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• Fecal microbiome of T2D patients undergoing semaglutide or empagliflozin treatment

  The gut microbiome has been shown to be affected by the use of many human-targeted medications, and the interaction can be bidirectional. This has been clearly demonstrated for type 2 diabetes medications that have been in clinical use for several decades. However, the bidirectional effects of novel type 2 diabetes drugs semaglutide, empagliflozin, and the gut microbiome have yet to be clearly described. We investigated the effect of semaglutide and empagliflozin initiation on the gut microbiome of type 2 diabetes patients. In addition, we analyzed whether the pre-treatment gut microbiome can predict the treatment efficacy. Twenty subjects (10 women and 10 men) were enrolled in the study between November 2019 and January 2023 from the University of Tartu Hospital, Tartu, Estonia. All participants had been diagnosed with type 2 diabetes. The study group taking semaglutide included 6 women and 4 men, and the group prescribed empagliflozin included 4 women and 6 men. Gut microbiome fecal samples donated at four timepoints (Baseline, Month 1, Month 3; Month 12) were studied using 16S ribosomal RNA gene sequencing and analysis.

  Dataset EGAD50000000756

• Mechanism of Decitabine response in MDS/AML patients

  Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) with complex or monosomy karyotype show high prevalence of TP53 mutations (TP53m), poor response to induction chemotherapy and adverse outcome. These diseases may respond to decitabine but the mechanisms are presently unclear. This study investigates MDS/AML patients who were treated with decitabine for 10 days in a Phase II clinical trial. Serial samples were collected from patients before and at completion of decitabine treatment, morphologic remission and relapse. The samples were interrogated using single-cell transcriptomics to investigate potential interactions between leukemic and immune populations."

  Study EGAS50000000924

• Single cell transcriptomic and genomic profiling of carcinogenesis in patients with familial adenomatous polyposis

  Familial Adenomatous Polyposis (FAP) is characterized by hundreds to thousands of adenocarcinomas at different evolutional stages in the colon and rectum. Much effort has been made to illuminate the key genomic alterations that facilitate the transition from adenoma to carcinoma. However, the strong heterogeneity of the tumors may hamper these efforts. Here, by sequencing matched adjacent normal tissues, adenomas at different stages and carcinomas from the same patient, we precisely traced the process of colorectal carcinogenesis. Our study offers an accurate genomic landscape during the initiation and progression of carcinogenesis, especially for the transition between adenomas and carcinomas.

  Study EGAS00001003598

• PAS Pedigrees: Identification of novel genetic variants contributing to cardiovascular disease in pedigrees with premature atherosclerosis.

  The heritability of CVD has been estimated to be between 40 and 55%. Due to the low MAF, PAS-causing mutations cannot be identified by indirect genotyping because their presence cannot be inferred from common haplotypes, as has been done successfully to uncover common risk variants by GWAS. It has been shown by Ng et al that the causative gene for rare syndromes can be unequivocally identified by sequencing the exomes of only four cases and eight controls. We expect exome sequencing to result in a high number of mutations and non-causitive coding variants.

  Study EGAS00001000052

• NOTCH-mutations drive immune-escape mechanisms in B cell malignancies

  Here we provide access to MCL expression data that were used for interrogating the molecular functions of NOTCH1 and NOTCH2, which are two of the most commonly mutated genes in CLL and MCL and associated with a poor clinical outcome. The mechanisms underlying how NOTCH1 contributes to disease progression, resistance to treatment and Richter’s transformation remain largely unknown. The main goal of this study is to compare the gene expression profile of primary MCL cells transduced with the intracellular part of NOTCH1 or NOTCH2 lacking of the PEST domain vs cells transduced with an empty vector.

  Study EGAS00001005793

• Measurement of SARS-CoV-2 variants fraction in infected alveolar cells

  With the continuous emergence of highly transmissible SARS-CoV-2 variants, the comparison of their infectivity has become a critical issue for public health. However, a direct assessment of the viral characteristic has been challenging due to the lack of appropriate experimental models and efficient methods. Here, we conducted full-length transcriptome sequencing of single human alveolar cells infected by multiple SARS-CoV-2 variants, including GR (B.1.1.119), Alpha (B.1.1.7), Delta (B.1.617.2), and Omicron (BA.1). Using unique mutations of each VOC, we calculated the fraction of VOCs in infected cells.

  Study EGAS00001006730

• Ovarian Cancer Organoid Biobank - RNASeq data

  Ovarian cancer (OC) is a heterogeneous disease usually diagnosed at a late stage. Experimental in vitro models that faithfully capture the hallmarks and tumor heterogeneity of OC are limited and hard to establish. We present a novel protocol that enables efficient derivation and long-term expansion of OC organoids. Utilizing this protocol, we have established 56 organoid lines from 32 patients, representing the spectrum of ovarian neoplasms, including non-malignant borderline tumors, as well as mucinous, clear-cell, endometrioid, low- and high-grade serous carcinomas. OC organoids recapitulate histological and genomic features of the pertinent lesion from which they were derived, illustrating intra- and inter-patient heterogeneity, and can be genetically modified. We show that OC organoids can be used for drug screening assays and capture different tumor subtype responses to the gold standard platinum-based chemotherapy, including acquisition of chemoresistance in recurrent disease. Finally, OC organoids can be xenografted, enabling in vivo drug sensitivity assays. Taken together, this demonstrates their potential application for research and personalized medicine.

  Dataset EGAD00001004509

• CRISPR screening in human trophoblast stem cells reveals both shared and distinct aspects of human and mouse placental development

  The placenta serves as the interface between the mother and fetus, facilitating the exchange of gases and nutrients between their separate blood circulation systems. Trophoblasts in the placenta play a central role in this process. Our current understanding of mammalian trophoblast development relies largely on mouse models. However, given the diversification of mammalian placentas, findings from the mouse placenta cannot be readily extrapolated to other mammalian species, including humans. To fill this knowledge gap, we performed CRISPR knockout (KO) screening in human trophoblast stem cells (hTSCs). We targeted genes essential for mouse placental development and identified more than 100 genes as critical regulators in both human hTSCs and mouse placentas. Among them, we further characterized in detail two transcription factors, DLX3 and GCM1, and revealed their essential roles in hTSC differentiation. Moreover, a gene function-based comparison between human and mouse trophoblast subtypes suggests that their relationship may differ significantly from previous assumptions based on tissue localization or cellular function. Notably, our data reveal that hTSCs may not be analogous to mouse TSCs or the extraembryonic ectoderm (ExE) in which in vivo TSCs reside. Instead, hTSCs may be analogous to progenitor cells in the mouse ectoplacental cone and chorion. This finding is consistent with the absence of ExE-like structures during human placental development. Our data not only deepen our understanding of human trophoblast development but also facilitate cross-species comparison of mammalian placentas.

  Study JGAS000659

• Genetic variability in exon 1 of the glucocorticoid receptor gene NR3C1 is associated with postoperative complications

  Patients having major surgery experience inflammation post-operatively, which may contribute to post-operative morbidity. Endogenous glucocorticoids (GCs) are an essential part of the stress response, but this response varies between individuals, which may in turn affect clinical outcome in general, and post-operative inflammation, specifically. Exon 1 of the NR3C1 gene, encoding the glucocorticoid receptor, contains an established region of differential regulation. DNA methylation patterns in this region have been found to differ between individuals. We investigated the methylation status and genotype in the Cytosine-phosphate-Guanine (CpG) island in exon 1 of NR3C1 in 24 patients who underwent major abdominal surgery and correlated it with post-operative complications. DNA was extracted from peripheral blood leukocytes and underwent targeted bisulfite sequencing of the CpG island. Complications were graded according to the Clavien-Dindo classification and 14 out of 24 had post-operative complications. Multifactorial and partial least square methods were used to analyse the data. A homogenous demethylated pattern was observed in all patients and no single CpG methylation was associated with post-operative complications. Four single nucleotide polymorphisms (SNPs) were significantly correlated with higher Clavien-Dindo scores. Genetic variability in the chr5:143,402,505-143,405,805 region of exon 1 of the glucocorticoid receptor gene NR3C1, but not DNA methylation, was associated with more severe post-operative complications in patients having major abdominal surgery. This indicates that the response to GCs may be of clinical importance for inflammatory conditions.

  Study EGAS00001005737

• Karyotype Evolution in Response to Chemoradiotherapy and Upon Recurrence of Esophageal Adenocarcinomas

  The genome of esophageal adenocarcinoma (EAC) is highly unstable and might evolve over time. Here, we track karyotype evolution in EACs in response to treatment and upon recurrence through multi-region and longitudinal analysis. To this end, we introduce L-PAC, a bio-informatics technique that allows inference of absolute copy number aberrations (CNA) of low-purity samples by leveraging information of high-purity samples from the same cancer. Quantitative analysis of matched absolute CNAs reveals that the amount of karyotype evolution induced by chemoradiotherapy (CRT) is predictive for early recurrence and depends on the initial level of karyotype intra-tumor heterogeneity. We observe that CNAs acquired in response to CRT are partially reversed back to the initial state upon recurrence. CRT hence alters the fitness landscape to which tumors can adjust by adapting their karyotype. Together, our results indicate that karyotype plasticity contributes to therapy resistance of EACs.

  Study EGAS00001007711

• Genome-Wide Association Study of Endometrial Cancer in the Epidemiology of Endometrial Cancer Consortium (E2C2)

  Endometrial cancer, the most common gynecological malignancy in the United States, has both an environmental and genetic component. To this end, we conducted a genome-wide association study to identify genes involved in endometrial cancer using studies from the NCI-supported Epidemiology of Endometrial Cancer Consortium (E2C2). For the discovery stage we included samples from 6 cohort and 7 case control studies through 2007. The total number of cases genotyped were 2,307, white women of European descent, and 2,307 matched controls using the Illumina HumanOmniExpress platform. We conducted the replication using the Infinium HumanExome BeadChip, which successfully genotyped 177,139 variants in 1055 cases and 1778 controls from four ethnically diverse studies that are part of the Epidemiology of Endometrial Cancer Consortium (E2C2). The overall goal is to determine whether certain genotypes are predictive of future endometrial cancer risk, and whether the genotypes interact with established endometrial risk factors.

  Study phs000893

• Interpreting molecular role of DNA variants associated with Crohn's Disease through integrative analysis of open chromatin, epigenome and transcriptome data in diverse and relevant tissues and cells

  Crohn's disease (CD), one of the two major inflammatory bowel diseases (IBD), results from an inappropriately directed inflammatory response to the enteric microbiota in a genetically susceptible host. Genome wide association studies (GWAS) have linked >200 specific single nucleotide polymorphisms (SNPs) to CD disease pathogenesis. Within these regions, there are over 5600 additional SNPs that are in linkage disequilibrium (LD) with the tag SNPs, and it is not known which of these contribute to CD. Most of these SNPs map to non-coding regions of the genome, suggesting that causal variants contribute to CD by modifying gene regulatory element activity. In ths study, we have generated genotype, open chromatin (FAIRE-seq), and transcriptome (RNA-seq) data from macroscopically uninflamed regions of colon tissue for 21 CD patients and 11 non-IBD controls. All patients are adults (>18 years old).

  Study phs001418

• Genetic Control of Expression and Splicing in Developing Human Brain

  Most genetic risk for human diseases lies within non-coding regions of the genome that are predicted to regulate gene expression in a tissue- and stage-specific manner. Given the importance of regulatory pathways during brain development, we characterized the genetic control of the transcriptome in 201 mid-gestational human brains, identifying 7962 eQTL and 4635 sQTL. By integration with GWAS, we characterized the genes and isoforms contributing to specific neuropsychiatric disorders, including SCZ and ASD, as well as other cognition or behavioral-related phenotypes. SCZ and ASD impact distinct developmental gene co-expression modules, yet in both disorders, common and rare genetic variation converge. These analyses demonstrate the highly distinctive effects of transcriptional control, as well as divergent age-related contributions to disease. More broadly, these findings demonstrate the genetic mechanisms by which early developmental events have a striking and widespread influence on adult anatomical and behavioral phenotypes.

  Study phs001900

• Unraveling the Genetic Architecture of Diabetic Retinopathy in South India

  This study aims to understand the genetic architecture of diabetic retinopathy in the South Indian population by examining participants with South Indian ancestry and type 2 diabetes (T2D) from two sources: the Sankara Nethralaya-Diabetic Retinopathy Epidemiology and Molecular Genetic Study (SN-DREAMS) and prospective recruitment at Sankara Nethralaya affiliates. A total of 2393 patients were recruited and included in the genetic analysis, with 1588 patients having no diabetic retinopathy (DR) serving as the controls and 805 patients with any level of DR serving as the cases. Enrolled individuals had genome-wide genotyping from DNA extracted from blood samples. In addition, whole genome sequencing (WGS) was performed on 31 members from 2 families. Clinical data, such as age, duration of diabetes, and hemoglobin A1C (HbA1c) were recorded for study participants. Diabetic retinopathy was assessed by clinical exam and/or fundus photography. The grading of diabetic retinopathy followed the International Clinical Diabetic Retinopathy Severity Scale.

  Study phs002116

• Identification of High-Risk PHF19 Expressing Cells in Myeloma Single-Cell Multiomics

  The aim of this study is to identify novel subsets of cells that are associated with progression and response to treatment. In this project, we study the tumor fraction from 49 myeloma patients across stages of progression. Samples were collected from 10 smoldering multiple myeloma (SMM), 22 newly diagnosed multiple myeloma (NDMM), and 17 relapsed refractory multiple myeloma (RRMM) patients. These samples were then sorted using magnetic-activated cell sorting (MACS) for CD138+ cells that represent the tumor fraction of each sample. The CD138+ fraction then underwent whole genome sequencing (WGS), where possible, and single-cell multiomics. Single-cell multiomics can now measure scRNA-seq and scATAC-seq simultaneously, which we use in this project. Using single-cell multiomics, we will study subclonal changes in gene expression, chromatin accessibility, and identify novel regulatory relationships within myeloma tumors. Furthermore, we will apply state of the art single-cell and single-cell multiomic techniques to better identify the more high-risk components of myeloma.

  Study phs003220

• Transcriptome changes in circulating immune cells of critical COVID-19 patients predict a specific metabolic and epigenetic imprint

  The progression to severe COVID-19 arises predominantly from a dysregulated host immune response, although the underlying regulatory mechanisms still remain partially elusive. This limits a prompt prediction of disease progression and restrains our understanding of “long COVID”. Here, we analyzed the transcriptomes of peripheral blood mononuclear cells collected from COVID-19 patients experiencing different degrees of the disease and control patients. In critical COVID-19 patients, we found an altered regulatory network involving microRNAs, long non-coding RNAs, and coding genes that control mRNA translation-related genes, epigenetics, and metabolism. We also observed an upregulation of tRNA aminoacylation genes and increased expression of coding genes enriched for the cognate amino acids. Collectively, our findings indicate a broad perturbation of the gene expression landscape that characterizes the aberrant host immune response in critical COVID-19 patients and is potentially coordinated by alterations in microRNA expression and tRNA metabolism.

  Study EGAS50000000965

• Myelodysplastic cells in patients re-program mesenchymal stromal cells to establish a transplantable stem cell-niche disease unit.

  Myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid neoplasms with defects in hematopoietic stem/progenitor cells (HSPCs) and possibly the HSPC niche. Here we show that patient-derived mesenchymal stromal cells (MDS MSCs) display a disturbed differentiation program and are essential for the propagation of MDS-initiating lin-CD34+CD38- stem cells in orthotopic xenografts. Overproduction of niche factors such as N-Cadherin, IGFBP2, VEGFA and LIF is associated with the ability of MDS MSCs to enhance MDS expansion. These factors represent putative therapeutic targets to disrupt critical hematopoietic-stromal interactions in MDS. Finally, healthy MSCs adopt "MDS-MSC like" molecular features when exposed to hematopoietic MDS cells, indicative of an instructive remodeling of their microenvironment. This patient-derived xenograft model therefore provides functional and molecular evidence that MDS is a complex disease involving both the hematopoietic and stromal compartments. The resulting deregulated expression of niche factors may well also be a feature of other hematopoietic malignancies.

  Study EGAS00001000716

• Transcriptome analysis in very preterm infants with chronic lung disease after birth

  Bronchopulmonary dysplasia (BPD) is the most common complication of prematurity and is characterized by impaired alveolar and vascular development. The aim of the study was to identify early BPD-relevant pathways by applying whole genome transcriptional profiling combined with protein measurements from umbilical arterial blood samples of preterm infants with and without BPD. Only newborn infants <32 weeks gestational age (GA) were prospectively included in this study. Blood was obtained from an indwelling umbilical artery catheter at birth and after 72 hours after birth and subjected to gene expression analysis using the Codelink Human I 10k Bioarray and the the Codelink Human Whole Genome Bioarray. The study reveals a monocyte-centered immune response at birth characterizing preterm infants later developing BPD. The findings provide potential markers for early risk stratification in the preterm infant with respect to the development of chronic pulmonary disease and may subsequently enable the development of new treatment strategies in this high risk patient cohort.

  Study EGAS00001002586

• Translation of non-canonical open reading frames as a cancer cell survival mechanism in childhood medulloblastoma

  A hallmark of high-risk childhood medulloblastoma is the dysregulation of RNA translation. Currently, it is unknown whether medulloblastoma dysregulates the translation of putatively oncogenic non-canonical open reading frames. To address this question, we performed ribosome profiling of 32 medulloblastoma tissues and cell lines and observed widespread non-canonical ORF translation. We then developed a step-wise approach to employ multiple CRISPR-Cas9 screens to elucidate functional non-canonical ORFs implicated in medulloblastoma cell survival. We determined that multiple lncRNA-ORFs and upstream open reading frames (uORFs) exhibited selective functionality independent of the main coding sequence. One of these, ASNSD1-uORF or ASDURF, was upregulated, associated with the MYC family oncogenes, and was required for medulloblastoma cell survival through engagement with the prefoldin-like chaperone complex. Our findings underscore the fundamental importance of non-canonical ORF translation in medulloblastoma and provide a rationale to include these ORFs in future cancer genomics studies seeking to define new cancer targets.

  Study EGAS00001007426

• SG10K_Pilot - Large-scale whole-genome sequencing of three diverse Asian populations in Singapore

  Underrepresentation of Asian genomes has hindered population and medical genetics research on Asians, leading to population disparities in precision medicine. By whole-genome sequencing of 4,810 Singapore Chinese, Malays, and Indians, we found 98.3 million SNPs and small insertions/deletions, over half of which are novel. Population structure analysis demonstrated great representation of Asian genetic diversity by three ethnicities in Singapore, and revealed a Malay-related novel ancestry component. Furthermore, demographic inference suggested that Malays split from Chinese ~24,800 years ago, and experienced significant admixture with East Asians ~1,700 years ago, coinciding with the Austronesian expansion. Additionally, we identified 20 candidate loci for natural selection, among which 14 harbored robust associations with complex traits and diseases. Finally, we showed that our data can substantially improve genotype imputation in diverse Asian and Oceanian populations. These results highlight the value of our data as a resource to empower human genetics discovery across broad geographic regions.

  Study EGAS00001003875

• Data from the paper Context-specific Effects of TGFβ/SMAD3 in Cancer Are Modulated by the Epigenome. Tufegdzic et al, Cell Reports 2015

  The transforming growth factor beta (TGFβ) signalling pathway exerts opposing effects on cancer cells, acting either as a tumor-promoter or as a tumor-suppressor. Here we show these opposing effects are a result of the synergy between SMAD3, a downstream effector of TGFβ signalling, and the distinct epigenomes of breast tumor initiating cells (BTICs). These effects of TGFβ are associated with distinct gene expression programs, but genomic SMAD3 binding patterns are highly similar in the BTIC-promoting and BTIC- suppressing contexts. Our data show cell type-specific epigenetic configurations provide a modulatory layer by determining accessibility of genes to regulation by TGFβ/SMAD3. LBH, one such context-specific target gene, is regulated according to its DNA methylation status, and is crucial for TGFβ-dependent promotion of BTICs. Overall, these results reveal that the epigenome plays a central and previously overlooked role in shaping the context-specific effects of TGFβ in cancer.

  Study EGAS00001001570

• The interface of malignant and immunologic clonal dynamics in high-grade serous ovarian cancer

  High-grade serous ovarian cancer exhibits extensive intratumoral heterogeneity coupled with widespread intraperitoneal disease. Despite this, metastatic spread of tumor clones is non-random, implying the existence of local microenvironmental factors that shape tumor progression. We interrogated the molecular interface between tumorinfiltrating lymphocytes (TIL) and cancer cells in 143 samples from 21 patients using whole-genome sequencing, immunohistochemistry, histologic image analysis, gene expression profiling, and T- and B-cell receptor sequencing. We identify 3 immunologic response categories, which frequently co-exist within individual patients. Furthermore, epithelial CD8+ TIL were inversely associated with malignant cell diversity, evidenced by subclonal neoepitope elimination and spatial tracking between tumor and T-cell clones. Intersecting mutational signatures and immune analysis showed that foldback inversion genomic aberrations lead to worse outcomes even in the presence of cytotoxic TIL (n=433). Thus, regional variation in immune contexture mirrors the pattern of intraperitoneal malignant spread, provoking new perspectives for treatment of this challenging disease.

  Study EGAS00001002839

• High number of somatic mutations found in the healthy blood compartment of a 115-year-old woman reveals oligoclonal hematopoiesis

  The somatic mutation burden in healthy white blood cells (WBCs) is not well known. Based on deep whole genome sequencing, we estimate that ~450 somatic mutations accumulated in the non-repetitive genome within the healthy blood compartment of a 115-year old woman. The detected mutations appear to have been harmless passenger mutations: they were enriched in non-coding, AT-rich regions that are not evolutionarily conserved, and they were depleted for genomic elements where mutations might have favorable or adverse effects on cellular fitness, such as regions with actively transcribed genes.The distribution of variant allele frequencies of these mutations suggests that the majority of the peripheral white blood cells were offspring of two related hematopoietic stem cell (HSC) clones. Moreover, telomere lengths of the WBCs were significantly shorter than telomere lengths from other tissues. Together, this suggests that the finite lifespan of HSCs, rather than somatic mutation effects, may lead to hematopoietic clonal evolution at extreme ages.

  Study EGAS00001000660

• Spatial and Temporal Homogeneity of Driver Mutations in Diffuse Intrinsic Pointine Glioma

  Diffuse Intrinsic Pontine Gliomas (DIPG) are deadly pediatric brain tumors where needle biopsies help guide diagnosis and targeted therapies. To address spatial heterogeneity, we analyzed 134 specimens from various neuroanatomical structures of whole autopsy brains from nine DIPG patients. Evolutionary reconstruction indicates histone 3 (H3)K27M – including novel H3.2K27M - mutations potentially arise first and are invariably associated with specific, high-fidelity obligate partners throughout the tumor and its spread, from diagnosis to end-stage disease, suggesting mutual need for tumorigenesis. These H3K27M ubiquitously-associated mutations involve alterations in TP53 cell-cycle (TP53/PPM1D) or specific growth factor pathways (ACVR1/PIK3R1). Later oncogenic alterations arise in sub-clones and often affect the PI3K pathway. Our findings are consistent with early tumor spread outside the brainstem including the cerebrum. The spatial and temporal homogeneity of driver mutations in DIPG implies they will be captured by limited biopsies and emphasizes the need to develop therapies specifically targeting obligate oncohistone partnerships.

  Study EGAS00001001654

• A novel TP53-KPNA3 translocation defines a de novo treatment-resistant clone in osteosarcoma

  Osteosarcoma is the most common primary bone cancer. It can be cured by aggressive surgery and chemotherapy, but outcomes for metastatic or chemoresistant disease remain dismal. Cancer sequencing studies have shown that the p53 pathway is dysregulated in nearly every case, often by translocation; however, no studies of osteosarcoma evolution or intratumor heterogeneity have been done to date. We studied a patient with chemoresistant, metastatic disease over the course of three years. We performed exome sequencing on germline DNA and DNA collected from tumor at three separate timepoints. We compared variant calls and variant allele frequencies between different samples. We identified subclonal driver mutations in several different genes in the primary tumor sample and found that one particular subclone dominated subsequent tumor samples at relapse. This clone was marked by a novel TP53-KPNA3 translocation and loss of the opposite-strand wild-type TP53 allele. Future research must focus on functional significance of such clones and strategies to eliminate them.

  Study EGAS00001001805