacement (Gibco, 10828010) and 0.1 mM β-mercaptoethanol (Merck-Millipore)). non-TC plates and dishes were used. At the day of plating, KSR medium was supplemented with Y-27632 (10 µM). The next day, medium was replaced with fresh KSR medium. Medium changes were performed every other day. EBs were transferred to 15 ml conical tubes and allowed to sediment at room temperature for 5 min. The supernatant was replaced with fresh KSR medium and cells were transferred onto non-TC treated plates and maintained at 37 °C, 5% CO2. On day 12 of differentiation, the KSR medium was replaced with Essential 6 medium (Gibco, A1516401). EBs were collected and subjected to SUM-seq library preparation as described in Lobato-Moreno et al. 2025 Nature Methods.

  Dataset EGAD50000001589

• Genomic and Genetic Analysis of Brain Tumors and Analysis of Their Clinicopathological Significance

  The treatment outcome of glioma patients remains disappointing, and more studies are needed to improve therapeutic strategies. In particular, it is crucial to understand the mechanisms underlying resistance to treatment and malignant transformation, as well as the intratumoral heterogeneity and interaction of tumor cells and host immunity. Recent advances in omics analysis techniques, such as next-generation sequencing (NGS), have enabled us to obtain omics data more easily and accelerated our ability to integrate this information and precisely characterize cases. In our project, we have already collected more than 100 pairs of human glioma/normal tissue samples, of which some are multiple specimens collected from initial and recurrent tumors, and some include multiple specimens collected from different regions within a single tumor. We used our in-house algorithms, composed of alignment and variant calling programs, to analyze omics data from multiple platforms, such as whole-exome sequencing (WES), RNA sequencing (RNA-seq), and methylation array, with our original cohort of glioma patients. Using several informatics tools, the information about genetic and epigenetic status and expression signatures were analyzed. Those data are expected to provide key information for investigating the mechanisms discussed above. Through this project, we hope to improve strategies for personalized therapy based on comprehensive omics data.

  Study JGAS000004

• Quantitative analysis of a novel DNA hypermethylation panel for lung cancer diagnosis using bronchial specimens

  Non-diagnostic findings in Transbronchial Lung Biopsy (TBLB) and Endobronchial Ultrasound-guided Transbronchial Lung Biopsy (EBUS-TBLB) are not uncommon. A challenge is to improve lung cancer detection by TBLB/EBUS-TBLB. In order to improve the diagnostic yield of bronchoscopy, we used 850K methylation chip to identify methylation sites that distinguish malignant from benign lung nodules.We found that the combination of HOXA7, SHOX2,and SCT methylation analysis has the best diagnostic yield in 123 bronchial washing (sensitivity: 74·1%; AUC: 0·851) and 172 brushing samples (sensitivity: 86·1%; AUC: 0·915). We developed a kit comprising these three genes and validated the kit in 329 unique bronchial washing samples, 397 unique brushing samples, and 179 unique patients with both washing and brushing samples. The diagnostic accuracy of the panel alone in lung cancer diagnosis was 86·9%, 91·2% and 95% in bronchial washing, brushing, and washing+brushing samples, respectively. The panel's sensitivity in combination with cytology, rapid on-site evaluation (ROSE), and histology in lung cancer diagnosis was 90·8% and 95.8% in bronchial washing and brushing samples, respectively, and 100% in washing+brushing samples. Quantitative analysis of the three-gene panel improves lung cancer diagnosis by bronchoscopy.

  Study EGAS00001007089

• Genomic Profiling of Thyroid Cancer Reveals a Role for Thyroglobulin in Metastasis -Part II

  Papillary thyroid carcinoma (PTC) has a wide geographic variation in incidence, being highest in Saudi Arabia where it is only second to breast cancer as the most common cancer among females. Genomic profiling of PTC from Saudi Arabia has not been attempted previously. We performed whole-exome sequencing of 101 PTC samples and the corresponding genomic DNA to identify genes with recurrent somatic mutations, followed by sequencing of these genes using a next-generation gene panel approach in further 785 samples. In addition to BRAF, N-RAS and H-RAS, which have previously been shown to be recurrently mutated in PTC, our analysis highlights additional genes, including thyroglobulin (TG), which harbored somatic mutations in 3% of the entire cohort. Surprisingly, although TG mutations were not exclusive to mutations in the RAS-MAP kinase pathway, their presence was associated with a significantly worse clinical outcome, which suggests a pathogenic role beyond driving initial oncogenesis. Analysis of metastatic PTC tissue revealed significant enrichment for TG mutations (p&lt;0.001), including events of apparent clonal expansion. Our results suggest a previously unknown role of TG somatic mutations in the pathogenesis of PTC and its malignant evolution.

  Study EGAS00001003357

• Genomic Profiling of Thyroid Cancer Reveals a Role for Thyroglobulin in Metastasis

  Papillary thyroid carcinoma (PTC) has a wide geographic variation in incidence, being highest in Saudi Arabia where it is only second to breast cancer as the most common cancer among females. Genomic profiling of PTC from Saudi Arabia has not been attempted previously. We performed whole-exome sequencing of 101 PTC samples and the corresponding genomic DNA to identify genes with recurrent somatic mutations, followed by sequencing of these genes using a next-generation gene panel approach in further 785 samples. In addition to BRAF, N-RAS and H-RAS, which have previously been shown to be recurrently mutated in PTC, our analysis highlights additional genes, including thyroglobulin (TG), which harbored somatic mutations in 3% of the entire cohort. Surprisingly, although TG mutations were not exclusive to mutations in the RAS-MAP kinase pathway, their presence was associated with a significantly worse clinical outcome, which suggests a pathogenic role beyond driving initial oncogenesis. Analysis of metastatic PTC tissue revealed significant enrichment for TG mutations (p&lt;0.001), including events of apparent clonal expansion. Our results suggest a previously unknown role of TG somatic mutations in the pathogenesis of PTC and its malignant evolution.

  Study EGAS00001001788

• COVID-19 Severity First Wave of Infection for Severe Patients in Madrid

  We recruited 98 hospitalised patients displaying severe COVID-19 symptoms from the first wave of infection. A stringent exclusion criteria based on non-genetic factors such as age, blood oxygen, radiologic findings and other typical COVID-19 signs was performed. Gingival or peripheral blood samples were taken for 98 individuals and whole exome sequencing performed using ExomeCapture-Seq capture KAPA HyperExome on Illumina machines.

  Dataset EGAD00001008464

• Long read mRNA sequencing of human neural retinal samples - Usher syndrome transcript landscape

  Long-read (PacBio) RNA sequencing dataset of three neural retinal samples. Three PacBio libraries were prepared according the 'standard workflow' optimized for sequencing transcripts centered around 2kb. Additionally one Library (input HNR_S2) was prepared according an optimized 'long workflow' to enrich for larger transcripts up to >10kb. To further enhance the capture of full-length transcripts for USH2A and ADGRV1 (USH2C) genes, we also employed a targeted enrichment approach using the Samplix Xdrop System, followed by PacBio long-read sequencing. USH2A and ADGRV1 enrichment was performed by targeting '5- mid and 3' targets of the respective genes. Finally, we also added ONT (Oxford Nanopore technology) long-read mRNA sequencing of three independent neural retina samples. These data were used for the validation of events observed from the Iso-Seq and Samplix data. The ONT datasets contain sequencing data of the Usher-associated genes. Files are raw BAM, and CRAM format files generated by a Sequel II machine. Additionally, the ccs3 BAM format files are included.

  Dataset EGAD50000000720

• Clinical genome sequencing uncovers potentially targetable truncations and fusions of MAP3K8 in spitzoid and other melanomas

  Spitzoid melanoma is a specific morphologic variant of melanoma that most commonly affects children and adolescents and ranges on the spectrum of malignancy from low-grade to overtly malignant. These tumors are generally driven by fusions of ALK, RET, NTRK1/3, MET, ROS1 and BRAF. However, in approximately 50% of cases, no genetic driver has been established. Clinical whole genome and transcriptome sequencing (RNA-Seq) of a spitzoid tumor from an adolescent revealed a novel gene fusion of MAP3K8, encoding a serine−threonine kinase that activates MEK. The patient who had exhausted all other therapeutic options was treated with a MEK inhibitor and underwent a transient clinical response. We subsequently analyzed spitzoid tumors from 49 patients by RNA-Seq and found in-frame fusions or C-terminal truncations in 33% of cases. The fusion transcripts and truncated genes all contained MAP3K8 exons 1-8 but lacked the autoinhibitory final exon. Data mining of RNA-Seq from the Cancer Genome Atlas (TCGA) uncovered analogous MAP3K8 rearrangements in 1.5% of adult melanomas. Thus, MAP3K8 rearrangements - uncovered by comprehensive clinical sequencing of a single case - are the most common genetic event in spitzoid melanoma, are present in adult melanomas, and could be amenable to MEK inhibition.

  Study EGAS00001003430

• Reconstructing oral cavity tumor evolution through brush biopsy

  Oral potentially malignant disorders (OPMDs) with genomic alterations have a heightened risk of evolving into oral squamous cell carcinoma (OSCC). Currently, genomic data are typically obtained through invasive tissue biopsy. However, brush biopsy is a non-invasive method that has been utilized for identifying dysplastic cells in OPMD but its effectiveness in reflecting the genomic landscape of OPMDs remains uncertain. This pilot study investigates the potential of brush biopsy samples in accurately reconstructing the genomic profile and tumor evolution in a patient with both OPMD and OSCC. We analyzed single nucleotide variants (SNVs), copy number aberrations (CNAs), and subclonal architectures in paired tissue and brush biopsy samples. The results showed that brush biopsy effectively captured 90% of SNVs and had similar CNA profiles as those seen in its paired tissue biopsies in all lesions. It was specific, as normal buccal mucosa did not share these genomic alterations. Interestingly, brush biopsy revealed shared SNVs and CNAs between the distinct OPMD and OSCC lesions from the same patient, indicating a common ancestral origin. Subclonal reconstruction confirmed this shared ancestry, followed by divergent evolution of the lesions. These findings highlight the potential of brush biopsies in accurately representing the genomic profile of OPL and OSCC, proving insight into reconstructing tumor evolution.

  Study EGAS50000000602

• Spatiotemporal Genomic Profiling of Intestinal Metaplasia Reveals Clonal Dynamics of Gastric Cancer Progression

  Intestinal metaplasia (IM) is a pre-malignant condition of the gastric mucosa associated with increased gastric cancer (GC) risk. We analyzed 1256 gastric samples (1152 IMs) from 692 subjects from a 10-year prospective study. We identified 26 IM driver genes in diverse pathways including chromatin regulation (ARID1A) and intestinal homeostasis (SOX9), largely occurring as subclonal events. Analysis of clonal dynamics between and within subjects, and also longitudinally across time, revealed that IM clones are likely transient but increase in size upon progression to dysplasia, with eventual transmission of genetic events to paired GCs. Single-cell and spatial profiling highlighted changes in tissue ecology and lineage heterogeneity in IM, including an intestinal stem-cell dominant cellular compartment linked to early malignancy. Expanded transcriptome profiling revealed expression-based molecular subtypes of IM, including a body-resident “pseudoantralized” subtype associated with incomplete histology, antral/intestinal cell types, ARID1A mutations, inflammation, and microbial communities normally associated with the healthy oral tract. We demonstrate that combined clinical-genomic models outperform clinical-only models in predicting IMs likely to progress. Our results raise opportunities for GC precision prevention and interception by highlighting strategies for accurately identifying IM patients at high GC risk and a role for microbial dysbiosis in IM progression.

  Study EGAS00001007067

• Molecular characteristics in Burkitt lymphoma over age groups

  Treatment optimization has improved the overall survival in Burkitt lymphoma (BL) patients but there are still relevant outcome differences between pediatric and adult patients. In both age groups survival remains poor for patients who suffer relapse. Therefore, new treatment approaches are warranted to improve survival. Thus, we conducted a comparative study in the largest pediatric cohort to date including 191 cases and 97 samples from adult patients and analyzed the mutational landscape. We detected overlapping molecular profiles but also significant differences in the mutational pattern. Samples from pediatric patients show a higher frequency of mutations in ID3, DDX3X and BAF-complex components ARID1A and SMARCA4, while YY1AP1 and BCL2 are more frequently mutated in cases from adult BL patients. Correlation of the mutational profile with clinical data was available for the pediatric cohort and identified TP53 mutations to be highly significantly associated with the incidence of relapse thus identifying the first molecular marker to be associated with the incidence of relapse in pediatric BL. As the hotspot analysis of TP53 mutations showed mostly gain of function mutations, it is tempting to speculate that drugs decreasing the amount of malignant TP53 or increase the abundance of wildtype TP53 could be a promising approach for future treatment regimens to further improve prognosis.

  Study EGAS00001005270

• Myeloid-specific KDM6B inhibition sensitizes Glioblastoma to PD1 blockade

  This data set include FASTQ files for five experiments: Human scRNA-Seq data (6 samples), Human Visium spatial transcriptomic data (3 samples), Mouse scRNA-seq data (4 samples), Mouse scATAC-seq data (2 samples), Mouse ChIP-seq data (8 samples). For the mouse scATAC-seq data (2 samples), there are originally three FASTQ files, R1, R2 and R3 files. The R1 and R2 FASTQ files were merged into one larger file ("R1R2") per sample for submission as paired-end sequencing setting to follow the EGA guidelines. They can be split into individual R1 and R2 files in order to be processed by Cell Ranger software. The files with IC1 suffix are CHIP-seq Input control for anti-KDM6B antibody pull down experiments and the files with IC2 suffix are CHIP-seq Input control for anti-H3K27ME3 antibody pull down experiments in murine model.

  Dataset EGAD00001010073

• Long-term organoid culture of a small intestinal neuroendocrine tumor rna-seq

  Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare and highly heterogeneous neoplasms whose incidence has markedly increased over the last decades. A grading system based on the tumor cells' proliferation index predicts high-risk for G3 NETs. However, low-to-intermediate grade (G1/G2) NETs have an unpredictable clinical course that varies from indolent to highly malignant. Cultures of human cancer cells enable to perform functional perturbation analyses that are instrumental to enhance our understanding of cancer biology. To date, no tractable and reliable long-term culture of G1/G2 NET has been reported to permit disease modeling and pharmacological screens. Here, we report of the first long-term culture of a G2 metastatic small intestinal NET that preserves the main genetic drivers of the tumor and retains expression patterns of the endocrine cell lineage. Replicating the tissue, this long-term culture showed a low proliferation index, and yet it could be propagated continuously without dramatic changes in the karyotype. The model was readily available for pharmacological screens using targeted agents and as expected, showed low tumorigenic capacity in vivo. Overall, this is the first long-term culture of NETs to faithfully recapitulate many aspects of the original neuroendocrine tumor.

  Study EGAS00001007108

• Long-term organoid culture of a small intestinal neuroendocrine tumor

  Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare and highly heterogeneous neoplasms whose incidence has markedly increased over the last decades. A grading system based on the tumor cells' proliferation index predicts high-risk for G3 NETs. However, low-to-intermediate grade (G1/G2) NETs have an unpredictable clinical course that varies from indolent to highly malignant. Cultures of human cancer cells enable to perform functional perturbation analyses that are instrumental to enhance our understanding of cancer biology. To date, no tractable and reliable long-term culture of G1/G2 NET has been reported to permit disease modeling and pharmacological screens. Here, we report of the first long-term culture of a G2 metastatic small intestinal NET that preserves the main genetic drivers of the tumor and retains expression patterns of the endocrine cell lineage. Replicating the tissue, this long-term culture showed a low proliferation index, and yet it could be propagated continuously without dramatic changes in the karyotype. The model was readily available for pharmacological screens using targeted agents and as expected, showed low tumorigenic capacity in vivo. Overall, this is the first long-term culture of NETs to faithfully recapitulate many aspects of the original neuroendocrine tumor.

  Study EGAS00001007093

• Whole transcriptome RNA sequencing as comprehensive diagnostic tool for acute myeloid leukemia.

  BackgroundAcute myeloid leukemia (AML) is characterized by uncontrolled proliferation of malignant hematopoietic cells in the bone marrow that are arrested in differentiation. In AML pathogenesis, hematopoietic progenitor cells acquire multiple genetic aberrations often occurring in the same set of genes that ultimately lead to malignant transformation. In the WHO classification 2016, six AML classes with different prognosis are identified by chromosomal translocations measured by standard cytogenetics. All balanced translocations produce fusion genes, except for t(3;3)/inv(3;3), which lead to overexpression of MECOM/EVI1 associated with poor prognosis. For accurate risk assessment of cytogenetically normal AML, four genes need to be screened to distinguish AML with mutated NPM1 in the absence of FLT3 mutations and AML with bi-allelic CEBPA mutations, which have a favorable prognosis, and AML with RUNX1 mutations which have a poor prognosis. Recently, a full genomic classification system has been proposed by Papaemmanuil et al. (NEJM 2016). In this system, the same six classes with chromosomal translocations are identified by standard cytogenetics as well as five additional classes characterized by genetic mutations in 14 different genes. AimThe aim of the study was to investigate whether whole transcriptome RNA-sequencing (RNAseq) can be used as single technology for classification of AML. MethodA panel of 100 AML were analyzed and a bio-informatics pipeline called HAMLET (Human AML Expedited Transcriptomics) was developed in which 4 modules are integrated to detect (1) fusion genes, (2) small variants in 13 recurrently mutated genes, (3) internal tandem duplications in FLT3 (FLT3-ITD) and partial tandem duplications in KMT2A (KMT2A-PTD) and (4) overexpression of MECOM/EVI1. All mutations that were called by HAMLET were validated by diagnostic data as available for all 100 AML or targeted PCR followed by Sanger or next generation sequencing on all positive AML and at least an equal number of negative cases. Results &amp; discussionThe data showed that HAMLET accurately identified all genetic aberrations with high sensitivity and specificity. In addition, in 7 AML, fusion transcripts were detected that are not measured by standard cytogenetics including three cases that lack any class-defining lesion according to Papaemmanuil et al. Moreover, overexpression of MECOM/EVI1 was detected in two AML with inv(3) as well as in five cases without inv(3)/t(3;3), and a gene signature was measured to distinguish AML with CEBPA mutations with favorable prognosis. In conclusion, HAMLET provides a comprehensive and flexible pipeline for RNAseq analysis to retrieve all relevant information for current classification of AML as well as additional information that may improve classification in the future.

  Study EGAS00001003096

• Whole-genome sequence data for The interface of malignant and immunologic clonal dynamics in high-grade serous ovarian cancer

  Each tumor sample was cut into three pieces, yielding two end-pieces for cryovials and a middle portion placed in 10% buffered formalin. End pieces were homogenized manually and with a paddle blender (Stomacher). All paraffin-embedded blocks, including formalin-fixed tumor samples and molecular-fixed fallopian tubes, were sectioned and stained with hematoxylin and eosin prior to expert histopathological review to confirm the presence of high grade serous carcinoma. Homogenized end pieces were then flash frozen and later used for WGS. For all tumor and matched normal (peripheral blood) samples, DNA was extracted with the Qiagen AllPrep DNA/RNA kit (tumor samples from patients 25,26,28-32) or the Qiagen Blood and Tissue Extraction Kit (tumor samples from patients 1-4,7,9-17, and all blood samples). For all tumor and normal samples, DNA extraction was followed by library construction and sequencing using Illumina HiSeq2500 whole genome shotgun v4 chemistry with paired-end 125bp reads.

  Dataset EGAD00001003984

• Shallow Whole Genome Sequencing of Patient Derived Xenografts

  Chemotherapy is the standard-of-care treatment for metastatic colorectal cancer (mCRC) and benefits some patients, but what distinguishes responders from non-responders is unclear. In this study, we leveraged a comprehensive collection of 27 molecularly annotated patient-derived xenografts to uncover functional predictors of response to 5-FU and irinotecan combination therapy (FOLFIRI) in mCRC. Genetic analyses revealed that treatment sensitivity was marked by genomic scars indicative of BRCAness, suggesting homologous recombination (HR) deficiency as a key determinant. Accordingly, we surveyed a manually curated panel of 44 genes with a documented role in HR for the potential presence of pathogenic mutations. We did not observe a specific enrichment of HR gene mutations based on response to FOLFIRI. This result, combined with the absence of widespread biallelic inactivation of the analyzed genes and the predominance of mutations categorized as variants of unknown significance, suggests that FOLFIRI sensitivity is not primarily governed by underlying mutations in HR genes responsible for mitigating the genotoxic effects of this therapeutic regimen.

  Dataset EGAD50000000277

• Co-amplification of MYC and CCNE1 in aggressive childhood osteosarcoma

  Osteosarcoma, the most common primary malignant tumour of bone, affects children and adults alike. No fundamental biological differences between paediatric and adult osteosarcoma are known. Here, we apply multi-region whole genome sequencing to an index case of a four-year old child whose aggressive tumour harboured high level, focal amplifications of MYC and CCNE1 connected by translocations. We re-analysed copy number readouts of 258 cases of high-grade osteosarcoma from three different cohorts and identified an additional three cases with MYC and CCNE1 co-amplification, confined to children and associated with aggressive disease. Examining the age distribution of MYC and CCNE1 amplicons across all cases revealed a significant enrichment of focal MYC amplification in children, whereas CCNE1 amplification is not strictly restricted to children. Our findings indicate that amplification of the MYC oncogene, known to be associated with a poor outcome, delineates a variant of osteosarcoma specific to childhood. When co-amplified with CCNE1, it may herald an aggressive disease course.

  Dataset EGAD00001006859

• The ALT pathway generates telomere fusions that can be detected in the blood of cancer patients

  Telomere fusions (TFs) can trigger the accumulation of oncogenic alterations leading to malignant transformation and drug resistance. Despite their relevance in tumour evolution, our understanding of the patterns and consequences of TFs in human cancers remains limited. Here, we characterize the rates and spectrum of somatic TFs across &gt;30 cancer types using whole-genome sequencing data. TFs are pervasive in human tumours with rates varying markedly across and within cancer types. In addition to end-to-end fusions, we find novel patterns of TFs that we mechanistically link to the activity of the alternative lengthening of telomeres (ALT) pathway. We show that TFs can be detected in the blood of cancer patients, which enables cancer detection with high specificity and sensitivity even for early-stage tumours and cancers of high unmet clinical need. Overall, we report a novel genomic footprint that enables characterization of the telomere maintenance mechanism of tumours and liquid biopsy analysis.

  Dataset EGAD00001012101

• bulk RNA sequencing, single cell RNA sequencing and nanopore sequencing of T-ALL patients with TCF7-SI1 fusion

  This dataset contains all sequencing data of the publication "Oncogenic cooperation between the TCF7-SPI1 fusion and NRAS(G12D) requires β-catenin activity to drive T-cell acute lymphoblastic leukemia." This is bulk RNA sequencing of 4 T-ALL patients (X09, XB37, XB41 and XB47) of which X09 has a TCF7-SPI1 fusion, single cell RNA sequencing of these 4 patients toghether with a PDX model of the X09 patient and two patients from another cohort (SJTALL030263 and SJTALL031201) which also have a TCF7-SPI1 fusion, and nanopore sequencing of all patients with the TCF7-SPI1 fusion. Moreover these patient samples with the fusion where treated with PKF 118-310, and bulk RNA sequencing was performed in triplicate to determine the differentially expressed genes.

  Dataset EGAD00001007010

• Pulmonary atypical carcinoid multi-omic dataset on up to 42 tumours from same patient

  Pulmonary atypical carcinoid. DNA WES and RNA-Seq on 42 tumour samples collected at autopsy, 10x Chromium linked read whole genome sequencing on four tumours plus one normal sample, and targeted DNA sequencing on two clinical biopsies and one blood plasma sample. Note – RNA-Seq dataset features complex batch effect attributable to tissue processing artefacts, as described in "Complex patterns of genomic heterogeneity identified in 42 tumor samples and ctDNA of a pulmonary atypical carcinoid patient" - Robb et al., 2022 and detailed in Supplementary Table S3. Note – RNA-Seq dataset features complex batch effect attributable to tissue processing artefacts, as described in "Complex patterns of genomic heterogeneity identified in 42 tumor samples and ctDNA of a pulmonary atypical carcinoid patient" - Robb et al., 2022 and detailed in Supplementary Table S3.

  Dataset EGAD00001009296

• Discrepancies in Tumour Mutation Burden (TMB) reporting from sequential Endobronchial ultrasound trans bronchial needle aspiration (EBUS TBNA) samples within single lymph node stations

  Introduction: Tumour Mutation Burden (TMB) is a potential biomarker for immune therapies. Identifying factors that may affect TMB prediction is key to its utility as biomarker for treatment options. Here we investigated parameters that might affect TMB using cytology smears obtained from endobronchial ultrasound transbronchial needle aspiration (EBUS TBNA)-sampled malignant lymph nodes, which are often the only diagnostic samples collected in patients with advanced lung cancer. Methods: Individual Diff-Quik cytology smears were prepared for each needle pass from the same enlarged malignant mediastinal lymph nodes. DNA extracted from smears of each pass underwent sequencing using a large gene panel sequencing (TSO500, Illumina). TMB was estimated for each individual needle pass using the TSO500 Local App v. 2.0 (Illumina). Results: Twenty patients had two or more Diff-Quik smears (total 45 smears) which passed sequencing quality control. Average TMB for all smears was 8.7 ± 5.0 mutations per megabase (Mb). Sixteen of the 20 patients had paired samples with minimal differences in TMB score (average difference 1.3 ± 0.85). Paired samples from 13 patients had concordant TMB in terms of scores being below or above a threshold of 10 mutations/Mb. Samples from seven patients had discrepant TMB, with four cases in particular exhibiting an average difference of 11.3 ± 2.7 mutations/Mb. Factors affecting TMB calling involved tumour content of the samples, the amount of DNA used in sequencing as well as bone fide intra tumour heterogeneity between paired samples. Conclusions: TMB assessment is feasible from EBUS-TBNA derived Diff-Quik slides from a single needle pass. Repeated samples of one or more lymph nodes have minimal variation in TMB in most cases (80%), suggesting accuracy of the test overall. To enhance accuracy of the result, care should be taken in relation to the tumour content of the cytology smear. Further, clinicians should be aware that even slight differences in lymph node site selection could give rise to variable genomics and discrepant TMB due to tumour heterogeneity. Therefore, it would be reasonable for multi-lymph node site analysis of TMB to be performed using EBUS TBNA aspirates from different easily accessible lymph nodes. Further investigations need to determine whether these samples should be combined as one sample or tested separately.

  Study EGAS00001007484

• Whole genome sequencing of tumour and normal paired samples of diffuse intrinsic pontine gliomas

  Diffuse intrinsic pontine glioma (DIPG) have a universally dismal prognosis (median 9-12 months), with neither chemotherapeutic nor targeted agents showing any substantial survival benefit in clinical trials in children with these tumours. DIPG are highly infiltrative malignant glial neoplasms of the ventral pons, which due to their location within the brain, make them unsuitable for surgical resection and consequently have a universally dismal clinical outcome. Recent high-throughput sequencing approaches have revealed a striking prevalence of K27M mutations in the genes encoding the histone variants H3.3 (H3F3A) or H3.1 (HIST1H3B) in the childhood brain tumour DIPG. This K-to-M substitution confers a trans-dominant ablation of global H3K27 trimethylation, which likely profoundly alters gene expression through de-repression of polycomb repressive complex 2 (PRC2) target genes. Despite these advances in our understanding of the distinct biology of these tumours, approaches for specific novel therapeutic interventions are not clear, and little has been reported of the secondary mutations accompanying these changes. We carried out whole genome sequencing on a series of 20 tumour normal pairs of pre-treatment biopsy samples of DIPG, for which the patients underwent a safe stereotactic procedure, and whole exome sequencing on a further six tumour normal pairs obtained at autopsy.

  Study EGAS00001000572

• Transcriptomic analysis of the NA-PHER2 clinical trial

  We performed whole transcriptome RNA sequencing on serial tumour biopsies collected at baseline, Day 14, and after completion of all neoadjuvant therapy from the NA-PHER2 trial. Patients received neoadjuvant treatment with the combined regimen of trastuzumab, pertuzumab, palbociclib with or without addition of fulvestrant. Transcriptomic profiles were generated from 143 samples (Baseline n = 53, Day 14 n = 49, Surgery n = 41) corresponding to 53 of the 58 patients enrolled in NA-PHER2 trial (91.4%). RNA sequencing was performed on total RNA samples derived from formalin-fixed, paraffin-embedded (FFPE) tissue sections. RNA-Seq libraries were produced using NEBNext® Ultra™ II Directional RNA Library Prep Kit. The capture was then performed on cDNA libraries with the Twist Human Core Exome Enrichment System according to supplier recommendations (Twist Bioscience). The obtained eluted-enriched DNA samples was then sequenced on an Illumina NovaSeq as paired-end 100bp reads. FASTQ files are provided.

  Dataset EGAD50000000363

• Spatial transcriptome sequence data from cross section of cancer containing prostates

  Spatial transcriptome sequence data from two tumour containing prostates. Entire cross section of organ divided into cubes to fit spatial transcriptomics arrays. The dataset contains paired-end sequences from 21 sections of 1k array sections and 9 sections of 10x Visium sections for patient 1 as well as 28 sections of 10x Visium sections for patient 2.

  Dataset EGAD00001008644

• Whole genome sequencing data of high-grade serous ovarian cancer samples (set 6)

  Whole genome sequencing data of 31 high-grade serous carcinoma (HGSC) patients (101 samples) sequenced with HiSeq X Ten and BGISEQ-500

  Dataset EGAD00001010202

• Transcriptional regulatory networks of tumor-associated macrophages that drive malignancy in mesenchymal glioblastoma

  Background: Glioblastoma (GBM) is a complex disease with extensive molecular and transcriptional heterogeneity. GBM can be subcategorized into four distinct subtypes; tumors that shift towards the mesenchymal phenotype upon recurrence are generally associated with treatment resistance, unfavorable prognosis, and the infiltration of pro-tumorigenic macrophages. Results: We explore the transcriptional regulatory networks of mesenchymal-associated tumor-associated macrophages (MA-TAMs), which drive the malignant phenotypic state of GBM, and identify macrophage receptor with collagenous structure (MARCO) as the most highly differentially expressed gene. MARCOhigh TAMs induce a phenotypic shift towards mesenchymal cellular state of glioma stem cells, promoting both invasive and proliferative activities, as well as therapeutic resistance to irradiation. MARCOhigh TAMs also significantly accelerate tumor engraftment and growth in vivo. Moreover, both MA-TAM master regulators and their target genes are significantly correlated with poor clinical outcomes, and are often associated with genomic aberrations in neurofibromin 1 (NF1) and phosphoinositide 3-kinases/mammalian target of rapamycin/Akt pathway (PI3K-mTOR-AKT)-related genes. We further demonstrate origination of MA-TAMs from peripheral blood, as well as their potential association with tumor-induced polarization states and immunosuppressive environments. Conclusions: Collectively, our study characterizes the global transcriptional profile of TAMs driving mesenchymal GBM pathogenesis, providing potential therapeutic targets for improving the effectiveness of GBM immunotherapy.

  Study EGAS00001002443

• Functional dissection of inherited non-coding variation influencing multiple myeloma risk

  This dataset contains ATAC sequencing of plasma cells from multiple myeloma (MM) patients. The data was used to investigate genotype-specific chromatin accessibility quantitative trait locus (caQTL) using caQTLseg (https://github.com/abhisheknrl/caQTLseg). This dataset contains 161 bam files.

  Dataset EGAD00001007814

• Etiological Investigation of Cancer Susceptibility in Inherited Bone Marrow Failure Syndromes: A Natural History Study

  Background: A prospective cohort of Inherited Bone Marrow Failure Syndrome (IBMFS) will provide new information regarding cancer rates and types in these disorders. Mutations in IBMFS genes are relevant to carcinogenesis in sporadic cancers. Patients with IBMFS who develop cancer differ in their genetic and/or environmental features from patients with IBMFS who do not develop cancer. These cancer-prone families are well suited for cancer screening and prevention trials targeting those at increased genetic risk of cancer. Carriers of IBMFS gene mutations are at increased risk of cancer. The prototype disorder is Fanconi Anemia (FA); other IBMFS will also be studied. Objectives: To determine the types and incidence of specific cancers in patients with an IBMFS. To investigate the relevance of IBMFS gene mutations in the carcinogenesis pathway of the sporadic counterparts of IBMFS-associated cancers. To identify risk factors for IBMFS-related cancers in addition to the primary germline mutations. To determine the risk of cancer in IBMFS carriers. Design: Natural history study, with questionnaires, clinical evaluations, clinical and research laboratory tests, review of medical records, cancer surveillance. Primary endpoints are all cancers, solid tumors, and cancers specific to each type of IBMFS. Secondary endpoints are markers of pre-malignant conditions, such as leukoplakia, serum or tissue evidence of carcinogenic viruses, and bone marrow morphologic myelodyplastic syndrome or cytogenetic clones.

  Study phs001481

• Whole genome sequencing

  Whole genome sequencing of high-grade serous ovarian cancer (HGSC) tumours and matched normals from 15 patients with homologous recombination deficiencies. The dataset includes fastq files from 56 HGSC tumours (1 primary, 1 relapse, 54 end-stage) and 15 matched normals. Sequence libraries were generated from tumour and matched normal genomic DNA using the KAPA HyperPrep PCR-free library preparation kit (Roche), or the Illumina TruSeq DNA Nano kit according to manufacturer’s instructions. Sequencing was carried out by the Kinghorn Centre for Clinical Genomics Sequencing Laboratory (Sydney, Australia) on the HiSeq X Ten System (Illumina) or by the Australian Genome Research Facility (Melbourne, Australia) on an Illumina NovaSeq to a minimum base coverage of 30-fold for normal DNA and 60-fold for tumour DNA samples.

  Dataset EGAD00001009746