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• Clinical data

  Clinical data for KATHERINE: Clinical data include Treatment Arm, Invasive Disease Free Survival (IDFS), Clinical Stage at Presentation, Hormone Receptor Status, Preoperative HER2 Directed Therapy, Pathological Node.

  Dataset EGAD00001008785

• 125 cfDNA samples from healthy patients

  BAM files corresponding to the sequencing of 125 circulating cell-free DNA from 125 healthy patients. Each sample was sequenced twice.

  Dataset EGAD00001005463

• DNA Methylomic Profiling of Preeclampsia Across Pregnancy

  Preeclampsia (PE) is a hypertensive, multi-system disorder of pregnancy that significantly impacts maternal and infant morbidity/mortality across the globe, as it increases risk of cardiovascular disease and remains a leading killer of women and babies. Despite PE's significant impact on morbidity/mortality, there are no clinically reliable biomarkers that predict PE. DNA methylation, a dynamic regulator of gene expression, represents a mechanism that is known to be impacted by the environment. Because PE stems from a dysfunctional placenta that releases debris into the maternal circulation, we hypothesized that the in-vivo environment created by the dysfunctional placenta will impact DNA methylation in the maternal circulation, and that these blood-based methylation profiles would serve as a systemic biomarker of the maternal response to placental dysfunction. Our overall objective of this pilot study was to longitudinally characterize DNA methylation profiles across the three trimesters of pregnancy in the maternal blood at time points before and after clinically overt PE using a targeted (endoglin and endoglin-related genes) and a discovery-based approach. For this pilot study, 28 normotensive control participants and 28 PE case participants enrolled in the NICHD funded pregnancy study entitled Prenatal Exposures and Preeclampsia Prevention: Mechanisms of Preeclampsia and the Impact of Obesity (PEPP3; P01HD30367) were 1:1 frequency matched on self-reported race, pre-pregnancy BMI, smoking history, and gestational age at sample collection. Methylation data were collected with the Infinium® MethylationEPIC Beadchip. Methylation assay data collection were carried out at Johns Hopkins University Genetic Resources Core Facility, The SNP Center, Baltimore, MD, USA.

  Study phs001937

• Evaluation of EBUS-TBNA Aspirates from Advanced NSCLC for Comprehensive Sequencing Platforms Including Whole Genome Sequencing

  Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is often the only source of tumor tissue from patients with advanced, inoperable lung cancer. EBUS-TBNA aspirates are used for the diagnosis, staging, and genomic testing to inform therapy options. Here we extracted DNA and RNA from 220 EBUS-TBNA aspirates to evaluate their suitability for whole genome (WGS), whole exome (WES), and comprehensive panel sequencing. For a subset of 40 cases, the same nucleic acid extraction was sequenced using WGS, WES, and the TruSight Oncology 500 assay. Genomic features were compared between sequencing platforms and compared with those reported by clinical testing. A total of 204 aspirates (92.7%) had sufficient DNA (100 ng) for comprehensive panel sequencing, and 109 aspirates (49.5%) had sufficient material for WGS. Comprehensive sequencing platforms detected all seven clinically reported tier 1 actionable mutations, an additional three (7%) tier 1 mutations, six (15%) tier 2–3 mutations, and biomarkers of potential immunotherapy benefit (tumor mutation burden and microsatellite instability). As expected, WGS was more suited for the detection and discovery of emerging novel biomarkers of treatment response. WGS could be performed in half of all EBUS-TBNA aspirates, which points to the enormous potential of EBUS-TBNA as source material for large, well-curated discovery-based studies for novel and more effective predictors of treatment response. Comprehensive panel sequencing is possible in the vast majority of fresh EBUS-TBNA aspirates and enhances the detection of actionable mutations over current clinical testing.

  Study EGAS00001007708

• Spatiotemporal evolution and inter-patient heterogeneity in primary and recurrent/metastatic head and neck squamous cell carcinoma

  Head and neck cancer squamous cell carcinomas (HNSCCs) are heterogeneous in terms of origin and aetiology. In addition, there is uncertainty about the spatiotemporal genetic evolution from initial diagnosis to recurrence/metastasis (R/M) after primary treatments and further disease progression following systemic treatment. Changes in the genetic profile have implications on the selection of appropriate treatments for patients, especially in the era of targeted therapies and immunotherapies. Here, we analysed a cohort of 11 HNSCC patients with metachronous R/M, among whom nine had paired primary and R/M samples suitable for next-generation sequencing (multiple R/M samples collected at different time points were available for some of the patients). At the genomic level, the R/M samples shared a fraction of the somatic single nucleotide variants (SNVs) with the index primary tumours, but they also acquired many additional mutations, while losing only a few others. A similar behaviour was also observed when examining the changes of mutational signatures between primary and R/M samples. Overall, R/M appeared thus more genetically diverse than the respective primary tumours. The transcriptomic analysis showed that R/M samples had lower immune cell infiltration and several genes related to immune response were significantly downregulated compared to the primary samples. Our results underline the importance of analysing multiple samples per patient to obtain a more complete picture of the patient’s tumour and advocates a re-biopsy in the event of R/M and treatment failure, in order to select the most appropriate therapeutic strategy.

  Study EGAS00001007464

• Healthspan and lifespan extension by fecal microbiota transplantation in progeroid mice

  The gut microbiome is emerging as a key regulator of several metabolic, immune and neuroendocrine pathways. Gut microbiome deregulation has been implicated in major conditions such as obesity, type 2 diabetes, cardiovascular disease, non-alcoholic fatty acid liver disease or cancer, but its precise role in aging remains to be elucidated. Here, we characterize the gut microbiome profile of accelerated aging and show that its external modulation is sufficient to extend healthspan and lifespan. We found that two different mouse models of progeria present with intestinal dysbiosis, which is characterized, among other alterations, by an increment in proteobacteria, cyanobacteria and a loss in verrucomicrobia, whereas long-lived humans (i.e., centenarians) exhibit a remarkable increase in verrucomicrobia and a reduction in proteobacteria. Fecal microbiota transplantation proved to be effective to enhance healthspan and lifespan in both progeroid mouse models and, more importantly, the solely transplantation with the verrucomicrobia Akkermansia muciniphila was sufficient to exert beneficial effects. Our results demonstrate that intestinal dysbiosis is a phenotype associated with accelerated aging and its correction provides health benefits. Moreover, metabolomic analysis of ileal content points to the restoration of secondary bile acids as a possible mechanism for the beneficial outcome of reestablishing a healthy microbiome. Our results suggest the existence of a link between gut aging and the microbiota, and can help to gain insight into the rationale for microbiome-based interventions against age-related diseases. Mouse sequence data have been deposited in ENA (https://www.ebi.ac.uk/ena) under accession number PRJEB34214

  Study EGAS00001003656

• Activating AKT1 and PIK3CA mutations in metastatic castration-resistant prostate cancer

  This dataset contains all available targeted exon sequencing bam files from our study, "Activating AKT1 and PIK3CA mutations in metastatic castration-resistant prostate cancer". Patient identifiers are denoted by the first segment of the sample aliases (e.g. "P1"), and additional information is appended to reflect which serial sample is referenced (1st, 2nd, 3rd, etc.), and whether the sample represents cell-free DNA ("cfdna") or paired white-blood cell control ("WBC"). All samples were sequenced using Illumina technology.

  Dataset EGAD00001006122

• Human CD4 Memory T Cell Activation Time Course

  We performed a high-resolution time course RNA-seq experiment on CD4+ memory T cells during activation with anti-CD3/CD28 beads. We performed this in 24 adult individuals of European ancestry with no autoimmune diseases. We used 1 million cells as starting material, per time point (up to 8 time points per individual from 0 to 72 hours). We identified widespread dynamic allele-specific expression (dynASE) across the genome, i.e. ASE that changes with time after activation, which reflects cell state-dependent genetic regulatory effects. DynASE events were enriched in risk loci for multiple autoimmune diseases. This highlights the importance of studying multiple cellular states in order to elucidate the mechanisms of autoimmune disease. It also provides a successful framework to do it in other cellular systems relevant for other traits. We also showed an unprecedented amount of regulatory variation for HLA genes. HLA-DQB1 has 3 distinct regulatory haplotypes with expression profiles that could come from 3 different genes. We performed ATAC-seq in replicate for CD4+ memory T cells stimulated for 72 hours from another healthy individual. These data, together with genetic fine-mapping, CRISPR editing, EMSA and luciferase assays, helped us find a SNP in the promoter of HLA-DQB1 that causes at least part of the large cell state-dependent change in expression, at the RNA and protein levels.

  Study phs002259

• Analysis_of_genomic_integrity_of_disease_corrected_human_induced_pluripotent_stem_cells_by_exome_sequencing

  Induced pluripotent stem (iPS) cells hold great promise for autologous cell transplantation. In order to apply this therapy to monogenic disorder, disease-causing mutations must be corrected prior to transplantation. We generated iPS cells from patients with alpha-1 antitrypsin deficiency, which is caused by homozygous non-synonymous mutation in the SERPINA1 gene. In vitro differentiation of patient-derived iPS cells to hepatocytes showed recapitulation of the disease phenotype. We corrected the mutations by gene targeting using zinc finger nuclease (ZFN) and piggyBac transposon technologies. Our mutation correction is highly accurate. There is no exogenous sequence left behind at the targeted site. The corrected iPS cell-derived hepatocytes were indistinguishable from healthy hepatocyte, suggesting that the corrected gene was fully functional. The genomic integrity was also analyzed by CGH and SNP array, showing no genomic alterations. These are important points to ensure clinical safety as well as functional restoration of the corrected gene. One remaining question is if these corrected iPS cells are clinically safe at the single base-pair level. Recent publications suggested that cancer-related mutations are significantly accumulated during iPS cell propagation. We aim to assess the clinical safety of the corrected iPS cells by using exome sequencing. Outcome from this project would bring iPS cell technology one step closer to clinical applications.

  Study EGAS00001000055

• Longitudinal_profiling_of_the_immune_response_to_Plasmodium_vivax_in_naive_hosts_by_RNA_sequencing

  Plasmodium vivax offers unique challenges for control and elimination, and may prove a tougher hurdle to overcome than Plasmodium falciparum. And yet compared to P. falciparum we know very little about the innate and adaptive immune responses that need to be harnessed to reduce disease and transmission. We recently generated a blood bank of a new clonal field isolate of P. vivax (PvW1) for human challenge studies and used systems immunology tools to track the host response throughout infection and convalescence. As part of this study, RNA-sequencing was used to resolve changes in whole blood gene expression through time in 6 volunteers (7-9 time-points per volunteer). In summary, these data show that P. vivax induces two distinct transcriptional programmes in whole blood during and after infection. During infection, transcriptional profiling reveals the rapid mobilisation of an emergency myeloid response, which leads to systemic inflammation and the recruitment of all major T cell subsets into lymphoid tissues. Six days after infection, this innate response subsides and a transcriptional signature of proliferation is revealed. This most likely represents widespread activation of lymphocytes, which return to the circulation after parasite clearance - transcriptional profiling of T cells at this time-point could therefore reveal the outcomes of critical cell-cell interactions that take place within the spleen during infection. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001003847