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• APOBEC3 mutagenesis drives therapy resistance in breast cancer

  Acquired genetic alterations commonly drive resistance to endocrine and targeted therapies in metastatic breast cancer, however the underlying processes engendering these diverse alterations are largely uncharacterized. To identify the mutational processes operant in breast cancer and their impact on clinical outcomes, we utilized a well-annotated cohort of 3,880 patient samples with paired tumor-normal sequencing data. The mutational signatures associated with apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) enzymes were highly prevalent and enriched in post-treatment compared to treatment-naïve hormone receptor-positive (HR+) cancers. APOBEC3 mutational signatures were independently associated with shorter progression-free survival on antiestrogen plus CDK4/6 inhibitor combination therapy in patients with HR+ metastatic breast cancer. Whole genome sequencing (WGS) of breast cancer models and selected paired primary-metastatic samples demonstrated that active APOBEC3 mutagenesis promoted resistance to both endocrine and targeted therapies through characteristic alterations such as RB1 loss-of-function mutations. Evidence of APOBEC3 activity in pre-treatment samples illustrated a pervasive role for this mutational process in breast cancer evolution. The study reveals APOBEC3 mutagenesis to be a frequent mediator of therapy resistance in breast cancer and highlights its potential as a biomarker and target for overcoming resistance.

  Study EGAS50000000875

• Phase I Study and Cell-Free DNA Analysis of T-DM1 and Metronomic Temozolomide for Secondary Prevention of HER2-Positive Breast Cancer Brain Metastases

  This study is a phase I trial combining ado-trastuzumab emtansine (T-DM1) with Temozolomide (TMZ) for the prevention of additional brain metastases after previous occurrence and local treatment in HER2+ breast cancer patients. Twelve patients were enrolled in this study. Data includes whole exome sequencing (WES) from patients' cerebrospinal fluid (CSF) and plasma samples. The CSF was collected from each patient at trial entry and after the initial two treatment cycles of TMZ and T-DM1 treatment. Blood was collected through a standard peripheral venipuncture at the following four time points: 1) upon trial entry, 2) after two treatment cycles, 3) the treatment cycle prior to the last follow-up, and 4) most recent follow-up. Whole exome libraries were captured by the SureSelect Human All Exon V8 Kit (Agilent, Santa Clara, CA, USA) and sequenced by NovaSeq 6000 S2 Sequencer in paired-end sequencing mode (Illumina, San Diego, CA, USA). Gene mutations in DNMT3A, ELP1, NOTCH4, KMT2B, CRLF2, and KCNJ18 were observed in patients' CSF.

  Study phs003165

• Mutational Landscape of MCPyV-Positive and MCPyV-Negative Merkel Cell Carcinomas

  Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin most commonly found on the sun-exposed skin of older Caucasian adults. Roughly one-third of patients with MCCs die of the disease; therefore, MCC is the most lethal skin cancer on a case-by-case basis. 49 cases were studied, and putative cancer driver gene mutations and tumor antigens in both MCPyV-negative and MCPyV-positive MCCs were identified.

  Study phs002515

• PDAC organoid genomic heterogeneity

  The establishment of patient-derived pancreatic cancer organoid culture in recent years creates an exciting opportunity for researchers to perform a wide range of in vitro studies on a model that closely recapitulates the tumor. Among the outstanding questions in pancreatic cancer biology are the causes and consequences of genomic heterogeneity observed in the disease. However, to use pancreatic cancer organoids as a model to study genomic variations, we need to first understand the degree of genomic heterogeneity and its stability within organoids. Here, we used single-cell whole-genome sequencing to investigate the genomic heterogeneity of two independent pancreatic cancer organoids, as well as their genomic stability with extended culture. Clonal populations with similar copy number profiles were observed within the organoids, and the proportion of these clones was shifted with extended culture, suggesting the growth advantage of some clones. However, sub-clonal genomic heterogeneity was also observed within each clonal population, indicating the genomic instability of the pancreatic cancer cells themselves. Furthermore, our transcriptomic analysis also revealed a positive correlation between copy number alterations and gene expression regulation, suggesting the “gene dosage” effect of these copy number alterations that translates to gene expression regulation.

  Study EGAS00001006782

• KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in NUP98-Rearranged Acute Myeloid Leukemia

  NUP98 fusion oncoproteins (FOs) are a hallmark of childhood acute myeloid leukemia (AML). NUP98 FOs drive leukemogenesis through phase-separated condensate formation and maintenance of an active chromatin landscape at stem cell-associated genes in cooperation with epigenetic regulators. Here we show that MYST family histone acetyltransferase (HAT) complex proteins including KAT6A/MOZ, KAT7/HBO1, and the common KAT6A/7 complex subunit BRPF1 associate with NUP98 FOs on chromatin and within condensates. MYST HATs are molecular dependencies in NUP98-rearranged (NUP98-r) leukemia, and genetic inactivation or pharmacologic inhibition of Kat6a and Kat7 impairs NUP98-r cell fitness. KAT6A/7 inhibition decreased global H3K23ac levels, displaced NUP98::HOXA9 from chromatin at the Meis1 locus, and led to myeloid cell differentiation. Additionally, KAT6A/7 inhibition decreased leukemic burden in multiple NUP98-r leukemia xenograft mouse models, synergized with Menin inhibitor treatment, and was efficacious in Menin inhibitor-resistant cells. In summary, we show that MYST family HATs are therapeutically actionable dependencies in NUP98-r AML.

  Study EGAS50000001075

• Cancer Research UK Manchester Institute/ Cancer Research UK National Biomarker Centre Data Access Committee

  Cancer Research UK Manchester Institute/Cancer Research UK National Biomarker Centre Data Access Committee is created to • Review and approve data access requests. • Ensure data security and compliance with institutional and legal obligations. • Maintain accurate records of access decisions For questions or further information, please contact: Chair of the Data Access Committee: Caroline Wilkinson Email: dac@cruk.manchester.ac.uk

  Dac EGAC50000000795

• Methylation Array data for: Three-dimensional patient-derived models of glioblastoma retain intra-tumoral heterogeneity

  3 sets of matched patient-derived-organoids (PDOs),  -neurospheres (PDNs), and parent glioblastoma tissue (9 samples total) underwent methylation array analysis. 200ng of each sample DNA extracted via a commercial kit (Qiagen) and loaded onto the Illumina EPIC v2.0 array. Data is provided as raw red and green .idat files.

  Dataset EGAD00010002745

• single-cell RNA-Seq samples of CRC patients

  The dataset contains samples of 11 CRC patients (2 samples for each patient, tumor and normal adjacent tissue site, 22 samples in total). Dataset is composed by fastq file (paired end) type from 10x single-cell RNA-Seq.

  Dataset EGAD00001009634

• RNA-Seq Dataset of Organoid drug profiling identifies methotrexate as a therapy for SCCOHT, a rare pediatric cancer

  We generated and characterized tumoroids from small cell carcinoma of the ovary, hypercalcemic type. Furthermore, we identified a drug that is selective and effective against SCCOHT tumoroids.

  Dataset EGAD00001015441

• In vitro reconstitution of epigenetic reprogramming in the human germ line

  Epigenetic reprogramming resets parental epigenetic memories and differentiates primordial germ cells (PGCs) into mitotic pro-spermatogonia or oogonia, ensuring sexually dimorphic germ-cell development for totipotency. In vitro reconstitution of epigenetic reprogramming in humans remains a fundamental challenge. Here, we establish a robust strategy for inducing epigenetic reprogramming and differentiation of pluripotent stem cell (PSC)-derived human PGC-like cells (hPGCLCs) into mitotic pro-spermatogonia or oogonia, coupled with their extensive amplification (~>1010-fold). Strikingly, bone morphogenetic protein (BMP) signalling is a key driver of these processes: BMP-driven hPGCLC differentiation involves an attenuation of the mitogen-activated protein kinase/extracellular-regulated kinase (MAPK/ERK) pathway and both de novo and maintenance DNA methyltransferase (DNMT) activities, likely promoting replication-coupled, passive DNA demethylation. On the other hand, hPGCLCs deficient in tens-eleven translocation (TET) 1, an active DNA demethylase abundant in human germ cells, differentiate into extraembryonic cells, including amnion, with de-repression of key genes bearing bivalent promoters; these cells fail to fully activate genes vital for spermatogenesis and oogenesis, with their promoters remaining methylated. Our study elucidates the framework of epigenetic reprogramming in humans, making a fundamental advance in human biology, and through the generation of abundant mitotic pro-spermatogonia and oogonia-like cells, represents a milestone for human in vitro gametogenesis (IVG) research and its potential translation into reproductive medicine.

  Study JGAS000690

• Transcriptome and epigenomic landscape of cytotrophoblasts from normal and HDP placentas

  Hypertensive isorders of pregnancy (HDP) is a severe pregnancy-related disorder that poses significant risks to both maternal and fetal health. Dysfunctional placental development is one of the major contributors to the onset of HDP. In this study, we investigated the gene expression and epigenomic modifications in cytotrophoblasts from normal and HDP placentas. The information obtained in this study contributes to the growing body of knowledge aimed at improving the diagnosis, management, and treatment of HDP.

  Study JGAS000667

• Gene_Discovery_in_Age_Related_Hearing_Loss

  The aim is to find new candidate genes associated with progressive hearing loss

  Study EGAS00001000295

• Placental_mosaicism

  The aim of this study is to survey somatic mutations in human placentas.

  Study EGAS00001003549

• A recessive PRDM13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia

  The PRDM13 (PR Domain containing 13) putative chromatin modifier and transcriptional regulator functions downstream of the transcription factor PTF1A, which controls GABAergic fate in the spinal cord and neurogenesis in the hypothalamus. Here, we report a novel, recessive syndrome associated with PRDM13 mutation. Patients exhibited intellectual disability, ataxia with cerebellar hypoplasia, scoliosis and delayed puberty with congenital hypogonadotropic hypogonadism (CHH). Expression studies revealed Prdm13/PRDM13 transcripts in the developing hypothalamus and cerebellum in mouse and human. An analysis of hypothalamus and cerebellum development in mice homozygous for a Prdm13 mutant allele revealed a significant reduction in the number of Kisspeptin (Kiss1) neurons in the hypothalamus and PAX2+ progenitors emerging from the cerebellar ventricular zone. The latter was accompanied by ectopic expression of the glutamatergic lineage marker TLX3. Prdm13-deficient mice displayed cerebellar hypoplasia, normal gonadal structure, but delayed pubertal onset. Together, these findings identify PRDM13 as a critical regulator of GABAergic cell fate in the cerebellum and of hypothalamic kisspeptin neuron development, providing a mechanistic explanation for the co-occurrence of CHH and cerebellar hypoplasia in this syndrome. To our knowledge, this is the first evidence linking disrupted PRDM13-mediated regulation of Kiss1 neurons to CHH in humans.

  Study EGAS00001005878

• ChIP-seq for G3-MB

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

  Dataset EGAD50000002303

• Maturation of Human Intestinal Epithelial Cell Layers Fortifies the Apical Surface against Salmonella Attack

  Pathogen invasion of intestinal epithelial cells (IECs) is a key gut infection event. The dynamics of this process in intact epithelia and the factors governing IEC susceptibility remain underexplored. We present a resource for live-cell infection imaging in human enteroid-/colonoid-derived IEC layers, across maturation states and in the presence or absence of soluble mucus production. Utilization of this resource shows how human IEC maturation fortifies the apical surface against invasion by Salmonella Typhimurium (S.Tm). Immature IEC layers appear permissive to S.Tm invasion, but maturation towards an enterocyte/colonocyte phenotype reduces the susceptibility by up to tenfold. This shift couples to downregulated expression of actin regulatory proteins exploited by the pathogen, an increased dependence on the S.Tm effector SipA, and the build-up of the apical IEC glycocalyx linked to surface-attached mucins like MUC13 and nullifiable by StcE-enzyme treatment. This underscores how the maturation state of human IECs governs susceptibility to bacterial invasion.

  Study EGAS50000001241

• The epigenetic landscape controlled by p63 in epidermal development

  Transcription factor p63 is a key regulator of epidermal keratinocyte proliferation and differentiation. Heterozygous mutations of TP63 encoding p63 cause a spectrum of developmental disorders. EEC syndrome is caused by point mutations in the p63 DNA-binding domain, and manifests ectodermal dysplasia with defects in the epidermis and epidermal related appendages, limb malformation and cleft lip/palate. Five hotspot mutations affecting amino acids, R204, R227, R279, R280 and R304, have been found in approximately 90% of the EEC population. Although the role of p63 in normal epidermal development and differentiation has been demonstrated, the molecular mechanism by which p63 mutations cause the epidermal phenotype in diseases is not yet understood. In the two related studies, we characterize p63 mutant keratinocytes (R204W, R279H and R304W) and p63 mutant iPSCs (R204W and R304W) and the molecular mechanisms underlying their differentiation defects.

  Study phs001737

• Access to "BMP9 controls pulmonary vascular growth and remodeling"

  Pulmonary arterial hypertension (PAH) and hereditary hemorrhagic telangiectasia (HHT) are two distinct vascular diseases linked to impaired signaling through bone morphogenetic protein (BMP) receptor complexes in endothelial cells. Although BMP-9 plays a central role in activating this pathway by binding to ALK1 and BMPR-II, its precise function in the pulmonary microvasculature has remained unclear. In this study, we uncover a previously unrecognized role for BMP-9 in regulating pulmonary vascular architecture and homeostasis. Our findings demonstrate that BMP-9 signaling intersects with VEGF pathways and contributes to the delicate balance between vascular growth and remodeling in the lungs. We also show that disruption of this pathway can shift vascular responses toward an HHT-like state, potentially altering disease susceptibility. These insights offer a unique perspective on how BMP-9 and ALK1 shape pulmonary vascular biology and suggest that targeting this axis could inform future strategies for treating complex vascular diseases such as PAH.

  Dac EGAC50000000640

• Patient-derived tumor organoids for personalized medicine in a rare case of hepatocellular carcinoma with neuroendocrine differentiation.

  We report the case of a 74-year-old man with a very rare subtype of hepatocellular carcinoma with neuroendocrine differentiation (HCC-NED). The patient presented with two independent tumors, a gastrointestinal stromal tumor in the stomach and a hepatocellular carcinoma in the liver. Both tumors were surgically removed in curative intent. Histopathological work-up of the liver tumor revealed poorly differentiated hepatocellular carcinoma (Edmondson-Steiner grade IV) with diffuse expression of neuroendocrine markers synaptophysin (SYP) and chromogranin (CHGA). Three months after resection, multifocal recurrence of the HCC with neuroendocrine differentiation (HCC-NED) was observed. In the meantime, tumor organoids have been generated from the resected HCC-NED and extensively characterized. Sensitivity to a number of drugs approved for the treatment of HCC or neuroendocrine carcinomas was tested in vitro. Based on their in vitro efficacy, etoposide and carboplatin were used as first line palliative combination treatment. Because genomic analysis revealed a NTRK1-mutation (kinase domain) and tumor organoids were sensitive to entrectinib, a pan-TRK inhibitor, the patient received entrectinib as second line therapy. After only two weeks, treatment had to be discontinued due to deterioration of the patient’s general condition. In conclusion, we demonstrate for the first time that preclinical drug testing using organoids is feasible in selected HCC cases.

  Study EGAS00001005887

• Chracterising cellur pathways underlying CD3/CD28 activation of human CD4+ cells

  We devised an approach to disentangle the TCR and CD28 pathways upon stimulation in naive and memory primary human CD4+ T cells (Tcons) in response to defined stimulatory signals. Isolated memory and naïve T cells were activated using anti-CD3, anti-CD28 or both in combination. As a control we cultured cells in the same conditions but without the stimuli. We carried Chipmentation using the H3K27ac antibody on 200,000 cross-linked cells. 1) This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute please see http://www.sanger.ac.uk/datasharing/ .

  Dataset EGAD00001006611

• Structural Expression of BMMF in tissues of colorectal, lung and pancreatic cancer patients

  Chronic inflammation, linked to the presence of bovine milk and meat factors (BMMF) and specific subsets of macrophages, results in oxygen radical synthesis and induction of mutations in DNA of actively replicating cells and replicating single stranded DNA (zur Hausen et al., 2017). Cancers arising from this process have been characterized as indirect carcinogenesis by infectious agents (without persistence of genes of the agent in premalignant or cancers cells). Here we investigate structural properties of pleomorphic vesicles, regularly identified by staining peritumour tissues of colorectal, lung and pancreatic cancer for expression of BMMF Rep. The latter represents a subgroup of BMMF1 proteins involved in replication of small single-stranded circular plasmids of BMMF, but most likely also contributing to pleomorphic vesicular structures found in the periphery of colorectal, lung and pancreatic cancers. Structurally dense regions are demonstrated in preselected areas of colorectal cancer, after staining with monoclonal antibodies against BMMF1 Rep. Similar structures were observed in human embryonic cells (HEK293TT) overexpressing Rep. These data suggest that Rep or Rep isoforms contribute to the structural formation of vesicles.

  Study EGAS00001006744

• Epigenetic analysis of clear cell renal cell carcinoma using ChIP-seq

  To investigate the epigenetic landscape of clear cell renal cell carcinoma (ccRCC), we performed ChIP-seq data for the CTCF, H3K4me1, H3K4me3, H3K27ac, H3K27me3, H3K36me3, and HIF1A marks in the 786-O, A-498, UM-RC-2 ccRCC cell lines, as well as the HK-2 normal renal epithelium cell line, cultured under normoxic (20% O2) and hypoxic (0.05% O2) conditions. Data are provided in raw fastq and narrowPeak formats. Data were processed using the nf-core chipseq pipeline.

  Dataset EGAD50000001886

• WGS dataset for two NUP98-Rearranged Acute Myeloid Leukemia PDX samples

  This dataset includes whole genome sequencing of two patient-derived xenograft (PDX) samples with NUP98-Rearranged Acute Myeloid Leukemia. Bam files are provided for each sample.

  Dataset EGAD50000001563

• KiCS WGS data for academic use only

  Data from samples that are marked for academic use only

  Dataset EGAD00001009698

• Origin of second malignancies in children

  Pediatric cancers are rare diseases, and children without known germline predisposing conditions who develop a second malignancy during developmental ages are extremely rare. We present four such clinical cases and through whole-genome and error-correcting ultra-deep duplex sequencing of tumor and normal samples, we explored the origin of the second malignancy in four children, uncovering different routes of development. The exposure to cytotoxic therapies was linked to the emergence of a secondary AML. A common somatic mutation acquired early during embryonic development was the driver of two solid malignancies in another child. In two cases, the two tumors developed from completely independent clones diverging during embryogenesis. Importantly, we demonstrate that platinum-based therapies contributed at least in one order of magnitude more mutations per day of exposure than aging to normal tissues in these children.

  Study EGAS50000000167

• Transfer Learning Associates CAFs with EMT and Inflammation in Tumor Cells in Human Tumors and Organoid Co-Culture in Pancreatic Ductal Adenocarcinoma

  This study examined the transcriptional changes induced by cancer associated fibroblasts (CAFs) in pancreatic ductal adenocarcinoma patient-derived tumor organoids. We hypothesized that cancer associated fibroblasts impacted tumor cell transcription to promote tumorigenic behavior. Using patient-matched cells from 3 patients, we compared the transcriptional profiles of patient-derived organoids in monoculture to patient-derived organoids co-cultured with CAFs. Similarly, we looked at the transcriptional changes in matched patient-derived cancer associated fibroblasts grown in monoculture or co-cultured with patient-derived organoids. With a focus on intercellular crosstalk, we identified crosstalk between cancer associated fibroblasts and patient-derived organoids through VEGFA and NRP1. This was identified by bulk RNA sequencing and examined dynamically in organoid-CAF co-culture. This dbGaP deposit is the bulk RNA sequencing data for these 3 patients.

  Study phs003563

• Exome sequencing data from two myelosarcomas

  Isolated myeloid sarcoma (MS, i.e. acute myeloid leukemia without detectable bone marrow infiltration) is rare and most patients subsequently develop overt AML. We prospectively performed whole exome sequencing of uterine MS, concomitant morphologically normal bone marrow (BM) and subsequently developing AML from two women. Both patients harbored preleukemic clones in the morphologically normal BM, including DNMT3A mutations. In addition, recurrent mutations were identified in the NFE2 gene, a gene not previously associated with AML or isolated MS. Retrospective studies of further MS samples, twelve with and four without preceding or concomitant bone marrow AML, revealed NFE2 mutations in two additional cases, both with isolated MS and prior myeloid malignancies. We conclude that DNMT3A mutated preleukemia may predispose for the frequent bone marrow relapses following isolated MS and that recurrent NFE2 mutations may have a role in the development of isolated MS.

  Study EGAS00001002562

• Nanopore sequencing from liquid biopsy: analysis of copy number variations from cell-free DNA of lung cancer patients

  Molecular cancer paper (https://doi.org/10.1186/s12943-021-01327-5): This dataset contain shallow whole-genome sequencing (sWGS) of plasma cell-free DNA from cancer patients and healthy subjects, obtained with both Nanopore and Illumina technology. A total of 6 cancer patients and 5 healthy subjects have been sequenced with Nanopore; 4 of the cancer patients have been also sequenced with Illumina. In addition, genomic DNA from white blood cells of one healthy subjects, genomic and 160bp DNA from HEK cells have been sequenced with Nanopore. Genome Biology paper: 3 additional healthy samples have been sequenced (HU), two different bioinformatic pipeline were applied. 2019: Fastqs from the molecular cancer paper were re-demultiplexed and adapter-trimmed (using guppy for multiplex samples, and porechop for singleplex) preserving 5' ends to allow fragmentomics analysis. HAC: All the samples were basecalled with the same updated High Accuracy model (the latest at the time of the analysis) and post-processed as the 2019 dataset. Raw FAST5 are currently available upon request, but will be uploaded soon.

  Dataset EGAD00001006888

• Genomic Advances in Sepsis (GAinS): RNA-seq

  Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. This cohort comprises a subset of patients enrolled in the Genomic Advances in Sepsis (GAinS) study, an established biobank of adult sepsis patients. Patients with sepsis due to community acquired pneumonia or faecal peritonitis were recruited from 34 hospitals across the UK from 2005-2018, with samples for functional genomics and detailed clinical information collected on the first, third and/or fifth day following ICU admission. RNA was extracted from leukocytes isolated at the bedside using LeukoLOCK kits. We have previously identified sepsis response signatures (SRSs), transcriptomic endotypes that are associated with differential early mortality (Davenport et al, Lancet Respir Med, 2016; Burnham et al, AJRCCM, 2017) and response to treatment in a clinical trial (Antcliffe et al, AJRCCM, 2018). We generated RNA sequencing data on 903 samples, including 134 samples repeated from our previously released microarray data. Libraries were prepared using NEB Ultra II Library Prep kits (Illumina) and sequenced on a NovaSeq 6000. Reads were aligned to the reference genome (GRCh38) using STAR and gene counts quantified using featureCounts (annotation Ensembl v99). Counts were TMM-normalised and log-transformed. Following QC, processed data were available on 864 samples from 667 unique patients.

  Dataset EGAD00001008730

• Analysis of ATL progression by CD30 signaling and its biomarkers (2)

  Adult T-cell leukemia/lymphoma (ATL) develops via stepwise accumulation of gene mutations and chromosome aberrations. However, the molecular mechanisms underlying this tumorigenic process are poorly understood. We aim to elucidate the mechanism of the tumorigenic process involving genomic aberrations by CD30 signaling in HTLV-1���infected T-cells.

  Study JGAS000537

• Mortality and risk of progression to adult T-cell leukemia/lymphoma in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis

  Human T-cell leukemia virus (HTLV)-1 causes the functionally debilitating disease HTLV-1-associated myelopathy/ tropical spastic paraparesis (HAM/TSP) as well as adult T-cell leukemia lymphoma (ATLL). Although there were concerns that the mortality of HAM/TSP could be affected by the development of ATLL, prospective evidence was lacking in this area. In this 5-year prospective cohort study, we determined the mortality, prevalence, and incidence of ATLL in 527 HAM/TSP patients. The standard mortality ratio of HAM/TSP patients was 2.25, and ATLL was one of the major causes of death (5/33 deaths). ATLL prevalence and incidence in these patients were 3.0% and 3.81 per 1,000 person-years, respectively. To identify patients at a high risk of developing ATLL, flow cytometry, Southern blotting, and targeted sequencing data were analyzed in a separate cohort of 218 HAM/TSP patients. In 17% of the HAM/TSP patients, we identified an increase in T-cells positive for cell adhesion molecule 1 (CADM1), a marker for ATLL and HTLV-1 infected cells. Genomic analysis of these patients revealed that somatic mutations of HTLV-1 infected cells were seen in 90% of the cases and 11% of them had dominant clone and developed ATLL in the longitudinal observation. In this study, we were able to demonstrate for the first time that the increased mortality in patients with HAM/TSP and a significant effect of ATLL on their prognosis. Having dominant clonal expansion of HTLV-1- infected cells with ATLL-associated somatic mutations may be important characteristics of patients with HAM/TSP who are at an increased risk of developing ATLL.

  Study JGAS000226

• 10X single cell sequencing of HNT34 cocultured with Tcells with or without antibody targeting SLAMF6

  This dataset contains fastq-files from single cell 5' RNA sequencing of the AML cell line HNT34 and normal T cells following co-culture with and without an antibody blocking SLAMF6 (TNC-1). The libraries were prepared using 10X GEM-X Universal 5' Gene Expression v3 Reagent Kit. In total, the dataset contains sequenced gene expression libraries from four samples (HNT34 co-cultured with T cells from two different donors; for both donors there is one sample with and one sample without the blocking antibody).

  Dataset EGAD50000001573

• SOFT study - sequencing premenopausal breast cancer (2017-11-22)

  Our project will examine the role of PIK3CA mutations and their sensitivity to endocrine therapies and its role, with the addition of complete ovarian suppression. We plan to test our hypotheses using tumour samples collected from patients enrolled in the SOFT/IBCSG24-02 clinical study (Suppression of Ovarian Function Trial - (NCT00066690). SOFT is a phase III trial that randomised 3066 premenopausal women to evaluate if adding ovarian suppression to adjuvant endocrine therapy will improve clinical outcomes. This dataset contains all the data available for this study on 2017-11-22.

  Dataset EGAD00001003811

• Single-cell RNA-seq of rheumatoid arthritis synovial tissue using low-cost microfluidic instrumentation

  Droplet-based single-cell RNA-seq has emerged as a powerful technique for massively parallel cellular profiling. While these approaches offer the exciting promise to deconvolute cellular heterogeneity in diseased tissues, the lack of cost-effective, reliable, and user-friendly instrumentation has hindered widespread adoption of droplet microfluidic techniques. To address this, we have developed a microfluidic control instrument that can be easily assembled from 3D printed parts and commercially available components costing approximately $575. We adapted this instrument for massively parallel scRNA-seq and deployed it in a clinical environment to perform single-cell transcriptome profiling of disaggregated synovial tissue from 5 rheumatoid arthritis patients. We sequenced 20,387 single cells from synovectomies, revealing 13 transcriptomically distinct clusters. These encompass a comprehensive and unbiased characterization of the autoimmune infiltrate, including inflammatory T and NK subsets that contribute to disease biology. Additionally, we identified fibroblast subpopulations that are demarcated via THY1 (CD90) and CD55 expression. Further experiments confirm that these represent synovial fibroblasts residing within the synovial intimal lining and subintimal lining, respectively, each under the influence of differing microenvironments. We envision that this instrument will have broad utility in basic and clinical settings, enabling low-cost and routine application of microfluidic techniques, and in particular single-cell transcriptome profiling. Reprinted from [Stephenson et al., Nature Communications, 2018], with permission from the Nature Publishing Group.

  Study phs001529

• Total RNAseq in the sporadic ALS and healthy control motor cortex

  Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the degeneration of upper and lower motor neurons leading to progressive muscle weakness, wasting and paralysis that result in death within a few years from disease onset. In order to characterize RNA alterations in ALS, total RNAseq was performed in the ALS motor cortex, which is an early and vulnerable region in ALS.

  Study EGAS00001004286

• The Genetic Landscape of Metastasis and Recurrence in Head and Neck Squamous Cell Carcinoma

  Recurrence and/or metastasis occur in more than half of patients with head and neck squamous cell carcinoma (HNSCC) and pose the greatest threats to long-term survival. The genetic alterations underlying recurrent/metastatic HNSCC are unknown. This study represents the first whole exome sequencing (WES) cohort study of patient-matched tumor pairs in recurrent or metastatic HNSCC. Synchronous lymph node metastases are genetically more similar to their paired index primary tumors than metachronous recurrent tumors are. Newly arisen mutations in recurrent or metastatic tumors, may have therapeutic implications. Several genes were found to be mutated in multiple metastatic or recurrent tumors, but not in their respective primaries, including C17orf104, ITPR3, and DDR2. DDR2 mutations have been shown to confer enhanced sensitivity to Src-family kinase (SFK) inhibitors in other malignancies. Similarly, we found HNSCC cell lines harboring endogenous and engineered DDR2 mutations to be more sensitive to the SFK inhibitor dasatinib, than those with WT DDR2. This study outlines the first compendium of somatic mutations in primary, metastatic and/or recurrent HNSCC cancers that arise in individual patients; and demonstrates how such data can be used to interrogate potential predictive/prognostic biomarkers to inform and guide personalized therapy.

  Study phs001007

• Chronic lymphocytic leukemia IGHV somatic hypermutation detection by targeted capture next-generation sequencing

  Somatic hypermutation (SHM) status of the immunoglobulin heavy variable (IGHV) gene locus plays a crucial role in determining the prognosis and treatment of patients with chronic lymphocytic leukemia (CLL). A common approach for determining SHM status is multiplex PCR of the IGH gene followed by Sanger sequencing; however, this technique is low throughput, vulnerable to failure, and does not allow multiplexing with other molecular diagnostic assays. Here we designed and validated a DNA targeted capture approach that allows the assessment of IGHV SHM status as a sub-module of a larger next-generation sequencing (NGS) assay. We developed an end-to-end assay that takes as input raw FASTQ files and outputs a report containing IGHV SHM status and V-allele usage following the guidelines of the European Research Initiative on CLL (ERIC). We validated the approach on 35 CLL patient samples, 34 of which were previously characterized using Sanger sequencing. The targeted capture NGS panel identified the SHM status of 34 of 35 CLL patients. We showed 100% sensitivity and specificity among the 33 CLL samples with both NGS and Sanger calls. Furthermore, we demonstrated that this panel can be combined with additional targeted capture panels to detect common and prognostically important CLL single nucleotide variants (SNV) and insertion/deletion (indel) variants as well as copy number variants (del17p). Thus, a targeted capture approach to IGHV SHM detection can be easily integrated into broader sequencing panels, allowing broad CLL prognostication in a single molecular assay.

  Study EGAS00001006887

• RNA-sequencing of ex vivo exhausted human antigen-specific T cells

  Tumor-specific T cells are frequently exhausted by chronic antigenic stimulation. To explore new pathways for reinvigoration of anti-tumor immune functions, we developed a human ex vivo exhaustion model by repetitive antigenic stimulation of primary CD8 T cells. This results in T cells that resemble patient-derived T cells in tumors on a phenotypic and transcriptional level.

  Study EGAS00001006794

• The Spatial Heterogeneity in Multiple Myeloma - from the Subclonal Architecture to the Immune Microenvironment (partly hipo_K08K)

  Multiple myeloma (MM) cells show pronounced heterogeneity not only within a given patient but also between spatially separated tumor loci in the bone marrow. Understanding this spatial heterogeneity is emerging as a critical challenge for the successful treatment of the disease. Yet, our understanding of spatial differences in the subclonal architecture, molecular signatures and interactions with the tumor microenvironment remains very limited. To address this shortcoming, we performed bulk and single-cell multi-region sequencing, including random bone marrow samples from the iliac crest and paired imaging-guided focal lesion specimens from 15 newly diagnosed MM patients. We found a median of 5 subclones per patient and unique subclones in focal lesions. Central features of spatial heterogeneity included a consistent down-regulation of the chemoattractant cytokines CXCL7 and CXCL12 in focal lesion tumor cells as well as a significant depletion of macrophages in the focal lesion microenvironment. In contrast, a site-specific expansion of T-cell clones was not detected in focal lesions. In conclusion, our results demonstrate the relevance of considering spatial heterogeneity with potential implications for immunotherapies and molecular studies analyzing the role of gene signatures and MM-microenvironment interactions in disease progression.

  Study EGAS00001006090

• Multisample genomic analysis of solid childhood cancers using high resolution SNP-arrays, Whole Exome Sequencing and Targeted Deep Sequencing.

  We mapped the prevalence of genetically distinct clones over 248 regions in 54 childhood cancers. This revealed that primary tumors can simultaneously follow up to four evolutionary patterns in different anatomic areas. The most common pattern consists of a fluctuating presence over anatomic space of subclones with very few mutations. The second most common is a surprisingly stable coexistence, over vast areas, of clones with different changes in chromosome numbers. This is contrasted by a third, less frequent, pattern where a novel clone harboring driver mutations or structural chromosome rearrangements completely replaces its progenitor. The fourth and rarest pattern is the local emergence of a myriad of clones with TP53 inactivation. Strikingly, death from disease was limited to tumors exhibiting the two latter, most dynamic patterns.

  Study EGAS00001002662

• MutWP5: CRUK Mutographs of Cancer: Lung: PD37920 (WG) (2020-02-20)

  Sequencing of LCM-derived microbiopsies from explanted lung from COPD patient. Goal to assess the mutational burden, spectrum, and clonal dynamics within the tissue. Deep sampling throughout multiple regions of the lung will determine whether there are differences in smoking-related mutation burden in different portions of the lung. Whole-genome sequencing will be conducted on samples identified as promising from the initial targeted data. Results from this portion of the study will be compared to other individuals with smoking-related diseases (COPD, pulmonary fibrosis, lung cancer), and normal, non-smoking lungs. . This dataset contains all the data available for this study on 2020-02-20.

  Dataset EGAD00001005990

• MutWP5: CRUK Mutographs of Cancer: Lung: PD38234 (WG) (2020-02-20)

  Sequencing of LCM-derived microbiopsies from explanted lung from pulmonary fibrosis patient. Goal to assess the mutational burden, spectrum, and clonal dynamics within the tissue. Deep sampling throughout multiple regions of the lung will determine whether there are differences in smoking-related mutation burden in different portions of the lung. Whole-genome sequencing will be conducted on samples identified as promising from the initial targeted data. Results from this portion of the study will be compared to other individuals with smoking-related diseases (COPD, pulmonary fibrosis, lung cancer), and normal, non-smoking lungs. . This dataset contains all the data available for this study on 2020-02-20.

  Dataset EGAD00001005991

• Paired WES and low coverage WGS of osteosarcoma

  Longitudinal genome-sequencing analysis of 12 patients with metastatic or refractory osteosarcoma. The study was approved at the University Hospital Basel, following the approval of the ethical committee for mutational analysis of anonymized samples (“Ethikkommission beider Basel” ref. 274/12). Informed consent was obtained from all 12 patients. All tumor samples were evaluated by an experienced bone pathologist to confirm the diagnosis. WES and low coverage WGS are aligned against the reference genome GRCh37. More details in the associated publication.

  Dataset EGAD00001007509

• Whole genome and RNA sequencing of paediatric glioblastoma in the ICGC PedBrain project

  Paediatric glioblastoma (pedGBM) is characterised by substantial intertumoural heterogeneity. In order to identify the genetic lesions underlying tumourigenesis, we analysed whole genomes and transcriptomes of pedGBMs and in vitro model systems by next generation sequencing. Novel fusions of the receptor tyrosine kinase MET lead us to investigate targeted therapy using MET inhibitors. This study is part of the International Cancer Genome Consortium PedBrain Tumor Project (ICGC PedBrain, http://www.pedbraintumor.org/).

  Study EGAS00001001139

• The Gut Microbiome of liver transplant recipients – Cross-sectional + Longitudinal (renal and liver)

  TransplantLines is designed as a single-center, prospective cohort study and biobank including all different types of solid organ transplant recipients as well as living organ donors. In the TransplantLines gut microbiome study the gut microbiome of solid organ transplant recipients is characterized and linked to clinical phenotypes. This batch contains the cross-sectional data from liver transplant recipients and longitudinal data from renal and liver transplant recipients.

  Study EGAS00001006258

• Transcriptome analysis of human longitudinal whole blood samples from PCR-positive and PCR-negative adults following controlled inoculation with Influenza A (H3N2) virus.

  Transcriptome analysis of influenza A (H3N2) human challenge samples. Understanding of the transcriptomic profile of individuals in early influenza infection is limited. To investigate this, longitudinal whole-blood samples (n=178) were taken from adult participants following controlled inoculation with Influenza A H3N2 virus (sampling at baseline (0) and days 1, 2, 3, 7, 10 and 14 post-challenge). Most participants became influenza PCR-positive; a minority remained PCR-negative. Total RNA was extracted from PAXgene tubes before undergoing globin and rRNA depletion. DNA libraries were constructed using the NEBNext® Ultra™ II Directional RNA Library Prep Kit for Illumina. All samples were then sequenced using Illumina NovaSeq 6000.

  Study EGAS50000000679

• DPY30_ChIP_seq

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

  Study EGAS00001001132

• Genetic heritage of the Baphuthi highlights an over-ethnicised notion of 'Bushman' in the Maloti-Drakensberg, southern Africa

  Using contemporary people as proxies for ancient communities is a contentious but necessary practice in anthropology. In southern Africa, the distinction between the Cape KhoeSan and eastern KhoeSan remains unclear as ethnicity labels have been changed through time and most communities were decimated if not extirpated. The eastern KhoeSan may have had genetic distinctions from neighbouring communities who speak Bantu languages and KhoeSan further away, alternatively the identity may not have been tied to any notion of biology, instead denoting communities with a nomadic 'lifeway' distinct from African agro-pastoralism. The Baphuthi of the 1800s in the Maloti-Drakensberg, southern Africa had a substantial KhoeSan constituency and a lifeway of nomadism, cattle raiding, and horticulture. Baphuthi heritage could provide insights into the history of the eastern KhoeSan. We examine genetic affinities of 23 Baphuthi to discern whether the narrative of KhoeSan descent reflects distinct genetic ancestry. Genome-wide SNP data (Illumina GSA) were merged with 52 global populations, for 160K SNPs. Genetic analyses show no support for a unique eastern KhoeSan ancestry distinct from other KhoeSan or southern Bantu-speakers. The Baphuthi have strong affinities with early-arriving southern Bantu-speaking (Nguni) communities, as the later-arriving non-Nguni show strong evidence of recent African admixture possibly related to Late-Iron Age migrations. The references to communities as 'San',and 'Bushman' in historic literature has often been misconstrued as notions of ethnic/biological distinctions. The terms may have reflected ambiguous references to non-sedentary polities instead, as seems to be the case for the eastern ‘Bushman’ heritage of the Baphuthi.

  Study EGAS00001007080

• Whole Genome Sequencing Data of High Grade Serous Ovarian Cancer

  Longitudinal whole genome sequencing data to study chemoresponse in ovarian cancer. These samples belong to an ongoing sample collection and the data already includes hundreds of samples from over 200 patients. Samples are from primary and metastatic tissues and ascites. All patients have been treated with platinum-taxane based chemotherapy and majority of them are diagnosed with high-grade serous ovarian cancer.

  Study EGAS00001006775

• ZFHX4 is necessary for dopaminergic neuron differentiation and controls cell cycle by regulating LIN28A

  ZFHX4 as a transcription factor specifically induced during the in vitro differentiation of iPSC-derived mDANs. Depletion of ZFHX4 during neuronal differentiation led to a significant reduction in the number of mDANs while its overexpression did not lead to any changes in mDAN count. Identification of ZFHX4 target genes using CUT&Tag profiling and RNA-seq upon ZFHX4 knock-down (KD) revealed its involvement in cell cycle regulation during mDAN differentiation

  Dataset EGAD50000001605