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• Single-cell Kinnex sequencing of Alzheimer's disease isoform profile

  Alzheimer’s disease (AD) is the most common cause of dementia, yet its molecular causes remain incompletely understood. RNA diversity in part arising from dysregulated splicing may contribute to AD pathogenesis; however, the ability to interrogate the resulting full-length isoforms in single brain cells has been technologically limited. Here we report the use of PacBio Kinnex long-read sequencing combined with 10X Genomics single-cell preparations to identify both annotated and unannotated RNA isoforms. Eight AD and seven non-diseased post-mortem human brains yielded ~70,000 single nuclei showing diverse, differentially expressed, and switched transcripts in multiple genes. Cell-type-specific isoform expression and variants with intra-exonic junctions associated with reverse transcriptase-mediated somatic gene recombination were also detected. Novel isoforms, including CHI3L1 and SEPTIN4, were altered in AD. Kinnex sequencing of RNA isoforms from single nuclei detected vast isoform diversity amongst brain cell types, representing an under-explored element in AD and other brain disorders.

  Study EGAS50000001476

• Spatial Dynamics of the Developing Heart (single-cell)

  Heart development relies on a topologically defined interplay between diverse cardiac cells. We finely curated spatial and single-cell measurements with high-resolution imaging-based transcriptomics validation to explore spatial dynamics during early human cardiogenesis. Analyzing almost 80,000 individual cells and 70,000 spatially barcoded tissue regions between the 5.5th and 14th postconceptional weeks, we identified 31 coarse- and 72 fine-grained cell states and mapped them to highly resolved cardiac cellular niches. We provide novel insight into the development of the cardiac pacemaker-conduction system, heart valves, and atrial septum, and decipher heterogeneity of the hitherto elusive cardiac fibroblast population. Furthermore, we describe the formation of the cardiac autonomic innervation and present the first spatial account of chromaffin cells in the fetal human heart. Our study, supported by an open-access, spatially centric interactive viewer, delineates the cellular and molecular architecture of the developing heart, offering links to genetic causes of heart disease.

  Study EGAS50000001029

• Sensitive neoantigen discovery by real-time mutanome-guided immunopeptidomics - WES

  Targeting cancer-specific HLA-peptide complexes is a promising immunotherapy approach, with mutated neoantigens offering high value for their immunogenicity and cancer-specificity. Selecting immunogenic targets requires personalized prioritization of cancer-specific immunopeptides. Mass spectrometry (MS)-based immunopeptidomics supports this process by directly identifying cancer-specific antigens and informing global presentation patterns to refine immunogenicity predictions. Clinical pipelines, however, must balance global depth and target sensitivity compounded by low input samples and time constraints. Here, we present NeoDiscMS, an extension of the NeoDisc pipeline, enabling personalized immunopeptidomics data acquisition. By leveraging real-time NGS-guided spectral acquisitions, NeoDiscMS maximizing sensitivity with minimal loss of global depth. NeoDiscMS improves TAA-derived peptide detection up to 20% and enhances neoantigen identification confidence compared to the clinical gold standard method. Designed for effectiveness and ease of use, it requires minimal effort for implementation. NeoDiscMS advances personalization in clinical antigen discovery by enabling more sensitive neoantigen detection while seamlessly integrating into existing workflows.

  Study EGAS50000000976

• Sensitive neoantigen discovery by real-time mutanome-guided immunopeptidomics - RNAseq

  Targeting cancer-specific HLA-peptide complexes is a promising immunotherapy approach, with mutated neoantigens offering high value for their immunogenicity and cancer-specificity. Selecting immunogenic targets requires personalized prioritization of cancer-specific immunopeptides. Mass spectrometry (MS)-based immunopeptidomics supports this process by directly identifying cancer-specific antigens and informing global presentation patterns to refine immunogenicity predictions. Clinical pipelines, however, must balance global depth and target sensitivity compounded by low input samples and time constraints. Here, we present NeoDiscMS, an extension of the NeoDisc pipeline, enabling personalized immunopeptidomics data acquisition. By leveraging real-time NGS-guided spectral acquisitions, NeoDiscMS maximizing sensitivity with minimal loss of global depth. NeoDiscMS improves TAA-derived peptide detection up to 20% and enhances neoantigen identification confidence compared to the clinical gold standard method. Designed for effectiveness and ease of use, it requires minimal effort for implementation. NeoDiscMS advances personalization in clinical antigen discovery by enabling more sensitive neoantigen detection while seamlessly integrating into existing workflows.

  Study EGAS50000000977

• MethylBERT enables read-level DNA methylation pattern identification and tumour deconvolution using a Transformer-based model

  DNA methylation (DNAm) is a key epigenetic mark that shows profound alterations in cancer. Read-level methylomes enable more in-depth DNAm analysis due to the broad coverage and preservation of rare cell-type signals, compared to array-based data such as 450K/EPIC array. Here, we propose MethylBERT, a novel Transformer-based model for read-level methylation pattern classification. MethylBERT identifies tumour-derived sequence reads based on their methylation patterns and genomic sequence and the method estimates tumour cell fractions within bulk samples. In our evaluation, MethylBERT outperforms existing deconvolution methods and demonstrates high accuracy regardless of methylation pattern complexity, read length and read coverage. Moreover, we show its applicability to cell-type deconvolution as well as non-invasive early cancer diagnostics using liquid biopsy samples. MethylBERT represents a significant advancement in read-level methylome analysis and enables accurate tumour purity estimation. The broad applicability of MethylBERT will enhance studies on both tumour and non-cancerous bulk methylomes.

  Study EGAS50000000806

• STimage: Robust and interpretable prediction of gene markers and cell types from spatial transcriptomics data

  Spatial transcriptomics (ST) links tissue morphology with gene expression values, opening new avenues for digital pathology. Deep learning models are used to predict gene expression or classify cell types directly from images, offering significant clinical potential but still requiring improvements in interpretability and robustness. We present STimage as a comprehensive suite of models to predict spatial gene expression and classify cell types directly from standard H\&E images. STimage enhances robustness by estimating gene expression distributions and quantifying both data-driven (aleatoric) and model-based (epistemic) uncertainty using ensemble approach with foundation models. Interpretability is achieved through attribution analysis at single-cell resolution integrated with histopathological annotations, functional genes, and latent representations. We validated STimage across diverse datasets, demonstrating its performance across various platforms. STimage-predicted gene expression can stratify patient survival and predict drug response. By enabling molecular and cellular prediction from routine histology, STimage offers a powerful tool to advance digital pathology.

  Study EGAS50000001503

• Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer: exploratory biomarker analyses from CheckMate 577

  Adjuvant nivolumab demonstrated a significant improvement in disease-free survival (DFS; primary endpoint) versus placebo in patients with resected esophageal or gastroesophageal junction cancer and residual pathologic disease following neoadjuvant chemoradiotherapy (CRT) in the phase III CheckMate 577 study, leading to global approval and widespread adoption. Exploratory biomarker analyses were performed using whole-exome sequencing, RNA sequencing, and immunohistochemistry. Hazard ratios for DFS favored nivolumab versus placebo in patients with higher inflammation and proliferation gene expression signature scores; lower M2 macrophage, endothelial, and stromal GES scores; and higher densities of CD3+/CD8- T cells and natural killer cells. Assessments of pre-CRT and post-CRT tumor tissue found post-CRT increases in programmed death ligand 1 combined positive score in 51% of patients, which appeared to be associated with greater DFS benefit. Through these analyses, we identified patient subpopulations that appear to derive improved DFS benefit from adjuvant nivolumab in this setting.

  Study EGAS50000001663

• A small cell lung cancer genome reports complex tobacco exposure signatures

  Cancer is driven by mutation. Worldwide, tobacco smoking is the major lifestyle exposure that causes cancer, exerting carcinogenicity through 60 chemicals that bind and mutate DNA. Using massively parallel sequencing technology, we sequenced a small cell lung cancer cell line, NCI-H209, to explore the mutational burden associated with tobacco smoking. 22,910 somatic substitutions were identified, including 132 in coding exons. Multiple mutation signatures testify to the cocktail of carcinogens in tobacco smoke and their proclivities for particular bases and surrounding sequence context. Effects of transcription-coupled repair and a second, more general expression-linked repair pathway were evident. We identified a tandem duplication that duplicates exons 3-8 of CHD7 in-frame, and another two lines carrying PVT1-CHD7 fusion genes, suggesting that CHD7 may be recurrently rearranged in this disease. These findings illustrate the potential for next-generation sequencing to provide unprecedented insights into mutational processes, cellular repair pathways and gene networks associated with cancer.

  Study EGAS00000000051

• Full genome sequencing of a monozygotic twin discordant for schizophrenia

  We sequenced the genomes from a monozygotic twin discordant for schizophrenia and a tumor-normal pair of an ovarian cancer patient. Using whole-genome twin data to discriminate between correctly identified single nucleotide variants (SNVs) and errors a strategy for the accurate detection of SNVs was developed. By applying stringent sequencing quality measures, excluding error-prone regions and selecting SNVs identified by different mapping and variation calling algorithms, error rates were ~37-fold reduced. This enabled us to identify the first discordant SNVs in monozygotic twins using whole-genome sequencing. In addition, by showing that novel SNVs are highly enriched in errors, accurate estimates of the number of novel and rare SNVs occurring in unrelated Caucasian individuals were obtained. Finally, somatic mutations in coding and regulatory sequences were reliably identified in the highly rearranged ovarian tumor. Overall, our data demonstrate that strategies to reduce error rates in whole-genomes are required for disease gene discovery.

  Study EGAS00001000152

• Single-cell Analysis of Neoplastic Plasma Cells Identifies Myeloma Pathobiology Mediators and Potential Targets

  Multiple myeloma is a clonal plasma cell (PC) dyscrasia that arises from precursors and has been studied utilizing approaches focused on CD138+ cells. By combining single-cell (sc)RNA- with scB-cell receptor (BCR)-sequencing, we differentiate monoclonal/neoplastic from polyclonal/normal PCs, and find more dysregulated genes, especially in precursor patients, than by analyzing bulk PCs. To determine if this approach can identify oncogenes that contribute to disease pathobiology, MAD2L1 and MAT2A are validated as targets with drug-like molecules that suppress myeloma growth in pre-clinical models. Moreover, functional studies show a role of LAMP5, which is uniquely expressed in neoplastic PCs, in tumor progression and aggressiveness via interactions with c-MYC. Finally, a monoclonal antibody recognizing cell-surface LAMP5 shows efficacy as an antibody-drug conjugate and in a chimeric antigen receptor-guided T-cell format. These studies provide additional insights into myeloma biology and identify potential targeted therapeutic approaches that can be applied to reverse myeloma progression.

  Study EGAS50000000802

• Spatial Dynamics of the Developing Human Heart

  Heart development relies on a topologically defined interplay between diverse cardiac cells. We finely curated spatial and single-cell measurements with high-resolution imaging-based transcriptomics validation to explore spatial dynamics during early human cardiogenesis. Analyzing almost 80,000 individual cells and 70,000 spatially barcoded tissue regions between the 5.5th and 14th postconceptional weeks, we identified 31 coarse- and 72 fine-grained cell states and mapped them to highly resolved cardiac cellular niches. We provide novel insight into the development of the cardiac pacemaker-conduction system, heart valves, and atrial septum, and decipher heterogeneity of the hitherto elusive cardiac fibroblast population. Furthermore, we describe the formation of the cardiac autonomic innervation and present the first spatial account of chromaffin cells in the fetal human heart. Our study, supported by an open-access, spatially centric interactive viewer, delineates the cellular and molecular architecture of the developing heart, offering links to genetic causes of heart disease.

  Study EGAS50000001122

• T cell receptor repertoire in cell-free DNA as a proxy for tumor infiltrates in patients treated with pembrolizumab

  Profiling tumour and systemic T-cell receptor (TCR) repertoires can identify features associated with clinical benefit of cancer patients on immune checkpoint blockade therapy. This study reports on diversity and specificity analysis of TCR sequences from 59 tumor, 306 peripheral blood (PBMC), and 73 cell-free DNA (cfDNA) samples from 81 patients with solid tumors treated with pembrolizumab. This analysis reveals that head and neck carcinomas have significantly lower PBMC diversity and shorter persistence of pembrolizumab-induced diversification compared to other cancers. Using GLIPHII (Grouping Lymphocyte Interactions with Paratope Hotspots), we find that tumor-derived clonotypes form non-microbial specificity signatures that are shared across patients and cancer types. Tumor-derived clonotypes are enriched in cfDNA compared to PBMCs, despite the diversity of cfDNA TCR repertories being two orders of magnitude lower than PBMCs. TCRs shared between tumors and cfDNAs persist in PBMCs beyond 50 weeks of treatment, suggesting cfDNA captures clonotypes contributing to anti-tumor immune surveillance.

  Study EGAS50000001306

• ucfDNA workflows for molecular profiling of malignant disease

  Urinary cell-free DNA (ucfDNA) is a promising liquid biopsy analyte obtained by a non-invasive sampling method, particularly valuable in urological cancers due to the proximity of biofluids to the tumor site. However, extremely high fragmentation and low abundance of ucfDNA pose significant analytical challenges. Improper handling and storage can severely affect ucfDNA quality, necessitating optimized pre-analytical workflows for clinical applications. We evaluated multiple pre-analytical workflows, including urine stabilization approaches against unstabilized urine samples. Our results demonstrated that without stabilization, ucfDNA degraded rapidly and minimal quantities remaining after 72 hours. In contrast, urine stabilization preserved ucfDNA integrity, enabling successful downstream analyses, including digital PCR and next-generation sequencing, for mutation detection in cancer-related genes and genome wide copy number profiling. These findings underscore the critical role of stabilization for a reliable ucfDNA analysis and highlight its potential in molecular diagnostics as a complementary tool to plasma-based liquid biopsies.

  Study EGAS50000001093

• Liquid Biopsy Detection of Tumor-specific Structural Variants in High Grade Serous Ovarian Cancer

  WGS Liquid Biopsy. Recurrence is frequent for most patients with high grade serous ovarian cancer (HGSOC), even after effective chemotherapy induced remission. However, after achievement of complete clinical response, the minimal residual disease is often insufficient for genomic analysis. Therefore, methods to interrogate the clonal composition and molecular properties of minimal residual disease are needed to better understand the mechanisms of HGSOC relapse. To address this unmet need, we developed and validated a novel cfDNA-based approach for tracking disease burden using NGS-informed tumor specific structural variants (SVs). Methods: The optimization of the methodology was first performed using synthetic cfDNA generated by ultrasonication of gDNA from ovarian cancer cell lines. Following the optimized workflow, whole genome sequencing of multisite biopsies from pre-treatment HGSOC patients were performed and high confidence SVs were called by consensus of multiple published SV callers. Real-time PCR and digital droplet PCR (ddPCR) were used for assays development.

  Study EGAS50000001044

• Single cell RNA sequencing of human embryonic forebrain after slice culturing for between four weeks and one month

  With the aim of verifying normal tissue development in our Organotypic Timelapse recording with Transcriptomic Readout (OTTR) live tissue imaging method, we performed single cell RNA sequencing in organotypic slice cultures containing labelled cells from virally delivered ubiquitous Enhanced yellow fluorescent protein (EYFP)-expression. Human fetal cortices of PCW 7.5-10.5 were cut into strips along the dorso-ventral axis and directly placed en face, ventricular side down, on PTFE culturing membranes. To assess tissue health with our culturing method, we performed single cell RNA-seq analysis of the cortical explants (using adjacent slices from the same samples subjected to timelapse imaging). We cultured these control slices for four days in vitro (mimicking the start of a live imaging experiment after lentiviral infection and expression of EYFP), 11 days in vitro (corresponding to the end of one week of live imaging), and for two weeks and one month in vitro.

  Study EGAS50000001185

• Origination of Ovarian Cancer is Dependent on Specific Aneuploidy Landscape

  Ovarian high-grade serous carcinoma (HGSC), a highly chromosomally instable malignancy, develops through sequential stages of precursors in fallopian tubes including histologically unremarkable but TP53 mutated clones (p53 signature) and serous tubal intraepithelial carcinoma (STIC). Here, we applied RealSeqS to assess aneuploidy in 127 microdissected tubal regions. We found nearly all p53 signatures lost the entire Chr17 chromosome, offering a “two-hit” mechanism of both TP53 and BRCA1 in BRCA1 germline mutation carriers. Proliferatively active STICs harbor gains of 19q12 (CCNE1), 19q13.2, 8q24 (MYCyc), or 8q arm, while proliferatively dormant STICs show 22q loss. Based on aneuploidy patterns in a training set (n= 67), we developed an algorithm, REAL-FAST, to classify NFTE and STICs into 5 clusters. In an independent validation set (n= 72), REAL-FAST was able to detect STIC/HGSC with high sensitivity and specificity. Taken together, REAL-FAST promises a molecular test for diagnosing HGSC precursor lesions based on specific aneuploidy patterns.

  Study EGAS00001007220

• Exome sequencing in HIV+ Viremic Non-Progressors (VNPs) and HIV+ Progressors

  Viremic Non-Progressors (VNPs) maintain normal CD4+ T-cell counts despite uncontrolled HIV-1 replication, but mechanisms leading to CD4+ T-cell preservation are incompletely characterized. We aim to generate a comprehensive understanding of this infrequent phenotype by comparing rates of cellular infection, immunophenotype, genomics, single-cell transcriptomics, metabolomics, and levels of plasma biomarkers in 16 VNPs and 29 HIV+ Progressors. During chronic infection VNPs show lower frequency of HIV-1-infected cells in periphery, which is associated with reduced CCR5 expression and higher prevalence of CCR5Δ32 heterozygosity. The CD8+ T-cell compartment displays a less cytotoxic and less activated phenotype in VNPs. Moreover, despite similar viremia, we found lower bystander CD4+ T-cell death in the VNPs, together with weaker IFN responses, reduced plasma levels of zonulin (a biomarker of intestinal permeability), altered tryptophan catabolism, and preserved LPS responsiveness in vitro. Overall, a complex multifactorial mechanism, suggesting gut-associated lymphoid tissue preservation, underlies resistance to HIV pathogenesis in VNPs.

  Study EGAS50000000079

• Peripheral blood DNA methylation and transcriptomics of vedolizumab and ustekinumab treatment response in patients with Crohn's disease

  Biological therapeutics are now widely used in Crohn’s disease (CD), with evidence of efficacy from randomised trials and real-world experience. Primary non-response is a common, poorly understood problem. We assessed blood methylation as a predictor of response to vedolizumab (VDZ, anti-a4b7 integrin) or ustekinumab (USTE, anti-IL-12/23p40). We report a two-center, prospective cohort study in which we profiled the peripheral blood DNA methylome of adult male and female CD patients. Samples were obtained prior to and during treatment with VDZ or USTE in a discovery and a validation cohort. Response to VDZ or USTE was defined based on a combination of ≥50% reduction in the endoscopic SES-CD score, corticosteroid-free clinical remission (≥3 point drop in HBI or HBI ≤4 and no systemic steroids) and/or biochemical response (C-reactive protein (CRP) and fecal calprotectin (FCP) reduction ≥50% or ≤5 mg/L and fecal calprotectin ≤250 µg/g).

  Study EGAS50000000263

• Genome sequencing identifies splice-disrupting variants in childhood heart disease

  We used genome sequencing (GS) to identify cardiac specific splice disrupting variants that were subsequently validated in a subset of participants. In turn, we developed a heart-specific model for canonical and non-canonical splice variants, which was applied to patients with congenital heart disease (CHD). These included patients with two of the most common forms of cyanotic CHD i.e. tetralogy of Fallot (TOF) and dextro-transposition of the great arteries (TGA). In addition to identifying canonical splice-disrupting variants in known CHD-related genes in 1% cases, this approach identified putatively damaging non-canonical splice-disrupting variants in 11% of isolated CHD, with deeply intronic variants representing 53% of non-canonical splice-disrupting variants in CHD genes. GS was critical for the identification of variants that would not be captured by routine clinical genetic tests including exome sequencing, while cardiac RNA-Seq allowed for high specificity in the interpretation of splice-disrupting effects in the heart.

  Study EGAS50000000586

• Nivolumab plus chemotherapy or ipilimumab in gastroesophageal cancer: CheckMate 649 biomarker analyses

  First-line nivolumab-plus-chemotherapy demonstrated superior overall survival (OS) versus chemotherapy for advanced gastroesophageal adenocarcinoma (CheckMate 649). Nivolumab-plus-ipilimumab provided durable responses and higher survival rates versus chemotherapy; however, the prespecified OS significance boundary was not met. To identify biomarkers predictive of differential efficacy outcomes, exploratory analyses were performed using whole-exome sequencing and RNA sequencing. Nivolumab-based therapies demonstrated improved efficacy versus chemotherapy in hypermutated and, to a lesser degree, Epstein Bar Virus-positive tumors compared with chromosomally unstable and genomically stable tumors. Within the KRAS-altered subgroup, only patients treated with nivolumab-plus-chemotherapy demonstrated improved OS benefit versus chemotherapy. Low stroma gene expression signature scores were associated with OS benefit with nivolumab-based regimens; high regulatory T-cell signatures were associated with OS benefit only with nivolumab-plus-ipilimumab. Our analyses suggest that distinct and overlapping pathways contribute to the efficacy of nivolumab-based regimens in gastroesophageal adenocarcinoma.

  Study EGAS50000000747

• Improving CLL Vγ9Vδ2-T cell fitness for cellular therapy by ex vivo activation and ibrutinib

  We studied whether Vγ9Vδ2-T cells can exploited as autologous effector lymphocytes in chronic lymphocytic leukemia (CLL). Healthy controls (HC) Vγ9Vδ2-T cells were activated by and had potent cytolytic activity against CLL cells, however CLL-derived Vγ9Vδ2-T cells proved dysfunctional with respect to effector cytokine production and cytotxicity. Dysfunction of Vγ9Vδ2-T cells was reversible upon activation with autologous monocyte-derived dendritic cells (mODCs). RNA sequencing confirmed that Vγ9Vδ2-T cells from CLL patients have a transcriptional profile that is distinct from HC Vγ9Vδ2-T cells prior to ex vivo expansion, although the profile after ex vivo expansion is similar between CLL and HC Vγ9Vδ2-T cells. Gene expression profiling implicated alterations in both synapse formation and exhaustion as conceivable contributors to compromised Vγ9Vδ2-T cell function in CLL patients. Taken together, CLL-mediated dysfunction of autologous Vγ9Vδ2-T cells is fully reversible, resulting in potent cytotoxicity towards CLL cells.

  Study EGAS00001003193

• Transcriptional and functional profiling defines human small intestinal macrophage subsets

  Macrophages (Mf) are instrumental in maintaining immune homeostasis in the intestine, yet studies on origin and heterogeneity of human intestinal Mf are scarce. Here, we identified four distinct Mf subpopulations in human small intestine (SI). Assessment of their turnover in duodenal transplants revealed that all Mf subsets were completely replaced over time; Mf1 and Mf2, phenotypically similar to peripheral blood monocytes (PBMo), were largely replaced within 3 weeks, whereas two subsets with features of mature Mf, Mf3 and Mf4, exhibited significantly slower replacement. Mf3 and Mf4 localized differently in SI; Mf3 formed a dense network in mucosal lamina propria, whereas Mf4 was enriched in submucosa. Transcriptomic analysis showed that all Mf subpopulations subsets were markedly distinct from PBMo and dendritic cells (DC). Compared to PBMo, Mf subpopulations showed reduced responsiveness to proinflammatory stimuli, but were proficient at endocytosis of particulate and soluble material. These data provide a comprehensive analysis of human SI Mf population and suggest a precursor-progeny relationship with PBMo.

  Study EGAS00001002093

• Dual targeting of polyamine synthesis and uptake in diffuse intrinsic pontine gliomas

  Diffuse intrinsic pontine glioma (DIPG) is an incurable malignant childhood brain tumour, with no active systemic therapies and a 5-year survival of less than 1%. Polyamines are small organic polycations that are essential for DNA replication, translation and cell proliferation. Ornithine decarboxylase 1 (ODC1), the rate limiting enzyme in polyamine synthesis, is irreversibly inhibited by difluoromethylornithine (DFMO). Herein we show that polyamine synthesis is upregulated in DIPG, leading to sensitivity to DFMO. DIPG cells compensate for ODC1 inhibition by upregulation of the polyamine transporter SLC3A2. Treatment with the polyamine transporter inhibitor AMXT 1501 reduced uptake of polyamines in DIPG cells, and co-administration of AMXT 1501 and DFMO led to potent in vitro activity, and significant extension of survival in three aggressive DIPG orthotopic animal models. Collectively, these results demonstrate the potential of dual targeting of polyamine synthesis and uptake as a therapeutic strategy for incurable DIPG.

  Study EGAS00001004905

• Human islet 3D chromatin maps provide insights into type 2 diabetes

  The transcriptional output of each cell type is controlled by thousands of enhancers, many of which contain genetic risk variants for common diseases such as type 2 diabetes (T2D). To gain insight into how enhancer variation influences diabetes risk, we created promoter capture Hi-C maps in human pancreatic islets. This linked diabetes-associated islet enhancers with their target genes, often located hundreds of kilobases away. We identified hubs that show spatial and functional connections between enhancersand target genes related to islet function and diabetes. We demonstrate that genetic variants distributed across hub enhancers have a major impact on T2D heritability, and use this knowledge to identify individuals in whom islet regulatory variation has a prominent role in T2D risk. Our results demonstrate the importance of 3D chromatin architecture for molecular interpretation of T2D genetic association signals, and define genomic spaces that harbor a distinct component of the T2D polygenic burden.

  Study EGAS00001002917

• Whole genome sequencing data for 10 hepatocellular carcinomas (HCC) and matched non-tumor liver tissues + optical mapping data for 4 HCC and 3 matched non-tumor liver tissues.

  Oncogene activation leads to replication stress and promotes genomic instability. Here we combine optical mapping and whole genome sequencing to explore in-depth the nature of structural variants (SVs) induced by replication stress in cyclin-activated hepatocellular carcinomas (CCN-HCC). In addition to classical tandem duplications, CCN-HCC display frequent intra- and inter-chromosomal templated insertion cycles (TIC) likely resulting from template switching events. Template switching preferentially involves active topologically associated domains that are close in the 3D genome organization. Template sizes depend on the type of cyclin activation and are coordinated within each TIC. Replication stress induces continuous accumulation of SVs during CCN-HCC progression, fostering the acquisition of new driver alterations and large-scale copy-number changes at TIC borders. Together, this analysis sheds light on the mechanisms, dynamics and consequences of SV accumulation in tumors with oncogene-induced replication stress.

  Study EGAS00001005629