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• Successful immune checkpoint blockade in a patient with advanced stage microsatellite unstable biliary tract cancer (H021)

  Cancers acquire multiple somatic mutations that can lead to the generation of immunogenic mutation-induced neoantigens. These neoantigens can be recognized by the host’s immune system. However, continuous stimulation of immune cells against tumor antigens can lead to immune cell exhaustion, which allows uncontrolled outgrowth of tumor cells. Recently, immune checkpoint inhibitors have emerged as a novel approach to overcome immune cell exhaustion and re-activate anti-tumor immune responses. In particular, antibodies blocking the exhaustion-mediating programmed death receptor (PD-1)/PD-L1 pathway have shown clinical efficacy. The effects were particularly pronounced in tumors with DNA mismatch repair deficiency and a high mutational load, which typically occur in the colon and endometrium. Here, we report on a 24-year old woman diagnosed with extrahepatic cholangiocarcinoma who showed strong and durable response to the immune checkpoint inhibitor pembrolizumab, although treatment was initiated at an advanced stage of disease. The patient’s tumor displayed DNA mismatch repair deficiency and microsatellite instability (MSI), but lacked other features commonly discussed as predictors of response towards checkpoint blockade, such as PD-L1 expression or dense infiltration with cytotoxic T cells. Notably, high levels of HLA class I and II antigen expression were detected in the tumor, suggesting a potential causal relation between functionality of the tumor’s antigen presentation machinery and the success of immune checkpoint blockade. We suggest determining MSI status in combination with HLA class I and II antigen expression in tumors potentially eligible for immune checkpoint blockade even in the absence of conventional markers predictive for anti-PD-1/PD-L1 therapy and in entities not commonly linked to MSI phenotype. Further studies are required to determine the value of these markers for predicting the success of immune checkpoint blockade. (H021)

  Study EGAS00001002441

• Molecular features of adenomas predicting metachronous colorectal cancer: a nested-case control study

  "Background & Aims: Current morphological features defining advanced adenomas (size ≥10 mm, high grade dysplasia or >25% villous component) cannot optimally distinguish individuals at high-risk or low-risk of metachronous colorectal cancer (me-CRC), which may result in suboptimal surveillance. Certain DNA copy number alterations are associated with adenoma-to-carcinoma progression (cancer-associated events; CAEs). We aimed to evaluate whether CAEs can better predict an individual’s risk of me-CRC than the morphological advanced adenoma features. Methods: In this nested case-control study, 529 individuals with a single adenoma at their first colonoscopy were selected from a Norwegian adenoma cohort. DNA copy number profiles were determined, by means of low-coverage whole genome sequencing. We assessed the prevalence of CAEs in advanced and non-advanced adenomas and its association with me-CRC. For the latter, cases (with CRC) were matched to controls (without CRC), with the same follow-up period as cases, as well as age and sex. Subsequently, odds ratios (OR) for the association of the presence of an advanced adenoma or a molecularly-defined high-risk adenoma with me-CRC were calculated. Results: Molecular high-risk features were observed in 85/267 (32%) of advanced adenomas and in 27/262 (10%) of non-advanced adenomas. Me-CRC was more strongly associated with advanced adenomas (OR 3.58; 95% CI 2.27-5.72) than with molecular high-risk adenomas (OR 1.90; 95% CI 1.14–3.16). After adjusting for other variables, only advanced adenoma remained significantly associated with me-CRC (OR 3.39; 95% CI 2.10–5.55). Conclusion: Molecularly-defined high-risk adenomas were associated with me-CRC, but the association of advanced adenoma with me-CRC was stronger. " Project goal: Evaluate the value of DNA copy numbers alterations detected in a baseline adenoma, in the prediction of risk of metachronous CRC

  Study EGAS00001007039

• scRNAseq data of CAP

  Fastq files from scRNAseq data of cancer associated pericytes-like from 3 patients. CAP were isolated from a total of 3 primary BC (surgical residues prior to any treatment) by using BDFACS ARIA III sorter (BD Biosciences). BC were collected directly from the operating room after surgical specimen macroscopic examination and selection of areas of interest by a pathologist. Samples were cut into small pieces (around 1 mm3) and digested in CO2-independent medium (Gibco #18045-054) supplemented with 150 μg/mL liberase (Roche #05401020001) and Dnase I (Roche #11284932001) for 40 min at 37°C with shaking (180 rpm). After digestion, cells were processed and stained as described above (#Flow Cytometry analysis of BC samples). CAP fibroblasts were then gated on the Live/Dead negative fraction and defined as EPCAM- CD45- CD31- CD235a- FAPMed CD29High. CAP scRNA-seq: Upon isolation, CAP cells were directly collected into RNase-free tubes (Thermo Fisher Scientific, #AM12450) precoated with DMEM (GE Life Sciences, #SH30243.01) supplemented with 10% FBS (Biosera, #1003/500). Single-cell capture, lysis, and cDNA library construction were performed using Chromium system from 10X Genomics, with the following kits: Chromium Single Cell 3′ Library & Gel Bead Kit v2 kit (10X Genomics, #120237) and Chromium Single Cell A Chip Kits (10X Genomics, #1000009). Generation of gel beads in Emulsion (GEM), barcoding, post GEM-reverse transcription cleanup and cDNA amplification were performed according to the manufacturer’s instructions. Cells were loaded accordingly on the Chromium Single cell A chips, and 12 cycles were performed for cDNA amplification. cDNA quality and quantity were checked on Agilent 2100 Bioanalyzer using Agilent High Sensitivity DNA Kit (Agilent, #5067-4626) and library construction followed according to 10X Genomics protocol. Libraries were next run on the Illumina HiSeq (for patients P1) and NovaSeq (for patients P2–3) with a depth of sequencing of 50,000 reads per cell.

  Dataset EGAD50000000321

• GeneScreen, a Population Based, Targeted Genomic Screening Study

  The GeneScreen research study was based at the University of North Carolina (UNC) at Chapel Hill. It brought together researchers from different disciplines, including genetics, clinical medicine, bioethics, sociology, anthropology, psychology, and public health, to study the best ways to offer targeted genetic screening to the general adult population. DNA samples were collected from people who joined GeneScreen to look at a targeted panel of 17 genes. It tested for genetic differences (called mutations) that can cause one of 11 rare, but preventable or treatable conditions, including certain types of cancer and heart disease. Each condition has specific medical advice people can follow with their doctors to prevent or treat a serious health problem. The GeneScreen study was approved by the UNC Institutional Review Board and by the Kaiser Permanente Center for Health Research Institutional Review Board. GeneScreen is funded by the National Human Genome Research Institute of the National Institutes of Health.

  Study phs001817

• A Genome-wide Association Study (GWAS) of Risk for Osteosarcoma

  This is a genome-wide association study (GWAS) of osteosarcoma, the most common primary bone malignancy. Osteosarcoma typically occurs in adolescents and young adults. It occurs at increased frequency in several inherited cancer predisposition syndromes but the genetic contribution to sporadic osteosarcoma is largely unexplored. The objective of this study was to identify genetic risk factors for osteosarcoma by conducting a genome-wide association study. We developed collaborations with multiple institutions in order to attain the necessary sample size required to discover novel loci in the genome associated with osteosarcoma using the GWAS approach. Genomic DNA (either blood or buccal in source) derived from osteosarcoma cases was obtained from each participating institution or research group. De-identified blood or buccal cell DNA samples from osteosarcoma cases were derived from existing biobanks at the collaborative institutions. Control subjects were derived from existing NCI cohorts and matched by gender and ethnicity.

  Study phs000734

• The Microbial Ecology of Bacterial Vaginosis: A Fine Scale Resolution Metagenomic Analysis

  Archived self-collected vaginal swabs were utilized from a pilot study of vaginal douching cessation (NIH/NIAID R03-AI061131). Thirty-nine non-pregnant, reproductive-age women who reported the use of vaginal douche products in the two months prior to screening were enrolled. Thirty-three of these successfully completed the 16-week longitudinal study. Participants self-collected vaginal swabs and smears twice weekly. We report sequences based on the analysis of 16S rRNA gene sequences amplified from whole genomic DNA isolated from the swabs. Bacterial vaginosis (BV) is defined by Gram's stain of vaginal fluid (Nugent's score =7). The large body of information generated will facilitate understanding of vaginal microbial community dynamics, the etiology of BV, and drive the development of better diagnostic tools for BV. Furthermore, it is hoped that the information will enable a more personalized treatment of BV and ultimately, prevent adverse sequelae associated with BV.

  Study phs000261

• Towards a Genomic Understanding of Myeloma

  This project was designed to describe genetic abnormalities in primary samples from patients with multiple myeloma by next generation sequencing. We generated sequence data from multiple myeloma (MM) patients analyzing DNA both from tumor cells (purified from bone marrow using CD138 selection as a marker of plasma cells) and from normal peripheral blood cells (either whole blood or Ficoll-purified mononuclear cells). Using massively parallel sequencing technology (Illumina GA-2 or HiSeq)), we performed whole-genome sequencing (WGS) and/or whole-exome sequencing (WES). The initial set currently deposited contains data from 38 MM patients (23 patients surveyed by WGS and 16 patients by WES, with one patient analyzed by both approaches). Genomes were sampled to high depth, obtaining an average of 33X coverage and 104X coverage for WGS and WES tumors, respectively. The normal samples had similar coverage. Our goal is to help researchers understand the complex genetic landscape of multiple myeloma and provide a resource for the generation of biological hypotheses.

  Study phs000348

• ROCHE PD 92 Multiome dataset

  This dataset contains 10X Multiome data generated on post-mortem brain from 92 individuals (70 PD, 22 controls). For the Roche_PD dataset, nuclei were isolated using Nuclei Pure Prep Nuclei Isolation Kit (Sigma Aldrich) with the following modifications. The tissue was lysed in Nuclei Pure Lysis Solution with 0.1% Triton X, 1mM DTT and 0.4U/ul SUPERase-In™ RNase Inhibitor (ThermoFisher Scientific) freshly added before use and homogenized with the help first of a 23G and then of a 29G syringe. Cold 1.8M Sucrose Cushion Solution, prepared immediately before use with the addition of1mM DTT and 0.4U/ul RNase Inhibitor, was added to the suspensions before they were filtered through a 30μm strainer. The lysates were then carefully and slowly layered on top of 1.8M Sucrose Cushion Solution previously added in new Eppendorf tubes. Samples were centrifuged for 45 minutes at 16000xg at 4°C. Pellets were re-suspended in Nuclei Storage Buffer with RNase Inhibitor, transferred in new Eppendorf tubes and centrifuged twice for 5 minutes at 500xg at 4°C. Finally purified nuclei were re-suspended in Nuclei Storage Buffer with RNase Inhibitor, stained with trypan blue and counted using Countess II (Life technology). After count, nuclei permeabilization was carried out following the demonstrated protocol for single cell multiome ATAC + Gene Expression sequencing from 10x Genomics. A total of 12,000 estimated nuclei from each sample was used for the transposition step and then loaded on the Chromium Next GEM Single Cell Chip J. ATAC library and gene expression library construction was performed using the Chromium Next GEM Single Cell Multiome ATAC + Gene Expression kit according to the manufacturer’s instructions. Libraries were sequenced using Illumina NovaSeq 6000 System and NovaSeq 6000 S2 Reagent Kit v1.5 (100 cycles), aiming at a minimum sequencing depth of 30K reads/nucleus. Genotype was generated as previously described (Bryois et al, Nature Neuroscience, 2022).

  Dataset EGAD50000000964

• Aberrant RNA-splicing (neojunctions) offers a new source for targets, and our neoantigen discovery platform (SNIPP) characterizes a novel class of clonally-expressed splicing-derived neoantigens that elicit a CD8+ T-cell-mediated tumor killing response.

  RESULTS: Our pipeline identified 789 public neojunctions, with 32 neojunctions concurrently identified in transcriptomic and proteomic glioma data and predicted to be presented by HLA-A*02:01 with high confidence. IVS and subsequent 10x VDJ scRNA-seq identified TCR clonotypes reactive against neojunctions in RPL22 (n=7) and GNAS (n=1), the latter being highly intratumorally-conserved (detected in > 90% of spatially-mapped biopsies across 17/56 patients (26.78%)). TCR-transduced T-cells demonstrated recognition and immunogenic activation against endogenously processed and presented neoantigens in multiple GBM PDX cell lines. Furthermore, IDH1-mutant oligodendroglioma samples demonstrated significantly elevated expression of neojunctions over IDH1-mutant astrocytoma and IDH1wt subtypes. Differential gene expression (DESeq2) identified decreased expression of splicing factors due to oligodendroglioma-specific co-deletion of Chromosomes 1p/19q. siRNA knockdown of these splicing factors (e.g. SF3A3, SNRPD2) in IDH1wt glioma cells resulted in significantly increased expression of corresponding neojunctions.

  Study EGAS00001007986

• A single-chain derivative of the integrin β1-activating TS2/16 antibody potentiates organoid growth in Matrigel and Collagen hydrogels.

  Culturing epithelial organoids from Adult Stem Cells (ASCs) requires interaction of their β1-integrins with extracellular matrix (ECM) components such as laminin or collagen. Matrigel and BME® (extracts from Engelbreth-Holm-Swarm tumor cells grown in the mouse abdomen) are a popular source of ECM proteins. Yet, these preparations are costly and subject to batch-to-batch variation due to animal-derived contaminations. Here, we describe a single chain version (scFv) of antibody TS2/16, allosterically activating integrin β1 function in organoids. Addition of 5 nM of monomeric scFv to organoid medium results in up to 5-fold higher yields of organoids in Matrigel/BME®. In addition, scTS2/16 generates 6-7-fold higher yields of intestinal organoids in collagen-I hydrogel, when grown both in 3D and in 2D. Collagen is well-defined, available at clinical grade, and in combination with scTS2/16, will enable the clinical use of gastrointestinal organoids.

  Study EGAS50000001113

• WFS1 mutation screening in a large series of Japanese hearing loss patients: Massively parallel DNA sequencing-based analysis

  A heterozygous mutation in the Wolfram syndrome type 1 gene (WFS1) causes autosomal dominant nonsyndromic hereditary hearing loss, DFNA6/14/38, or Wolfram-like syndrome. To date, more than 40 different mutations have been reported to be responsible for DFNA6/14/38. In the present study, WFS1 variants were screened in a large series of Japanese hearing loss (HL) patients to clarify the prevalence and clinical characteristics of DFNA6/14/38 and Wolfram-like syndrome. Massively parallel DNA sequencing of 68 target genes was performed in 2,549 unrelated Japanese HL patients to identify genomic variations responsible for HL. The detailed clinical features in patients with WFS1 variants were collected from medical charts and analyzed. We successfully identified 13 WFS1 variants in 19 probands: eight of the 13 variants were previously reported mutations, including three mutations (p.A684V, p.K836N, and p.E864K) known to cause Wolfram-like syndrome, and five were novel mutations.

  Study JGAS000123

• A comprehensive human gastric cancer organoid biobank captures tumor subtype heterogeneity and enables therapeutic screening​

  Gastric cancer displays marked molecular heterogeneity with aggressive behavior and treatment resistance. Therefore, good in vitro models that encompass unique subtypes are urgently needed for precision medicine development. Here, we have established a primary gastric cancer organoid (GCO) biobank that comprises normal, dysplastic, cancer and lymph node metastases (n=63) from 34 patients, including detailed whole-exome and transcriptome analysis. The cohort encompasses most known molecular subtypes (including EBV, MSI, intestinal/CIN, and diffuse/GS, with CLDN18-ARHGAP6 or CTNND1-ARHGAP26 fusions or RHOA mutations), capturing regional heterogeneity and subclonal architecture, while their morphology, transcriptome, and genomic profiles remain closely similar to in vivo tumors, even after long-term culture. Large-scale drug screening revealed sensitivity to unexpected drugs that were recently approved or in clinical trials, including Napabucasin, Abemaciclib, and the ATR inhibitor VE-822. Overall, this new GCO biobank, with linked genomic data, provides a useful resource for studying both cancer cell biology and precision cancer therapy.

  Study EGAS00001003145

• Epigenomics and Single-cell Sequencing Define a Developmental Hierarchy in Langerhans Cell Histiocytosis

  Langerhans cell histiocytosis (LCH) is a rare neoplasm predominantly affecting children. It occupies a hybrid position between cancers and inflammatory diseases, and it provides an attractive model for studying cancer development. To explore the molecular mechanisms underlying the pathophysiology of LCH and its characteristic clinical heterogeneity, we investigated the transcriptomic and epigenomic diversity in primary LCH lesions. Using single-cell RNA sequencing, we identified multiple recurrent types of LCH cells within these biopsies, including putative LCH progenitor cells and several subsets of differentiated LCH cells. We confirmed the presence of proliferative LCH cells in all analysed biopsies using immunohistochemistry, and we defined an epigenomic and gene-regulatory basis of the different LCH cell subsets by chromatin accessibility profiling. In summary, our single-cell analysis of LCH uncovered an unexpected degree of cellular, transcriptomic, and epigenomic heterogeneity among LCH cells, indicative of complex developmental hierarchies in LCH lesions.

  Study EGAS00001003822

• A novel subset of human CD33+ haematopoietic stem cells characterized at single-cell resolution

  Elucidation of the identity and diversity of mechanisms that sustain long-term human blood cell production remains an important challenge. Previous studies indicate that, in adult mice, this property is ultimately vested in cells uniquely identified by their ability to clonally regenerate detectable levels of mature blood cells in serially transplanted recipients. We now present a combined multi-parameter analysis of the molecular features of very primitive human cord blood cells that display different cell output activities in vitro and in vivo. These analyses identified a new, prospectively separable, but still functionally heterogeneous, subset of long-term human blood-forming cells. Single-cell measurements of their transcriptional, DNA methylation and 40-protein content and of closely related phenotypes revealed numerous subtle, but consistent differences both within and between each subset analyzed. These results suggest that multiple regulatory mechanisms underlie the functional heterogeneity exhibited by clonally tracked human blood cell precursors with long-term output abilities.

  Study EGAS00001002826

• Single cell RNA sequencing and Whole Genome Sequencing on different cells from the same sample for a triple negative patient derived xenograft and ovarian cancer cell lines.

  Measuring gene expression of genomically defined tumour clones at single cell resolution would associate functional consequences to somatic alterations, as a prelude to elucidating pathways driving cell population growth, resistance and relapse. In the absence of scalable methods to simultaneously assay DNA and RNA from the same single cell, independent sampling of cell populations for parallel measurement of single cell DNA and single cell RNA must be computationally mapped for genome-transcriptome association. Here we present clonealign, a robust statistical framework to assign gene expression states to cancer clones using single-cell RNA-seq and DNA-seq independently sampled from an heterogeneous cancer cell population. We apply clonealign to triple-negative breast cancer patient derived xenografts and high-grade serous ovarian cancer cell lines and discover clone-specific dysregulated biological pathways not visible using either DNA-Seq or RNA-Seq alone.

  Study EGAS00001003387

• A Universal Gut Metagenomic-Derived Signature Predicts Cirrhosis

  Dysregulation of the gut microbiome has been implicated in the progression of nonalcoholic fatty liver disease (NAFLD) to advanced fibrosis and cirrhosis. To determine the diagnostic capacity of this association, stool microbiomes were compared across 163 well-characterized participants encompassing non-NAFLD controls, NAFLD-cirrhosis patients and their first-degree relatives. Interrogation of shotgun metagenomic and untargeted metabolomic profiles using the Random Forest machine learning algorithm and differential abundance analysis identified discrete metagenomic and metabolomic signatures that were similarly effective in detecting cirrhosis (diagnostic accuracy 0.91, AUC). Combining the metagenomic signature with age and serum albumin levels accurately distinguished cirrhosis in etiologically and genetically distinct cohorts from geographically separated regions. Additional inclusion of serum aspartate aminotransferase levels, which are increased in cirrhosis patients, enabled discrimination of cirrhosis from earlier stages of fibrosis. These findings demonstrate that a core set of gut microbiome species may offer universal utility as a non-invasive diagnostic test for cirrhosis.

  Study EGAS00001004600

• A Single-Cell Atlas of the Multicellular Ecosystem of Primary and Metastatic Hepatocellular Carcinoma

  Hepatocellular carcinoma (HCC) represents a paradigm of the relation between tumor microenvironment (TME) and tumor development. Here, we generated a single-cell atlas of the multicellular ecosystem of HCCs from four relevant sites. Antitumor central memory T (TCM) cells were found in tertiary lymphoid structures (TLSs). Chronic HBV/HCV infection increases infiltration of CD8+ T cells in tumors but aggravates T cell exhaustion. We identified CD11b+ macrophages to be terminally differentiated tumor-associated macrophages (TAMs) and two distinct differentiation trajectories contribute to their accumulation. We further demonstrated CD11b+ TAMs promote HCC cells invasion and migration, and angiogenesis. We characterized the heterogeneous subpopulations of malignant hepatocytes and their multifaceted roles in shaping the immune microenvironment. Finally, we identified seven TME subtypes that can predict patient prognosis. Collectively, this large-scale atlas deepens our understanding of the ecosystem in primary and metastatic HCCs, might facilitating the development of new immune therapy strategies for this malignancy.

  Study EGAS00001004468

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

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

  Study EGAS00001005963

• Identification of the Global miR-130a Targetome Reveals a Novel Role for TBL1XR1 in Hematopoietic Stem Cell Self-Renewal and t(8;21) AML

  In this study, we identified miR-130a as a regulator of HSC self-renewal and differentiation. To characterize gene expression changes following enforced expression of miR-130a OE, we performed RNA-seq in CD34+ cord blood (CB) cells transduced with control and miR-130a OE lentiviruses. To capture miRNA targets in an unbiased, transcriptome-wide manner, we perfomed enhanced CLIPseq procol in 2 replicates of CD34+ CB cells and Kasumi-1 cell line, which represent a model system for t(8;21) AML. We chose this cell line, as we found miR-130a to be highly expressed in this AML subtype where it is critical for maintaining the oncogenic molecular program mediated by AML1-ETO. Chimeric Ago2 eCLIPseq in CD34+ CB cells combined with Mass Spectrometry data analysis identified TBL1XR1 as a principal target of miR-130a. To elucidate gene expression changes associated with TBL1XR1 loss of function, we performed RNA-seq in CD34+CD38- CB cells transduced with control and shRNA targeted against TBL1XR1. To determine the functional significance of high miR-130a expression levels in Kasumi-1 cells on the molecular network controlled by AML1-ETO, we performed CUT&RUN assay and RNA-seq in Kasumi-1 cells following miR-130a knock-down (KD). Collectively, our findings reveal a unique role of miR-130a in regulating normal hematopoietic stem cell self-renewal and how elevated levels of miR-130a in t(8;21) AML contribute to the leukemogenesis of this AML subtype.

  Dataset EGAD00001008412

• Diagnostic utility of whole genome sequencing in adults with B-other acute lymphoblastic leukemia

  Genomic profiling at diagnosis of B-cell precursor Acute Lymphoblastic Leukemia (BCP-ALL) in adults is used to guide disease classification, risk stratification and treatment decisions. Patients for which diagnostic screening fails to identify disease defining or risk stratifying lesions are classified as B-other ALL. We screened a cohort of 652 BCP-ALL cases enrolled in UKALL14 to identify and perform whole genome sequencing (WGS) on paired tumor-normal samples. For 52 B-other patients we compared WGS findings to data from clinical and research cytogenetics. WGS identifies a cancer associated event in 51/52 cases, this includes an established subtype defining genetic alteration in 5/52 that were previously missed by standard-of-care genetics. Of the 47 true B-other ALL we identified a recurrent driver in 87% (41).  Complex karyotype by cytogenetics emerges as a heterogeneous group, underlied by distinct genetic alterations associated with either favorable (DUX4-r) or poor outcomes (MEF2D-r, IGK::BCL2). For a subset of 31 cases, we integrate findings from RNA-sequencing (RNA-seq) analysis to include fusion gene detection, and classification by gene expression. Compared to RNA-seq, WGS was sufficient to detect and resolve recurrent genetic subtypes, however RNA-seq can provide orthogonal validation of findings. In conclusion, we demonstrate that WGS can identify clinically relevant genetic abnormalities missed by standard-of-care testing and identify leukemia driver events in virtually all cases of B-other ALL.

  Dataset EGAD00001009304

• Ancestry and somatic profile predict acral melanoma origin and prognosis – WXS

  Acral melanoma, which is not ultraviolet (UV)-associated, is the most common type of melanoma in several low- and middle-income countries including Mexico. Latin American samples are significantly underrepresented in global cancer genomics studies, which directly affects patients in these regions as it is known that cancer risk and incidence may be influenced by ancestry and environmental exposures. To address this, we characterise the genome and transcriptome of 123 acral melanoma tumours from 92 Mexican patients, a population notable because of its genetic admixture. Compared with other studies of melanoma, we found fewer frequent mutations in classical driver genes such as BRAF, NRAS or NF1. While most patients had predominantly Amerindian genetic ancestry, those with higher European ancestry had increased frequency of BRAF mutations and a lower median number of structural variants. The tumours with activating BRAF mutations have a transcriptional profile more similar to cutaneous non-volar melanocytes, suggesting that acral melanomas in these patients may arise from a distinct cell of origin compared to other tumours arising in these locations. KIT mutations were found in a subset of these tumours, and quadruple wild-type samples (non BRAF/NRAS/NF1/KIT) differed from mutated samples in their structural genomic profile and overall and recurrence-free survival patterns. Transcriptional profiling defined three expression clusters; these characteristics were associated with recurrence-free and overall survival. We highlight potential novel low-frequency drivers, such as PTPRJ, NF2 and RDH5. Our study enhances knowledge of this understudied disease and underscores the importance of including samples from diverse ancestries in cancer genomics studies.

  Dataset EGAD00001015755

• Spiradenocarcinoma (2018-10-29)

  Spiradenocarcinoma is a rare cutaneous sweat gland adnexal cancer with potential for aggressive behaviour. They are classified histologically into low- and high-grade tumours, with morphologically low-grade tumours thought to behave more favourably. However, limited information is available, with only 18 published cases. We have collected morphologically low-grade spiroadenocarcinomas (one with a lung metastasis) and high-grade spiroadenocarcinomas, as well as some spiradenomas (benign lesions), cylindromas (another type of malignant cutaneous sweat gland adnexal tumour) and hybrid spiradenoma-cylindromas. H&E-stained sections were reviewed, follow-up was obtained, and immunohistochemistry for Ki-67, p53 and, MYB has been performed. The tumours were solitary, measuring 0.8-7?cm (median: 2.7?cm), with a predilection for the head and neck of elderly patients (median age: 72 years; range 53-92) without gender bias. Histologically, the tumours were multinodular and located in deep dermis and subcutis. A pre-existing spiradenoma was present in all cases. The malignant component was characterized by expansile growth with loss of the dual cell population, up to moderate cytological atypia and increased mitotic activity (median: 10/10 HPF; range 1-28). Additional findings included squamoid differentiation (n=9), necrosis (n=7), and ulceration (n=5). P53 expression was variable and no significant differences were noted in the benign compared with the malignant parts of the tumours. In contrast, in the malignant components the Ki-67 proliferative index was slightly increased, and MYB expression was lost. Follow-up (median: 67 months; range: 13-132) available for 16 patients (84%) revealed a local recurrence rate of 19% but no metastases or disease-related mortality. Here we wish to exome sequence these cases to define the first genomic landscape for this malignancy. This dataset contains all the data available for this study on 2018-10-29.

  Dataset EGAD00001004426

• Determination of cell specific regulatory enhancers in hematopoetic models

  The BLUEPRINT project is a large-scale project investigating epigenetic mechanisms involved in blood formation, in health and disease. The human variation workpackage (WP10, led by NS) of the project seeks to characterize the effect of common sequence variation on the epigenome status of a cell. To do this, the project will use highly purified blood cells to minimise "experimental noise" and therefore enhance the power to discover modest effects. Two peripheral blood cell types, the CD14+CD16- monocyte (an important central orchestrator of adaptive immunity and a bridge between innate and adaptive immunity) and the CD65+CD9- neutrophilic granulocyte (the frontline cell for innate immunity) have been selected for this purpose. The two types of cells will be obtained at high purity from adult blood (AB) of 200 healthy males and females, respectively. Cells will be purified by using already validated and fully operational protocols that are based on density gradient centrifugation of the buffy coat obtained from whole blood, followed by magnetic bead-based purification using monoclonal antibodies against Cluster of Differentiation (CD) lineage-specific cell surface markers. Units of 475 ml of AB will be obtained from consenting volunteers of the Cambridge BioResource (CBR), a panel of 10,000 healthy volunteers local to Cambridge who have already consented to participate in biomedical research and of whom biological samples (DNA, plasma, serum) and lifestyle data have been deposited in a repository and database, respectively. We are requesting funding from the Human Diversity project to sequence the genomes of the 200 CBR volunteers at low pass (6x coverage). Nuclei, DNA and RNA will be recovered from the purified cells and made available for RNA-seq, DNA-seq and ChIP-seq and genomic DNA for entire genome sequencing will be recovered from the DNA repository.

  Dataset EGAD00001002205

• Quick Guide for data submission

  Quick Guide This is a quick guide to submit data to the EGA. Please select data type to display the right detailed instructions. Sequence data Array-based data Get your submission account You first need to create your EGA user. Then, once your account has been verified by the Help Desk team, request your submission account and provide details of the data type and platform(s) in your submission. Register Study/DAC Use Submitter Portal to register your study, samples, Data Access Committee (DAC) and Policy. Upload data Encrypt your data files using the and upload it to your inbox using SFTP. Register experiments and runs Associate each data file to a registered sample and study by Linking files to samples. Details of the experimental procedure you followed must be provided. Finalise your submission Group your runs/analysis into datasets and link them to your new or existing DAC and policy using DAC Portal. Data request are done at a dataset level, thus files within a datasets must share release conditions. Release and admin When finalising the submission, set a released date to instruct our Helpdesk to release your study. All registered studies are automatically placed on hold until the named submission or DAC contact instructs our Helpdesk for the study to be released. Get your submission account Fill the submission form and provide details of the data type and platform(s) in your submission. Register Study/DAC Use EGA Programmatic submission to register your study, samples, Data Access Committee (DAC) and Policy. Upload data Encrypt your data files using the EgaCryptor and upload it using default FTP clients or Aspera. Complete the Array-Format (AF) spreadsheet Download the AF spreadsheet and complete all four sections. Return the spreadsheet to the EGA helpdesk. Release and admin Instruct our Helpdesk to release your study. All registered studies are automatically placed on hold until the named submission or DAC contact instructs our Helpdesk for the study to be released.

  Documentation submission/quickguide

• A National Translational Science Network of Precision-Based Immunotherapy for Primary Liver Cancer (PLC)

  The primary objective of the NCI-CLARITY study is to establish a biospecimen repository for genomic, genetic and epigenetic analysis to study the biology of primary liver cancer (PLC) development and progression. Secondary objectives include predicting overall and progression-free survival following immunotherapy. In the retrospective phase, anonymous archival tissue from PLC patients was obtained from five participating sites. Whole exome and transcriptome sequencing was generated and used to predict overall survival in response to immunotherapy.

  Study phs003074