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• Integrative Gene Regulatory Network Analysis Discloses Key Driver Genes of Fibromuscular Dysplasia

  Fibromuscular dysplasia (FMD) is a poorly understood vascular disease that can lead to hypertension, stroke, myocardial infarction and even death. In 2013 we initiated the DEFINE study (ClinicalTrials.gov Identifier: NCT01967511), which has now recruited > 440 subjects and which aims to unravel the pathobiological mechanisms of this disease. Here, by integrating DNA genotype and RNA sequence data from primary fibroblasts of 83 FMD patients and 71 matched healthy controls from the DEFINE study, and its precursor the CAUSE study, we inferred 18 gene regulatory co-expression networks, four of which were found to act together as an FMD-associated super network in the arterial wall. Molecular studies indicated that this super network, termed SN-A and with the top key driver gene UBR4, governs multiple aspects of vascular cell physiology and functionality, including collagen/matrix production. The effects of UBR4 knockdown were also investigated in commercially available aortic smooth muscle and fibroblast cell lines by RNA sequencing, and these results are included in these datasets.Note, that of the 154 subjects in this analysis, 62 did not provide consent to have their genomic data made publicly available. Therefore the human subject data available here is from the 92 study participants who provided written informed consent to share their deidentified genomic data publicly.

  Study phs003674

• Transcriptome sequencing of human colon organoid after co-cultivation with Bifidobacterium longum

  The large intestine has a dense milieu of indigenous bacteria, generating a complex ecosystem with crosstalk between individual bacteria and host cells. In vitro host cell modeling and bacterial interactions at the anaerobic interphase have elucidated the crosstalk molecular basis. Although classical cell lines derived from patients with colorectal cancer including Caco-2 cells are used, whether they adequately mimic normal colonic epithelial physiology is unclear. To address this, we performed transcriptome profiling of Caco-2 and Monolayer cells derived from healthy Human Colonic Organoid (MHCO) cultured hemi-anaerobically. Coculture with the anaerobic gut bacteria, Bifidobacterium longum subsp. longum differentiated the probiotic effects of test cells from those of physiologically normal intestinal and colorectal cancer cells. We cataloged non- or overlapping gene signatures where gene profiles of Caco-2 cells represented absorptive cells in the small intestinal epithelium, and MHCO cells showed complete colonic epithelium signature, including stem/progenitor, goblet, and enteroendocrine cells colonocytes. Characteristic gene expression changes related to lipid metabolism, inflammation, and cell-cell adhesion were observed in cocultured live Bifidobacterium longum and Caco-2 or MHCO cells. B. longum-stimulated MHCO cells exhibited barrier-enhancing characteristics, as demonstrated in clinical trials. Our data represent a valuable resource for understanding gut microbe and host cell communication.

  Study JGAS000740

• Bruno et al.: Interferon gamma rebalances immunopathological signatures in Chronic Granulomatous Disease through metabolic rewiring

  Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by recurrent life-threatening infections and hyperinflammatory complications. It is caused by mutations in the NADPH oxidase complex and the consequent loss of reactive oxygen species (ROS) production. Recombinant human interferon gamma (rIFN-γ) prophylaxis reduces the risk of severe infections, but the mechanisms behind its efficacy in CGD are still an open question, as it does not restore NADPH oxidase-dependent ROS production. Here, we show that myeloid innate immune cells of CGD patients are transcriptionally and functionally reprogrammed to a hyperactive inflammatory status, displaying an impaired in vitro induction of trained immunity. CGD monocytes have reduced intracellular amino acids concentrations and profound functional metabolic defects, both at the level of glycolysis and mitochondrial respiration. Ex vivo and in vivo treatment with IFN-γ restored these metabolic defects and reduced excessive IL-1β and IL-6 production in response to fungal stimuli in CGD monocytes. These data suggest that prophylactic rIFNγ modulates the metabolic status of innate immune cells in CGD. These data shed light on the effects of NADPH-derived ROS deficiency to the metabolic programs of immune cells and pose the basis for targeting this immunometabolic axis, potentially beyond CGD, with IFN-γ immunotherapy.

  Study EGAS00001005463

• Genentech Colon Cancer Screen

  Identifying and understanding changes in cancer genomes is essential for the development of targeted therapeutics. Here we analyse systematically more than 70 pairs of primary human colon tumours by applying next-generation sequencing to characterize their exomes, transcriptomes and copy-number alterations. We have identified 36,303 protein-altering somatic changes that include several new recurrent mutations in the Wnt pathway gene TCF7L2, chromatin-remodelling genes such as TET2 and TET3 and receptor tyrosine kinases including ERBB3. Our analysis for significantly mutated cancer genes identified 23 candidates, including the cell cycle checkpoint kinase ATM. Copy-number and RNA-seq data analysis identified amplifications and corresponding overexpression of IGF2 in a subset of colon tumours. Furthermore, using RNA-seq data we identified multiple fusion transcripts including recurrent gene fusions involving R-spondin family members RSPO2 and RSPO3 that together occur in 10% of colon tumours. The RSPO fusions were mutually exclusive with APC mutations, indicating that they probably have a role in the activation of Wnt signalling and tumorigenesis. Consistent with this we show that the RSPO fusion proteins were capable of potentiating Wnt signalling. The R-spondin gene fusions and several other gene mutations identified in this study provide new potential opportunities for therapeutic intervention in colon cancer.

  Study EGAS00001000288

• Single cell sequencing of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis

  The quantity of tumor infiltrating lymphocytes (TILs) in breast cancer (BC) is a robust prognostic factor for improved patient survival particularly in triple negative and HER2-overexpressing BC subtypes. Whilst T cells are the predominant TIL population, the relationship between quantitative and qualitative differences in T cell subpopulations and patient prognosis remains unknown. We performed single-cell RNA sequencing (scRNA-seq) of 6311 T cells isolated from human BCs, and show for the first time that significant heterogeneity exists in the infiltrating T cell population. We demonstrated that high TIL BCs contained significant numbers of CD8+ T cells with features of tissue-resident memory T (TRM) cell differentiation and that these CD8+ TRM cells expressed high levels of immune checkpoint molecules and effector proteins. A CD8+ TRM gene signature developed from the scRNA-seq data was significantly associated with improved patient survival in early-stage triple negative breast cancer (TNBC) and provided better prognostication compared with CD8 expression alone. Our data suggests that CD8+ TRM contribute to BC immunosurveillance and are the key targets of modulation through immune checkpoint inhibition. Further understanding of the development, maintenance and regulation of TRM cells will be crucial for successful immunotherapeutic development in BC.

  Study EGAS00001002845

• UK10K NEURO ABERDEEN

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches. This sample set comprises cases of schizophrenia with additional cognitive measurements, collected in Aberdeen, Scotland.For further information on the Aberdeen cohort please contact David St Clair (d.stclair@abdn.ac.uk).

  Study EGAS00001000109

• Developmental_Dysplasia_of_the_Hip__DDH_

  The National Joint Registry for England and Wales (NJR) has become established as one of the largest repositories of clinical information about patients undergoing hip and knee replacement. The primary aim of this proposal is to examine the feasibility of adding value to that clinical information by partnering it with a DNA dataset to allow its use to be extended to the study of the underlying pathogenesis of diseases of the hip and knee, and the complications of their treatment. We will do this 1) by establishing a mechanism for accessing and linking pseudo-anonymised demographic and phenotype data between the NJR database and the proposed DNA Biobank; 2) by validating the collection of postal DNA samples from consenting NJR patients; and 3) by genotyping genome-wide 900 patients with the condition developmental dysplasia of the hip (DDH) to find variants that play a role in this heritable condition. The successful demonstration that the NJR can be used to establish a DNA Biobank will provide a powerful platform to examine the genetic basis for a wide range of joint diseases, and the complications of their treatment. This proposal is to carry out the genotyping portion of this project on the current CoreExome array

  Study EGAS00001000916

• High Grade Serous Ovarian Carcinomas Originate in the Fallopian Tube

  High-grade serous ovarian carcinoma (HGSOC) is the most frequent type of ovarian cancer and has a poor outcome. It has been proposed that fallopian tube cancers may be precursors of HGSOC but evolutionary evidence for this hypothesis has been limited. To provide insights into the origins of HGSOC, we We performed whole-exome sequence and copy number analyses of laser-capture microdissected fallopian tube lesions (p53 signatures, serous tubal intraepithelial carcinomas (STICs), and fallopian tube carcinomas), ovarian cancers, and metastases from nine patients with HGSOC. The majority of tumor-specific sequence and structural alterations in ovarian cancers were present in STICs, including those affecting TP53, BRCA1, BRCA2 or PTEN genes. An eEvolutionary analyseis revealed that p53 signatures and STICs were are the precursors of ovarian carcinoma which in turn gave rise to metastatic lesionsand identify a. In one patient we identified a second STIC as a metastasis in the fallopian tube opposite from the affected ovary. These analyses revealed a window of seven years between the development of a STIC and the initiation of ovarian carcinomas, with development of metastases following rapidly thereafter. Our results provide insights into the etiology of ovarian cancer and have implications for the prevention, early detection and therapeutic intervention of this disease.

  Study EGAS00001002589

• UK10K OBESITY TWINSUK

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches. These TwinsUK samples are a subset of the TwinsUK cohort samples with a BMI>=40 that will be exome sequenced by the Obesity group.

  Study EGAS00001000306

• The Molecular Landscape of Asian Breast Cancers Reveals Clinically Relevant Population-Specific Differences

  Molecular profiles of breast cancer have contributed to an improved understanding of the disease, enabled development of molecular prognostic signatures to guide treatment decisions and unveiled new or more accurate therapeutic options for breast cancer patients. However, the extent to which differences in genetic, environmental and lifestyle factors influence molecular profiles in different populations remains poorly characterised, as relatively few large-scale molecular studies of breast tumours in non-Caucasian populations have hitherto been reported. Here, we present the molecular profiles of 560 Asian breast tumours and a comparative analysis of breast cancers arising in Asian and Caucasian women. Compared to the breast tumours in predominantly Caucasian women reported in TCGA and METABRIC, we show an increased prevalence of Her2-enriched molecular subtypes and higher prevalence of TP53 somatic mutations in ER+ Asian breast tumours. Using gene expression and immunohistochemistry, we observed elevated immune scores in Asian breast tumours, suggesting potential clinical response to immune checkpoint inhibitors. Whilst Her2-subtype and enriched immune score are associated with improved survival, presence of TP53 somatic mutations is associated with poorer survival in ER+ tumours. Taken together, these population differences unveil new opportunities to improve the understanding of this disease and lay the foundation for precision medicine in different populations.

  Study EGAS00001004518