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• Metagenomics-Guided Pathogen Discovery in Travelers' Diarrhea

  Traveler's diarrhea (TD) is caused by enterotoxigenic Escherichia coli (ETEC), other pathogenic gram-negative pathogens, norovirus and some parasites. Nevertheless, standard diagnostic methods fail to identify pathogens in more than 30% of TD patients, so it is predicted that new pathogens or groups of pathogens may be causative agents of disease. A comprehensive metagenomic study of the fecal microbiomes from 23 TD patients and seven healthy travelers was performed, all of which tested negative for the known etiologic agents of TD in standard tests. Metagenomic reads were assembled and the resulting contigs were subjected to semi-manual binning to assemble independent genomes from metagenomic pools. Taxonomic and functional annotations were conducted to assist identification of putative pathogens. We extracted 560 draft genomes, 320 of which were complete enough to be enough characterized as cellular genomes and 160 of which were bacteriophage genomes. We made predictions of the etiology of disease in individual subjects based on the properties and features of the recovered cellular genomes. Three subtypes of samples were observed. First were four patients with low diversity metagenomes that were predominated by one or more pathogenic E. coli strains. Annotation allowed prediction of pathogenic type in most cases. Second, five patients were co-infected with E. coli and other members of the Enterobacteriaceae, including antibiotic resistant Enterobacter, Klebsiella, and Citrobacter. Finally, several samples contained genomes that represented dark matter. In one of these samples we identified a TM7 genome that phylogenetically clustered with a strain isolated from wastewater and carries genes encoding potential virulence factors. We also observed a very high proportion of bacteriophage reads in some samples. The relative abundance of phage was significantly higher in healthy travelers when compared to TD patients. Our results highlight that assembly-based analysis revealed that diarrhea is often polymicrobial and includes members of the Enterobacteriaceae not normally associated with TD and have implicated a new member of the TM7 phylum as a potential player in diarrheal disease.

  Study phs001352

• Mutations in PNPLA6 are linked to photoreceptor degeneration and various forms of childhood blindness

  In this work, using exome sequencing, we identified biallelic PNLPA6 mutations in patients with childhood blindness due to severe photoreceptor death and clinical features of Leber congenital amaurosis (LCA) and, interestingly, also of the rare Oliver McFarlane Syndrome

  Study EGAS00001001013

• Newborn Screening Translational Research Network (NBSTRN): Newborn Sequencing in Genomic Medicine and Public Health (NSIGHT2)

  Large-scale studies of whole genome sequencing (WGS) in neonates have largely been neglected. Thus, the clinical and social implications of this absence are largely unknown. The proposed study aims to increase scientific knowledge for acutely ill neonates. This population may stand to benefit largely from WGS given the severity of illness. The proposed clinical study is a prospective, randomized, partially-blinded study that has both quantitative and qualitative assessments of the risks and benefits of the use of STATseq, a 2-day genome test, in acutely ill neonates at Children's Mercy Hospital. Study participants include neonates, their parents, and clinicians caring for them. The overall aims will provide a nuanced understanding of the role of rapid diagnostic WGS for acutely ill neonates, including relative diagnostic sensitivity and change in management both for broad NICU populations and subpopulations, accuracy, reproducibility, and relative value of proband WGS and familial triads. The technological aims include improving diagnostic sensitivity without sacrificing the rapid turnaround time. The clinical aims include looking at increased diagnostic yield, shorter time to diagnosis and clinician perception of management changes that result from implementation of STAT-seq. Finally, the study will investigate the perceived value of STAT-seq in parents and clinicians using structural equation modeling. The studies also are designed for long-term continuation of assessment of the enrollees (beyond the current funding period) and in additional sample types (via a biorepository). Long-term continuation studies will test effects on long-term morbidity, mortality, quality of life and cost of care. We hope that the study results will be sufficient to provide an evidence base for physician adoption and provider reimbursement of WGS in Level 3 and 4 NICUs.

  Study phs002094

• THE GENOMIC LANDSCAPE OF ACTINIC KERATOSIS

  Actinic keratoses (AK) are lesions of epidermal keratinocyte dysplasia and are precursors for invasive cutaneous squamous cell carcinoma (CSCC). Identifying the specific genomic alterations driving progression from normal skin-AK-invasive CSCC is challenging due to the massive ultraviolet radiation-induced mutational burden characteristic at all stages of this progression. Here, we report the largest AK whole exome sequencing study to date and perform mutational signature and candidate driver gene analysis on these lesions. We demonstrate in 37 AK, from both immunosuppressed and immunocompetent patients, that there are significant similarities to CSCC in terms of mutational burden, copy number alterations, mutational signatures and patterns of driver gene mutations. We identify 44 significantly mutated AK driver genes and confirm that these genes are similarly altered in CSCC. We identify the azathioprine mutational signature in all AK from patients exposed to the drug, providing further evidence for its role in keratinocyte carcinogenesis. CSCC differ from AK in having higher levels of intra-sample heterogeneity. Alterations in signaling pathways also differ, with immune-related signaling and TGF-β signaling significantly more mutated in CSCC. Integrating our findings with independent gene expression datasets confirms that dysregulated TGF-β signaling may represent an important event in AK-CSCC progression.

  Dataset EGAD00001006894

• MOSAIC - Multi-Omics Spatial Atlas In Cancer

  MOSAIC is a collaborative initiative founded by Owkin, Lausanne University Hospital (CHUV), Charité Universitätsmedizin Berlin, University Hospital Erlangen (UKER), Gustave Roussy Institute in Paris, and University of Pittsburgh. The goal of MOSAIC is to build the largest collection of spatial omics data in cancer. By integrating comprehensive high quality clinical annotations with advanced deep profiling techniques, MOSAIC aims to uncover novel cancer subtypes and identify key drug targets and biomarkers within them.

  Study EGAS50000000689

• Deep intronic homozygous variation in PSMC3 causes a syndromic neurosensory disorder combining deafness and cataract

  The association of congenital deafness and early-onset cataracts inherited as a recessive trait is a rare combination described in only a few syndromes with very few genes identified to date. We propose that the PSMC3 proteasome subunit dysfunction leads to a novel human syndrome that includes early-onset cataracts and deafness and suggest that Rpt5 plays a major role in inner ear and lens development.

  Study EGAS00001003942

• Whole-exome sequencing of ovarian clear cell carcinoma in clinical outliers

  Whole-exome sequencing dataset for the Australian Ovarian Cancer Study (AOCS) and The Jikei University School of Medicine (JIKEI) ovarian clear cell carcinoma (OCCC) clinical outliers project, representing 10 donors. Although OCCC are commonly resistant to platinum based chemotherapy, good clinical outcomes are observed in a subset of patients. Exome sequencing was performed in 10 patients who had either unusually long survival (N=5) or had a very short time to progression (N=5).

  Study EGAS00001004248

• Whole Exome Sequencing for Colorectal Cancer

  This project was designed to use next generation sequencing technology to screen the protein coding regions of the genome for low frequency variants in a panel of high-risk colorectal adenocarcinoma cases. Blood and cell-line DNA for colorectal cancer patients and a subset of quality control samples that had existing whole exome sequence data were analyzed using Illumina HiSeq sequencers. Samples from this project were from participants in the Women's Health Initiative (WHI) and the Diet, Activity, and Lifestyle Study (DALS).

  Study phs000410

• Segmental Overgrowth/Vascular Anomalies/Dermatologic Disorders

  This study was designed to determine the molecular etiology of disorders characterized by segmental overgrowth, vascular anomalies, or dermatologic conditions that are part of the diagnostic criteria for Proteus syndrome or PIK3CA-related overgrowth spectrum (PROS). Somatic variants in AKT1 or PIK3CA have been identified as causative for Proteus syndrome and PROS respectively, and this study aimed to determine the extent of allelic and genetic heterogeneity in individuals who fully met the diagnostic criteria, had some aspects of, or had isolated manifestations of either syndrome.

  Study phs002006

• Paired Analysis of Host and Pathogen Genomes Identifies Determinants of Human Tuberculosis

  The outcome of infectious diseases may depend on the interaction between human and pathogen genomic variations. This study was designed to explore and validate this relationship in tuberculosis (TB) by conducting a genome-to-genome study of paired genomes from human hosts and the infectious agent Mycobacterium tuberculosis.Blood samples were collected from 699 TB patients in Lima, Peru, as part of a 2020 cohort study during the COVID-19 pandemic. Genotyping data for these individuals are available through dbGaP.

  Study phs003718

• Sequencing of an adolescent patient with germline RET mutant alveolar rhabdomyosarcoma

  An adolescent patient presented with an alveolar rhabdomyosarcoma made more unique by the presence of a germline RET mutation ordinarily associated with and a known driver of multiple endocrine neoplasia type 2A (MEN2A) cancer. To better understand the role of this germline RET mutation in the genetics and phenotypic response of this unique alveolar rhabdomyosarcoma, we performed DNA and RNA sequencing of the patients in addition to functional studies on patient-derived cultures and genetically similar similar cell models.

  Study EGAS00001004359

• Beacon v2 and Federated EGA, part of the GDI project Starter Kit to enable access to genomic and phenotypic data across borders

  The European Genomic Data Infrastructure project has released a ‘Starter Kit’ based on the rare disease and cancer proof-of-concepts from the Beyond 1 Million Genomes (B1MG) project. The Starter Kit, freely available to any interested parties, contains a set of software applications and components co-developed by the 20 GDI nodes and based on open community standards from the Global Alliance for Genomics and Health (GA4GH). Products in the Starter Kit give all countries the technical capability to access synthetic genomic and phenotypic data across borders. The image above shows the full workflow of the GDI Starter Kit user journey. The dotted circles are not included in the Starter Kit yet The EGA’s work is represented in the Starter Kit with Beacon v2 and Federated EGA among the software applications and components. About Beacon v2 Beacon is a protocol for data discovery. This API allows the search of genomic variants and associated information without breaching the datasets privacy. The European Genome-phenome Archive (EGA) is a key contributor to the Beacon v2 Protocol, the Beacon v2 Reference Implementation (B2RI) and the EGA Beacon(s). About Federated EGA The Federated EGA network offers a tool for data storage and sharing. Officially launched in 2022, this network of connected resources enables transnational discovery of and access to human omics data for research, while also respecting jurisdictional data protection regulations. The Federated EGA Onboarding Website contains all the information related to the establishment of a Federated Node.

  Blog beacon-v2-and-federated-ega-part-of-the-gdi-project-starter-kit

• NRG-GY017: Atezolizumab before and/or with Chemoradiotherapy in Immune System Activation in Patients with Node Positive Stage IB2, II, IIIB, or IVA Cervical Cancer

  Locally advanced cervical cancer remains an area of high therapeutic unmet need, with ~50% of patients developing disease recurrence despite treatment with chemotherapy combined with radiation. Combination of immune checkpoint blockade with chemoradiation has been explored in this setting, but optimal sequencing of these modalities is unknown. To address this question, we developed and conducted the NCI sponsored trial “Anti PD-L1 (Atezolizumab) as an Immune Primer and Concurrently with Extended Field Chemoradiotherapy for Node Positive Locally Advanced Cervical Cancer”, randomizing patients to atezolizumab administration prior to and concurrent with chemoradiation therapy (CRT) vs. concurrent with CRT (NRG-GY017; N=40, ClinicalTrials.gov Identifier: NCT03738228). Patients were randomized to atezolizumab neoadjuvant and concurrent (Arm A) or concurrent with CRT (Arm B). The study closed to successful accrual of 36 evaluable patients in June 2020. Out of 40 patients consented patients, 4 were never treated. The reasons for that are: 2 were screen failures, 1 withdrew consent, and 1 was not treated due to physician preference. The study incorporated comprehensive collection of pre- and on-treatment tumor biopsies as well as multitime point blood collections. T cell receptor (TCR) sequencing was performed on the tumors as well as pre- and on-treatment peripheral blood, and the data are included with dbGaP submission. Among the 36 eligible and treated patients, there were 30 (17 on Arm A and 13 on Arm B) with pre- and on-treatment peripheral TCR sequencing data. Twenty-five patients (14 in Arm A and 11 in Arm B) had additional tumor TCR sequencing data available, which enabled tracking of tumor-associated TCR clones in peripheral blood. We demonstrate that neoadjuvant atezolizumab administration results in peripheral expansion of higher proportion of tumor-associated TCR clones in Arm A than in Arm B and is associated with favorable 2-year disease-free survival (DFS). No new safety signals were identified. These findings support further evaluation of the neoadjuvant IO and CRT sequencing strategy in locally advanced cervical cancer.

  Study phs003833

• RNA-seq analysis of transcriptome variation with human ESC subclones

  Many studies over the past 10 years, culminating in the recent report of the International Stem Cell Initiative (ISCI, 2011) have shown that hPSC acquire genetic and epigenetic changes during their time in culture. Many of the genetic changes are non-random and recurrent, probably because they provide a selective growth advantage to the undifferentiated cells. Some are shared by embryonal carcinoma cells, the malignant counterparts of ES cells. The origins of these growth advantages are poorly understood, but may come from altered cell cycle dynamics, resistance to apoptosis or altered patterns of differentiation. Less is known about the nature and consequences of epigenetic changes, but it is likely that these similarly affect hPSC behaviour; e.g., enhanced expression of DLK1, an imprinted gene, is associated with altered hPSC growth (Enver et al 2005). Inevitably, these genetic and epigenetic changes will impact on our ability to use hPSC for regenerative medicine, either because malignant transformation of the undifferentiated cells or their differentiated derivatives to be used for transplantation compromises safety, or because they impede the function of those differentiated derivatives, or because they affect the efficiency with which the undifferentiated cells can be expanded and differentiated into desired cell types. Focusing initially upon the existing clinical grade hESC lines, later moving to iPSC, we will Consolidate and extend knowledge of the rate, type and functional impact of the genetic variations that occur during hPSC culture. We will use whole genome and exome sequencing as well as SNP arrays, together with clonal analysis and other cytogenetics techniques. Common changes will be compared with those found in the normal human population, at low frequency in the original cell population or observed during iPSC generation in the HIPSCI project currently based at the WTSI. These studies will provide a better understanding of the range of genetic changes that occur in hPSC beyond the CNVs already identified. In conjunction with cancer genome resources and expertise at WTSI, bioinformatic analyses of these hPSC data will allow us to assess potential impact on hPSC behaviour pertinent to applications in regenerative medicine, notably the likelihood that specific changes arising in undifferentiated PSC cultures may be associated with potential malignant transformation of differentiated progeny 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/ .

  Dataset EGAD00001004266

• Investigation of molecular diagnosis by molecular biological analysis using next-generation sequencer for actionable endocrine diseases (including neoplastic diseases)

  Fructose-1,6-bisphosphatase (FBPase) deficiency, caused by an FBP1 mutation, is an autosomal recessive disorder characterized by hypoglycemic lactic acidosis. Due to the rarity of FBPase deficiency, the mechanism by which the mutations cause enzyme activity loss still remains unclear. Here we identify compound heterozygous missense mutations of FBP1, c.491G>A (p.G164D) and c.581T>C (p.F194S), in an adult patient with hypoglycemic lactic acidosis. The G164D and F194S FBP1 mutants exhibit decreased FBP1 protein expression and a loss of FBPase enzyme activity. The biochemical phenotypes of all previously reported FBP1 missense mutations in addition to G164D and F194S are classified into three functional categories. Type 1 mutations are located at pivotal residues in enzyme activity motifs and have no effects on protein expression. Type 2 mutations structurally cluster around the substrate binding pocket and are associated with decreased protein expression due to protein misfolding. Type 3 mutations are likely nonpathogenic. These findings demonstrate a key role of protein misfolding in mediating the pathogenesis of FBPase deficiency, particularly for Type 2 mutations. This study provides important insights that certain patients with Type 2 mutations may respond to chaperone molecules.

  Study JGAS000625

• Ultra-Fast Patient-Derived Xenografts Identify Functional and Spatial Tumour Heterogeneities that Drive Therapeutic Resistance

  Treatment of patients with advanced cancers increasingly relies on agents targeting specific molecular or cellular aberrations. These expensive therapies often fail because of pre-existing drug resistance. Intra-tumoural molecular and micro-environmental heterogeneity resistance can create resistance in one or more subclones of a tumour, leading to spatio-functional heterogeneity. We created a rapid approach for quantifying tumour functional phenotypes based on tumour-implantation into the chorioallantoic membrane of chick embryos. We apply this technique to 43 separate biopsies from 6 patients with renal cell carcinoma (RCC) with 36 replicates per biopsy, achieving a 93.6% engraftment rate (1449/1548). Challenging these models with sunitinib, an anti-angiogenic therapy frequently used in RCC allowed us to quantify spatio-functional heterogeneity in individual patients. Prediction of de novo drug resistance in advanced cancer patients would facilitate precision medicine by tailoring systemic therapies and improve clinical trial design outcome measures. We describe a patient-derived xenograft platform where fresh patient tumour samples are implanted into the chorioallantoic membrane (CAM) of chick embryos at high engraftment efficiencies, permitting large scale “tumour avatar” studies to guide the selection of drugs and to predict clinical drug resistance outcomes in renal cell carcinoma (RCC) patients. Applying this “tumour avatar” model in a co-clinical trial on RCC patients, we observe intra-tumoural functional heterogeneity with sunitinib treatment, revealing the presence of drug-resistant clones prior to the initiation of therapy. Multi-regional exome Matched DNA sequencing of the primary tumour and metastases revealed DNA mutational signatures associated with sunitinib resistance at baseline and after treatment. These These studies demonstrate a rapid and affordable method of findings confirm the existence of genetic and surveying functional tumour heterogeneities heterogeneity.

  Study EGAS00001002627

• Paired Acute Myeloid Leukemia (AML) Epigenetics Study on Epialleles and Clonality

  We describe methclone, a novel method to identify epigenetic loci that harbor large changes in the clonality of their epialleles (epigenetic alleles). Methclone efficiently analyzes genome-wide DNA methylation sequencing data. We quantify the changes using a composition entropy difference calculation and also introduce a new measure of global clonality shift, loci with epiallele shift per million loci covered, which enables comparisons between different samples to gauge overall epiallelic dynamics. Finally, we demonstrate the utility of methclone in capturing functional epiallele shifts in leukemia patients from diagnosis to relapse. Methclone is open-source and freely available at https://code.google.com/p/methclone. Reprinted with permission from BMC Publishing (Genome Biology).

  Study phs000793

• An analysis of humoral and cellular immune responses following COVID-19 vaccination.

  Two dose mRNA vaccination provides excellent protection against SARS-CoV-2. However, there are few data on vaccine efficacy in elderly individuals above the age of 801. Additionally, new variants of concern (VOC) with reduced sensitivity to neutralising antibodies have raised fears for vulnerable groups. Here we assessed humoral and cellular immune responses following vaccination with mRNA vaccine BNT162b22 in elderly participants prospectively recruited from the community and younger health care workers. Median age was 72 years and 51% were females amongst 140 participants. Neutralising antibody responses after the first vaccine dose diminished with increasing age, with a steep drop in participants over 80 years old. Sera from participants below and above 80 showed significantly lower neutralisation potency against B.1.1.7, B.1.351 and P.1. variants of concern as compared to wild type. Those over 80 were more likely to lack any neutralisation against VOC compared younger participants following first dose. Binding IgG and IgA antibodies were lower in the elderly, as was the frequency of SARS-CoV-2 Spike specific B- cells. We observed a trend towards lower somatic hypermutation in participants with suboptimal neutralisation, and elderly participants demonstrated clear reduction in class switched somatic hypermutation, driven by the IgA1/2 isotype. SARS-CoV-2 Spike specific T- cell IFN?? and IL-2 responses were secreted primarily by CD4 T cells, and impaired in the older age group. We conclude that the elderly are a high risk population that warrant specific measures in order to mitigate against vaccine failure, particularly where variants of concern are circulating. Specifically, the dosing interval should not be extended in this group.

  Study EGAS00001005380

• National Cancer Institute (NCI) Non-Hodgkin Lymphoma Genome-wide Association Study (GWAS)

  Within the framework of the International Lymphoma Epidemiology Consortium (InterLymph) Consortium and NCI-sponsored Cohort Consortium, investigators from 22 studies came together to conduct a genome-wide association study (GWAS) of non-Hodgkin lymphoma (NHL). The goal of the study was to identify common genetic variants associated with the risk of NHL. As described previously (Berndt SI et al., Nature Genetics, 2013, PMID: 23770605 ), cases and controls from 22 studies, including nine prospective cohort studies, eight population-based case-control studies, and five clinic or hospital-based case-control studies were included in this effort. Cases of NHL were ascertained from cancer registries, clinics or hospitals, or through self-report verified by medical and pathology reports. The phenotype information for all NHL cases was reviewed centrally at the InterLymph Data Coordinating Center and harmonized according to the hierarchical classification proposed by the InterLymph Pathology Working Group based on the World Health Organization (WHO) classification (2008). Controls were frequency matched to cases on age and gender by study, and the study was limited to subjects of European ancestry. Participants were genotyped using the Illumina Omni Express. The NCI Non-Hodgkin Lymphoma GWAS is utilized in the following dbGaP sub-studies. To view genotypes and derived variables collected in these sub-studies, please click on the following sub-studies below or in the "Sub-studies" box located on the right hand side of this top-level study page phs000801 NCI Non-Hodgkin Lymphoma GWAS. phs000802 NCI Non-Hodgkin Lymphoma GWAS: CLL phs000818 NCI Non-Hodgkin Lymphoma GWAS: Controls phs000889 NCI Non-Hodgkin Lymphoma GWAS: DLBCL phs000890 NCI Non-Hodgkin Lymphoma GWAS: FL phs000891 NCI Non-Hodgkin Lymphoma GWAS: MZL

  Study phs000801

• Whole-genome sequencing across 449 samples spanning 47 ethnolinguistic groups provides insights into genetic diversity in Nigeria

  African populations have been drastically underrepresented in genomics research and failure to capture the genetic diversity across the numerous ethnolinguistic groups (ELGs) found in the continent has hindered the equity of precision medicine initiatives globally. Here, we describe the whole-genome sequencing of 449 Nigerian individuals across 47 unique self-reported ELGs. Population structure analysis reveals genetic differentiation amongst our ELGs, consistent with previous findings. From the 36 million SNPs and indels discovered in our dataset, we provide a high-level catalog of both novel and medically-relevant variation present across the ELGs. These results emphasize the value of this resource for genomics research, with added granularity by representing multiple ELGs from Nigeria. Our results also underscore the potential of using these cohorts with larger sample sizes to improve our understanding of human ancestry and health in Africa.

  Study EGAS00001007036

• Mutant KIT as imatinib-sensitive target in metastatic sinonasal carcinoma (H021)

  Sinonasal carcinomas (SNCs) comprise various rare tumor types that are characterized by marked histologic diversity and largely unknown molecular profiles, yet share an overall poor prognosis owing to an aggressive clinical course and frequent late-stage diagnosis. The lack of effective systemic therapies for locally advanced or metastatic SNC poses a major challenge to therapeutic decision making for individual patients. Here, we used whole-exome and transcriptome sequencing to identify a KIT exon 11 mutation (c.1733_1735del, p.578_579del) as actionable target in a patient with metastatic SNC whose tumor, despite all diagnostic efforts, could not be assigned to any known SNC category and was refractory to multimodal therapy. Molecularly guided treatment with imatinib resulted in a dramatic and durable response with remission of nearly all tumor manifestations, indicating a dominant driver function of mutant KIT in this tumor. This observation highlights the potential of unbiased genomic profiling for uncovering the vulnerabilities of individual malignancies, particularly in rare and unclassifiable tumors, and underscores that KIT exon 11 mutations represent tractable therapeutic targets across different histologies.H021

  Study EGAS00001001845

• The Mutational Landscape of Head and Neck Squamous Cell Carcinoma

  This study was the first-known large-scale effort to uncover the mutational spectrum of head and neck cancers. We analyzed whole-exome sequence from 92 tumor-normal pairs and retained 74 of them for significance analysis. The majority exhibited a mutational profile consistent with tobacco exposure; human papilloma virus sequence was detectable in 15% of cases. In addition to identifying previously known HNSCC genes (TP53, CDKN2A, PTEN, PIK3CA, and HRAS), the analysis revealed many genes not previously implicated in this malignancy. At least 30% of cases harbor mutations in genes (such as NOTCH1, IRF6, TP63) that regulate squamous differentiation, implicating alterations in this process as a major driver of HNSCC carcinogenesis. Altogether, the results suggest that large-scale exome sequencing may illuminate fundamental tumorigenic mechanisms with important therapeutic implications.

  Study phs000370

• Whole genome shotgun sequencing and somatic mutations data in Hepatocellular carcinoma

  Hepatocellular carcinoma (HCC) is the most common malignancy of the liver. Genomic analysis is conducted to identify genetic alterations in driver genes which are all druggable targets for cancer therapy.

  Study EGAS00001002578

• Investigation of BK Polyomavirus (BKPyV) and Molecular Signatures in UC specimens from Taiwan

  Urothelial carcinoma (UC) is the most prevalent cancer of kidney transplant recipients in some regions. The integration of BK polyomavirus (BKPyV) genome into the human genome is observed in some cases of UC. The prevalence of aristolochic acid (AA) mutational signatures in urothelial carcinoma is high in the general population of Taiwan. To better understand the mechanisms of UC carcinogenesis in kidney transplant recipients, 19 UC specimens were analyzed by whole genome sequencing (WGS) and Hybrid Sequencing.

  Study EGAS50000001063

• Identification and characterization of tertiary lymphoid structures in brain metastases

  Brain metastases (BrM) are the most common cancers in the brain. We performed transcriptome-wide gene expression profiling combined with spatial immune cell profiling to characterize the tumor immune microenvironment in BrM from different primary tumors. We found that BrM from lung carcinoma and malignant melanoma showed overall higher immune cell infiltration as compared to BrM from breast carcinoma. RNA sequencing-based immune cell deconvolution revealed gene expression signatures indicative of tertiary lymphoid structures (TLS) in subsets of BrM from lung cancer and melanoma. This finding was corroborated by multiplex immunofluorescence staining of immune cells in BrM tissue sections. Detection of TLS signatures was associated with prolonged survival after BrM diagnosis in lung cancer patients. Our findings highlight the cellular diversity of the tumor immune microenvironment in BrM of different cancer types and suggest a role of TLS formation for BrM patient outcome.

  Study EGAS50000000563

• A mechanistic classification of clinical phenotypes in neuroblastoma

  Clinical courses of the pediatric tumor neuroblastoma range from fatal progression to spontaneous regression. To gain insights into the pathogenesis of these divergent subtypes, we performed massively parallel sequencing of 416 pretreatment neuroblastomas and assessed telomere maintenance mechanisms in 208/416 cases. We observed that telomere maintenance and mutations in RAS or p53 pathway genes strongly affected disease courses. Fatal outcome occurred only in the presence of telomere maintenance, whereas patients whose tumors lacked such mechanisms had excellent outcome. In patients with telomere maintenance-positive tumors, survival was dramatically inferior when additional RAS/p53 pathway mutations were present. By contrast, spontaneous regression occurred both in the presence and absence of RAS/p53 pathway mutations in patients with telomere maintenance-negative tumors. Together, our data provide a precise mechanistic classification of clinical neuroblastoma phenotypes based on telomere maintenance mechanisms and genetic alterations of the tumor.

  Study EGAS00001003244

• Hereditary Gastric Cancer Syndromes: An Integrated Genomic and Clinicopathologic Study of the Predisposition to Gastric Cancer

  Gastric cancers are cancers of the stomach. Hereditary cancers are passed from parent to child. Researchers want to gather data about hereditary gastric cancers. Bulk RNA sequencing (RNA-seq) of signet ring cells (SRCs) and adjacent non-SRC epithelium (NEP) was performed on laser-capture microdissected (LCM) regions of interest found in risk-reducing total gastrectomy specimens from hereditary diffuse gastric cancer (HDGC) patients (Clinicaltrials.gov ID: NCT03030404). Twenty patients (6 male, 14 female) with confirmed HDGC were identified. Analysis of differentially expressed genes (DEGs) demonstrated upregulation of certain individual epithelial–mesenchymal transition (EMT) and proliferation genes. SRC regions had significant enrichment in pathways involved in T cell signaling. CIBERSORTx predicted significant increases in the presence of regulatory T cells (Tregs) specific to SRC regions.

  Study phs003422

• University of Miami Udall Center of Excellence Identification of Rare Variants in PD through Whole Exome Sequencing

  The focus of this study is to identify a new level of genetic variation, i.e. rare genetic variants with a population frequency less than 5%, usually less than 1%, which are believed to provide a stronger risk per variant than those studied to date in the large genome wide association studies (GWAS). To do this we are generating whole exome sequencing data on the Illumina HiSeq. Each HiSeq produces at least 600 billion base pairs of DNA sequence in one run. Whole exome sequencing sequence data, about 50 million base pairs, or about 1.5% of the total DNA of each person's genome, is generated. We are using this data to look for new DNA variations that give risk for Parkinson disease, as well as "modifiers", that may lead to having more severe or milder disease or later or earlier ages of onset.

  Study phs000908

• Exome sequencing in bipolar disorder families

  Bipolar disorder (BD) is a major psychiatric disorder affecting around 1% of the global population. BD is characterized by recurrent manic and depressive episodes, and has an estimated heritability of around 70% Research has identified the first BD susceptibility genes. However, the underlying pathways and regulatory networks remain largely unknown. Since research has shown that the cumulative impact of common alleles with small effect appears to explain only around 25-38% of the phenotypic variance for BD, rare variants of high penetrance may also contribute to BD risk. The present study investigated the role of rare, nonsynonymous, and potentially functional variants via whole exome sequencing in 15 BD cases from two large, multiply affected families from Cuba. The high prevalence of BD in these pedigrees renders them promising in terms of the identification of genetic risk variants with large effect sizes. In addition, SNP array data were used to calculate polygenic risk scores for affected and unaffected family members. After correction for multiple testing, polygenic risk scores for common, BD-associated genetic variants were not significantly higher in BD cases than in healthy relatives. Exome sequencing identified a total of 17 rare and potentially damaging variants in 17 genes. The identified variants were shared by all investigated BD cases in the respective pedigree. The most promising variant was located in the gene SERPING1 (p.L349F), which has been reported as a genome-wide significant risk gene for schizophrenia. A further promising variant was located in CAPN2, which has been implicated in synaptic plasticity. The present data suggest novel candidate genes for BD susceptibility, and may facilitate the discovery of disease-relevant pathways and regulatory networks.

  Study EGAS00001003085

• Indonesian Genome Diversity Project 3

  Low coverage whole genome sequences were collected to study the population history in Eastern Indonesia, in particular Wallacea and Papua region. We have sequenced the genomes of 254 individuals from 12 Wallacean and 3 Papuan populations spanning this geographical region.

  Study EGAS50000000447

• Comprehensive molecular and clinicopathological profiling of desmoid tumors

  Previous studies have not clearly identified a prognostic factor for desmoid tumors (DT). Whole-exome sequencing and/or RNA sequencing were performed in 64 cases of DT to investigate the molecular profiles in combination with the clinicopathological characteristics.

  Study JGAS000270

• Genomics Define Malignant Transformation in Myeloma Precursor Conditions

  Multiple myeloma (MM) is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). While these precursor conditions are asymptomatic, they are not entirely benign and carry a lifelong risk of progression to MM. Unlike other cancers defined by pathology, malignant transformation from MGUS or SMM to MM has so far relied on demonstration of clinical end-organ damage as morphology and cytogenetics cannot reliably distinguish them. In this study, using genomic data from 374 patients with MGUS or SMM (277 training, 97 validation), to our knowledge, we demonstrate for the first time the ability to identify malignant transformation in MGUS and SMM. We introduce the concept of genomic MM and genomic MGUS to differentiate the subsets of MGUS and SMM that are biologically malignant with genomic features indistinguishable from MM from the subset that is premalignant and unlikely to progress to malignancy. Importantly, we find that most SMM has biological features of malignant transformation indistinguishable from MM. As expected, this subset that we consider having genomic MM is associated with a high risk of progression to MM although some patients remained progression-free beyond 5 years. Conversely, 60% of MGUS and 10% of SMM have no evidence of malignant transformation (genomic MGUS), with no progression during follow-up. Integration of genomic features with the 2/20/20 International Myeloma Working Group model significantly improved the prediction of progression among genomic MM. These findings support the use of genomic criteria to refine the classification and the risk stratification in myeloma precursor conditions.

  Dataset EGAD00001015768

• Molecular dissection of germline chromothripsis in a developmental context

  Complex germline genomic rearrangements can affect many genes and regulatory elements, but the precise mechanisms that caused the phenotype of patients with such rearrangements are often unknown. To dissect the impact of germline chromothripsis in a relevant developmental context, we performed trio-based RNA expression analysis on blood cells,induced pluripotent stem (iPS) cells and iPS-cell derived neuronal cells from a patient with de novo germline chromothripsis and both healthy parents. In addition, we performed Hi-C on iPS cell-derived neural progenitors of the patient and the father to study the effects of the chromothripsis rearrangements on the architecture of the derivative chromosomes. We demonstrate that a combination of patient-derived iPS cell differentiation and trio-based molecular profiling is a powerful approach to improve the interpretation of pathogenic complex genomic rearrangements.

  Study EGAS00001001896

• Gabriella Miller Kids First Pediatric Research Program: An Integrated Clinical and Genomic Analysis of Treatment Failure in Pediatric Osteosarcoma

  The Gabriella Miller Kids First Pediatric Research Program (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in childhood cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource). Both childhood cancers and structural birth defects are critical and costly conditions associated with substantial morbidity and mortality. Elucidating the underlying genetic etiology of these diseases has the potential to profoundly improve preventative measures, diagnostics, and therapeutic interventions. All of the WGS and phenotypic data from this study are accessible through dbGaP and kidsfirstdrc.org, where other Kids First datasets can also be accessed. Although the survival of children with relapsed osteosarcoma is very poor, little is known about the etiology of treatment failure in this disease. The purpose of this project is to perform whole genome sequencing on serial samples from patients with osteosarcoma obtained before treatment, after treatment, and at relapse/metastasis in order to identify the mutations and pathways that are drivers of drug resistance. If successful, our results may help identify patients at high risk for treatment failure and may yield new treatments for children who cannot currently be cured.

  Study phs001714

• HipSci_RNASEQ_PID

  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 perform RNAseq on iPS lines from Platelet and bleeding disorders patients

  Study EGAS00001001990

• HipSci_RNASEQ_Usher syndrome and congenital eye defects

  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 perform RNAseq on iPS lines from Usher syndrome and congenital eye defects.

  Study EGAS00001001997

• Transcriptome of CD4+ T cells and CD8+ T cells in glioblastoma multiforme

  Patients included in this study were over 18 years of age and had a histology-confirmed diagnosis of glioblastoma multiforme (GBM). Exclusion criteria were the previous administration of any anti-tumor therapy including radiation therapy. All patients gave written informed consent. The study was approved by the local ethics committee (TUM Medical school) and conducted following the Declaration of Helsinki. During resection of the tumors, tumor tissue and tissue from normal appearing brain within the operative channel was collected. Blood was drawn during the surgical procedure. Single cell suspensions were prepared from the tumor tissue, the normal appearing brain, and the blood. CD4+ T cells and CD8+ T cells were sorted by flow cytometry. Only patients with a complete set of specimens (CD4+ tumor infiltrating lymphocytes (TIL), CD8+ TIL, CD4+ T cells from normal appearing brain, CD8+ T cells from normal appearing brain, blood-derived CD4+ and CD8+ T cells) containing a minimum of 1000 cells in each sorted sample were further analyzed (n=9). Total RNA was isolated from sorted cell populations using the RNAeasy Plus micro kit (Qiagen, 74034). Quality and integrity of total RNA was controlled on a Bioanalyzer 2100 (Agilent Technologies). Library preparation for bulk-sequencing of poly(A)-RNA was done as described previously (Parekh et al., 2016). Briefly, barcoded cDNA of each sample was generated with a Maxima RT polymerase (ThermoFisher Scientific, EP0742) using oligo-dT primer containing barcodes, unique molecular identifiers (UMIs) and an adaptor. Ends of the cDNAs were extended by a template switch oligo (TSO) and full-length cDNA was amplified with primers binding to the TSO-site and the adaptor. NEB UltraII FS kit was used to fragment cDNA. After end repair and A-tailing, a TruSeq adapter was ligated and 3'-end-fragments were finally amplified using primers with Illumina P5 and P7 overhangs. In comparison to previous descriptions (Parekh et al., 2016), the P5 and P7 sites were exchanged to allow sequencing of the cDNA in read 1 and barcodes and UMIs in read 2 to achieve a better cluster recognition. The library was sequenced on a NextSeq 500 (Illumina) with 59 cycles for the cDNA in read 1 and 16 cycles for the barcodes and UMIs in read 2. Data were processed using the published Drop-seq pipeline (v1.0) to generate sample- and gene-wise UMI tables (Macosko et al., 2015). Reference genome (GRCh38) was used for alignment. Transcript and gene definitions were used according to the Genecode Annotation Version 35.

  Study EGAS50000000156

• Possible DNA damage after paternal exposure to ionizing radiation in radar technicians

  Effects of accidental and prolonged radiation exposure on the human germline remain a topic of medical interest. Transgenerational signatures of ionizing radiation exposure are primarily implicated to be clustered de-novo mutations (cDNMs, multiple de-novo mutations within 20bp). We sequenced the whole genome of 110 children from 70 families (Radar cohort). The father in this cohort were exposed to 0-353mSv of ionizing radiation and serve as exposed samples.

  Study EGAS00001007321

• Maintenance of Brain Tumor Profile on Organotypic Brain Slice Culture (OBSC)

  We used uncultured tumor resection tissue from an NF2 mutation-driven grade II meningioma (MG-II) to investigate whether tumors engrafted onto organotypic brain slice cultures (OBSCs) maintained the genetic profile of the parent tumor. We prepared three groups of samples for whole exome sequencing (WES) from the same pool of dissociated MG-II tissue. Group HT is the original uncultured human tumor tissue (n = 3). Group CL is the parent tumor tissue expanded in standard in vitro cell culture until the minimum number of cells required for WES had grown. Because of initial cell loss and subsequent clonal expansion, this required six passages over the span of approximately one month (n = 3). Group BSHT is the uncultured tumor resection tissue engrafted onto OBSCs and subsequently dissected from the OBSCs at the conclusion of our standardized assay length (4 days; n = 4). WES analysis showed that tumor tissue engrafted onto OBSCs maintained a significant genetic resemblance to the parent tumor, while tumor tissue expanded in vitro displayed a distinctly different profile. Furthermore, the mutational profiles of all four BSHT biological replicates were markedly similar, indicating that each OBSC-engrafted tumor indeed contained a representative sample of the original patient tumor. A closer look at the hallmark NF2 mutations existing within all samples revealed that while all samples from the original tumor (HT1-3) and the OBSC-engrafted tumor (BSHT1-4) maintain the frame shift deletion at V24, this mutation was lost in all samples expanded in vitro (CL1-3) and replaced by mutations in other areas. Together, this data suggests that the rapid assay design and tumor-accommodating niche of our OBSC platform enables effective maintenance of the original patient tumor profile. The BBsplit algorithm from the BBtools suite was run on all samples to eliminate rat DNA contamination in the BSHT samples as well as to account for any biases that may result as a part of that process. Only the reads that were binned to the human reference were used for subsequent analysis. Reads were then mapped to the GRCh38 version of the human genome with BWA v0.7.17 and realigned together with ABRA2 v.23. Quality control was implemented using the GATK/Picard v4.1.7.0 toolkit. Somatic variants were called for each sample using the MuTect2 algorithm v4.1.7.0. Variants were merged into a single cohort variant call file and then converted to MAF via vcf2maf v1.6.21 tool. Variants were annotated using VEP v87. To identify mutations with potentially high biological impact, multiple filtering steps were applied to somatic mutation calling. First, we selected only the somatic variants that passed all filters from the MuTect2 FilterMutectCalls algorithm and second, only high/moderate impact (change coding) variants as defined by the VEP annotation were further analyzed. Over 1900 single nucleotide variants (SNVs) were detected across all samples. Figures that summarized the results were generated using maftools.

  Study phs003268

• Melanoma_brain_metastases

  This is a whole exome study of brain metastases in melanoma. We are studying the genomic evolution of primary cutaneous melanoma to brain met in patients with brain-only metastatic disease. We are also looking at the genomic heterogeneity in patients with temporally, anatomically and regionally separated brian metastases.

  Study EGAS00001002107

• Primary Neuroblastoma Circle-seq

  We generated Circle-seq data for primary neuroblastoma to describe the landscape of extrachromosomal circular DNA in neuroblastoma.

  Study EGAS00001004797

• Dynamics of Tumor Heterogeneity from Primary to Metastatic Dissemination in Prostate Cancer

  PRO-SPeCT: PROstate cancer heterogeneity deconvolution through Single cell Profiling of Chromatin accessibility and Transcriptomic output Identifying drivers of cancer progression to guide treatment selection is hindered by limited abilities to understand tumor heterogeneity’s impact on evolution. Here, we delineated the phenotypic variability across ~300,000 prostate tumor cells collected from multiple loci in primary and matched locoregional metastases. We found inter-patient heterogeneity to be confined to malignant populations. While malignant cell populations exhibit intra-locus heterogeneity, they maintain inter-loci phenotypic similarity within a patient’s prostate gland. In addition, the intra-locus heterogeneity between malignant cell populations is paired with a common clonal architecture. Lastly, we show that malignant cell populations disseminating to locoregional lymph nodes mirror the clonal architecture and phenotypic heterogeneity observed across primary tumor loci while showcasing cell state transition toward inflammatory phenotypes. These findings provide insights into distinct measures of tumor heterogeneity, revealing diverse evolutionary paths across patients converging to common phenotypic adaptations in early prostate cancer progression.

  Study EGAS50000000524

• MutWP5__CRUK_Mutographs_of_Cancer__Lung__PD38233__WG_

  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.

  Study EGAS00001003322

• MutWP5__CRUK_Mutographs_of_Cancer__Lung__PD37920__WG_

  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.

  Study EGAS00001003320

• MutWP5__CRUK_Mutographs_of_Cancer__Lung__PD38234__WG_

  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.

  Study EGAS00001003324

• MutWP5__CRUK_Mutographs_of_Cancer__Lung__PD43291_Novaseq__Exome_

  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 mutaiton 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 poriton of the study will be compared to other individuals with smoking-related diseases (COPD, pulmonary fibrosis, lung cancer), and normal, non-smoking lungs.

  Study EGAS00001003503

• Sample Multiplexing Oligo Comparison

  In this study, we compared various multiplexing reagents, including MULTI-Seq, Hashtag antibody, and CellPlex, in patient-derived xenografts (PDXs). We found that all multiplexing reagents worked well in cell types robust to ex vivo manipulation but suffered from signal-to-noise issues in more delicate sample types. We also compared the performance of fixed scRNA-Seq kits and CRISPR-based destruction of non-informative genes.

  Study EGAS50000000153

• Multi-Omic Profiling of Glioma Patient Tumors and Patient-Derived Model Systems

  We have created a resource of transcriptomic (RNAseq), genomic (whole-exome seq), and lipidomic (untargeted shotgun) profiling data from over 175 molecularly diverse glioma tumors and derivative models in orthotopic mouse xenografts and gliomasphere cultures from over 110 unique patient tumor lines. Provided in this dataset are matched bulk RNA and whole-exome paired-end sequencing data from resected gliomas and derived model systems performed on Illumina HiSeq and NovaSeq sequencing instruments. This comprehensive dataset powers multiple studies aiming to derive molecular signatures of intertumoral heterogeneity and perturbation responses in glioma. Through integrative multi-omic analyses in Minami, et al., 2023, PMID: 37236196, we identified that CDKN2A deletion remodels the GBM lipidome and consequently primes CDKN2A-deleted tumors for ferroptosis. Lipidomics data related to this study are publicly available here. In another study, we used a combination of molecular profiling and functional profiling of apoptotic potential to stratify patients into groups with differential vulnerability to the current standard-of-care in gliomas, and in combination with drugs targeting intrinsic apoptosis, largely informed but not limited to TP53 mutation status.

  Study phs003286

• A prospective study identifies MisMatch Repair genes as candidate predisposing genes for uveal melanoma.

  Objective: The aim of this study is to identify new predisposing genes for uveal melanoma (UM), the most common intraocular malignancy in adults. Design: Prospective cohort study from Institut Curie. Participants: 381 unselected patients diagnosed with UM between July 2021 and February 2023 at Institut Curie. Methods: All patients received genetic counseling and consented to extended genetic testing. A panel of 122 genes was analyzed by targeted sequencing on germline DNA from these patients. Main outcomes measures: UM was diagnosed by ophthalmologists at Institut Curie, and a senior pathologist confirmed the diagnosis when tumor or biopsy was available. Classification of the germline genetic variants was performed according to the ACMG guidelines. Results: We identified at least one pathogenic variant (PV) in 79 patients. Among those variants, 20 were found in clinically relevant genes for the patient’s follow-up and genetic counseling. We found a significant enrichment of germline pathogenic variants in Mismatch Repair (MMR) MLH1, MSH2 and MSH6 genes in this UM cohort, suggesting that MMR germline alterations could predispose to UM. From this cohort, one tumor was available from a patient carrying a MLH1 germline mutation. The tumor was characterized by a monosomy 3, in line with a loss of heterozygosity (LOH) of MLH1, located on chromosome 3. Loss of expression of MLH1 and PMS2 was observed by immunohistochemistry, and MMR mutational signatures SBS6, ID1 and ID2 were identified from the whole genome sequencing of the tumor. These data suggest that MLH1 is implicated in the oncogenesis of this UM. Conclusions: This study is the largest prospective constitutional study performed on UM patients, and the first demonstrating that MMR germline alterations are significantly enriched among these patients. Further analyses will be needed to estimate the risk of developing UM for patients with Lynch syndrome

  Study EGAS50000000914

• Regenerative effects of MSC treatment on busulfan-induced small intestine damaged organoids.

  Allogenic hematopoietic stem cell transplantation (HSCT) is a curative treatment for leukemia and a range of non-malignant disorders. The success of the therapy is hampered by occurrence of acute graft-versus-host disease (aGvHD); an inflammatory response damaging recipient organs, with gut, liver, and skin being the most susceptible. Intestinal GvHD injury is often a life-threatening complication in patients unresponsive to steroid treatment. Second-line available therapies are immunosuppressants or mesenchymal stromal/stem cell (MSC) infusions. Data from our institution and others demonstrate rescue of approximately 40-50% of patients suffering from aGvHD with mesenchymal stromal/stem cells (MSCs) and minor side effects. Although promising, the better understanding of MSC mode of action and patient response to MSC-based therapy is essential to improve this lifesaving treatment. Here, we developed a novel 3D co-culture model of human small intestinal organoids and MSCs, which allows to study the regenerative effects of MSCs on intestinal epithelium in a more physiologically relevant setting than existing in vitro systems. Using this model we mimicked chemotherapy-mediated damage of the intestinal epithelium. The treatment with busulfan, the chemotherapeutic commonly used as conditioning regiment before the HSCT, affected pathways regulating EMT, proliferation, and apoptosis in small intestinal organoids, as shown by transcriptomic and proteomic analysis. The co-culture of busulfan treated intestinal organoids with MSCs reversed the effects of busulfan on the transcriptome and proteome of intestinal epithelium, which we also confirmed by functional evaluation of proliferation and apoptosis. Collectively, we demonstrate that our novel in vitro co-culture system is a new valuable tool to facilitate the investigation of the molecular mechanisms behind the therapeutic effects of MSCs on damaged intestinal epithelium.

  Study EGAS00001007432