3994 results for "*geneti*"

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• Comprehensive epigenomic profiling reveals the extent of disease-specific chromatin states and informs drug target discovery in ankylosing spondylitis

  Ankylosing spondylitis (AS) is a common, highly heritable inflammatory arthritis characterised by enthesitis of the spine and sacroiliac joints. Genome-wide association studies have revealed >100 genetic associations but their functional effects remain largely unresolved. Here, we present a comprehensive transcriptomic and epigenomic map of disease-relevant blood immune cell subsets from AS patients and healthy controls. We report differential disease signatures for specific genomic regions from individual -omic modalities and multi-omic integration, showing enrichment at genetically associated loci and evidence for altered monocyte function in AS. We link putative functional SNPs with cognate genes using high-resolution Capture-C at 10 loci, including PTGER4 and ETS1. We also show how disease-specific functional genomic data can be integrated with GWAS evidence to enhance therapeutic target discovery. This study combines multiple epigenetic and transcriptional analysis with GWAS to identify cell types, candidate drug target genes and transcriptional regulation of likely pathogenic relevance.

  Study EGAS00001006233

• Human genome-wide variations in the Massim region

  The Massim, a cultural region encompassing the southeastern tip of mainland Papua New Guinea (PNG) and nearby islands, is famous for the Kula trading network, in which different valuables circulate in different directions among the islands. To explore Massim genetic history, we generated genome-wide data from across the region and found variable levels of Papuan-related (indigenous) ancestry, including a novel ancestry associated with Rossel Island, and Austronesian-related ancestry that arrived later. We find genetic evidence for different patterns of contact across PNG, the Massim, and the Bismarck and Solomon Archipelagoes for Austronesian-related vs. Papuan-related ancestry, with more geographic restriction for the latter. Moreover, Kula-practicing groups share more genetic similarity than do other groups, and this likely predates the origin of Kula, suggesting that high between-group contact facilitated the formation of Kula. Our study provides the first comprehensive genome-wide assessment of Massim inhabitants and new insights into the fascinating Kula system.

  Study EGAS00001006010

• Drug-induced epigenomic plasticity reprograms circadian rhythm regulation to drive prostate cancer towards androgen-independence (ChIP-seq)

  Understanding how prostate cancer cells adapt to AR-targeted interventions is critical for identifying novel drug targets to improve the clinical management of treatment-resistant disease. Our study revealed an enzalutamide-induced epigenetic plasticity towards pro-survival signaling, and uncovered circadian regulator ARNTL as an acquired vulnerability after AR inhibition, presenting a novel clinical lead for therapeutic development.

  Study EGAS00001006017

• EXCEED Study

  EXCEED is a longitudinal population-based cohort which facilitates investigation of genetic, environmental and lifestyle-related determinants of a broad range of diseases and of multiple morbidity through data collected at baseline and via electronic healthcare record linkage. Recruitment has taken place in Leicester, Leicestershire and Rutland since 2013 and is ongoing, with approximately 10,000 participants aged 30-69 to date. The population of Leicester is diverse and additional recruitment from the local South Asian community is ongoing.

  Study EGAS00001003499

• Genetic regulation of gene expression in human brain cell types

  We leveraged single nuclei RNA-seq from 192 human brain samples to map cis-eQTLs in 8 brain cell types. We found extensive cell-type specific genetic effect on gene expression and integrated our results with GWAS to identify putative novel risk genes for brain disorders and the cell types in which the disease mechanisms are likely active.

  Study EGAS00001006345

• Conserved features of TERT promoter duplications reveal an activation mechanism that mimics hotspot mutations in cancer

  Mutations in the TERT promoter are the single most common non-coding mutation in cancer and represent the genetic underpinnings of tumor cell immortality. Beyond the two most common point mutations, G228A and G250A, which selectively recruit the ETS factor GABP to activate TERT, the significance of other variants in the TERT promoter are unknown. We identified duplications of wildtype sequence within the core promoter region of TERT in 7 different cancer types that have strikingly similar features including size, insertion position, and inclusion of one of the native ETS motifs. Each duplication activates the TERT promoter to a similar level as G228A and G250A and is critically dependent on the insertion site. The GABP tetramer binds to the TERT duplicated promoter sequence by virtue of the native ETS motif and its duplicated version with precise spacing, and it is necessary for the transcriptional activation by all duplications tested. Spatiotemporal analysis in a multifocal glioblastoma shows the duplication is clonal and its activation of TERT is readily detectable at the single cell level and in bulk tumor tissue. We conclude that recurrent TERT promoter duplications of the native ETS sequence are functionally and mechanistically equivalent to the hotspot mutations that confer tumor cell immortality. The shared mechanism of these divergent somatic genetic alterations suggests a strong selective pressure for recruitment of the GABP tetramer to activate TERT.

  Study EGAS00001006118

• Genetic immune escape landscape in primary and metastatic cancer

  Immune surveillance escape is a hallmark of tumorigenesis1. Multiple studies have characterized the immune escape landscape across several untreated early-stage primary cancer types2–4. However, whether late-stage treated metastatic tumors present differences in genetic immune escape (GIE) prevalence and dynamics remains unclear. Here, we performed a pan-cancer characterization of GIE prevalence across six immune escape pathways in 6,457 uniformly processed Whole Genome Sequencing (WGS) tumor samples including 58 cancer types from 1,943 primary untreated patients and 4,514 metastatic patients. To effectively address the complexity of the Human Leukocyte Antigen (HLA-I) locus and to characterize its tumor status, we developed LILAC, an open-source integrative framework. We demonstrate that one in four tumors harbor GIE alterations, with high mechanistic and frequency variability across cancer types. GIE prevalence is highly consistent between primary and metastatic tumors for most cancer types with few exceptions such as prostate and thyroid carcinomas that have increased immune evasion frequencies in metastatic tumors. Positive selection analysis revealed that GIE alterations are frequently selected for in tumor evolution and that focal LOH of HLA-I, unlike non-focal LOH of HLA-I, tends to lose the HLA allele that presents the largest neoepitope repertoire. We also unraveled tumor genomic features contributing to immune escape incidence, including DNA repair deficiency, APOBEC activity, tobacco associated mutation load and viral DNA integration. Finally, there is a strong tendency for mid and high tumor mutation burden (TMB) tumors to preferentially select LOH of HLA-I for GIE whereas hypermutated samples favor global immune evasion strategies. Our results indicate that genetic immune escape is generally a pre-metastatic event during tumor evolution and that tumors adapt different strategies depending on their neoepitope burden.

  Study EGAS00001006123

• MutWP4__CRUK_Grand_Challenge_Mutographs_of_Cancer__Pancreatic_Organoids

  The Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Different patterns of somatic mutation are generated by the different environmental, lifestyle and genetic factors that cause cancer, many of them are still unknown. Within Mutographs, Kings College London will characterise the mutational signatures induced by putative human carcinogens in order to identify the origins of mutational signatures found in human cancers. To achieve this human organoid cell cultures will be exposed to a representative catalogue of known or suspected human carcinogens and mutagens and, using whole genome sequencing, the patterns of mutations induced by them will be determined. Somatic mutational signatures will be subsequently extracted by non-negative matrix factorisation methods and correlated with exposure data. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development.

  Study EGAS00001003520

• Loss of Epigenetic Barrier is Required for Enhancer Hijacking-Mediated Oncogenic Transcription

  Structural variants (SVs) involving enhancer hijacking can disrupt chromatin topologies to cause oncogene activation in cancer genomes, yet the molecular determinants for the transcriptional output of enhancer hijacking remain largely unknown. We developed a multimodal approach to integrate genome sequencing, chromosome conformation, and sequence-based deep learning for quantitative analysis of transcriptional effects and structural reorganization imposed by SVs in leukemic genomes. We identified candidate pathogenic SVs including recurrent t(5;14) translocations that cause the hijacking of BCL11B enhancers for oncogenic activation of TLX3-dependent transcriptional programs. By engineering patient-associated t(5;14) in isogenic leukemia cells, we uncovered an uncharacterized mechanism whereby DNA methylation serves as an epigenetic barrier to enhancer hijacking and loss of epigenetic barrier is a molecular determinant for the transcriptional output of pathogenic SVs. Hence, leveraging the epigenetic barriers of SV-mediated oncogenic programs may provide new opportunities to reprogram gene regulation as epigenetic therapies in human disease.

  Study EGAS00001006140

• Single cell multi-omic data of glioblastoma evolution under therapy

  We report a single-cell multi-omics atlas of GBM longitudinal specimens that represents decades of biobanking. We identify novel cell-intrinsic and cell-extrinsic targets for therapy development which we validate in situ and in low-passage patient-derived cell lines. We identify novel genetic correlates of the mesenchymal cellular phenotype. These studies integrate disparate findings in the literature around hypermutation status and immunogenicity as well as the source of the mesenchymal shift at recurrence.

  Study EGAS00001004909

• DNA methylation-based prognostic subtypes of chordoma tumors in tissue

  Chordomas are rare malignant bone cancers of the skull-base and spine. Patient survival is variable and not reliably predicted using clinical factors or molecular features. This study identifies prognostic epigenetic chordoma subtypes that are detected noninvasively using plasma methylomes. Methylation profiles of 68 chordoma surgical samples were obtained between 1996 and 2018 across three international centers along with matched plasma methylomes where available. Consensus clustering identified two stable tissue clusters with a disease-specific survival difference that was independent of clinical factors in a multivariate Cox analysis (HR = 14.2, 95%CI: 2.1–94.8, P = 0.0063). Immune-related pathways with genes hypomethylated at promoters and increased immune cell abundance were observed in the poorperforming “Immune-infiltrated” subtype. Cell-to-cell interaction plus extracellular matrix pathway hypomethylation and higher tumor purity were observed in the better-performing “Cellular” subtype. The findings were validated in additional DNA methylation and RNA sequencing datasets as well as with immunohistochemical staining. Plasma methylomes distinguished chordomas from other clinical differential diagnoses by applying fifty chordoma-versusother binomial generalized linear models in random 20% testing sets (mean AUROC = 0.84, 95%CI: 0.52–1.00). Tissue-based and plasma-based methylation signals were highly correlated in both prognostic clusters. Additionally, leave-one-out models accurately classified all tumors into their correct cluster based on plasma methylation data. Here, we show the first identification of prognostic epigenetic chordoma subtypes and first use of plasma methylome based biomarkers to noninvasively diagnose and subtype chordomas. These results may transform patient management by allowing treatment aggressiveness to be balanced with patient risk according to prognosis.

  Study EGAS00001006406

• Mapping genetic effects on cell type-specific chromatin accessibility using single nucleus ATAC-seq

  Gene regulation is highly cell type-specific and understanding the function of non-coding genetic variants associated with complex traits requires molecular phenotyping at cell type resolution. In this study we performed single nucleus ATAC-seq (snATAC-seq) and genotyping in peripheral blood mononuclear cells from 13 individuals. We mapped chromatin accessibility QTLs (caQTLs) in each immune cell type and sub-type in a subset of 10 samples of European genetic ancestry.

  Study EGAS00001006184

• Atypical teratoid/rhabdoid tumoroids reveal subgroup-specific drug vulnerabilities

  Atypical teratoid/rhabdoid tumors (ATRTs) represent a rare, but aggressive pediatric brain tumor entity. They are genetically defined by mutations in SWI/SNF chromatin remodeling complex members SMARCB1 or SMARCA4. ATRTs can be subdivided in different molecular subgroups based on their epigenetic profiles. Although recent studies suggest that the different subgroups have distinct clinical features, subgroup-specific treatment regimens have not been developed thus far. This is hampered by the lack of pre-clinical in vitro models representative of the different molecular subgroups. Here, we describe the establishment of ATRT tumoroid models from the ATRT-MYC and ATRT-SHH subgroups. We demonstrate that ATRT tumoroids retain subtype-specific epigenetic and gene expression profiles. High throughput drug screens on our ATRT tumoroids revealed distinct drug sensitivities between and within ATRT subgroups. Our ATRT tumoroids represent the first pediatric brain tumor organoid model, providing representative pre-clinical models allowing for the development of subtype-specific therapies.

  Study EGAS00001006422

• MutWP5__CRUK_Mutographs_of_Cancer__Cancer_Mastectomy__Exome__Novaseq_

  Cancer is a genetic disease caused by an accumulation of mutations, however many of these mutations have been identified in pathologically normal tissue. We aim to use laser-capture microscopy (LCM) to sample individual clones from breast tissue to identify whether cancer-associated mutations appear in this normal tissue, assess the mutational burden present, and identify the mutational processes causing these mutations. We will sample from a wide age range of individuals (<20 to >60 years old) to determine whether these processes differ in pre- and post-menopausal women. We will also be comparing the tissue from healthy individuals (samples from breast reduction surgery) to those at elevated risk of breast cancer (mastectomy from BRCA1/2 patients) and those who have breast cancer (adjacent normal, distal normal, and tumour tissue from mastectomy). This will allow us to determine how these processes are different between these groups of individuals, and gain insight into the earliest stages of tumor development.

  Study EGAS00001003528

• Long-term temporal stability of peripheral blood DNA methylation alterations in patients with inflammatory bowel disease.

  Introduction There is great current interest in the potential application of DNA methylation alterations in peripheral blood as biomarkers of susceptibility, progression, and treatment response in inflammatory bowel disease (IBD). To date, the intra-individual stability of peripheral blood leukocyte (PBL) methylation in IBD patients, a key consideration in biomarker development, has not been characterised. Here, we studied the long-term stability of all probes located on the Illumina HumanMethylation EPIC BeadChip array. Methods We followed a cohort of 46 adult IBD patients (36 Crohn’s disease (CD), 10 ulcerative colitis (UC), median age 44 (IQR: 27-56), 50% female) that received standard care without any intervention at the Amsterdam UMC. Paired PBL samples were collected at two time points with a median 7 (range: 2-9) years in between. Differential methylation and intra-class correlation (ICC) analyses were used to identify time-associated differences and temporally stable CpGs, respectively. Results Around 60% of all CpG loci on the EPIC array presented poor (ICC <0.50); 119,388 (≈14%) and 41,274 (≈5%) showed good (ICC ≥0.75) or excellent (ICC ≥0.90) intra-individual stability. Functional over-representation analyses of the stable methylated CpGs implicated genes involved in cell-cell signaling, adhesion and neurogenesis. Focusing on previously identified consistently differentially methylated positions indicated that 22 CD-, 11 UC-, and 24 IBD-associated loci demonstrated good stability (ICC ≥0.75) over time, where we observed a marked stability of CpG loci associated to the HLA genes. Conclusion Our data provide insight into the long-term stability of the PBL DNA methylome within an IBD context, facilitating the selection of biologically relevant and robust IBD-associated epigenetic biomarkers with increased potential for independent validation.

  Study EGAS00001006501

• MutWP1__CRUK_Grand_Challenge_Mutographs_of_Cancer__clear_cell_renal_cell_carcinoma___2

  The Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Different patterns of somatic mutation are generated by the different environmental, lifestyle and genetic factors that cause cancer, many of them are still unknown. Within Mutographs, the International Agency for Research on Cancer is coordinating the recruitment of 5000 individuals with cancer (colorectal, renal, pancreatic, oesophageal adenocarcinoma or oesophageal squamous cancers) across 5 continents to explore whether different mutational signatures explain marked variation in incidence. In brief, through an international network of collaborators around the world, biological materials are collected, along with demographic, histological, clinical and questionnaire data. Whole genome sequences of tumour-germline DNA pairs are generated at the Wellcome Trust Sanger Institute. Somatic mutational signatures are subsequently extracted by non-negative matrix factorisation methods and correlated with risk factors data. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development.

  Study EGAS00001003542

• Rare coding variants in lupus risk genes

  Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease. It is thought that many common variant gene loci of weak effect act additively to predispose to common autoimmune diseases, while the contribution of rare variants remains unclear. Here we describe that rare coding variants in lupus-risk genes are present in most SLE patients and healthy controls. We demonstrate the functional consequences of rare and low frequency missense variants in the interacting proteins BLK and BANK1, which are present alone, or in combination, in a substantial proportion of lupus patients. The rare variants found in patients, but not those found exclusively in controls, impair suppression of IRF5 and type-I IFN in human B cell lines and increase pathogenic lymphocytes in lupus-prone mice. Thus, rare gene variants are common in SLE and likely contribute to genetic risk.

  Study EGAS00001003548

• Genetic and epigenetic variation at regulatory regions contribute to cancer evolution under endocrine treatment

  Comprehensive profiling of hormone-dependent breast cancer (HDBC) has identified hundreds of protein-coding alterations contributing to cancer initiation, but only a handful have been linked to endocrine therapy resistance, potentially contributing to 40% of relapses. If other mechanisms underlie the evolution of HDBC under adjuvant therapy is currently unknown. In this work, we employ integrative functional genomics to dissect the contribution of cis-regulatory elements (CREs) to cancer evolution by focusing on 12 megabases of non-coding DNA, including clonal enhancers, gene promoters, and boundaries of topologically associating domains. Massive parallel perturbation in vitro reveals context-dependent roles for many of these CREs, with a specific impact on dormancy entrance and endocrine therapy resistance9. Profiling of CRE somatic alterations in a unique, longitudinal cohort of patients treated with endocrine therapies identifies non-coding changes involved in therapy resistance. Overall, our data uncover actionable transient transcriptional programs critical for dormant persister cells and unveil new regulatory nodes driving evolutionary trajectories towards disease progression.

  Study EGAS00001006340

• Insights from genome-wide data from Thailand and Laos

  We provide the first detailed insights into the genetic profiles of Thai/Lao ethnolinguistic groups, which should be helpful for reconstructing human genetic history in MSEA and selecting populations for participation in ongoing whole genome sequence and biomedical studies

  Study EGAS00001006053

• Presence of rare potential pathogenic variants in subjects under 65 years old with very severe or fatal COVID‑19

  Rare variants affecting host defense against pathogens could be involved in COVID‑19 severity and may help explain fatal outcomes in young and middle‑aged patients. Our aim was to report the presence of rare genetic variants in certain genes, by using whole exome sequencing, in a selected group of COVID‑19 patients under 65 years who required intubation or resulting in death (n = 44). To this end, different etiopathogenic mechanisms were explored using gene prioritization‑based analysis in which genes involved in immune response, immunodeficiencies or blood coagulation were studied. We detected 44 different variants of interest, in 29 different patients (66%). Some of these variants were previously described as pathogenic and were located in genes mainly involved in immune response. A network analysis, including the 42 genes with candidate variants, showed three main components, consisting of 25 highly interconnected genes related to immune response and two additional networks composed by genes enriched in carbohydrate metabolism and in DNA metabolism and repair processes. In conclusion, we have detected candidate variants that may potentially influence COVID‑19 outcome in our cohort of patients. Further studies are needed to confirm the ultimate role of the genetic variants described in the present study on COVID‑19 severity.

  Study EGAS00001006372

• Bulk-tissue RNA-sequencing paired nuclear and cytoplasmic fractions of anterior prefrontal cortex, cerebellar cortex and putamen tissues from post-mortem neuropathologically-confirmed control individuals.

  Gaining insight into the genetic regulation of gene expression in human brain is key to the interpretation of genome-wide association studies for major neurological and neuropsychiatric diseases. Expression quantitative trait loci (eQTL) analyses have largely been used to achieve this, providing valuable insights into the genetic regulation of steady-state RNA in human brain, but not distinguishing between molecular processes regulating transcription and stability. RNA quantification within cellular fractions can disentangle these processes in cell types and tissues which are challenging to model in vitro. We investigated the underlying molecular processes driving the genetic regulation of gene expression specific to a cellular fraction using allele-specific expression (ASE). Applying ASE analysis to genomic and transcriptomic data from paired nuclear and cytoplasmic fractions of anterior prefrontal cortex, cerebellar cortex and putamen tissues from 4 post-mortem neuropathologically-confirmed control human brains, we demonstrate that a significant proportion of genetic regulation of gene expression occurs post-transcriptionally in the cytoplasm, with genes undergoing this form of regulation more likely to be synaptic. These findings have implications for understanding the structure of gene expression regulation in human brain, and importantly the interpretation of rapidly growing single-nucleus brain RNA-sequencing and eQTL datasets, where cytoplasm-specific regulatory events could be missed.

  Study EGAS00001006380

• Genetic Alterations in Benign Breast Biopsies of Subsequent Breast Cancer Patients

  Fibrocystic changes are associated with an increased risk of breast cancer (approximately 1.5-2 times that of the general population). Although the relative risk seems low, because of the high frequency of such changes, the absolute risk is significant. Genetic alterations have been found in fibrocystic changes with or without epithelial changes, suggesting that critical oncogenic events are occurring at an early stage. We investigated a unique collective of 17 breast cancer patients who, prior to the diagnosis of invasive breast cancer, underwent open surgical biopsy showing fibrocystic changes of the breast. Massive parallel sequencing targeting genes frequently mutated in breast cancer was performed on the fibrocystic breast tissue as well as the ensuing cancer tissue.

  Study EGAS00001003563

• Disease and phenotype relevant genetic variants identified from histone acetylomes in human hearts

  Identifying genetic markers for heterogeneous complex diseases such as heart failure has been challenging, and may require prohibitively large cohort sizes in genome-wide association studies (GWAS) in order to demonstrate statistical significance1. On the other hand, chromatin quantitative trait loci (QTL), elucidated by direct epigenetic profiling of specific human tissues, may contribute towards prioritising variants for disease-association. Here, we captured non-coding genetic variants by performing enhancer H3K27ac ChIP-seq in 70 human control and end-stage failing hearts, mapping out a comprehensive catalogue of 47,321 putative human heart enhancers. 3,897 differential acetylation peaks (FDR < 0.05) pointed to recognizable pathways altered in heart failure (HF). To identify cardiac histone acetylation QTLs (haQTLs), we regressed out confounding factors including HF disease status, and employed the G-SCI test2 to call out 1,680 haQTLs (FDR < 0.1). A subset of these showed significant association to gene expression, either in cis (180), or through long range interactions (81), identified by Hi-C and Hi-ChIP performed on a subset of hearts. Furthermore, a concordant relationship was found between the gain or disruption of specific transcription factor (TF) binding motifs, inferred from alternative alleles at the haQTLs, associated with altered H3K27ac peak heights. Finally, colocalisation of our haQTLs with heart-related GWAS datasets allowed us to identify 62 unique loci. Disease-association for these new loci may indeed be mediated through modification of H3K27-acetylation enrichment and their corresponding gene expression differences.

  Study EGAS00001003586

• A catalog of the genetic causes of Hereditary Angioedema in the Canary Islands (Spain)

  Hereditary angioedema (HAE) is a rare disease where known causes involve C1 inhibitor dysfunction or dysregulation of the kinin cascade. The updated HAE management guidelines recommend performing genetic tests to reach a precise diagnosis. Unfortunately, genetic tests are still uncommon in the diagnosis routine. Here, we characterized for the first time the genetic causes of HAE in affected families from the Canary Islands (Spain). Whole-exome sequencing data was obtained from 41 affected patients and unaffected relatives from 29 unrelated families identified in the archipelago. The Hereditary Angioedema Database Annotation (HADA) tool was used for pathogenicity classification and causal variant prioritization among the genes known to cause HAE. Manual reclassification of prioritized variants was used in those families lacking known causal variants. We detected a total of eight different variants causing HAE in this patient series, affecting essentially SERPING1 and F12 genes, one of them being a novel SERPING1 variant (c.686-12A>G) with a predicted splicing effect which was reclassified as likely pathogenic in one family. Altogether, the diagnostic yield by assessing previously reported causal genes and considering variant reclassifications according to the American College of Medical Genetics guidelines reached 66.7% (95% Confidence Interval [CI]: 30.1-91.0) in families with more than one affected member and 10.0% (95% CI: 1.8-33.1) among cases without family information for the disease. Despite the genetic causes of many patients remain to be identified, our results reinforce the need of genetic tests as first-tier diagnostic tool in this disease, as recommended by the international WAO/EAACI guidelines for the management of HAE.

  Study EGAS00001006547

• 5- FU treated organoids

  5-Fluorouracil (5-FU) is a chemotherapeutic drug component that is commonly used for the treatment of solid cancers. The anticancer properties of 5-FU have been attributed to interference with nucleotide synthesis and through direct incorporation into the DNA as being a pyrimidine analog. As both mechanisms of action may have a mutational impact on surviving tumor cells, we performed three independent analyses to characterize the genomic consequences of 5-FU treatment: i) in vitro treatment of intestinal organoids with 5-FU followed by whole genome sequencing, ii) genome-wide mutation analyses in tumor samples from 5-FU treated patients with breast or colorectal cancer, and iii) analysis of paired biopsies from patients treated with 5-FU between biopsies. Our results demonstrate that both in vitro and in vivo 5-FU causes a mutational pattern that is dominated by T>G substitutions in a CTT context and with strong resemblance to COSMIC signature 17. Interestingly, this signature is also found in non 5-FU treated patients, most prominently in esophageal tumors, indicating that distinct endogenous and exogenous triggers can converge into highly similar mutational signatures. Furthermore, our results suggest that 5-FU may have adverse mutagenic effects on healthy cells and contributes to genetic variability in surviving cancer cells thereby contributing to tumor evolution.

  Study EGAS00001003592