7296 results for "canc*"

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• Plasma mutation profile of precursor lesions and colorectal cancer using the Oncomine Colon cfDNA Assay

  Colorectal cancer (CRC) is the second leading cause of cancer death worldwide. Early detection of precursor lesions or early-stage cancer could hamper cancer development or improve survival rates. Liquid biopsy, which detects tumor biomarkers, such as mutations, in blood, is a promising avenue for cancer screening. To assess the presence of genetic variants in plasma cell-free tumor DNA from patients with precursor lesions and colorectal cancer using the commercial Oncomine Colon cfDNA Assay. Cell-free DNA (cfDNA) samples from the blood plasma of 52 Brazilian patients were analyzed. Eight patients did not have any significant lesions (five normal colonoscopies and three hyperplastic polyps), 24 exhibited precursor lesions (13 nonadvanced adenomas, ten advanced adenomas, and one sessile serrated lesion), and 20 patients with cancer (CRC). The mutation profile of 14 CRC-associated genes were determined by next-generation sequencing (NGS) using the Oncomine Colon cfDNA Assay in the Ion Torrent PGM/S5 sequencer.

  Study EGAS50000000471

• Large B cell lymphomas with CCND1 rearrangement have different immunoglobulin gene breakpoints and genomic profile than mantle cell lymphoma

  Next-generation sequencig data including whole-genome sequencing, whole-exome sequencing, and capture-based gene panels of large B cell lymphomas with CCND1 rearrangementas described in Özoğul,Montaner, Pol et al 2024.

  Study EGAS50000000564

• Chromatin immunoprecipitation linked to next-generation whole genome sequencing (ChIP-Seq) for H3K36me3 in paediatric high grade glioma cell lines KKNS4 and SF188 with and without a G34V mutation in H3F3A

  Glioblastomas of children and young adults have a median survival of only 12-15months and are clinically and biologically distinct from histologically similar cancers in older adults1. They are defined by highly specific mutations in the gene encoding the histone H3.3 variant H3F3A2, occurring either at or close to key residues marked by methylation for regulation of transcription – K27 and G34. We performed chromatin immunoprecipitation linked to next-generation whole genome sequencing (ChIP-Seq) for H3K36me3 in order to test the hypothesis that, rather than total H3K36me3, the G34V mutation may instead result in differential binding of the trimethyl mark throughout the genome. Compared with H3F3A wild-type SF188 paediatric GBM cells, H3K36me3 was found to be significantly differentially bound in KNS42 cells at 5130 distinct regions of the genome corresponding to 156 genes. Concurrent whole genome DNA sequencing demonstrated that this was not confounded by copy number alterations. The cerebral hemispheric-specific G34 mutation drives a distinct expression signature through differential genomic binding of the K36 trimethylation mark (H3K36me3). The transcriptional program induced recapitulates that of the developing forebrain, and involves numerous markers of stem cell maintenance, cell fate decisions and self-renewal. Critically, H3F3A G34 mutations cause profound upregulation of MYCN, a potent oncogene which is causative of glioblastomas when expressed in the correct developmental context. This driving aberration is selectively targetable in this patient population by inhibiting kinases responsible for stabilisation of the protein.

  Study EGAS00001001437

• Targeted_sequencing_of_genes_recurrently_mutated_in_AML___part2

  Genomic libraries will be generated from total genomic DNA derived from 4000 samples with Acute Myeloid Leukaemia. Libraries will be enriched for a selected panel of genes using a bespoke pulldown protocol. 64 Samples will be individually barcoded and subjected to up to one lanes of Illumina HiSeq. Paired reads will be mapped to build 37 of the human reference genome to facilitate the characterisation of known gene mutations in cancer as well as the validation of potentially novel variants identified by prior exome sequencing.

  Study EGAS00001000570

• Synergy study: "Tissue resident CD8+ T cell clonal expansion in advanced triple negative breast cancer is associated with response to chemoimmunotherapy"

  Dataset of 10x Genomics 5'prime single-cell RNA sequencing of 40 tumor biopsy samples or triple negative breast cancer. Samples are taken before and after immuno checkpoint blockade treatment. Processed according the 10X genomics protocol, sequenced on Immumina NovaSeq6000. Raw sequencing reads are further processed with Cellranger 3.0 to get gene-expression matrices.

  Study EGAS50000000527

• Integrating molecular imaging and transcriptomic profiling in advanced HER2-positive breast cancer receiving trastuzumab emtansine (T-DM1): an analysis of the ZEPHIR clinical trial

  Purpose: The ZEPHIR clinical trial evaluated the role of [89Zr]trastuzumab-PET/CT (HER2-PET/CT) and 2-[18F]fluoro-2-deoxy-D-glucose PET/CT ([18F]FDG-PET/CT) in predicting outcomes in patients with advanced HER2-positive breast cancer treated with trastuzumab emtansine (T-DM1). Here, we combined molecular/metabolic imaging and transcriptomic data to investigate the biological processes associated with [89Zr]trastuzumab and [18F]FDG uptake, and to dissect the mechanisms involved in T-DM1 resistance. Experimental design: RNA was extracted from metastasis biopsies obtained at study inclusion in the ZEPHIR trial. HER2-PET/CT and [18F]FDG-PET/CT imaging data of biopsied lesions were integrated with RNA sequencing data. Lesions were compared based on the level of [89Zr]trastuzumab uptake (dichotomized into high/low classes) as well as on the presence/absence of metabolic response, defined comparing baseline and on-treatment [18F]FDG-PET/CT. Results: We analyzed matched transcriptomic and molecular/metabolic imaging data for 24 metastases (one lesion/patient). Pathways involved in extracellular matrix (ECM) organization, glycosylphosphatidylinositol synthesis, and collagen formation were enriched in lesions presenting low [89Zr]trastuzumab uptake. [18F]FDG uptake at baseline correlated with proliferation and immune-related processes. Hypoxia and ECM-related processes were enriched in lesions that showed no metabolic response to T-DM1. Interestingly, immune-related processes (e.g., Fc gamma receptor activation, complement cascade) were associated with high [89Zr]trastuzumab uptake and metabolic response. Conclusions: To our knowledge, this study represents the first correlative analysis between [89Zr]trastuzumab tumor uptake and gene expression profiling in humans. Our findings point toward a role of ECM in impairing [89Zr]trastuzumab tumor uptake and T-DM1 metabolic response in advanced HER2-positive breast cancer, and highlight the potential of molecular imaging to depict tumor microenvironment features.

  Study EGAS50000000470

• Ballett

  TSO500 study: The project, called "BALLETT" (Belgian Approach of Local Laboratory Extensive Tumor Testing), has a double goal: (1) show the relevance of broad molecular profiling to improve oncological patients care, (2) demonstrate that broad molecular testing can be performed in a decentralized setting by local diagnostics laboratories in a fully standardized and uniform way while complying with the highest quality standards. NCT05058937 The publication number is: Your manuscript ID is bcr-2023-256124. Title: CUP and BRAF V600E meeting the BEACON combination.

  Study EGAS50000000478

• Neoadjuvant immune checkpoint blockade in women with mismatch repair deficient endometrial cancer

  Neoadjuvant immune checkpoint blockade (ICB) has shown unprecedented activity in mismatch repair deficient (MMRd) colorectal cancers, but its effectiveness in MMRd endometrial cancer (EC) remains unknown. In this investigator-driven, phase I, feasibility study (NCT04262089), 10 women with MMRd EC of any grade, planned for primary surgery, received two cycles of neoadjuvant pembrolizumab (200 mg IV) every three weeks. A pathologic response (primary objective) was observed in 5/10 patients, with 2 patients showing a major pathologic response. No patient achieved a complete pathologic response. A partial radiologic response (secondary objective) was observed in 3/10 patients, 5/10 patients had stable disease and 2/10 patients were non-evaluable on Magnetic Resonance Imaging (MRI). All patients completed treatment without severe toxicity (exploratory objective). At median duration of follow-up of 22.5 months, two non-responders experienced disease recurrence. In-depth analysis of the loco-regional and systemic immune response (predefined exploratory objective) showed that monoclonal T cell expansion significantly correlated with treatment response. Tumour-draining lymph nodes displayed clonal overlap with intra-tumoural T cell expansion. All pre-specified endpoints, efficacy in terms of pathologic response as primary endpoint, radiologic response as secondary outcome and safety and tolerability as exploratory endpoint, were reached. Neoadjuvant ICB with pembrolizumab proved safe and induced pathologic, radiologic, and immunologic responses in MMRd EC, warranting further exploration of extended neoadjuvant treatment.

  Study EGAS50000000483

• Early detection of ovarian cancer using cell-free DNA fragmentomes and protein biomarkers

  Ovarian cancer is the leading cause of death from gynecological cancers worldwide. No effective screening methods exist, and tumors are commonly detected at advanced stages where treatment is much less effective. In this study, we used whole-genome cell-free DNA (cfDNA) fragmentome and protein biomarker (CA-125 and HE4) analyses to evaluate 591 women from the European Union or the United States with ovarian cancer, benign adnexal masses, or without ovarian lesions. Using a machine learning model that incorporated multi-analyte fragmentome data and protein measurements, we detected ovarian cancer with high specificity >99% and sensitivity of 72%, 69%, 87%, and 100% for stages I–IV, respectively (AUC=0.96, 95% CI: 0.94-0.99), including 90% of high grade serous ovarian cancers. At the same specificity, CA-125 alone detected 34%, 62%, 63%, and 100% of ovarian cancers for stages I–IV (p=0.001, two-sided test of equal proportions). Additionally, our approach distinguished benign masses from ovarian cancers with high accuracy (AUC of 0.88, 95% CI=0.83-0.92). These results were validated in an independent population. These findings show that integrated cfDNA fragmentome and protein analyses detect ovarian cancers with high performance, enabling a new accessible approach for noninvasive ovarian cancer screening and diagnostic evaluation.

  Study EGAS50000000484

• Base-excision repair pathway shapes 5-methylcytosine deamination signatures in pan-cancer genomes

  Transition of cytosine to thymine in CpG dinucleotides is the most frequent type of mutation in cancer. This increased mutability is commonly attributed to spontaneous deamination of 5-methylcytosine (5mC), which is normally repaired by the base-excision repair (BER) pathway. However, the contribution of 5mC deamination in the increasing diversity of cancer mutational signatures remains poorly explored. Here, we integrate mutational signatures analysis in a large series of tumor whole genomes with lineage-specific epigenomic data to draw a detailed view on 5mC deamination in cancer. We uncover tumor type-specific patterns of 5mC deamination signatures in CpG and non-CpG contexts. We demonstrate that the BER glycosylase MBD4 preferentially binds to open chromatin domains, which correlates with lower mutational burden in these domains. We validate our findings by modelling BER deficiencies in isogenic cell models. Overall, we establish MBD4 as the main actor responsible for 5mC deamination repair in humans.

  Study EGAS50000000536

• Duplex sequencing of selected breast cancer patients

  This study assessed the variant profiles of 22 samples from 11 breast cancer patients with adverse survival outcomes, including paired uninvolved mammary gland samples collected at various distances from primary lesions. Ultra-deep sequencing was performed to identify the presence of low-frequency pathogenic post-zygotic variants in PIK3CA and TP53 genes.

  Study EGAS50000000538

• WES of breast cancer patients and controls

  This study assessed the variant profiles of 408 samples from 126 breast cancer patients with various survival outcomes, including paired uninvolved mammary gland samples collected at proximal distances from primary lesions. As a reference, control samples from 15 mammoplasty individuals without cancer history were studied. Whole exome sequencing was performed to identify post-zygotic and germline variants present in the studied samples. Variant annotation in known databases, interpretation, and statistical analyses followed to discern the clinical relevance of called variants.

  Study EGAS50000000539

• Pipeline Olympics: Continuous benchmarking of computational workflows for DNA methylation sequencing data

  DNA methylation is a widely studied epigenetic mark and a powerful biomarker of cell type, age, environmental exposure, and disease. Genome-wide DNA methylation profiling is usually performed using whole-genome sequencing following selective conversion of unmethylated cytosines into thymines via bisulfite treatment or enzymatic methods. Numerous software tools facilitate processing of raw sequencing data for DNA methylation profiling, but a comprehensive benchmarking has been lacking. In this study, we systematically compared methods and tools for processing DNA methylation sequencing data. We established a dedicated benchmarking dataset comprising genome-wide DNA methylation profiling data for four reference samples using five experimental protocols each. The results of data processing were compared to highly quantitative locus-specific DNA methylation measurements available for 46 genomic loci. Based on this gold-standard reference dataset, we identified workflows that consistently demonstrated high performance. We present our results in an interactive application that provides a “living benchmark” ready for continuous updating as new workflows are proposed and require benchmarking against existing methods. In summary, our study provides guidance for any laboratory studying DNA methylation on a genome-wide scale.

  Study EGAS50000000541

• Single cell RNA and ATAC sequencing data from GBM patients

  Glioblastoma cells infiltrate and incorporate into the normal brain parenchyma. We conduct unbiased multimodal single-cell and spatial sequencing to capture GBM cells and the surrounding tumor microenvironment using a regional sampling strategy. For each patient, we profile the peritumoral region, tumor edge, and tumor core, providing a comprehensive characterization of the transcriptional and epigenetic landscape of GBM spatial heterogeneity, with a specific focus on infiltrative cells.

  Study EGAS50000000547

• Divergent WNT Signaling and Drug Sensitivity Profiles within Hepatoblastoma Tumors and Organoids

  Hepatoblastoma, the most prevalent pediatric liver cancer, almost always carries a WNT-activating CTNNB1 mutation, yet exhibits notable molecular heterogeneity. To characterize this heterogeneity and identify novel targeted therapies, we perform comprehensive analysis of hepatoblastomas and tumor-derived organoids using single-cell RNA-seq/ATAC-seq, spatial transcriptomics, and high-throughput drug profiling. We identify two distinct tumor epithelial signatures: hepatic ‘fetal’ and WNT-high ‘embryonal’, displaying divergent WNT signaling patterns. The fetal group is enriched for liver-specific WNT targets, while the embryonal group is enriched in canonical WNT target genes.

  Study EGAS50000000561

• Rapid brain tumor classification from sparse epigenomic data

  Although the intraoperative, molecular differential diagnosis of the approximately one hundred different brain tumor entities described to date has been a goal of neuropathology in the last decade, this has not yet been achieved in a clinically relevant time frame of less than one hour after biopsy collection. Recent advances in third-generation sequencing technologies have brought this once-elusive goal within reach. However, established machine learning techniques rely on concepts and methods, impractical for live diagnostic workflows in clinical applications. Here, we present MethyLYZR, a Naïve Bayesian framework enabling fully tractable live classification of cancer epigenomes. MethyLYZR can be run in parallel with an ongoing Nanopore experiment with negligible computational cost and provides clinically relevant and accurate cancer classification results within 15 minutes of sequencing. Therefore, only the time required for DNA extraction and the Nanopore sequencer's maximum parallel throughput remain limiting factors for even faster time-to-results. We demonstrate the potential utility of the MethyLYZR framework not only for the neurosurgical intraoperative use case but also for other oncologic indications and cell-free DNA from liquid biopsies.

  Study EGAS50000000559

• Identification and characterization of tertiary lymphoid structures in brain metastases

  Brain metastases (BrM) are the most common cancers in the brain. We performed transcriptome-wide gene expression profiling combined with spatial immune cell profiling to characterize the tumor immune microenvironment in BrM from different primary tumors. We found that BrM from lung carcinoma and malignant melanoma showed overall higher immune cell infiltration as compared to BrM from breast carcinoma. RNA sequencing-based immune cell deconvolution revealed gene expression signatures indicative of tertiary lymphoid structures (TLS) in subsets of BrM from lung cancer and melanoma. This finding was corroborated by multiplex immunofluorescence staining of immune cells in BrM tissue sections. Detection of TLS signatures was associated with prolonged survival after BrM diagnosis in lung cancer patients. Our findings highlight the cellular diversity of the tumor immune microenvironment in BrM of different cancer types and suggest a role of TLS formation for BrM patient outcome.

  Study EGAS50000000563

• PLCRC_study

  Genomic libraries (500 bps) will be generated from total genomic DNA derived from Colorectal cancer patients and subjected to short paired end sequencing on the llumina platform. Paired reads will be mapped to build 37 of the human reference genome to facilitate the generation of genome wide copy number information, and the identification of novel rearranged cancer genes and gene fusions.

  Study EGAS00001000612

• MutWP5__CRUK_Mutographs_of_Cancer__Lung__PD37920__WG_

  Sequencing of LCM-derived microbiopsies from explanted lung from COPD patient. Goal to assess the mutational burden, spectrum, and clonal dynamics within the tissue. Deep sampling throughout multiple regions of the lung will determine whether there are differences in smoking-related mutation burden in different portions of the lung. Whole-genome sequencing will be conducted on samples identified as promising from the initial targeted data. Results from this portion of the study will be compared to other individuals with smoking-related diseases (COPD, pulmonary fibrosis, lung cancer), and normal, non-smoking lungs.

  Study EGAS00001003320

• Neoadjuvant nivolumab or nivolumab plus ipilimumab in early-stage triple negative breast cancer: phase 2 adaptive BELLINI trial. WES

  The adaptive BELLINI trial explored whether short combination ICI induces immune activation (primary endpoint: two-fold increase in CD8+ T cells or IFNG), providing rationale for neoadjuvant ICI without chemotherapy. In window of opportunity cohorts A (4 weeks anti-PD1) and B (4 weeks anti-PD1 + anti-CTLA4), we observed immune activation in 53% (8/15) and 60% (9/15) of patients, respectively. High tumor-infiltrating lymphocytes (TILs) correlated with response. Based on these data, we opened cohort C for patients with high TILs (≥50%) who received 6 weeks neoadjuvant anti-PD1 + anti-CTLA4 followed by surgery (primary endpoint: pathological complete response, pCR). 53% (8/15) of patients had major pathological response (< 10% viable tumor) at resection, with 33% (5/15) having pCR. All cohorts met Simon’s two-stage threshold for expansion to stage II. In conclusion, neoadjuvant immunotherapy without chemotherapy demonstrates potential efficacy and warrants further investigation in patients with early TNBC.

  Study EGAS50000000568

• Whole-genome sequencing of BRCA-mutant breast cancer patient samples from tumour, germline tissue and plasma

  The use of circulating tumor DNA (ctDNA) to profile mutational signatures presents a non-invasive opportunity for understanding cancer mutational processes. In this study we developed MisMatchFinder, a liquid biopsy approach for mutational signature detection using low- coverage whole-genome sequencing of ctDNA. Through analysis of plasma samples across multiple different cancers, we demonstrated that MisMatchFinder accurately infers single-base and doublet-base substitutions as well as indels to enhance detection of ctDNA and clinically relevant mutational signatures. This study contains fastq files from whole-genome sequencing of temporally matched tumour (fresh frozen biopsies), blood germline and plasma samples collected from a BRCA1-mutant breast cancer patient to directly compare mutation signature analysis using gold-standard tumour-germline paired variant calling with our novel ctDNA-based method (MisMatchFinder).

  Study EGAS50000000569

• Identification of HER2-positive breast cancer molecular subtypes with potential clinical implications in the ALTTO clinical trial

  In HER2-positive breast cancer, clinical outcome and sensitivity to HER2-targeted therapies are influenced by both tumor and microenvironment features. However, we are currently unable to depict the molecular heterogeneity of this disease with sufficient granularity. Here, by performing gene expression profiling in HER2-positive breast cancers from patients receiving adjuvant trastuzumab in the ALTTO clinical trial, we identified and characterized five molecular subtypes associated with the risk of distant recurrence: immune-enriched (IM), proliferative/metabolic-enriched (P/Met), mesenchymal/stroma-enriched (Mes/S), luminal (LUM), and ERBB2-enrichedERBB2-dependent (ERBB2-EERBB2-D). We next validated the biological profiles of the subtypes and explored their prognostic/predictive value in external cohorts, namely the NeoALTTO trial, SCAN-B, I-SPY2, METABRIC and TCGA. IM tumors presented better survival outcomes, in contrast to Mes/S and P/Met tumors, while LUM tumors and ERBB2-EERBB2-D were characterized by low and high rates of pathological complete response, respectively. Of note, these molecular subtypes provide the rationale for treatment approaches leveraging the heterogeneous biology of HER2-positive breast cancer.

  Study EGAS50000000525

• Mutational context and diverse clonal development in early and late bladder cancer

  Bladder cancer shows multiple recurrences probably originating from a malignant field disease in the mucosa. Deep sequencing was used on a series of tumors to look into the clonal composition, mutational spectrum in non-aggressive tumors, and mutational context.

  Study EGAS00001000641

• Sensitive urothelial cancer detection via high volume urine DNA analysis

  Cystoscopy and imaging are the gold standard for urothelial cancer (UC) detection and surveillance, but cystoscopy is an uncomfortable procedure associated with adverse effects and a low diagnostic yield as only 10% of hematuria patients have UC. Urine tumor DNA (utDNA) is a non-invasive UC biomarker that has suffered from poor sensitivity for Ta stage tumors (<80%). We hypothesized that high urine volume analysis with a multi-gene panel could overcome these limitations, and developed a 100 mL utDNA laboratory platform (UroScout) that analyzes 25 commonly mutated UC genes and 8 copy number-altered loci for somatic alterations to detect UC.

  Study EGAS50000000630

• Exploiting evolutionary steering in cancer therapy

  Drug resistance, mediated by intra-tumour heterogeneity and clonal evolution, is arguably the biggest problem in cancer therapy today. However, evolving resistance to one drug may come at the cost of increased sensitivity to another due to so-called evolutionary trade-offs. This weakness can be exploited in the clinic using an approach called ‘evolutionary herding’ that aims at controlling the tumour cell population to delay or prevent resistance. However, model systems able to recapitulate cancer evolution experimentally are lacking and current in vitro techniques based on small populations, re-plating and escalating dose, are unsuitable to develop evolutionary herding strategies. We present a novel methodology for evolutionary herding in vitro and ex vivo using patient-derived organoids. Our approach is based on a combination of single-cell barcoding, very large populations of 108-109 cells grown without re-plating, realistic high drug doses, time-course monitoring of cancer clones, and mathematical modelling of tumour evolutionary dynamics. We demonstrate evolutionary herding in non-small cell lung cancer in vitro and in patient-derived colorectal cancer organoids (PDO). We show that herding causes controlled evolutionary bottlenecks that lead to collateral sensitivity. Through genomic analysis, we were also able to determine the mechanisms that drive such sensitivity. Our approach allows modelling evolutionary trade-offs experimentally to test patient-specific evolutionary herding strategies that can be translated into the clinic to control treatment resistance.

  Study EGAS00001003200

• Tumor Profiler AML Study

  Multi-omics data generated from 22 samples from the Tumor Profiler AML cohort

  Study EGAS50000000577

• Exploring_the_landscape_of_somatic_mutations_in_normal_tissue___GI___MAP___WGS

  Somatic mutations (burdens and signatures) and clonal dynamics in normal human tissues from the gastrointestinal tract of individuals with tumour predisposition syndromes and DNA damage repair defects.

  Study EGAS00001004122

• TransNEO neoadjuvant breast cancer study

  Study EGAS00001004582

• Neoadjuvant nivolumab or nivolumab plus ipilimumab in early-stage triple negative breast cancer: phase 2 adaptive BELLINI trial. RNA-Seq

  The adaptive BELLINI trial explored whether short combination ICI induces immune activation (primary endpoint: two-fold increase in CD8+ T cells or IFNG), providing rationale for neoadjuvant ICI without chemotherapy. In window of opportunity cohorts A (4 weeks anti-PD1) and B (4 weeks anti-PD1 + anti-CTLA4), we observed immune activation in 53% (8/15) and 60% (9/15) of patients, respectively. High tumor-infiltrating lymphocytes (TILs) correlated with response. Based on these data, we opened cohort C for patients with high TILs (≥50%) who received 6 weeks neoadjuvant anti-PD1 + anti-CTLA4 followed by surgery (primary endpoint: pathological complete response, pCR). 53% (8/15) of patients had major pathological response (< 10% viable tumor) at resection, with 33% (5/15) having pCR. All cohorts met Simon’s two-stage threshold for expansion to stage II. In conclusion, neoadjuvant immunotherapy without chemotherapy demonstrates potential efficacy and warrants further investigation in patients with early TNBC.

  Study EGAS50000000567

• Single-cell targeted DNA-sequencing and protein sequencing

  We performed single-cell targeted DNA sequencing (MissionBio) on 13 high hyperdiploid B-ALL patients at diagnosis to study the genetic heterogeneity. For a number of patients single-cell surface protein antibody sequencing was added (DAB-seq) to better characterize the different cell types. Furthermore, additional samples during treatment were collected and analysed for some patients. In this way we want to study the clonal heterogeneity of these B-ALL samples, based both on mutations and CNVs, and identify resistant clones that could be targeted after relapse.

  Study EGAS50000000580

• MutWP5__CRUK_Mutographs_of_Cancer__Lung__PD38233__WG_

  Sequencing of LCM-derived microbiopsies from explanted lung from COPD patient. Goal to assess the mutational burden, spectrum, and clonal dynamics within the tissue. Deep sampling throughout multiple regions of the lung will determine whether there are differences in smoking-related mutation burden in different portions of the lung. Whole-genome sequencing will be conducted on samples identified as promising from the initial targeted data. Results from this portion of the study will be compared to other individuals with smoking-related diseases (COPD, pulmonary fibrosis, lung cancer), and normal, non-smoking lungs.

  Study EGAS00001003322

• Lactate metabolism in cancer stem cell fate regulation

  Tumors arise as a result of uncontrolled cell proliferation driven by mutations in the signaling pathways that regulate the balance between cell division and differentiation. Despite of that, in the tumor, cancer stem cells seem to retain their capability to differentiate, which can lead to differential chemotherapy response. We previously showed that intestinal stem cells and differentiated cells display specific metabolic features and that they interact through metabolites. Moreover, we found that altering mitochondrial metabolism is sufficient to lead and define stem cell differentiation. In cancer, cellular metabolism is highly derailed. However, how metabolic changes in the cancer cell contribute to cell fate decisions remains unknown. Recently, the crosstalk between metabolism and epigenetics has emerged as one of the players in tumor development. Here we aim to address the impact of the altered metabolism of cancer cells on their epigenome as a regulatory axis of cell identity and fate. We use human-derived tumor organoids where we introduce genetic encoded fluorescent-based reporters to visualize cell identity and metabolism at single cell level. We combine 4D live imaging with a recently developed machine learning method to re-construct cell-lineages, trace stem cell state and metabolic changes during tumor organoid development. We find that, mimicking the tumor metabolic microenvironment (Warburg effect-driven low-glucose high-lactate) leads to changes cellular metabolism and histone acetylation. Strikingly, these alterations provoke profound changes in tumor development by increasing the population of cancer stem cells and their proliferation and differentiation dynamics.

  Study EGAS50000000063

• Selective Elimination of Immunosuppressive T cells in Patients with Multiple Myeloma

  Study EGAS00001004915

• MutWP5__CRUK_Mutographs_of_Cancer__Lung__PD38234__Targeted_

  Sequencing of LCM-derived microbiopsies from explanted lung from pulmonary fibrosis patient. Goal to assess the mutational burden, spectrum, and clonal dynamics within the tissue. Deep sampling throughout multiple regions of the lung will determine whether there are differences in smoking-related mutation burden in different portions of the lung. Targeted sequencing will be conducted on samples to identify drivers of interest and clonality of the samples, well-performing samples will be sent for subsequent whole-genome sequencing. Results from this portion of the study will be compared to other individuals with smoking-related diseases (COPD, pulmonary fibrosis, lung cancer), and normal, non-smoking lungs.

  Study EGAS00001003325

• Characterization of copy number quiet oral cancer

  Copy number quiet head and neck squamous cell carcinoma are a distinct subset with relatively good prognosis. Previous work has indicated this subset is most commonly found in the oral cavity and is highly enriched for HRAS and CASP8 mutations. TP53 mutations are much less common than in CNA-quiet oral cancers. In this study we corroborate the validity of CNA-quiet tumors as a distinct subset in a large OSCC cohort and further chart clinical, genomic, and immunological characteristics of this subset.

  Study EGAS50000000558

• Cancer cell and tumor microenvironment biomarkers associated with disease-free survival with adjuvant nivolumab in the phase 3 CheckMate 274 trial

  In the CheckMate 274 trial, adjuvant nivolumab versus placebo demonstrated an improvement in the primary endpoint of disease-free survival (DFS) in patients with high-risk muscle-invasive urothelial carcinoma after radical resection. An extensive analysis of tumor biomarkers, including their associations with DFS, was performed. Analysis of genome-wide differential gene expression and known gene signatures found that immune-related genes and pathways, in particular an IFNγ signature, were predictive of DFS in nivolumab-treated patients. Predictive and prognostic associations, respectively, were found for tumor-infiltrating CD4 and CD8 T cells. Analysis of a composite predictive model suggested that CD4 gene expression and tumor cell PD-L1 expression had the greatest contributions to predicting outcomes in nivolumab-treated patients. These results reinforce recent studies establishing the importance of biomarkers of adaptive immunity, and in particular CD4 T cells, in influencing response to PD-1/PD-L1 blockade and establish the potential predictive rather than solely prognostic nature of such findings.

  Study EGAS50000000560

• Ex vivo modeling of precision immuno-oncology responses in lung cancer

  Single-cell RNA-sequencing (scRNA-seq) data from paired lung cancer organoids and immune cells. The experiment was performed using the Single Cell 5' solution of 10X Genomics. The dataset includes 15 samples from 4 multiplexed experiments. The multiplexing was performed using the Feature Barcoding technology of 10X Genomics.

  Study EGAS50000000593

• HKU Gastric Cancer Genomics study - WGS, DNA genotyping array, expression and methylation profiling

  HKU Gastric Cancer Genomics study - Whole Genome Sequencing, DNA genotyping array, Expression profiling and Methylation profiling

  Study EGAS00001000597

• Targeted gene panel sequencing of leiomyosarcoma

  We conducted MSK-IMPACT sequencing of leiomyosarcoma.

  Study EGAS50000000595

• Whole-exome sequencing identifies new pathogenic germline variants in patients with colorectal polyposis

  Adenomatous polyposis confers an increased risk of colorectal cancer development. Here, we investigated probably underlying predisposition variants in patients with suspected colorectal polyposis without variants in APC and MUTYH genes by whole exome sequencing (WES). Twenty-seven patients were included and subjected to germline WES. After filtering out variants for sequencing quality, variant allele fraction frequency, and population frequency, variants were manually prioritized by the ACMG criteria. Among the variants identified, 17 were classified as pathogenic or likely pathogenic (in 12 patients). This study gives information of probably associated polyposis variants in Brazilian patients without germline pathogenic variants in APC and MUTYH genes, supporting the utilization of next-generation sequencing for screening in these patients beyond these genes.

  Study EGAS50000000591

• Exome sequencing of a novel cervical cancer cell line

  Human cancer cell lines are largely used in the searching for new antineoplastic agents. However, due to the artifacts of a long-term in culture, cell lines do not always represent the realistic tumor cell behavior. This has motivated the development of models that better mimetics the tumor tissue, among them, the establishment of primary cell cultures. In this work, we establish and characterized a low-passage cervix cancer cell line from a Brazilian patient with squamous cell carcinoma. The phenotype confirms the epithelial and tumor origin, through cytokeratins, EpCAM, and p16 staining. Whole exome sequencing showed relevant somatic mutations in several genes including BRCA2, TGFBR1, and IRX2 genes. CNV analysis by nanostring and WGS revealed amplification in genes related mainly with kinases proteins, involved in proliferation, migration and cell differentiation, such as EGFR, PIK3CA, and MAPK7. Overexpression of EGFR was confirmed by phospho RTK-array and western blot analysis. Furthermore, the cell was sensitivity to cisplatin, with IC50 13 times lower than SiHa cell line. In conclusion, this cervical cancer cell line presents molecular alterations that are an important tool for leading pre-clinical studies of new drugs that target one or more of the altered pathways.

  Study EGAS00001003343

• Somatic mutations in healthy and leukemic blood progenitors reveal evolutionary mechanisms underlying childhood leukemia and differential patient outcome

  Study EGAS00001004593

• Korean Lung Cancer - 36 pair WES data

  This study includes 36 paired samples of Korean Lung Cancer paitients.36 Lung Cnacer samples are paired with each normal(Saliva derived for control) sequencing data.The results of this WES study were analyzed by Mutect and GATK for ranking germline variants and cancer variants to make mutational profile matrix.

  Study EGAS00001002843

• Tumor Profiler Melanoma Study

  The Tumor Profiler Study is an observational trial combining a prospective diagnostic approach to assess the relevance of in-depth tumor profiling to support clinical decision-making with an exploratory approach to improve the biological understanding of the disease. Technologies used are digital pathology, targeted NGS, single-cell RNA, single-cell DNA, bulk RNA, bulk proteotyping, single-cell CyTOF, imaging mass cytometry, pharmacoscopy, 4i Drug Response Profiling, and cell-free DNA. These technologies were applied to 240 tumor samples collected over 3 years across three cancer indications: metastatic melanoma, metastatic epithelial ovarian cancer, and acute myeloid leukemia (AML). Here, we publish the scRNA, scDNA, and bkRNA data of the melanoma cohort.

  Study EGAS50000000599

• Circulating tumour DNA abundance and potential utility in de novo metastatic prostate cancer

  Several systemic therapeutic options exist for metastatic castration sensitive prostate cancer (mCSPC). Circulating tumour DNA can profile metastatic castration resistant prostate cancer and influence treatment decisions, but remains untested in mCSPC. We set out to determine ctDNA abundance at de novo mCSPC diagnosis and whether ctDNA provides complementary clinically relevant information to a prostate biopsy. We collected and sequenced 77 plasma cell-free DNA samples from 53 newly diagnosed patients with mCSPC. Targeted sequencing was also performed on DNA from 48 diagnostic prostate tissue samples.

  Study EGAS00001003351

• RNA-seq of CRC patient-derived xenograft tumors

  We developed a novel antibody-drug conjugate (ADC), 84-EBET. To analyze mechanism of action of 84-EBET, we obtained bulk RNA-seq data of the patient-derived xenograft (PDX) model derived from colorectal cancer (CRC) patient. The PDX model was treated with 5-fluorouracil + oxaliplatin, 84-EBET or vehicle, and then gene expression changes were analyzed with bulk RNA-seq.

  Study EGAS50000000598

• ICARUS-BREAST01-ExomeSeq

  Efficacy, safety and biomarker analysis of ICARUS-BREAST01: a phase 2 Study of Patritumab Deruxtecan in patients with HR+/HER2- advanced breast cancer. Whole-exome sequencing (WES) is available for 43 tumor samples and 43 blood samples collected at entry into the trial.

  Study EGAS50000000542

• ICARUS-BREAST01-RNAseq

  Efficacy, safety and biomarker analysis of ICARUS-BREAST01: a phase 2 Study of Patritumab Deruxtecan in patients with HR+/HER2- advanced breast cancer. RNA-squencing is available for 44 samples comprising 22 samples collected at entry into the trial and 22 samples collected during treatment (cycle 1 day 3, cycle 1 day 19, or cycle 2 day 3) from 22 patients.

  Study EGAS50000000543

• Neoadjuvant chemotherapy alters the genomic landscape and immune microenvironment of breast cancers

  To characterize the effects of neoadjuvant chemotherapy (NAC) on the genome, transcriptome and tumor infiltrating leukocytes (TILs), we have conducted whole exome and whole transcriptome sequencing of a comprehensive, longitudinal breast cancer cohort consisting of 146 cases and 281 paired tumor samples. In total, 52 (38%) patients achieved pathologic complete response (pCR) while 85 patients (62%) had residual disease with standard chemotherapy regimen. Tumor biopsies were collected for each patient at three time points – pre-treatment, three weeks after the first cycle of anthracycline and cyclophosphamide (AC) and at the time of surgery after 3 more cycles of AC followed by 4 cycles of taxane or taxane plus Herceptin in case of HER2+ subtype.

  Study EGAS00001003354

• Genomic Profiling of Thyroid Cancer Reveals a Role for Thyroglobulin in Metastasis -Part II

  Papillary thyroid carcinoma (PTC) has a wide geographic variation in incidence, being highest in Saudi Arabia where it is only second to breast cancer as the most common cancer among females. Genomic profiling of PTC from Saudi Arabia has not been attempted previously. We performed whole-exome sequencing of 101 PTC samples and the corresponding genomic DNA to identify genes with recurrent somatic mutations, followed by sequencing of these genes using a next-generation gene panel approach in further 785 samples. In addition to BRAF, N-RAS and H-RAS, which have previously been shown to be recurrently mutated in PTC, our analysis highlights additional genes, including thyroglobulin (TG), which harbored somatic mutations in 3% of the entire cohort. Surprisingly, although TG mutations were not exclusive to mutations in the RAS-MAP kinase pathway, their presence was associated with a significantly worse clinical outcome, which suggests a pathogenic role beyond driving initial oncogenesis. Analysis of metastatic PTC tissue revealed significant enrichment for TG mutations (p&lt;0.001), including events of apparent clonal expansion. Our results suggest a previously unknown role of TG somatic mutations in the pathogenesis of PTC and its malignant evolution.

  Study EGAS00001003357

• IMPRESS: Improved methylation profiling using restriction enzymes and smMIP sequencing, combined with a new biomarker panel, creating a multi-cancer detection assay

  Background Despite the worldwide progress in cancer diagnostics, more sensitive diagnostic biomarkers are needed. The methylome has been extensively investigated in the last decades, but a low-cost, bisulfite-free detection method for multiplex analysis is still lacking. Methods We developed a methylation detection technique called IMPRESS, which combines methylation-sensitive restriction enzymes and single-molecule Molecular Inversion Probes. We used this technique for the development of a multi-cancer detection assay for eight of the most lethal cancer types worldwide. We selected 1791 CpG sites that can distinguish tumor from normal tissue based on DNA methylation. These sites were analysed with IMPRESS in 35 blood, 111 tumor and 114 normal samples. Finally, a classifier model was built. Results We present the successful development of IMPRESS and validated it with ddPCR. The final classifier model discriminating tumor from normal samples was built with 358 CpG target sites and reached a sensitivity of 0.95 and a specificity of 0.91. Moreover, we provide data that highlight IMPRESS’s potential for liquid biopsies. Conclusions We successfully created an innovative DNA methylation detection technique. By combining this method with a new multi-cancer biomarker panel, we developed a sensitive and specific multi-cancer assay, with potential use in liquid biopsies.

  Study EGAS50000000624

• Anaplastic_Meningioma_WGS_X10

  Anaplastic meningiomas are a rare, malignant variant of meningioma. At present there is no effective treatment for this cancer. The aim of the study is to identify somatic mutations in anaplastic meningiomas. We plan to sequence a set of 500 known cancer genes in 50 anaplastic meningioma and corresponding peripheral blood DNA samples. Bioinformatics will be used to analyse the results to assess the probability of these mutations being causal and so likely of critical importance for the tumour growth. Identification of these mutations will guide selection of appropriate compounds to effectively treat the disease.

  Study EGAS00001000859

• ctDNA multigenic panel for non-small cell lung cancer

  Detection of actionable mutations in liquid biopsies constitute an important tool for management of non-small cell lung cancer (NSCLC) patients in the era of oncology precision medicine. We aimed to evaluate the actionable alterations using a commercial multi-gene panel in circulating tumor DNA (ctDNA) derived from plasma samples of treatment naïve and prior-treated non-small cell lung cancer (NSCLC) patients. For this, we analyze plasma samples of 30 subjects with non-small cell lung cancer.

  Study EGAS50000000643

• Comprehensive molecular portrait reveals genetic diversity and distinct molecular subtypes of small intestinal neuroendocrine tumors

  This study aims to characterize neuroendocrine tumors of the small intestine (siNETs) from genomic, transcriptomic, epigenomic, and clinical perspectives. Involving 122 patients and 219 samples, we generated whole-genome sequencing data, RNA sequencing data, genotyping arrays, and methylation arrays to conduct an integrative analysis of this rare tumor type. Our findings identify distinct molecular subtypes that correlate with siNET clinical features.

  Study EGAS50000000642

• Single-cell RNA-seq of immune cells sorted from human melanoma tumors

  Tumor immune cell compositions play a major role in response to immunotherapy but the heterogeneity and dynamics of immune infiltrates in human cancer lesions remain poorly characterized. Here we identify conserved intratumoral CD4 and CD8 T cell behaviors in scRNA-seq data from 25 melanoma patients. We discover a large population of CD8 T cells showing continuous progression from an early effector "transitional" into a dysfunctional T cell state. CD8 T cells that express a complete cytotoxic gene set are rare, and TCR sharing data suggest their independence from the transitional and dysfunctional cell states. Notably, we demonstrate that dysfunctional T cells are the major intratumoral proliferating immune cell compartment and that the intensity of the dysfunctional signature is associated with tumor-reactivity. Our data demonstrate that CD8 T cells previously defined as exhausted, are in fact a highly proliferating, clonal and dynamically differentiating cell population within the human tumor microenvironment.

  Study EGAS00001003363

• Singapore Gastric Cancer Consortium GeoMx DSP tissue microarray (SGCC TMA) cohort

  Gastric cancer (GC) remains a significant global health challenge due to its high heterogeneity, with intratumoral heterogeneity (ITH) posing a major obstacle to effective patient outcomes. In this study, utilizing GeoMx Digital Spatial Profiler (DSP) technology, we specifically investigated ITH within GC patients by comparing tumor core regions to tumor edge regions. Our findings indicate that tumor edge regions exhibit more advanced tumor activity, akin to the G2-like progressed state, compared to tumor core regions. The findings confirm the spatial locations of G2 RNA-ITH subregions and support the conclusions drawn from the discovery cohort.

  Study EGAS50000000640

• Spatial Profiling of Patient-Matched HER2 Positive Gastric Cancer Reveals Resistance Mechanisms to Trastuzumab and Trastuzumab Deruxtecan Sequencing

  HER2-positive gastric cancer (HER2+ GC) exhibits significant intra-tumoral heterogeneity and frequent development of resistance to HER2-targeted therapies. This study aimed to characterize the spatial tumor microenvironment (TME) and identify mechanisms of resistance to HER2 blockade including trastuzumab and trastuzumab deruxtecan (T-DXd) in HER2+ GC, with the goal of informing novel therapeutic strategies. We performed spatial transcriptomics on pre- and post-treatment samples from patients with HER2+ metastatic GC who received trastuzumab-based therapy.

  Study EGAS50000000636

• Arcagen - Extra-pulmonary neuroendocrine tumour or cancer grade 3 (NET / NEC G3) domain

  Arcagen is an EORTC/SPECTA pan-European project that aims to recruit 1000 rare cancer patients from different tumour domains of EURACAN. This study collected samples from advanced or metastatic rare cancer from patients older than 12, and analysed them using Foundation Medicine next-generation sequencing (NGS) panels (FoundationOne CDx for FFPE samples or FoundationOne Liquid CDx for blood samples). Here were are submitting the dataset that contains NGS files from patients with extra-pulmonary neuroendocrine tumour or cancer grade 3 (NET / NEC G3) (n=85).

  Study EGAS50000000644

• 10x genomics single cell RNA-seq and ATAC-seq from 10 pre-menopausal patients fimbriae and ampullary part of the fallopian tube

  The fallopian tube, connecting the uterus with the ovary, is a dynamic organ that undergoes cyclical changes and is the site of several diseases, including serous cancer. Here, we use single-cell technologies to construct a comprehensive cell map of healthy pre-menopausal fallopian tubes, capturing the impact of the menstrual cycle and menopause on different fallopian tube cells at the molecular level. The comparative analysis between pre- and post-menopausal fallopian tubes reveals substantial shifts in cellular abundance and gene expression patterns, highlighting the physiological changes associated with menopause. Further investigations into menstrual cycle phases illuminate distinct molecular states in secretory epithelial cells caused by hormonal fluctuations. The markers we identified characterizing secretory epithelial cells provide a valuable tool for classifying ovarian cancer subtypes.

  Study EGAS50000000628

• analysis of immune infiltration in colorectal cancer metastasis

  Metastatic colorectal cancer (mCRC) is the main cause of CRC mortality, with limited treatment options. Although immunotherapy has benefited some cancer patients, mCRC typically lacks the molecular features that respond to this treatment. However, recent studies indicate that the immune microenvironment of mCRC may be modified to enhance the effect of immune checkpoint inhibitors. This study aimed to explore the metastatic immune microenvironment by comparing immune cell populations in colorectal liver (CLM), lung (mLu) and peritoneal (PM) metastases.

  Study EGAS50000000652

• Diversity of the immune microenvironment and response to checkpoint inhibitor immunotherapy in mucosal melanoma

  Mucosal melanoma (MucM) is a rare cancer with a poor prognosis and low response rate to immune checkpoint inhibition (ICI) compared to cutaneous melanoma (CM). To explore the immune microenvironment and potential drivers of MucM’s relative resistance to ICI drugs, we characterized 101 MucM tumors (43 head and neck, 31 female urogenital, 13 male urogenital, 11 anorectal, and 3 other gastro-intestinal) using bulk RNA-sequencing (RNAseq). The original publication is written by JL Vos, JJH Traets, et al. and published in JCI Insight in 2024.

  Study EGAS50000000631

• Plasma ctDNA is a tumor tissue surrogate and enables clinical-genomic stratification of metastatic bladder cancer

  Study EGAS00001004615

• Ultra-sensitive ctDNA monitoring required for predicting response and resistance to immunotherapy in advanced melanoma

  Circulating tumor DNA (ctDNA) monitoring in peripheral blood has shown promise for disease surveillance and prognostication of ICI response. Yet even in the metastatic context, ctDNA signals can be missed, suggesting the need for increased assay sensitivity. We used a tumor-informed ctDNA assay capable of detection down to 1 part-per-million (PPM) ctDNA to profile 188 plasma samples from 23 melanoma patients receiving ICI over several years. Residual disease was detected in ctDNA over a broad range, from 130,000 PPM down to 2.3 PPM, with approximately a quarter of detections below 50 PPM. Early on-treatment increases in ctDNA level, and both ctDNA-based molecular clearance (mCR) and molecular progression (mPD) were all prognostic of both OS and PFS. Additionally, mCR consistently preceded radiographic imaging. Our results show the importance and utility of an ultra-sensitive ctDNA assay in advanced melanoma treated by ICI with potential implications for other cancers.

  Study EGAS50000000550

• Microsatellite unstable colorectal cancers

  Immune escape has been recognised as one of the hallmarks of cancer. Overcoming this immunomodulatory process by tumour cells has become a major therapeutic target. Here we utilize organoid technology to study immune-cancer interactions and assess immunomodulation by colorectal cancer (CRC). Transcriptional profiling and flow cytometry revealed that organoids maintain differential expression of immunomodulatory molecules present in primary tumours. Finally, we established a method to model antigen-specific epithelial cell killing and cancer immunomodulation in vitro using CRC organoids co-cultured with cytotoxic T cells. Our method may serve as a first step to rebuilding the tumor microenvironment in vitro.

  Study EGAS00001003366

• Integrated genomic characterization of adrenocortical carcinoma

  Adrenocortical carcinomas (ACC) are aggressive cancers originating in the cortex of the adrenal glands. Despite the overall poor prognosis, ACC outcome is heterogeneous. CTNNB1 and TP53 mutations are frequent in these tumors, but the complete spectrum of genetic changes remains undefined. Exome sequencing and SNP array analysis of 45 ACC revealed recurrent alterations in known drivers (CTNNB1, TP53, CDKN2A, RB1, MEN1) and genes not previously reported to be altered in ACC (ZNRF3, DAXX, TERT and MED12), which were validated in an independent cohort of 77 ACC. The cell-surface transmembrane E3 ubiquitin ligase ZNRF36 was the gene the most frequently altered (21%), and appears as a potential novel tumor suppressor gene related to the ß-catenin pathway. Our integrated genomic analyses led to the identification of two distinct molecular subgroups with opposite outcome. The C1A group of poor outcome ACC was characterized by numerous mutations and DNA methylation alterations, whereas the C1B group with good prognosis displayed a specific deregulation of two miRNA clusters. Thus, aggressive and indolent ACC correspond to two distinct molecular entities, driven by different oncogenic alterations.Array based dataset for this study has been made public at:http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE49280.

  Study EGAS00001000665

• Oncogenic FOXL2C134W has gain-of-function chromatin remodeling activity that reprograms glucocorticoid receptor occupancy to promote ovarian granulosa cell tumor growth

  Adult type ovarian granulosa cell tumors (AGCTs) are rare malignancies with near universal somatic mutation c.C402G (p.Cys134Trp) in FOXL2, a forkhead box-family transcription factor important for ovarian function. Relapsed AGCT is incurable and the mechanism of the unique FOXL2 mutation remains incompletely understood. To identify FOXL2C134W-dependent pharmacologic synergies, we created and characterized endogenous FOXL2 isogenic AGCT cells and an AGCT tumoroid biobank. A drug screen identified that glucocorticoids promote FOXL2C134W-dependent AGCT growth. Epigenetic investigation revealed that the Cys134Trp mutation exposes latent DNA sequence-specific pioneering activity in FOXL2, a unique oncogenic mechanism. FOXL2C134W pioneering activity redirects glucocorticoid receptor chromatin occupancy to drive hyaluronan synthase 2 gene expression and increase extracellular hyaluronan secretion. Treatment of AGCT models with hyaluronidase reduces viability and this effect can be rescued by dexamethasone. Thus, gain-of-function pioneering activity contributes to the oncogenic mechanism of FOXL2C134W and creates a potentially targetable synergy with glucocorticoid signaling.

  Study EGAS50000000622

• Chromatin run-on and RNA sequencing of fibrolamellar carcinoma

  Fibrolamellar carcinoma (FLC) is a rare, therapeutically intractable liver cancer that disproportionately affects youth. Here we used chromatin run-on sequencing to characterize the enhancer landscape in FLC and RNA sequencing to identify dysregulated genes in FLC.

  Study EGAS00001004169

• WGS of liver cancer in the Japanese population

  Hepatocellular carcinoma (HCC) is the third leading cancer-related cause of death and the seventh most common form of cancer worldwide, with an estimate of more than 700,000 new cases each year. The most established risk factors of HCC are chronic HBV and HCV infection. HBV infection is responsible for over 50% of the worldwide attributable risk of HCC, especially in East Asia and Africa, while in Japan and several Western countries HCV infection is the most common risk factor for HCC. To gain insights into the molecular alterations of virus-associated HCC, we performed whole genome sequencing (WGS) of 321 HCC tumors from 159 patients. This work was performed as a part of the ICGC (International Cancer Genome Consortium) project.

  Study EGAS00001000678

• DNA-methylation variability in normal mucosa of patients with adenomatous polyps: a marker of field cancerization

  A study linking DNA methylation modifications in the normal mucosa of the right colon in individuals with adenomatous polyp formation

  Study EGAS00001007666

• Detection of mutational patterns in cell free DNA (cfDNA) of colorectal cancer by custom amplicon sequencing

  Monitoring the mutational patterns of solid tumors during cancer therapy is a major challenge in oncology. Analysis of mutations in cell free (cf) DNA offers a non-invasive approach to detect mutations that may be prognostic for disease survival or predictive for primary or secondary drug resistance. A main challenge for the application of cfDNA as a diagnostic tool is the diverse mutational landscape of cancer. Here, we developed a flexible end-to-end experimental and bioinformatics workflow to analyze mutations in cfDNA using custom amplicon sequencing. Our approach relies on open software tools to select primers suitable for multiplex PCR using minimal cfDNA as input. In addition, we developed a robust linear model to identify specific genetic alterations from sequencing data of cfDNA. We used our method to design a custom amplicon panel suitable for detection of hotspot mutations relevant for colorectal cancer and analyzed mutations in serial cfDNA samples from 34 patients with advanced colorectal cancer. Our data demonstrates that recurrent and patient-specific mutational patterns can be reliably detected for the majority of patients. Furthermore, we show that the allele frequency of mutations in cfDNA correlates well with disease progression. Finally, we demonstrate that monitoring of cfDNA can outperform the predictive power of currently used tumor markers and reveal mechanisms of resistance to anti-EGFR antibody treatment.

  Study EGAS00001003382

• Single cell multi-omics analysis of chromothriptic medulloblastoma highlights genomic and transcriptomic consequences of genome instability

  Chromothripsis is a form of genome instability, whereby a presumably single catastrophic event generates extensive genomic rearrangements of one or few chromosome(s). However, little is known about the heterogeneity of chromothripsis across different clones from the same tumor, as well as changes in response to treatment. We analyzed single-cell genomic and transcriptomic alterations linked with chromothripsis in human p53-deficient medulloblastoma (n=7). We reconstructed the order of somatic events, identified early alterations likely linked to chromothripsis and depicted the contribution of chromothripsis to malignancy. We characterized subclonal variation of chromothripsis and its effects on double-minute chromosomes, cancer drivers and putatively druggable targets. Furthermore, we highlighted the causative role and the fitness consequences of specific rearrangements in neural progenitors.

  Study EGAS00001005410

• MutWP6__CRUK_Grand_Challenge_Mutographs_of_Cancer__alkylating_agents

  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. Within Mutographs, work lead by the Sanger Institute will investigate whether detection of somatic mutations and mutational signatures in circulating white blood cells can be developed into a practical, generic system for surveying and monitoring multiple different endogenous and exogenous exposures, providing an ‘observatory’ on somatic mutational processes in humans. Whole genome sequences are generated at the Wellcome Sanger Institute (Illumina HiSeqX). Somatic mutational signatures are subsequently extracted by non-negative matrix factorisation methods. 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 EGAS00001003637

• MutWP6__CRUK_Grand_Challenge_Mutographs_of_Cancer__oncology_agents

  he 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. Within Mutographs, work lead by the Sanger Institute will investigate whether detection of somatic mutations and mutational signatures in circulating white blood cells can be developed into a practical, generic system for surveying and monitoring multiple different endogenous and exogenous exposures, providing an ‘observatory’ on somatic mutational processes in humans. Whole genome sequences are generated at the Wellcome Sanger Institute (Illumina HiSeqX). Somatic mutational signatures are subsequently extracted by non-negative matrix factorisation methods. 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 EGAS00001004125

• HSC_population_dynamics___PX001_samples

  My research project aims to use the clonal dynamics of spontaneously occurring somatic mutations to answer fundamental questions about human haematopoietic stem cell (HSC) biology. The four major questions I will address are: 1. How do age and aging affect normal human HSC dynamics in vivo? 2. How do in vivo perturbations, particularly chemotherapy and increased levels of reactive oxygen species, affect HSC population dynamics? 3. Is response to in vitro perturbation heritable and/or correlated with other features such as age of individual and contribution of the lineage to peripheral blood? 4. How are HSC dynamics altered in people with early driver mutations (clonal haematopoiesis)?

  Study EGAS00001004146

• HSC_population_dynamics___KX009_samples

  My research project aims to use the clonal dynamics of spontaneously occurring somatic mutations to answer fundamental questions about human haematopoietic stem cell (HSC) biology. The four major questions I will address are: 1. How do age and aging affect normal human HSC dynamics in vivo? 2. How do in vivo perturbations, particularly chemotherapy and increased levels of reactive oxygen species, affect HSC population dynamics? 3. Is response to in vitro perturbation heritable and/or correlated with other features such as age of individual and contribution of the lineage to peripheral blood? 4. How are HSC dynamics altered in people with early driver mutations (clonal haematopoiesis)?

  Study EGAS00001004580

• HSC_population_dynamics___KX010_samples

  My research project aims to use the clonal dynamics of spontaneously occurring somatic mutations to answer fundamental questions about human haematopoietic stem cell (HSC) biology. The four major questions I will address are: 1. How do age and aging affect normal human HSC dynamics in vivo? 2. How do in vivo perturbations, particularly chemotherapy and increased levels of reactive oxygen species, affect HSC population dynamics? 3. Is response to in vitro perturbation heritable and/or correlated with other features such as age of individual and contribution of the lineage to peripheral blood? 4. How are HSC dynamics altered in people with early driver mutations (clonal haematopoiesis)?

  Study EGAS00001004581

• Circulating tumour DNA (ctDNA) data of High Grade Serous Ovarian Cancer Patients

  This study contains circulating tumour DNA (ctDNA) data derived from longitudinal plasma samples of High Grade Serous Ovarian Cancer (HGSC) patients belonging to the DECIDER study (NCT04846933). Ovarian cancer kills more than 40 000 women in Europe each year, and HGSC is the most common and most difficult to treat subtype of this disease. This study contains different sequencing datasets with samples from different stages during the treatment of the patients.

  Study EGAS50000000674

• FFPE_CPA_Accreditation_Study__Part_2

  FFPE CPA accreditation of genome-scale sequencing in routinely collected formalin-fixed paraffin-embedded (FFPE) cancer specimens versus matched fresh-frozen samples using targeted pulldown capture prior to Illumina sequencing.

  Study EGAS00001000692

• Lymphocyte_LCM_WGS

  Using whole genome sequencing of lymphocytes excised from human tissue using laser capture microscopy (LCM), we identify the mutations arising in these microenvironments. This work will contribute towards developing a catalogue of mutations present in tissue resident lymphocytes across a range of tissues, and will characterize the mutational signatures that result from each microenvironment.

  Study EGAS00001003384

• HSC_population_dynamics___CB001_samples

  My research project aims to use the clonal dynamics of spontaneously occurring somatic mutations to answer fundamental questions about human haematopoietic stem cell (HSC) biology. The four major questions I will address are: 1. How do age and aging affect normal human HSC dynamics in vivo? 2. How do in vivo perturbations, particularly chemotherapy and increased levels of reactive oxygen species, affect HSC population dynamics? 3. Is response to in vitro perturbation heritable and/or correlated with other features such as age of individual and contribution of the lineage to peripheral blood? 4. How are HSC dynamics altered in people with early driver mutations (clonal haematopoiesis)?

  Study EGAS00001003397

• Study of biomarkers implicated in radio-immunotherapy response in metastatic cancer

  Immuno-radiotherapy may improve outcomes for patients with advanced solid tumors, although optimized combination modalities remain unclear. Here, we report the analysis from the SABR-PDL1 (NCT02992912) trial that evaluated the PD-L1 inhibitor atezolizumab in combination with stereotactic body radiation therapy (SBRT) in patients with advanced cancer.

  Study EGAS50000000681

• MOSAIC - Multi-Omics Spatial Atlas In Cancer

  MOSAIC is a collaborative initiative founded by Owkin, Lausanne University Hospital (CHUV), Charité Universitätsmedizin Berlin, University Hospital Erlangen (UKER), Gustave Roussy Institute in Paris, and University of Pittsburgh. The goal of MOSAIC is to build the largest collection of spatial omics data in cancer. By integrating comprehensive high quality clinical annotations with advanced deep profiling techniques, MOSAIC aims to uncover novel cancer subtypes and identify key drug targets and biomarkers within them.

  Study EGAS50000000689

• RNA sequencing data from patient derived colorectal cancer organoids

  This study aimed to develop NovumRNA, a bioinformatics pipeline designed to predict non-canonical tumor-specific antigens (ncTSAs) from human tumor RNA-sequencing data, potentially broadening the target pool for cancer neo-epitope-based immunotherapies. The pipeline was utilized to analyze RNA-seq data from ten patient-derived colorectal cancer (CRC) organoids, representing seven microsatellite stable (MSS) and three microsatellite instable (MSI) tumors. The goal was to explore the ncTSA landscape in CRC, particularly in MSS cases, which typically exhibit low tumor mutational burden and limited response to current immunotherapies. The study identified comparable ncTSA burdens across MSI and MSS tumors, suggesting new avenues for immunotherapy targeting non-canonical antigens in CRC. NovumRNA is available at: https://github.com/ComputationalBiomedicineGroup/NovumRNA.

  Study EGAS50000000685

• Expression quantitative trait loci influence DNA damage-induced apoptosis in cancer

  The analysis of e2QTL allows for the identification of context-specific eQTL effects (Kim-Hellmuth et al. (2017), PMID: 28814792). To evaluate how inter-individual genetic variability influences the regulation of DNA damage-induced apoptosis, we performed e2QTL analysis of CD8+ T cells from 461 healthy European participants stimulated with high doses of 5 different carcinogens. These include Methyl-methanesulfonate (MMS), tert-butyl-hydroperoxide (TBOOH), benzo(a)pyrene-7,8-diol-9,10-epoxide (BPDE), 4-hydroxycyclophosphamide (HC) and UVC radiation.

  Study EGAS50000000666

• RNA sequencing data from glioblastoma primary cell lines treated with indisulam

  This study aimed to develop NovumRNA, a bioinformatics pipeline designed to predict non-canonical tumor-specific antigens (ncTSAs) from human tumor RNA-sequencing data, potentially broadening the target pool for cancer neo-epitope-based immunotherapies. The splicing-modulating drug indisulam was investigated for its potential to induce aberrant transcriptomes, potentially increasing ncTSAs, subsequently predicted by NovumRNA. Four glioblastoma primary cell lines were derived from patient Cavitron Ultrasonic Aspirator (CUSA) material, cultured as neurospheres, and treated with indisulam or vehicle control. RNA was extracted at 6 and 16 hours post-treatment and sequenced using the NovaSeq platform. The resulting RNA-seq data was analyzed with NovumRNA, using healthy brain GTEx samples as controls, to identify and validate ncTSAs induced by indisulam treatment. NovumRNA is available at: https://github.com/ComputationalBiomedicineGroup/NovumRNA.

  Study EGAS50000000680

• Genome-wide NanoRCS of cfDNA from plasma of healthy individuals

  Levels of circulating tumor DNA (ctDNA) in liquid biopsies may serve as a sensitive biomarker for real-time, minimally-invasive tumor diagnostics and monitoring. However, detecting ctDNA is challenging, as much fewer than 5% of the cell-free DNA in the blood typically originates from the tumor. To detect lowly abundant molecules, extremely sensitive sequencing methods are required. We adapted a new technique, NanoRCS, which is based on Oxford Nanopore sequencing of concatenated copies of a single DNA molecule for genome-wide sequencing, and applied this to plasma of healthy controls.

  Study EGAS50000000695

• IL-27 promotes tumour control by enhancing cytotoxic T cell function

  Cytotoxic CD8+ T lymphocytes (CTL) are essential for anti-tumour immunity but are frequently dysfunctional in established tumours. Here, we show that expression of a CTL signature is strongly associated with IL-27 expression in diverse human and murine tumours. In mice, IL-27 acts directly on tumour-specific CTL to promote their persistence and effector function in the tumor microenvironment. Moreover, treatment with inducible IL-27 overexpression or a half-life-extended IL-27 protein in vivo is well tolerated, induces regression of large established tumours, drives an enhanced cytotoxic program in anti-tumour CTL, and synergizes with PD-L1 blockade. In cancer patients treated with anti-PD-1 or anti-PD-L1 therapy, high expression of IL-27 is associated with improved clinical response. Finally, IL-27 increases cytotoxicity and limits terminal differentiation of human CD8+ T cells during chronic antigen exposure. Our data demonstrate that endogenous IL-27 is essential for anti-tumour immunity and that IL-27 receptor agonism can safely improve anti-tumor T cell responses alone or in combination with PD-L1 blockade.

  Study EGAS50000000694

• Targeted pancancer RNA-Seq

  This dataset contains targeted RNA-Seq generated with the Illumina RNA Pan-Cancer panel. It comprises 2200 cancers from children and adults. The cancers represent a wide range of CNS, solid and haematopoeitic tumours. Samples are from pathology specimens including FFPE, fresh frozen, bone marrow aspirate and peripheral blood.The data is used for tumour driver identification. SNVs, indels and fusion detection.

  Study EGAS50000000700

• ESGI_Exome_sequencing_in_Circulating_Tumor_Cells_to_determine_therapy_related_markers_____

  The objectives of this project are the identification of markers related to cancer therapy resistance in the blood of breast cancer patients and to study the genetic changes in cancer cells during this development of resistance. Whole genome amplified DNA from Circulating Tumor Cells (CTCs), selected during the course of systemic treatment from blood of metastatic breast cancer patients, will be exome sequenced . The patients selected for this study did not respond to therapy.

  Study EGAS00001000747

• Characterization of stromal tumor-infiltrating lymphocytes and genomic alterations in metastatic lobular breast cancer

  Study EGAS00001004641

• RNA sequencing of follicular T cell lymphoma

  Study EGAS00001004646

• A comprehensive DNA methylation landscape of human and mouse cell lines derived from hematological malignancies

  Human cancer cell lines constitute useful models to study the primary disease and many relevant findings in tumor biology have been originated from them since the first immortalized cell line (HeLa) was obtained. The easy experimental intervention, the purity of the transformed cells and their versatility to undergo high-throughput screenings represent advantageous features of the established cancer cell lines. In recent years, major efforts have characterized in detail the multiomics make-up of hundreds of cancer cell lines and studied their association with sensitivity to anticancer drugs. Most of these studies have been genetic-centric and have not characterized in detail the epigenetic profiles underlying the characteristics of these cells or their impact on the efficacy of antitumoral compounds. In this regard, a past version of a DNA methylation microarray or a less accessible and more time-consuming such as reduced representation bisulfite sequencing have been used in those attempts to interrogate the epigenetic setting. Herein, we have obtained the DNA methylation profiles of 210 cell lines derived from hematological malignancies utilizing comprehensive DNA methylation microarrays that interrogates more than 850,000 and 285,000 CpG sites from human and mouse genomes, respectively. Importantly, we also provide a pharmacoepigenetic example of the potential use of this resource by showing how DNA methylation can predict response to nucleoside analogues.

  Study EGAS50000000627

• WES for CNV-verified CTCs enriched by high-throughout microfluidic device from entire cancer patient leukopak

  WES analysis (illumina platform, PE150, 100x coverage) was performed on a pool of copy number variation (CNV)-verified CTCs that were enriched using high-throughout microfluidic device from entire leukopak from patients with metastatic prostate cancer (GU-1 and GU-2).

  Study EGAS50000000724

• WGS of CTCs enriched using high-throughout microfluidic device from entire cancer patient leukopak

  Single-cell low-pass WGS analysis (illumina platform, PE150, 1-2x coverage) was performed on CTCs enriched using high-throughout microfluidic device from entire leukopak from patients with metastatic prostate cancer (GU-1 and GU-2) and metastatic hepatocellular carcinoma (HCC-1 and HCC-2).

  Study EGAS50000000723

• Unraveling metastatic progression of breast cancer

  To reconstruct the trajectories of BC progression, we performed exome sequencing (Illumina HiSeq2000, Truseq DNA sample preparation kit v2 and Exome Enrichment Kit v2; alignement done with BWA, substitutions and indels called with GATK and DINDEL respectively) coupled to validation by Sequenom and deep re-sequencing (ongoing), as well as copy number (CN) analyses (Oncoscan, Affymetrix) on DNA from matched primary (n=1-6/pt), axillary lymph node (ALN, n=1-6 for 4 pts), local recurrence (for 1 pt) and distant metastatic (n=1-5/pt) FFPE samples obtained from an autopsy series of 10 BC pts.

  Study EGAS00001000760

• SAPCS Blood RNA-seq of prostate cancer patients

  The study aims to quantify the gene expression in blood samples in 20 prostate cancer patients under the Southern African Prostate Cancer Study (SAPCS). The objective is to identify a list of differentially expressed genes.

  Study EGAS50000000702

• Childhood B-cell acute lymphoblastic leukemia genomic and transcriptomic data

  The aim of the two studies was: 1) to genetically characterise childhood leukemia patients that lacked established cytogenetic abnormalities (termed B-other leukemia) and assess the clinical features of recurrent genetic abnormalities. 2) Assess the accuracy of whole genome sequencing as a diagnostic genetic test in childhood leukemia, relative to other traditional methods (karyotyping, FISH, MLPA) and whole transcriptome sequencing. As a result, this study includes targeted DNA-sequencing, whole genome sequencing and whole transcriptome sequencing data on childhood leukemia patients enrolled on UK clinical trials (UKALL2003 and UKALL2011).

  Study EGAS00001006863

• Dynamics of tumor ecosystems and microbiome in response to neoadjuvant atezolizumab, bevacizumab, and FOLFOX treatment in patients with unresectable colorectal cancer with liver metastasis

  This study aims to explore the effects of neoadjuvant atezolizumab, bevacizumab, leucovorin, 5-fluorouracil, and oxaliplatin (ABFOLFOX) in patients with unresectable colorectal liver metastases (CRLM), focusing on the molecular dynamics of tumor ecosystems (TE) of CRLM and their impact on treatment outcomes. The study comprises two cohorts with CRLM tissue samples analyzed with RNA sequencing and immunohistochemical staining: cross-sectional cohort A (n = 60, CRLM treated with or without neoadjuvant chemotherapy) and prospective cohort B (n = 20 with serial sampling and treated with ABFOLFOX). Shotgun metagenomic sequencing was done for stool samples from cohort B.

  Study EGAS50000000677

• Molecular counting enables accurate and precise quantification of methylated ctDNA for tumor-naive cancer therapy response monitoring

  Personalized cancer treatment can significantly extend survival and improve quality of life for many patients, but accurate and real-time therapy response monitoring remains challenging. To overcome logistical and technical challenges associated with therapy response monitoring via imaging scans or assays that track the variant allele fraction (VAF) of somatic mutations in circulating tumor DNA (ctDNA), we developed a tumor-naive liquid biopsy assay that leverages Quantitative Counting Template (QCT) technology to accurately and precisely quantify methylated ctDNA (Northstar ResponseTM).

  Study EGAS50000000734

• Molecular correlates for HPV-negative head and neck cancer engraftment prognosticate patient outcomes

  Head and neck squamous cell carcinoma (HNSCC) tumors were sampled from 88 patients. Samples were implanted subcutaenously into the flank of NOD/SCID/IL2R-/- mice. Mice were then monitored weekly for tumor growth and the time of initial palpation was recorded. Mice were euthanized when tumors reached 15 mm in diameter or after 6 months. If no tumor formed by 6 months, the patient tumor was defined as Non-engrafter (N). RNA-seq was performed on all primary tumor samples and successfully engrafted patient-derived xenograft (PDX) samples.

  Study EGAS50000000714