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• Multiomics characterisation of the response to stimulation in Long Covid patients

  We generated 10X, droplet-based paired snRNAseq+snATACseq (Multiome) of the response to P. Aeruginosa or RPMI in patients suffering from Long Covid. In total, we included 15 patients. Single nuclei libraries are genetically multiplexed across donors, genotype files are available to enable demultiplexing. Phenotype sheets provide information of pools/donors as well as donor phenotype.

  Dataset EGAD50000000203

• RNA-Seq of GM adipose tissue samples

  This dataset contains 210 fastq files (RNA sequencing was performed in two centers) from 105 individuals (106 files in subcutaneous tissue and 104 files in visceral tissue). Of the 210 fastq files, 129 files are in PEx100 mode (appeared in a single fastq file) and 81 files are in PEx49bp mode (appeared in two separate fastq files). Sequencing was done on the Illumina HiSeq2000 platform.

  Dataset EGAD00001010253

• Single-Cell Analysis of Somatic Mutations in Human Bronchial Epithelial Cells in Relation to Aging and Smoking

  While lung cancer risk among smokers is dependent on smoking dose, it remains unknown if this increased risk reflects an increased rate of somatic mutation accumulation in normal lung cells. Here we applied single-cell whole genome sequencing of proximal bronchial basal cells from 33 subjects, aged between 11 and 86 years, with smoking histories varying from never smoking to 116 pack years. We found an increase in the frequency of single-nucleotide variants and small insertions and deletions with chronological age in never-smokers, with mutation frequencies significantly elevated among smokers. However, when plotted against smoking pack-years, mutations were found to follow the linear increase in cancer risk only until about 23 pack years, after which no further increase in mutation frequency was observed, pointing towards individual selection for mutation avoidance. Known lung cancer-defined global mutation signatures tracked with both age and smoking. Within study power limits, no significant enrichment for somatic mutations in lung cancer driver genes was observed.

  Study phs002758

• 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

• Successful immune checkpoint blockade in a patient with advanced stage microsatellite unstable biliary tract cancer (H021)

  Cancers acquire multiple somatic mutations that can lead to the generation of immunogenic mutation-induced neoantigens. These neoantigens can be recognized by the host’s immune system. However, continuous stimulation of immune cells against tumor antigens can lead to immune cell exhaustion, which allows uncontrolled outgrowth of tumor cells. Recently, immune checkpoint inhibitors have emerged as a novel approach to overcome immune cell exhaustion and re-activate anti-tumor immune responses. In particular, antibodies blocking the exhaustion-mediating programmed death receptor (PD-1)/PD-L1 pathway have shown clinical efficacy. The effects were particularly pronounced in tumors with DNA mismatch repair deficiency and a high mutational load, which typically occur in the colon and endometrium. Here, we report on a 24-year old woman diagnosed with extrahepatic cholangiocarcinoma who showed strong and durable response to the immune checkpoint inhibitor pembrolizumab, although treatment was initiated at an advanced stage of disease. The patient’s tumor displayed DNA mismatch repair deficiency and microsatellite instability (MSI), but lacked other features commonly discussed as predictors of response towards checkpoint blockade, such as PD-L1 expression or dense infiltration with cytotoxic T cells. Notably, high levels of HLA class I and II antigen expression were detected in the tumor, suggesting a potential causal relation between functionality of the tumor’s antigen presentation machinery and the success of immune checkpoint blockade. We suggest determining MSI status in combination with HLA class I and II antigen expression in tumors potentially eligible for immune checkpoint blockade even in the absence of conventional markers predictive for anti-PD-1/PD-L1 therapy and in entities not commonly linked to MSI phenotype. Further studies are required to determine the value of these markers for predicting the success of immune checkpoint blockade. (H021)

  Study EGAS00001002441

• 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

• MutWP5: CRUK Mutographs of Cancer: Breast: Reduction Mammoplasty (Exome)

  Sequencing of LCM-derived microbiopsies from 10 women who underwent reduction mammoplasty. Goal to assess the mutational burden, spectrum, and clonal dynamics within the tissue. Exome data will be used as a driver and clonality screen, highly clonal or driver-containing samples will subsequently be sent for whole-genome sequencing. Results from this portion of the study will be compared to women who are BRCA1/2 germline carriers and those with cancer. . This dataset contains all the data available for this study on 2023-03-08.

  Dataset EGAD00001010110

• MutWP5: CRUK Mutographs of Cancer: Breast: Reduction Mammoplasty (WG)(Novaseq)

  Sequencing of LCM-derived microbiopsies from 10 women who underwent reduction mammoplasty. Goal to assess the mutational burden, spectrum, and clonal dynamics within the tissue. Exome data will be used as a driver and clonality screen, highly clonal or driver-containing samples will subsequenctly be sent for whole-genome sequencing. Results from this poriton of the study will be compared to women who are BRCA1/2 germline carriers and those with cancer. . This dataset contains all the data available for this study on 2023-03-08.

  Dataset EGAD00001010113

• MutWP5: CRUK Mutographs of Cancer: Breast: Reduction Mammoplasty (Exome)(Novaseq)

  Sequencing of LCM-derived microbiopsies from 10 women who underwent reduction mammoplasty. Goal to assess the mutational burden, spectrum, and clonal dynamics within the tissue. Exome data will be used as a driver and clonality screen, highly clonal or driver-containing samples will subsequenctly be sent for whole-genome sequencing. Results from this poriton of the study will be compared to women who are BRCA1/2 germline carriers and those with cancer. . This dataset contains all the data available for this study on 2023-03-08.

  Dataset EGAD00001010116

• Whole_exome_sequencing_of_rare_autoimmune_related_phenotypes

  We aim to whole-exome sequence DNA samples from 75 individuals with severe forms of Inflammatory Bowel Disease and related autoimmune diseases to identify the rare, highly penetrant, variants that we believe underlie these phenotypes. Case samples will be obtained from both new and existing (UK IBD Genetics Consortium) collaborators to ensure only the most extreme cases are sequenced.

  Study EGAS00001000228