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• Transcriptome_human_nasal_epithelium

  1. Odors are detected, firstly, by olfactory sensory neurons (OSNs) in the olfactory epithelium of the nose. This neurons then project directly to the olfactory bulb in the brain. Olfaction depends on cellular regeneration of the OE, olfactory bulb and hippocampus, and on their continual re-wiring. The olfactory neural pathway includes regions of the frontal, temporal and limbic brain, which in turn overlap with brain areas involved in brain disorders. OSNs are the only aspect of the human brain exposed to the external environment. This not only makes them vulnerable to environmental changes, but also accessible for biomedical studies.We have already sequenced and developed a protocol for analyzing the transcriptome of mouse main olfactory epithelium and single OSNs. We propose here to perform a similar study for samples from the human olfactory epithelium. We have developed a minimally invasive method for obtaining human OSNs, among other cells from the nasal epithelium. In this experiment, we have obtained cell samples from the olfactory epithelium, including OSN, from healthy volunteers. We would like to further characterize them by RNA sequencing. This will give us valuable insight into human olfaction. It will also provide a first step into a new avenue to study, and find biomarkers for, brain diseases though the analysis of these easily available neurons. 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 EGAS00001001294

• MGMT genomic rearrangements contribute to chemotherapy resistance in gliomas

  Temozolomide (TMZ) is an oral alkylating agent used for the treatment of glioblastoma and is now becoming a chemotherapeutic option in patients diagnosed with high-risk low-grade gliomas1. The O-6-methylguanine-DNA methyltransferase (MGMT) is responsible for the direct repair of the main TMZ-induced toxic DNA adduct, the O6-Methylguanine lesion. MGMT promoter hypermethylation is currently the only known biomarker for TMZ response in glioblastoma patients2. Here we show that a subset of recurrent gliomas carry MGMT genomic rearrangements that lead to MGMT overexpression, independently from changes in its promoter methylation. By leveraging the CRISPR/Cas9 technology we generated some of these MGMT rearrangements in glioma cells and demonstrated that they lead to TMZ resistance both in vitro and in vivo. Lastly we showed that such fusions can be detected in tumor-derived exosomes and could potentially represent an early detection marker of tumor recurrence in a subset of patients treated with TMZ.

  Study EGAS00001004544

• Whole Exome Sequencing of Diffuse Large B-Cell Lymphoma

  We performed massively parallel whole exome sequencing of 55 primary tumor samples from patients with diffuse large B cell lymphoma (DLBCL) and matched normal tissue. We identified recurrent mutations in genes that are well known to be functionally relevant in DLBCL, as well as in genes for which a functional role in DLBCL has not been previously suspected. Significantly mutated genes include MYD88, CARD11, EZH2, CREBBP, as well as MEF2B, MLL2, BTG1, GNA13, ACTB, P2RY8, PCLO and TNFRSF14. Analysis of somatic mutations in patients with DLBCL also revealed that BCL2 mutations commonly occur in patients with BCL2/IgH rearrangements as a result of somatic hypermutation normally occurring at the IgH locus. The BCL2 point mutations are primarily synonymous, likely caused by activation-induced cytidine deaminase (AID)-mediated somatic hypermutation, and those non-synonymous mutations that are observed tend to be found outside of the functionally important BH domains of the protein, suggesting that strong negative selection against BCL2 loss-of-function mutations is at play. We further identified genes with mutations that are likely to be functionally relevant despite being mutated at a low rate. These genes include KRAS, BRAF and NOTCH1 as likely drivers of DLBCL pathogenesis in some patients.In order to facilitate additional in vitro and in vivo analyses of the discrete molecular clusters and associated targeted therapies in preclinical models, we also performed our subtyping analysis on 28 Diffuse Large B-Cell Lymphoma (DLBCL) cell lines. We performed whole exome sequencing (WES) on these cell lines to capture structural variants (SVs), from which we obtained full genetic characterization and segregation of these cell lines into our previously defined molecular clusters by DLBclass assignment. These analyses are available in an interactive DLBclass portal available to the public. Our data provide an unbiased view of the landscape of mutations in DLBCL. These data may point towards new targets for the treatment of DLBCL.

  Study phs000450

• All you need to know about the new Submitter Portal

  In September we launched new services for all EGA users, including a new version of the former Submitter Portal. Our main objective with this Portal is to transform the metadata submission in a simplified and user-friendly method. Although it is possible to find documentation about the Submitter Portal on our website, we wanted to highlight the new features in this article. Enjoy! Credentials: who needs to create a new user to access the Submitter Portal and who doesn't? Users with an old submission account (ega-box) can already access the new Submitter Portal. If it is the first time that you want to access, it is time to request a submitter role linked to the EGA User. In the form, it is mandatory to explain which type of data you want to deposit, the size of your submission, add any comment you’d like us to read, and manage the EGA Data Processing Agreement (DPA) document. This document should be checked by the legal department of your institution and signed by a person with authority to sign contracts on behalf of the institution. Note that we provide a DPA template for new Users; it can be found and downloaded in the Submitter Request section. With the DPA signed and the Submitter Request sent, it is time to wait for our Helpdesk team to validate the request. Metadata submission now can be collaborative It is possible to add collaborator(s) to your submissions. Only registered EGA Users will appear on the search bar. When adding a collaborator, it is mandatory to define the permission granted: Read only: collaborators with this permission can check if the information of the submission is correct but cannot modify anything. Read & write: collaborators with this label can register new objects and modify the registered ones. We wanted to save time for submitters that usually rely on the same collaborators. For that, we have implemented the possibility of adding the same collaborators from previous submissions; all you need to do is to search the submission, and the exact set of EGA users will have access to your submission. You can check the collaborators and their permissions at any point of the submission by going to the collaborators section. Even adding more people to complete the submission is allowed by following the same steps: looking for the EGA User and defining the permission granted (please, note that during the submission it is not possible to add collaborators from previous submissions). Use external links to complement the study information When filling the information about the study we recommend users to enrich the submission with complementary fields such as PubMeds IDs, custom tags and external links. External links are used to connect a study to an external repository. We have implemented an external link to Euro-Bioimaging for a European Project (EuCanImage). Now, we are looking forward to keeping increasing the list of external repositories! Choose the expected release date for your metadata to be searchable on our website Once all the metadata objects are registered it is time to finalise the submission so that the Helpdesk team can approve it. In the new version of the Submitter Portal users can choose the expected release date for the metadata to be searchable on the EGA website. Please, note that the selected date will have a minimum of one week margin from the day of finalisation. This time is necessary for your files to be archived and for the submission to be validated by the Helpdesk Team. Are you looking for the Array submission within the Submitter Portal? Our Submitter Portal does not support array submissions. The submission of Array-based metadata must be done using the EGA programmatic submission. You will find our Array-based format template and all the necessary information on our website, and you can find all the steps in our submission quickguide! More information about the submission process at the EGA Our Team has developed an extended documentation related to metadata submission. A good first step is to take a closer look at the Submission FAQ. To have a general overview of all the metadata submission process we recommend taking a glimpse of our take-the-tour or watching the tutorial available on our YouTube Channel. Don't miss our section on EGA Schemas, to learn more about how the EGA is built. It can be useful to fully ensure that your submissions comply with the EGA's standards and contribute to a valuable and accessible genomic resource.

  Blog new-submitter-portal

• Exome-seq, RNA-Seq, SNP array profiling of gastric tumor samples and cell lines.

  Gastric cancer is the second leading cause of worldwide cancer mortality, yet the underlying genomic alterations remain poorly understood. Here we performed exome and transcriptome sequencing and SNP array assays to characterize 51 primary gastric tumors and 32 cell lines. Meta-analysis of the exome data and previously published data sets revealed 24 significantly mutated genes in MSS tumors, and 16 in MSI tumors. More than half of the patients in our collection could potentially benefit from targeted therapies. We identified 55 splice-site mutations accompanied by aberrant splicing products, in addition to mutation-independent differential isoform usage in tumors. The ZAK kinase isoform TV1 is preferentially upregulated in gastric tumors and cell lines relative to normal samples. This pattern is also observed in colorectal, bladder, and breast cancers. Overexpression of this particular isoform activated multiple cancer-related transcription factor reporters, while depletion of ZAK in gastric cell lines inhibited proliferation. These results reveal the spectrum of genomic and transcriptomic alterations in gastric cancer, and identify isoform-specific oncogenic properties of ZAK.

  Study EGAS00001000736

• Spatial Transcriptomics of Vaccine Therapy With or Without Cyclophosphamide in Treating Patients Undergoing Chemotherapy and Radiation Therapy for Stage I or Stage II Pancreatic Cancer That Can Be Removed by Surgery

  Pancreatic ductal adenocarcinoma (PDAC) is a rapidly progressing cancer that responds poorly to immunotherapies. Intratumoral tertiary lymphoid structures (TLS) have been associated with rare long-term PDAC survivors, but the role of TLS in PDAC and their spatial relationships within the context of the broader tumor microenvironment remain unknown. Here, spatial transcriptomics data were generated from 16 pancreatic cancer patients treated with GVAX, whose tumors presented with induced intratumoral TLS. Resected tumor specimens were embedded in OCT media and freshly frozen. Sections were cut into 6.5 x 6.5 mm dimensions compatible with Visium spatial transcriptomics slides. TLS-positive tumor sections from 14 patients (14 tumor samples in total) and lymph nodes from remaining patients (2 lymph node samples in total) were selected by an expert pathologist for profiling. We used 4 Visium slides and covered the 16 capture areas with sections cut in a cryostat at 10 µm. The fresh frozen Visium protocol was followed according to manufacturer's recommendations (10x Genomics Spatial 3' v1). Tissue permeabilization and library construction was carried out according to the manufacturer's protocols. Permeabilization time was optimized to 30 minutes. The captured tissue sections were permeabilized to allow RNA to be captured onto the slide where it reverse-transcribed to cDNA. The cDNA was then amplified, and sequencing libraries were prepared using the 10x Genomics Visium Spatial Gene Expression Reagent Kit for Library Preparation. The libraries were then sequenced using an Illumina NovaSeq sequencer. The raw data obtained from the sequencing were processed using the SpaceRanger (spaceranger-1.2.0) pipeline for alignment onto the GRCh38-2020-A reference transcriptome quantification of gene expression. Unsupervised learning generated a TLS-specific spatial gene expression signature that significantly associates with improved survival in PDAC patients. These analyses demonstrate TLS-associated intratumoral B cell maturation.

  Study phs003862

• HipSci genotyping microarray for embryonic stem cell control lines

  The HipSci project brings together diverse constituents in genomics, proteomics, cell biology and clinical genetics to create a UK national iPS cell resource and use it to carry out cellular genetic studies. In this sub-study we use commercially available embryonic stem cell lines as control samples against which to compare HipSci's iPS cell lines. We performed genotyping analysis using the Infinium HumanExome BeadChip.

  Study EGAS00001001730

• HipSci Methylation analysis for embryonic stem cell control lines

  The HipSci project brings together diverse constituents in genomics, proteomics, cell biology and clinical genetics to create a UK national iPS cell resource and use it to carry out cellular genetic studies. In this sub-study we use commercially available embryonic stem cell lines as control samples against which to compare HipSci's iPS cell lines. We performed Methylation analysis using the Infinium HumanMethylation450 BeadChip.

  Study EGAS00001001728

• Probabilistic modeling of personalized drug combinations from integrated chemical screen and molecular data in sarcoma

  Background: Cancer patients with advanced disease exhaust available clinical regimens and lack actionable genomic medicine results, leaving a large patient population without effective treatments options when their disease inevitably progresses. To address the unmet clinical need for evidence-based therapy assignment when standard clinical approaches have failed, we have developed a probabilistic computational modeling approach which integrates sequencing data with functional assay data to develop patient-specific combination cancer treatments. Methods: Tissue taken from a murine model of alveolar rhabdomyosarcoma was used to perform single agent drug screening and DNA/RNA sequencing experiments; results integrated via our computational modeling approach identified a synergistic personalized two-drug combination. Cells derived from the tumor were allografted into mouse models and used to validate the personalized two-drug combination. Computational modeling of single agent drug screening and RNA sequencing of multiple heterogenous sites from a single patient’s epithelioid sarcoma identified a personalized two-drug combination effective across all tumor regions. The heterogeneity-consensus combination was validated in a xenograft model derived from the patient’s primary tumor. Cell cultures derived from human and canine undifferentiated pleomorphic sarcoma were assayed by drug screen; computational modeling identified a resistance-abrogating two-drug combination common to both cell cultures. This combination was validated in vitro via a cell regrowth assay. Results Our computational modeling approach addresses three major challenges in personalized cancer therapy: synergistic drug combination predictions (validated in vitro and in vivo in a genetically engineered murine cancer model), identification of unifying therapeutic targets to overcome intra-tumor heterogeneity (validated in vivo in a human cancer xenograft), and mitigation of cancer cell resistance and rewiring mechanisms (validated in vitro in a human and canine cancer model). Conclusions These proof-of-concept studies support the use of an integrative functional approach to personalized combination therapy prediction for the population of high-risk cancer patients lacking viable clinical options and without actionable DNA sequencing-based therapy.

  Study EGAS00001003564

• Capturing sex-specific and infertility-linked effects of assisted reproductive technologies on the cord blood DNA methylome

  Background: Children conceived through assisted reproduction are at an increased risk for growth and genomic imprinting disorders, often linked to DNA methylation defects. It has been suggested that assisted reproductive technologies (ART) and the underlying parental infertility can induce epigenetic instability, specifically interfering with DNA methylation reprogramming events during germ cell and preimplantation development. To date, human studies exploring the association between ART and DNA methylation defects report inconsistent or inconclusive results, likely due to population heterogeneity and the use of technologies with limited coverage of the epigenome. In our study, we explore the epigenetic risk of ART by comprehensively profiling the DNA methylome of 73 human cord blood samples from singleton pregnancies (n=36 control group, n=37 ART/infertility group) from a human prospective longitudinal birth cohort, the Design, Develop, Discover (3D) Study using a high resolution sequencing based custom capture panel that interrogates over 2.4 million autosomal CpGs in the genome. Results: the main findings We identified striking sex-specific effects of ART on cord blood DNA methylation patterning both genome-wide and for imprinted genes. When compared to less invasive procedures such as in utero insemination, more invasive ARTs (IVF, ICSI, embryo culture) resulted in more marked and distinct effects on the cord blood DNA methylome, including targeting of loci involved in development. Background: Children conceived through assisted reproduction are at an increased risk for growth and genomic imprinting disorders, often linked to DNA methylation defects. It has been suggested that assisted reproductive technologies (ART) and the underlying parental infertility can induce epigenetic instability, specifically interfering with DNA methylation reprogramming events during germ cell and preimplantation development. To date, human studies exploring the association between ART and DNA methylation defects report inconsistent or inconclusive results, likely due to population heterogeneity and the use of technologies with limited coverage of the epigenome. In our study, we explore the epigenetic risk of ART by comprehensively profiling the DNA methylome of 73 human cord blood samples from singleton pregnancies (n=36 control group, n=37 ART/infertility group) from a human prospective longitudinal birth cohort, the Design, Develop, Discover (3D) Study, using a high resolution sequencing based custom capture panel that interrogates over 2.4 million autosomal CpGs in the genome. Results: We identified striking sex-specific effects of ART on cord blood DNA methylation patterning both genome-wide and for imprinted genes. When compared to less invasive procedures such as in utero insemination, more invasive ARTs (in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), embryo culture) resulted in more marked and distinct effects on the cord blood DNA methylome, including targeting of loci involved in development. Conclusions: Our study highlights the ability of a sensitive, targeted, sequencing based approach to uncover DNA methylation perturbations in cord blood associated with infertility and ART and influenced by offspring sex and ART technique invasiveness.

  Study EGAS00001006643