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• RaScALL: Rapid screening of RNA-seq in acute lymphoblastic leukaemia

  RNA-sequencing (RNA-seq) efforts in acute lymphoblastic leukaemia (ALL) have identified numerous prognostically significant genomic alterations which can guide diagnostic risk stratification and treatment choices when detected early. However, a full RNA-seq Bioinformatics workflow is time-consuming and costly in a clinical setting where rapid detection and accurate reporting of clinically relevant alterations are essential. To accelerate the identification of ALL-specific alterations (including gene fusions, single nucleotide variants and focal gene deletions), we developed the rapid screening tool RaScALL, capable of identifying more than 100 prognostically significant lesions directly from raw sequencing reads. RaScALL uses the k-mer based targeted detection tool km and known ALL variant information to achieve a high degree of accuracy for reporting subtype defining genomic alterations compared to standard alignment-based pipelines. Gene fusions, including difficult to detect fusions involving EPOR and DUX4, were accurately identified in 98% (164 samples) of reported cases in a 180-patient Australian study cohort and 95% (n=63) of samples in a North American validation cohort. Pathogenic sequence variants were correctly identified in 75% of tested samples, including all cases involving subtype defining variants PAX5 p.P80R (n=12) and IKZF1 p.N159Y (n=4). Accurate detection of intragenic IKZF1 deletions resulting in aberrant transcript isoforms was also detectable with 98% accuracy. Importantly, the median analysis time for detection of all targeted alterations averaged 22 minutes per sample, significantly shorter than standard alignment-based approaches, ensuring accerelated risk-stratification and therapeutic triage.

  Study EGAS00001006460

• Integrative genomic analysis identifies key pathogenic mechanisms in primary mediastinal large B-cell lymphoma

  Primary mediastinal large B-cell lymphoma (PMBL) represents a clinically and pathologically distinct subtype of large B-cell lymphomas. Furthermore, molecular studies, including global gene expression profiling, have provided evidence that PMBL is more closely related to classical Hodgkin lymphoma (cHL). Although targeted sequencing studies have revealed a number of mutations involved in PMBL pathogenesis, a comprehensive description of disease-associated genetic alterations and perturbed pathways is still lacking. Here, we performed whole-exome sequencing of 95 PMBL tumors to inform on oncogenic driver genes and recurrent copy number alterations. The integration of somatic gene mutations with gene expression signatures provides further insights into genotype-phenotype interrelation in PMBL. We identified highly recurrent oncogenic mutations in the JAK-STAT and NF-kB pathways, and provide additional evidence of the importance of immune evasion in PMBL (CIITA, CD58, B2M, CD274, PDCD1LG2). Our analyses highlight the IRF-pathway as a putative novel hallmark with frequent alterations in multiple pathway members (IRF2BP2, IRF4, IRF8). In addition, our integrative analysis illustrates the importance of JAK1, RELB and EP300 mutations driving oncogenic signaling. The identified driver genes were significantly more frequently mutated in PMBL as compared to diffuse large B-cell lymphoma, whereas only a limited number of genes were significantly different between PMBL and cHL, emphasizing the close relationship between these entities. Our study, performed on a large cohort of PMBL, highlights the importance of distinctive genetic alterations for disease taxonomy with relevance for diagnostic work-up and therapeutic decision-making.

  Study EGAS00001003746

• Epigenome-wide methylation analysis of colorectal carcinoma, adenoma and normal tissue reveals novel biomarkers addressing unmet clinical needs

  Studies about CRC biomarker discovery have focused on methylation patterns in normal and colorectal tumor tissue, leading to a lack of knowledge of methylation in adenomas. Therefore, we performed the first epigenome-wide study to compare the epigenomes of all three tissue types combined, and to identify discriminatory biomarkers. Public Illumina MethylEPIC® data was collected from 552 normal, 118 carcinoma and 116 adenoma samples. Pairwise analyses were performed for discovery of differentially methylated probes (DMPs). We identified 693 813, 620 643 and 558 897 DMPs when comparing normal vs carcinoma, normal vs adenoma and adenoma vs carcinoma respectively. To double evidence (DE) these DMPs, analysis of Illumina 450K data from public datasets was performed. Through this analysis, 13 DE DMPs with │Δβ│≥0.3 were identified for adenoma vs carcinoma. A binary logistic regression model was generated to evaluate the discriminatory potential of these DE DMPS. The model was validated in an in-house experimental methylation dataset of 13 adenoma and 9 carcinoma samples. Our classifier reached a cross-validated AUC of 0.996 and 0.855 in the discovery and validation datasets respectively. A sensitivity and specificity of 96% and 95% were reached, with an overall accuracy of 96%. Our analysis show that methylation biomarkers have the potential to discriminate between normal, precursor and carcinoma tissues of the colorectum. More importantly, we highlight the power of the methylome, showing that DMPs can be used as biomarkers in the clinic to identify colorectal adenoma and carcinoma. 

  Study EGAS00001007017

• Clinical and genetic factors associated with tumor response to neoadjuvant (chemo)radiotherapy, survival and recurrence risk in rectal cancer

  Rectal cancer poses challenges in preoperative treatment response, with up to 30% achieving a complete response (CR). Personalized treatment relies on accurate identification of responders at diagnosis. This study aimed to unravel CR determinants, overall survival (OS), and time to recurrence (TTR) using clinical and targeted sequencing data. Analyzing 402 patients undergoing preoperative treatment, tumor stage, size, and treatment emerged as robust response predictors. CR rates were higher in smaller, early-stage, and intensively treated tumors. Targeted sequencing analyzed 216 cases, while 120 patients provided hotspot mutation data. KRAS mutation dramatically reduced CR odds by over 50% (odds ratio [OR]=0.3 in the targeted sequencing and OR=0.4 hotspot cohorts, respectively). In contrast, SMAD4 and SYNE1 mutations were associated with higher CR rates (OR=6.0 and 6.8, respectively). Favorable OS was linked to younger age, CR, and low baseline carcinoembryonic antigen levels. Notably, CR and an APC mutation increased TTR, while a BRAF mutation negatively affected TTR. Beyond tumor burden, SMAD4 and SYNE1 mutations significantly influenced CR. KRAS mutations independently correlated with radiotherapy resistance, and BRAF mutations heightened recurrence risk. Intriguingly, nonresponding tumors with initially small sizes carried a higher risk of recurrence. These findings offer insights into rectal cancer treatment response, guiding personalized therapeutic strategies. By uncovering factors impacting CR, OS, and TTR, this study underscores the importance of tailored approaches for rectal cancer patients. These findings, based on extensive analysis and mutation data, pave the way for personalized interventions, optimizing outcomes in the challenges of rectal cancer preoperative treatment.

  Study EGAS00001007501

• The University of Hong Kong Intestinal Metaplasia Organoids Study

  Background: Gastric intestinal metaplasia (IM) is a pre-cancerous stage spanning a morphological spectrum that is poorly represented by human cell line models. Objective: We aim to establish and characterize human IM cell models to better understand IM progression along the cancer spectrum. Design: A large human gastric IM organoid (IMO) cohort (n=28), their clonal derivatives and normal gastric organoids (n=42) for comparison were established. Comprehensive multi-omics profiling and functional characterization were performed. Results: Single-cell transcriptomes revealed IMO cells spanning a spectrum from hybrid gastric/intestinal to advanced intestinal differentiation. Their lineage trajectories connected different cycling and quiescent stem and progenitors, highlighting differences in gastric to IM transition and the potential origin of IM from STMN1 cycling isthmus stem cells. Hybrid IMOs showed impaired differentiation potential, high lineage plasticity beyond gastric or intestinal fates, and reactivation of a fetal gene program. Cell populations in gastric IM and cancer tissues were highly similar to those derived from IMOs and exhibited a fetal signature. Genomically, IMOs showed elevated mutation burden, frequent chromosome 20 gain, and epigenetic de-regulation of many intestinal and gastric genes. Functionally, IMOs were FGF10 independent and showed downregulated FGFR2. Several IMOs exhibited a cell-matrix adhesion independent (CMi) subpopulation that displayed chromosome 20 gain but lacked key cancer driver mutations, potentially representing the earliest neoplastic precursor of IM-induced gastric cancer. Conclusions: Overall, our IM organoid biobank captured the heterogeneous nature of IM, revealing mechanistic insights on IM pathogenesis and progression, offering an ideal platform for studying early gastric neoplastic transformation and chemoprevention.

  Study EGAS00001007899

• KiCS WGS data for academic and for-profit use

  Data from samples that are marked for both academic and for-profit use.

  Dataset EGAD00001009699

• WTCCC case-control study for Coronary Artery Disease, Hypertension, T2D - combined cases

  WTCCC genome-wide case-control association study using the cardiovascular disease CAD, HT and T2D as combined case collection and the 1958 British Birth Cohort and the UK National Blood Service collections as controls.

  Study EGAS00000000005

• Epigenome-wide association study of asthma remission in whole blood and nasal epithelium

  Clinical remission (ClinR) was defined as the absence of asthma symptoms and medication for at least 12 months, and complete remission (ComR) was defined as ClinR with normal lung function and absence of airway hyperresponsiveness. We analyzed differential DNA methylation of ClinR and ComR comparing to persistent asthma (PersA) in whole blood samples (n=72) and nasal brushing samples (n=97) in a longitudinal cohort of well characterized asthma patients.

  Dataset EGAD00010002026

• FFPE cohort with RNA-seq data of tumor samples

  This dataset contains RNA-seq raw data in fastq format from 14 tumor samples. The samples are from primary tumors or metastasis and represent various cancer entities. The samples are formalin-fixed paraffin-embedded (FFPE) treated. For target enrichment SureSelect XT Human All Exon V6 was used. The libraries were sequenced in paired-end mode (2 x 50 nt) on a NovaSeq6000 S2 flow cell.

  Dataset EGAD00001006781

• imputed_bacterial_meningitis

  This study includes 1146 samples of host genotyping data (imputed) from Illumina Omni arrays, using https://imputation.sanger.ac.uk/ with the Haplotype Reference Consortium v1.1. Samples were collected from adults (>16 yrs) patients with CSF confirmed bacterial meningitis in the Netherlands between 2006 and 2015. Metadata includes patient outcome, species of bacteria, and for 467 samples a link to an ENA run with the associated bacterial genome (S. pneumoniae only).

  Dataset EGAD00010002327