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• DERMATLAS__Tubular_adenoma_RNAseq

  IVirtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are tubular adenomas.

  Study EGAS00001006685

• Effective reprogramming of patient-derived M2-polarized glioblastoma-associated microglia/macrophages by treatment with GW2580

  Purpose: Targeting immunosuppressive and pro-tumorigenic glioblastoma-associated macrophages and microglial cells (GAMs) has great potential to improve patient outcomes. Colony stimulating factor-1 receptor (CSF1R) has emerged as a promising target for reprogramming anti-inflammatory M2-like GAMs. However, treatment data on patient-derived, tumor-educated GAMs and their influence on the adaptive immunity are lacking. Experimental Design: CD11b+-GAMs freshly isolated from patient tumors were treated with CSF1R-targeting drugs PLX3397, BLZ945, and GW2580. Phenotypical changes upon treatment were assessed using RNAseq. Changes in GAM activation were confirmed in a complex patient-derived 3D tumor organoid model serving as a tumor avatar. Results: The most effective reprogramming of GAMs was observed upon GW2580 treatment, which led to the downregulation of M2-related markers, IL-6, and IL-10, ERK1/2 and MAPK signaling pathways, while M1-like markers and gene set enrichment indicating activated MHC-II presentation were substantially increased. Moreover, treatment of patient-derived glioblastoma organoids with GW2580 confirmed successful reprogramming.

  Study EGAS00001007466

• DERMATLAS__Leiomyosarcoma_RNAseq

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are leiomyosarcomas.

  Study EGAS00001007631

• DERMATLAS__Leiomyoma_WES

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are leiomyomas.

  Study EGAS00001007629

• DERMATLAS__Leiomyoma_RNAseq

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are leiomyomas.

  Study EGAS00001007630

• Synthetic - FEGA Sweden Heilsa synthetic dataset December 2023

  Synthetic - This submission contains a subset of a synthetic dataset derived from the project Heilsa Tryggvedottir - a Nordic collaboration on sharing sensitive human data. Heilsa Tryggvedottir is funded by the Nordic e-Infrastructure Collaboration (NeIC), the ELIXIR nodes of Finland, Norway, and Sweden, Computerome in Denmark, and the Estonian Scientific Computing Infrastructure (ETAIS). In the synthetic data creation process, it was attempted to strike a fine balance between the usability of the datasets (e.g. technical FEGA development, testing, user training, and basic bioinformatics) and compliance with GDPR. File names and file content (e.g. headers in fastq) are anonymized. Moreover, the X, Y, and mitochondrial sequences have been discarded from the original data since these data can be used for maternal, paternal, or ethnic origin tracing. The dataset does not follow natural haplotype distribution (inherent to imputation panels). The only inputs derived from real sequence data are variant distribution density per chromosome and learning sequencing error models. The synthetic dataset consists of two fastq files, a cram file, a vcf file, and two index files.

  Study EGAS50000000086

• Hyperdiploidy impairs fetal hematopoietic progenitor cell fitness and differentiation enabling persistence of rare preleukemic aneuploid clones

  Cells previously cryopreserved in FBS-10%DMSO were thawed and resuspended in 1mL of cold lysis buffer (10 mM Tris-HCl pH 7.4, 154 mM NaCl, 0.2% BSA, 0.1% NP-40, 1 mM CaCl₂, 0.5 mM MgCl₂ in ultra-pure water) to lyse the cell membrane and release intact nuclei. The nuclei were stained with propidium iodide (10 µg/mL) and Hoechst 33258 (10µg/mL) to facilitate sorting based on cell cycle state and viability. Single nuclei from 48 cells per sample were isolated into 96-well plates containing 5µL of freeze buffer (1X PBS, 7.5% DMSO, and 40% ProFreeze freezing medium (Lonza)) using a MoFlo Astrios cell sorter (Beckman Coulter) at the Flow Cytometry Unit of the University Medical Center Groningen (UMCG), Netherlands. The plates were centrifuged at 500 g and stored at -80°C until library preparation. Single-nuclei libraries were prepared using a Bravo Automated Liquid Handling Platform (Agilent Technologies). Nuclei were lysed, and DNA was labelled with unique 10 bp dual barcodes and amplified as previously described. Sequencing was performed on an Illumina NextSeq 2000 platform with 77bp single end reads. The generated data were subsequently demultiplexed using sample-specific barcodes and converted to FASTQ files with bcl2fastq. Sequencing reads were aligned to the GRCh38/hg38 human reference genome using Bowtie2 (v2.2.4), and duplicate reads were marked with BamUtil (v1.0.3). Single-cell karyotypes were determined by performing copy number analysis using AneuFinder (v4.3.3) (https://github.com/ataudt/aneufinder). The analysis included GC-content correction and blacklisting of artifact regions identified from euploid controls. Copy number calling was conducted with the dnacopy and edivisive algorithms, employing a bin size of 1 Mb and a step size of 500 Kb. Libraries with an average of fewer than 10 reads per chromosome copy per bin or less than 95% concordance between the two algorithms were excluded from analysis. Whole-chromosome aneuploidies were identified when over 95% of bins exhibited deviation from the disomic state. Aneuploidy scores were calculated as weighted averages of absolute copy number deviations from the euploid state. 

  Dataset EGAD50000002314

• Endocrine therapy reprogramming of breast cancer facilitates metastatic escape via upregulation of P-Rex1/Rac1 signalling

  The estrogen receptor (ER) drives growth in ~70% of breast cancers, and endocrine therapies prevent recurrence. However, 30% of patients recur, with many fatal cases occurring late (after >5 years), presenting a challenge due to their often non-proliferative nature and limited options. To study this, we generated slow-growing resistant cells that form small primary tumours but readily metastasize. Single-cell RNA sequencing (scRNAseq) revealed that endocrine therapy reprograms these cells, notably upregulating the Rac1 signalling component P-Rex1. We found in clinical cohorts that P-Rex1 in high in ER+ breast cancer. Intravital imaging demonstrated that Rac1 signalling is active in ER+ cells following endocrine therapy. Targeting the Rac1 pathway with small molecule inhibitors (NSC23766, R-ketorolac) reduced survival and motility in resistant cells, inhibited in vivo Rac1 activity, and reduced tumour burden when combined with tamoxifen in a drug-refractory patient-derived xenograft. This work identifies the P-Rex1/Rac1 axis, as a potential therapeutic target for late recurring ER+ breast cancer.

  Study EGAS00001008353

• TGF-β attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells.

  We examined tumours from a large cohort of patients with metastatic urothelial bladder cancer (mUC) treated with an anti–PD-L1 agent (atezolizumab) and identified major determinants of clinical response and immune escape. Whole transcriptome profiles were generated for 368 patients using TruSeq RNA Access technology (Illumina). Somatic mutations were determined via whole exome sequencing for a subset of these patients. - Response was associated with CD8+ T effector cell phenotype and, to an even greater extent, high neoantigen or tumour mutation burden (TMB). On the other hand, lack of response was associated with a transforming growth factor β (TGF-β) signature, particularly in patients with CD8+ T cells preferentially residing in collagen-rich matrix surrounding tumours. Integration of these three independent biological features provided the best basis for understanding outcome in this setting. -

  Study EGAS00001002556

• WGS BAM files fromxa0Genomic Features and Classification of Homologous Recombination Deficient Pancreatic Ductal Adenocarcinoma

  Background and Aims: Homologous recombination deficiency (HRD) in pancreatic ductal adenocarcinoma (PDAC), remains poorly defined beyond germline(g) alterations in BRCA1, BRCA2 and PALB2. Methods: We interrogated whole genome sequencing (WGS) data on 391 patients including 49 carriers of pathogenic variants (PVs) in g_BRCA_ and PALB2. HRD classifiers were applied to the dataset and included: 1) the genomic instability score (GIS) used by Myriad MyChoice HRD assay; 2) substitution base signature 3 (SBS3); 3) HRDetect; and, 4) Structural Variant (SV) burden. Clinical outcomes and responses to chemotherapy were correlated with HRD status. Results: Biallelic tumour inactivation of g_BRCA_ or PALB2 was evident in 43/49 germline carriers identifying HRD-PDAC. HRDetect (score ?0.7) predicted gBRCA1/PALB2 deficiency with highest sensitivity (98%) and specificity (100%). HRD genomic tumour classifiers suggested that 7-10% of PDAC that do not harbor g_BRCA/PALB2_ have features of HRD. Of the somatic HRDetect cases, 69% were attributed to alterations in BRCA1/2, PALB2, RAD51C/D and XRCC2, and a tandem duplicator phenotype. TP53 loss was more common in BRCA1- compared to BRCA2-associated HRD-PDAC. HRD status was not prognostic in resected PDAC. However in advanced disease the GIS (p=0.02), SBS3 (p=0.03) and HRDetect score (p=0.005) were predictive of platinum response and superior survival. PVs in g_ATM_ (n=6) or g_CHEK2_ (n=2) did not result in HRD-PDAC by any of the classifiers. In four patients, BRCA2 reversion mutations associated with platinum resistance. Conclusions: Germline and parallel somatic profiling of PDAC outperforms germline testing alone in identifying HRD-PDAC. An additional 7-10% of patients without gBRCA/PALB2 mutations may benefit from DNA damage response agents.

  Dataset EGAD00001007571