4779 results for "*oma"

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• Brain tumor sequencing data

  This study contains tumor DNA (with matched normal) for 1 medulloblastoma and 1 ependymoma patient. Tumor RNA sequencing data is also present for the medulloblastoma patient

  Study EGAS00001006352

• Glioma sequencing data

  This study contains sequencing data for various glioma subtypes (astrocytoma, glioblastoma, diffuse midline glioma).

  Study EGAS00001006355

• Clonal dominance defines metastatic dissemination in pancreatic cancer

  Using patient-derived cells from a pancreatic ductal adenocarcinoma, we created orthotopic clonal replica tumors to trace in an unbiased fashion clonal lineage dynamics of unperturbed tumor expansion and dissemination over time. The model revealed the complex multifaced nature of tumor clonal expansion and uncovered brisk changes in fitness that lead to a continuous reshuffling of tumor clonal architecture and alternating clonal dominance as a distinct feature of cancer growth. Paired analysis of clonal lineages in primary and secondary sites revealed fitness in the primary tumor as a major contributor to dissemination, although other clonal intrinsic and extrinsic factors may contribute to metastatic process. Molecular characterization of lineages with differential metastatic potential identified actionable strategy to suppress dissemination at the subclonal level.

  Study EGAS00001006358

• Revealing active mutational processes in tumours using DigiPico/MutLX at unprecedented accuracy

  Active mutational processes in a tumor result in genetic micro-heterogeneity that can determine the tumor’s evolutionary trajectory. Identification of these processes by studying micro-heterogeneity can unveil novel aspects of tumor evolution with potential therapeutic implications. Such studies, however, are inherently problematic because of the discovery of excessive false positive mutations. Here we report the optimization and validation of a robust whole genome sequencing and analysis pipeline (DigiPico/MutLX) that virtually eliminates false positive results. Using our method, we identified, for the first time, a sub-clonal local hyper-mutation (kataegis) event in a recurrent ovarian carcinoma, which was unidentifiable from the bulk WGS data of the same tumor. Overall, we propose DigiPico/MutLX method as a powerful framework for the reliable study of genetic micro-heterogeneity in tumor and normal tissues.

  Study EGAS00001003555

• Analysis of four key cell types (epithelial, fbroblast, myeloid and T cells)

  Alterations of the normal prostate epithelial cell genome trigger the emergence of carcinoma, however cancer-only analyses of genomic aberrations have resulted in little clinical translation. A deep understanding of the tumor microenvironment is likely to inform on key drivers of disease progression and novel therapeutic opportunities. We investigated the role of key cell types along disease progression, profiling the RNA abundance of 52 samples from 13 patients enriched for one of four key cell types, spanning a wide CAPRA-S risk score range. Using a novel differential transcription Bayes method, TABI, we avoided a priori patient stratification, and mapped transcriptional alteration events to specific risk scores. The developmental and cell-type resolution yielded a landscape of concurrent transcriptional alterations from the tumour microenvironment, including key hallmarks. These transcriptional signatures permitted the identification of a “high survival” patient cluster in an independent prostate cancer dataset. Most importantly, together with our integrated transcriptional analysis, differential tissue composition analysis provided evidence for a key role for monocytes and macrophages in prostate cancer progression and disease recurrence.

  Study EGAS00001003579

• Detection and genomic analysis of BRAF fusions in Juvenile Pilocytic Astrocytoma through the combination and integration of multi-omic data

  Juvenile Pilocytic Astrocytoma (JPAs) are highly vascular tumors and show pervasive immune infiltration, which can lead to low tumor cell purity in clinical samples. In some instances, this results in gene fusions that are difficult to detect with conventional omics approaches including RNA-Seq. To this effect, we applied RNA-Seq as well as linked-read whole-genome sequencing and in situ Hi-C as new approaches to detect and characterize low-frequency gene fusions at the genomic, transcriptomic and spatial level. Overall, we demonstrate the power of integrating multi-omic datasets to identify low frequency fusions and characterize the JPA genome at high resolution.

  Study EGAS00001006388

• Profiling of childhood neuroblastoma and the immune microenvironment by single-cell sequencing of RNA and TCR

  Neuroblastoma tumor cells and their tumor microenvironment are studied by single-cell RNA sequencing of primary neuroblastoma tumors and neuroblastoma-infiltrated tissues/metastases. Both diagnostic samples, taken pre-treatment and samples taken after induction chemotherapy at surgical resection and biopsies from relapse samples are included.  For a number of patients single-cell RNA sequencing of blood samples (controls) are included and additionally we performed single-cell T cell receptor sequencing (TCR) on the tumor and blood samples. With this study, we will focus on identifying differences in tumor cells and their (immune) microenvironment 1) before and after treatment or at relapse and 2) between primary tumors and infiltrated tissues/metastases. Moreover, with TCR sequencing we aim to unveil immune cell dynamics in patients with neuroblastoma.

  Study EGAS00001006823

• Proteogenomics reveals two distinct biological pilocytic astrocytoma subgroups

  Pilocytic astrocytoma (PA) is the most common pediatric brain tumor and driven by aberrant MAPK signaling, typically mediated by BRAF alterations. While five-year overall survival rates exceed 95%, tumor recurrence constitutes a major clinical challenge in incompletely resected tumors despite chemotherapeutic or radiation based therapies. Therefore, we used proteogenomics to discern the biological heterogeneity of PA to improve classification of this tumor entity and identify novel therapeutic targets. Our proteogenomics approach integrates RNA sequencing and LC/MS-based proteomic profiling data from a cohort of 58 confirmed, primary PA samples. An integrative genomics approach was conducted to discern the biological heterogeneity of PA and to identify aberrant pathway activation in these biological subgroups. In summary, Pilocytic astrocytomas segregate into two groups where younger patients are significantly associated with Group 1. Importantly, we validate the two distinct biological subgroups in two non-overlapping cohorts. The biological heterogeneity seen here may improve biological classification and reveal novel therapeutic targets specifically useful for non-resectable tumors with high risk of recurrent or progressive disease.

  Study EGAS00001006402

• Dedifferentiated_Melanoma_RNAseq

  De- and transdifferentiation of melanoma is a rare histopathological phenomenon that has not be characterised genetically. In this project we plan to sequence the genomes of de and transdifferentiated cases so as to define their genetic make-up.

  Study EGAS00001003601

• Y90 radioembolization followed by intravenous Nivolumab for advanced hepatocellular carcinoma

  To evaluate the efficacy of combination therapy with ICI and RT in patients, a Phase II trial (CA209-678) was conducted to investigate the efficacy and safety of Y90-RE followed by nivolumab in patients with advanced HCC (NCT03033446, n = 36). Interestingly, the ORR was found to be 30.6% in all patients and 43.5% when restricted to patients with only intrahepatic tumors, suggesting possible synergism between Y90-RE and ICI. Here we present whole exome sequencing (WES) and RNA-seq data for 33 patients treated with Y90 radioembolization followed with Nivolumab.

  Study EGAS00001006834

• Repurposing azacitidine and carboplatin to prime immune checkpoint blockade-resistant melanoma for anti-PD-L1 re-challenge

  Purpose: Drug repurposing offers the opportunity for chemotherapy to be used to re-establish sensitivity to immune checkpoint blockade (ICB) therapy. Here we investigated the clinical and translational aspects of an early phase II study of azacitidine and carboplatin priming for anti-PDL1 immunotherapy (Avelumab) in patients with advanced ICB-resistant melanoma. Experimental Design: 20 participants with ICB resistant metastatic melanoma received 2 x 4-week cycles of azacitidine and carboplatin followed by ICB re-challenge with anti-PD-L1 avelumab. The primary objective was overall response rate after priming and ICB re-challenge. Secondary objectives were Clinical benefit rate (CBR), progression-free survival (PFS) and overall survival (OS). Translational correlation analysis of HLA-A and PD-L1 expression, RNA-seq and reduced representation bisulfite sequencing (RRBS) of biopsies at baseline, after priming and after 6 cycles of avelmuab was performed. Results: The ORR determined after azacitidine and carboplatin priming was 10% (2/20) with 2 partial responses (PR). The ORR determined after priming followed by 6 cycles of avelumab (week 22) was 10%, with 2/20 participants achieving iPR. The CBR for azacitidine and carboplatin priming was 65% (13/20) and after priming followed by 6 cycles of avelumab CBR was 35% (n = 7/20). The median PFS was 18.0 weeks (95% CI: 14.87 – 21.13 weeks) and the median OS was 47.86 weeks (95% CI: 9.67 – 86.06 weeks). Translational correlation analysis confirmed HLA-A generally increased after priming with azacitidine and carboplatin, particularly if it was absent at the start of treatment. Average methylation of CpGs across the HLA-A locus was decreased after priming and T-cells, in particular CD8+, showed the greatest increase in infiltration. Conclusions: Priming with azacitidine and carboplatin can induce disease stabilization and re-sensitisation to ICB for metastatic melanoma.

  Study EGAS00001006419

• Repurposing azacitidine and carboplatin to prime immune checkpoint blockade-resistant melanoma for anti-PD-L1 re-challenge

  Purpose: Drug repurposing offers the opportunity for chemotherapy to be used to re-establish sensitivity to immune checkpoint blockade (ICB) therapy. Here we investigated the clinical and translational aspects of an early phase II study of azacitidine and carboplatin priming for anti-PDL1 immunotherapy (Avelumab) in patients with advanced ICB-resistant melanoma. Experimental Design: 20 participants with ICB resistant metastatic melanoma received 2 x 4-week cycles of azacitidine and carboplatin followed by ICB re-challenge with anti-PD-L1 avelumab. The primary objective was overall response rate after priming and ICB re-challenge. Secondary objectives were Clinical benefit rate (CBR), progression-free survival (PFS) and overall survival (OS). Translational correlation analysis of HLA-A and PD-L1 expression, RNA-seq and reduced representation bisulfite sequencing (RRBS) of biopsies at baseline, after priming and after 6 cycles of avelmuab was performed. Results: The ORR determined after azacitidine and carboplatin priming was 10% (2/20) with 2 partial responses (PR). The ORR determined after priming followed by 6 cycles of avelumab (week 22) was 10%, with 2/20 participants achieving iPR. The CBR for azacitidine and carboplatin priming was 65% (13/20) and after priming followed by 6 cycles of avelumab CBR was 35% (n = 7/20). The median PFS was 18.0 weeks (95% CI: 14.87 – 21.13 weeks) and the median OS was 47.86 weeks (95% CI: 9.67 – 86.06 weeks). Translational correlation analysis confirmed HLA-A generally increased after priming with azacitidine and carboplatin, particularly if it was absent at the start of treatment. Average methylation of CpGs across the HLA-A locus was decreased after priming and T-cells, in particular CD8+, showed the greatest increase in infiltration. Conclusions: Priming with azacitidine and carboplatin can induce disease stabilization and re-sensitisation to ICB for metastatic melanoma.

  Study EGAS00001006420

• Whole exome-sequencing of pediatric and adult H3-K27M diffuse midline glioma

  H3-K27M mutant difffuse midline gliomas across different age groups and anatomical locations were profiled by WES.

  Study EGAS00001006431

• ctDNA quantification in Ewing sarcoma patients

  Background. Treatment stratification and response assessment in pediatric sarcomas has relied on imaging studies and surgical/histopathological evidence of vital tumor cells. Such studies and evidence collection processes often involve radiation and/or general anesthesia in children. Cell-free circulating tumor DNA (ctDNA) detection in blood plasma is one available method of so-called liquid biopsies that has been shown to correlate qualitatively and quantitatively to some extent with the existence of vital tumor cells in the body. Our clinical observational study focused on the utility and feasibility of ctDNA detection in pediatric Ewing sarcoma (EWS) as a marker of minimal residual disease (MRD). Patients and Methods. We performed whole genome sequencing to identify the exact breakpoints in tumors known to carry the EWS-FLI1 fusion gene. Patient-specific fusion breakpoints were tracked in peripheral blood plasma using digital droplet PCR (ddPCR) before, during, and after therapy in six consecutive children and young adults with EWS. Presence and levels of fusion breakpoints were correlated with clinical disease courses. The genetic changes in the tumors were defined, and inter- and intra-individual changes in the tumor DNA copy loads were observed over time. Results. We show that the detection of ctDNA in the peripheral blood of EWS patients i) is feasible in the clinical routine and ii) allows for the longitudinal real-time monitoring of MRD activity in children and young adults. Although changing ctDNA levels correlated well with clinical outcome within patients, between patients, a high variability was observed (inter-individually) for the six patients described here. Conclusions. ctDNA detection by ddPCR is a highly sensitive, specific, feasible, and highly accurate method that can be applied in EWS for follow-up assessments as an additional surrogate parameter for clinical MRD monitoring and, potentially, also for treatment stratification in the near future.

  Study EGAS00001006433

• T cell reactivity of MHC epitopes

  By using >36,000 immunogenicity assay results, we developed a method to identify peptide-MHC complexes whose structural alignment facilitates T cell reaction. Our method accurately predicted neoepitopes for MHC II as well as MHC I that were responsive to checkpoint blockade when applied to >1,200 samples of various tumor types and on-therapy melanoma samples. To investigate selection by spontaneous immunity at the single epitope level, we analyzed the frequency spectrum of >25 million mutations in >9,000 treatment-naïve tumors in association with >100 immune phenotypes. MHC II immunogenicity specifically lowered variant frequencies in tumors under high immune pressure particularly with high TCR clonality and MHC II expression.

  Study EGAS00001006445

• Tissue and plasma RNA from esophageal cancer and precursor lesions

  In the past decades, the incidence of esophageal adenocarcinoma has increased dramatically in Western populations. Better understanding of disease etiology along with the identification of novel prognostic and predictive biomarkers are urgently needed to improve the dismal survival probabilities. Here, we performed comprehensive RNA (both coding and non-coding) profiling in various samples from 17 patients diagnosed with esophageal adenocarcinoma, high-grade dysplastic or non-dysplastic Barrett’s esophagus. Per patient, a blood plasma sample, and a healthy esophageal and disease tissue sample were included. In total, this comprehensive dataset consists of 102 RNA-seq libraries from 51 samples. This unique resource allows for discovery of novel biomarkers and disease mechanisms, comparison of tissue and liquid biopsy profiles, integration of coding and non-coding RNA patterns, and can serve as a validation dataset in other RNA landscaping studies. Moreover, structural RNA differences can be identified in this dataset, including protein coding mutations fusion genes, and circular RNAs.

  Study EGAS00001004939

• OAC RNASeq

  Please see our related publication, 'Molecular profiling to predict immunochemotherapy outcomes in esophageal adenocarcinoma'

  Study EGAS00001006468

• OAC scRNASeq

  Please see our related publication, 'Molecular profiling to predict immunochemotherapy outcomes in esophageal adenocarcinoma'

  Study EGAS00001006469

• Genomic insights into the pathogenesis of Epstein-Barr virus-associated diffuse large B-cell lymphoma by whole-genome and targeted amplicon-based sequencing

  Epstein–Barr virus (EBV)-associated diffuse large B-cell lymphoma not otherwise specified (DLBCL NOS) constitutes a distinct clinicopathological entity in the current World Health Organization (WHO) classification, yet its genomic features remain sparsely characterized. Combining whole-genome sequencing (WGS), targeted amplicon sequencing (tNGS) and fluorescence in-situ hybridization (FISH) of tumours from 47 cases of EBV+ DLBCL we delineate the genomic landscape of this rare disease. Interrogating WGS data by sequential gene-set enrichment and network-diffusion we describe an accumulation of mutations affecting the nuclear factor κB (NFκB) pathway (CSNK2A2, CARD10), IL-6/JAK/STAT (SOCS1/3, STAT3) and WNT signalling (FRAT1, SFRP5) alongside aberrations in immunological processes like interferon-response. Further, WGS uncovered structural aberrations including 6q deletions (5/8 patients), which were subsequently validated by FISH (14/32 cases). Integrated WGS and tNGS analysis emphasized a profile distinct from EBV-negative DLBCL enriched for mutations in ARID1A (45%), KMT2A/D (32/30%), ANKRD11 (32%), NOTCH2 (32%). Expanding on previous reports, we identified recurrent alterations in CCR6 (15%), DAPK1 (15%), TNFRSF21 (13%), CCR7 (11%) and YY1 (6%). Our comprehensive description of the mutational landscape in EBV+ DLBCL substantiates the evidence of its pathobiological independence. Further, these observations aid in the refinement of the molecular taxonomy for aggressive lymphomas and guides future therapeutic strategies.

  Study EGAS00001004941

• 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

• SPECIAL: Dissecting the melanoma ecosystem one cell at the time during immunotherapy

  The aim of this study was to identify potential biomarkers of response to immunotherapy (anti-PD1-based) as well as gain understanding of the biological mechanism of therapy resistance (either intrinsic or acquired) in melanoma patients. Single cell RNA sequencing was performed from pre- and on-treatment (2-3 weeks after immunotherapy) metastatic biopsies from stage III and IV melanoma patients.

  Study EGAS00001006488

• Colorectal cancer study

  Matrix metalloproteinase-11 (MMP11) is an enzyme with proteolytic activity against matrix and non-matrix proteins. Although most MMPs are secreted as inactive proenzymes and they are later activated extracellularly, MMP11 is activated intracellularly by furin within the constitutive secretory pathway. It is a key factor in physiological tissue remodeling and its alteration may play an important role in the progression of epithelial malignancies and other diseases. TCGA colon and colorectal adenocarcinoma data showed that upregulation of MMP11 expression correlates with tumorigenesis and malignancy. Here, we provide evidence that a germline variant in the MMP11 gene (NM_005940: c.232C>T; p.(Pro78Ser)), identified by whole exome sequencing, can increase the tumorigenic properties of colorectal cancer (CRC) cells. P78S is located in the prodomain region, which is responsible for blocking MMP11’s protease activity. This variant was detected in the proband and all the cancer-affected family members analyzed, while it was not detected in healthy relatives. In silico analyses predict that P78S could have an impact on the activation of the enzyme. Furthermore, our in vitro analyses show that the expression of P78S in HCT116 cells increases tumor cell invasion and proliferation. In summary, our results show that this variant could modify the structure of the MMP11 prodomain, producing a premature or uncontrolled activation of the enzyme that may contribute to an early CRC onset in these patients. The study of this gene in other CRC cases will provide further information about its role in CRC development, which might improve patient treatment in the future.

  Study EGAS00001006489

• Population_based_analysis_of_POT1_variants_in_a_cutaneous_melanoma_case_control_cohort

  Pathogenic germline variants in the protection of telomeres 1 gene (POT1) have been associated with predisposition to a range of tumor types, including melanoma, glioma, leukemia and cardioangiosarcoma. We sequenced all coding exons of the POT1 gene in 2,929 European-descent melanoma cases and 3,298 controls, identifying 43 protein-changing genetic variants. We performed functional studies on each of these variants and explored their possible contribution to disease risk.

  Study EGAS00001006870

• Immune microenvironment and lineage tracing help deciphering Rosette-forming GlioNeuronal Tumors: a multi-omic analysis of 9 cases

  Rosette-forming GlioNeuronal Tumor (RGNT) is a rare central nervous system neoplasm containing two components, glial and neuronal. The delineation of histological diagnosis of RGNT from similar low-grade tumors such as pilocytic astrocytoma (PA) and ganglioglioma (GG) may be challenging. We performed here a comprehensive molecular analysis of a cohort of tumors with same histology features to identify molecular characteristics of RGNT. A cohort of 9 rosette-forming tumors histologically-diagnosed were analyzed at molecular level using multimodal approaches as Whole Exome Sequencing (WES), RNAseq and methylome. In our cohort, 3 tumors were plotted within the Methylation Class-RGNT (MC-RGNT) characterized by FGFR1 mutation associated with PIK3CA or NF1 mutations. Transcriptome analysis was performed in 7 cases. RNAseq identified a “Hot” and a “Cold” transcriptomic group; the latter includes the 3 MC-RGNT and 1 MC-Pilocytic Astrocytoma and exhibited a “Cold” immune tumor microenvironment in comparison with the “Hot” group. The distinct immune cell content of both groups was confirmed by quantitative immunostainings. Get Set Enrichment Analysis showed that the “Cold” group had upregulated NOTCH pathway and mainly oligodendrocyte precursor cell and neuronal phenotypes while the “Hot” group exhibited predominantly astrocytic and neural stem cell phenotypes. In silico deconvolution identified the cerebellar granule cell lineage as a putative origin and as the cell context to understand the effects of genetic alterations and NOTCH signaling. Histological diagnosis of rosette-forming tumors encompasses heterogeneous tumor entities. Our study identified distinct tumor cell contexts and microenvironments as key features to better understand and manage these neoplasms.

  Study EGAS00001006502

• WGS of MAPKi acquired resistant samples from patients and PDX models

  Blocking cancer genomic instability, which generates diverse variants that enable rapid adaptations, may prevent tumor escape from therapies. We show that, after MAPK inhibitor (MAPKi) therapy in patients and patient-derived xenografts, acquired-resistant genomes of metastatic cutaneous melanoma accumulate amplicons of resistance-driver, non-homologous end-joining (NHEJ), and homologous recombination repair (HRR) genes within complex genomic rearrangements (CGRs) and extrachromosomal circular DNAs (ecDNAs). Also, chromothriptic genomic regions enrich for mutations and may engender ecDNAs and CGRs. Overall, somatic mutations within ecDNA- and CGR-amplicons enrich for HRR signatures, and, in acquired resistance, ecDNA (versus CGR) mutations enrich for APOBEC3 signatures. Breakpoint-sequence analysis suggests NHEJ as critical to double-stranded DNA break repair underlying CGR and ecDNA formation. In vivo, NHEJ-targeting by a DNA-PKCS inhibitor prevented acquired MAPKi-resistance by reducing the size of ecDNAs and CGRs early on combination treatment. Thus, targeting the cause(s), as opposed to the consequences, of genomic instability prevents acquired resistance.

  Study EGAS00001006874

• Renal Cell Carcinoma Tumors From S-TRAC trial (NCT00375674) Exome Sequencing

  We report a comprehensive genomic and transcriptomic analysis of tumor samples from 171 patients at high risk for recurrent renal cell carcinoma post nephrectomy from the S-TRAC trial (NCT00375674). We identify gene expression signatures, including STRAC11 (derived from the sunitinib-treated population). The overlap in key elements captured in these gene expression signatures, which include genes representative of the tumor stroma microenvironment, regulatory T cell, and myeloid cells, suggests they are likely to be both prognostic and predictive of the anti-angiogenic effect in the adjuvant setting. These signatures also point to the identification of potential therapeutic targets for development in adjuvant renal cell carcinoma, such as MERTK and TDO2. Finally, our findings suggest that while anti-angiogenic adjuvant therapy might be important, it may not be sufficient to prevent recurrence and other factors such as immune response and that tumor environment may be of greater importance.

  Study EGAS00001006529

• Neuroblastoma Evolution

  Here, we quantify the somatic evolution of neuroblastomas by deep (80x) whole-genome sequencing, molecular clock analysis and population-genetic modeling in a comprehensive cohort (Hipo_K09R) covering all subtypes.

  Study EGAS00001006533

• Molecular evolution of classic Hodgkin lymphoma revealed through whole genome sequencing of Hodgkin and Reed Sternberg cells

  Here we leveraged whole genome structural variant copy number analysis to report the first whole genome sequencing landscape of HRS cells and reconstruct the chronology and likely etiology of pathogenic events prior to the clinical diagnosis of cHL.

  Study EGAS00001006884

• Single-cell multi-omics of relapse/refractory multiple myeloma patients (Hipo K08K/H067/K43R)

  Therapy resistance in cancers is ingrained in complex clonal dynamics. While the major clonal population in a tumour might respond well to the employed intervention, minor clones will eventually mutate, consequently acquiring a selective advantage and drug resistance. Hence, to improve cancer therapy, it is crucial to understand the mechanisms behind clonal evolution. Here, we applied single-cell transcriptomics and epigenomics, as well as whole-genome sequencing to 15 patients with relapsed/refractory multiple myeloma (RRMM). By profiling longitudinal samples throughout varying treatment regimens, we were able to interrogate patterns of evolution across patients. In particular, by defining clones based on copy number aberrations (CNAs), we found evidence for the majority of clones being diminished but not fully eradicated during treatment.

  Study EGAS00001006538

• Significant and pervasive effects of RNA degradation on Nanopore direct RNA sequencing

  Abstract Oxford Nanopore direct RNA sequencing (DRS) is capable of sequencing complete RNA molecules and accurately measuring gene and isoform expression. However, as DRS is designed to profile intact RNA, expression quantification may be more heavily dependent upon RNA integrity than alternate RNA-seq methodologies. It is currently unclear how RNA degradation impacts DRS or if it can be corrected for. To assess the impact of RNA integrity on DRS we performed a degradation time-series using SH-SY5Y neuroblastoma cells. Our results demonstrate that degradation is a significant and pervasive factor that can bias DRS measurements, including a reduction in library complexity resulting in an overrepresentation of short genes and isoforms. Degradation also biases differential expression analyses; however, we find explicit correction can almost fully recover meaningful biological signal. In addition, DRS provided less biased profiling of partially degraded samples than nanopore cDNA-PCR sequencing. Overall, we find samples with RIN > 9.5 can be treated as undegraded and samples with RIN > 7 can be utilised for DRS with appropriate correction. These results establish the suitability of DRS for a wide range of samples, including partially degraded in-vivo clinical and post-mortem samples, whilst limiting the confounding effect of degradation on expression quantification.

  Study EGAS00001006542

• Immuno-genomic landscape of osteosarcoma

  Osteosarcoma is an orphan disease affecting children and young adults that has seen little to no progress in survival outcomes for >30 years. Despite having heavily rearranged genomes, to date, clinical trials with immunotherapy have shown no benefit for patients with osteosarcoma. In this study, we conducted the first multi-platform immune profiling (whole genome, transcriptome, T-cell receptor sequencing, immunohistochemistry and reverse phase protein array) on every available pediatric and adult osteosarcoma patients from our institution (N = 48) with the goal of describing immune features that may contribute to immunotherapy resistance.

  Study EGAS00001003887

• A living biobank of patient-derived ductal carcinoma in situ Mouse-INtraDuctal xenografts identifies factors associated with risk of invasive progression

  Create a living biobank of patient-derived ductal carcinoma in situ (DCIS) Mouse-INtraDuctal (MIND) xenografts to find factors explaining invasive growth. Samples exist of both primary and pdx samples. Invasive growth was scored in the pdx.

  Study EGAS00001006554

• Vitamin C boosts DNA demethylation in TET2 germline mutation carriers

  We recently identified a family with lymphoma predisposition where a heterozygous truncating germline mutation in TET2 segregated with nodular lymphocyte predominant Hodgkin lymphoma. In a clinical trial of one year, we investigated the effects of oral 1 g/day vitamin C supplementation on DNA methylation by analyzing genome-wide DNA methylation and gene expression patterns from the family members.

  Study EGAS00001006916

• Genomic and epigenomic study of Japanese renal cell carcinoma including WGS, RNA-seq, ATAC-seq, and methyl-seq

  We performed whole-genomic and transcriptomic sequencing of more than 100 Japanese renal cell carcinoma (RCC) cases, including clear cell RCC, papillary RCC, chromophobe RCC, and TFE3-translocated RCC. In addition, we conducted epigenome sequencing analyses: the assay for transposase-accessible chromatin sequencing (ATAC-seq) and enzymatic methyl sequencing.

  Study EGAS00001006919

• Long-read sequencing for cell-free DNA analysis (human pacbio)

  8 pregnant women at the 3rd trimesters, 4 hepatitis B carriers, and 4 patients with hepatocellular carcinoma

  Study EGAS00001006609

• Uncovering tumor intrinsic and extrinsic factors that regulate hepatocellular carcinoma growth using patient derived xenograft assays

  Several major factors limit our understanding of hepatocellular carcinoma (HCC). First, human HCCs are infrequently biopsied for diagnosis and thus are not often biologically interrogated. Second, HCC initiation and progression are strongly influenced by the cirrhotic microenvironment, and the exact contributions of intrinsic and extrinsic tumor factors are unclear. A powerful approach to examine the personalized biology of liver cancers and the influence of host tissues is with patient derived xenograft (PDX) models. In Asia, HCCs from hepatitis B virus patients have been efficiently converted into PDXs, but few parallel efforts from the west have been reported. In a large-scale analysis, we implanted 93 HCCs and 8 cholangiocarcinomas (CCAs) to systematically analyze host factors and to define an optimized platform for PDX development from both surgical and biopsy samples. NSG mice that had undergone partial hepatectomy (PHx) represented the best combination of engraftability, growth, and passageability, but overall rates were low and indicative of a unique intrinsic biology for HCCs in the US. PDX models preserved the histology and genetic features of parental tumors, and ultimately, 9 new models were usable for pre-clinical studies. Intriguingly, HCC PDXs were differentially sensitive to regorafenib and sorafenib and CCA PDXs were also highly sensitive to regorafenib. PDX models functionalize early and advanced stage HCCs and revealed unique biological features of liver cancers from the US.

  Study EGAS00001004020

• Whole transcriptome profiling of liquid biopsies from tumour xenografted mouse models: validation cohort

  While cell-free DNA (cfDNA) in liquid biopsies is widely being used and investigated, free circulating RNA (extracellular RNA, exRNA) has the potential to improve therapy response monitoring and cancer detection due to its dynamic nature. A fundamental open question hampering the initiation of large-scale liquid biopsy collections for tumour exRNA analysis is that it remains unclear in which blood subcompartment tumour-derived exRNAs primarily reside. We set out to develop a host-xenograft deconvolution framework, exRNAxeno, with cDNA mapping strategies to either a combined human-mouse reference genome or both species genomes in parallel, that can be applied to exRNA sequencing data from liquid biopsies of human xenograft mouse models, enabling to distinguish (human) tumoural RNA from (murine) host RNA, and as such to specifically analyse tumour-derived exRNA. Subsequently, the preferred exRNAxeno combination pipeline was applied to total exRNA sequencing data from blood platelets and three plasma fractions from a breast cancer patient-derived and neuroblastoma cell line-derived xenograft mouse model. We show that tumoural exRNA concentrations are not determined by plasma platelet levels, while host exRNA concentrations increase with platelet content. Furthermore, a large variability in exRNA levels and gene content across individual mice is observed. In general, the tumoural gene detectability in plasma is correlated with the RNA expression levels in the tumour tissue or cancer cell line. Our results unravel new aspects of tumour-derived exRNA biology in xenograft mouse models.

  Study EGAS00001006582

• Multiome_HB

  Hepatoblastoma (HB) cells display strong phenotypic heterogeneity with a major impact on drug response, but the underlying mechanisms are poorly understood. Here, we use a single-cell multi-omic strategy to unravel the molecular determinants of this plasticity. HB display a continuum of single-cell states between hepatocytic (scH), liver progenitor (scLP) and mesenchymal (scM) differentiation poles, with an intermediate scH/LP population bordering scLP and scH areas in spatial transcriptomics. Chromatin accessibility landscapes reveal the gene regulatory networks of each differentiation pole, and the sequence of transcription factor activation underlying cell state transitions. Single-cell mapping of somatic alterations reveals the clonal architecture of each tumor, showing that each genetic subclone displays its own range of cellular plasticity across differentiation poles. The most scLP subclones, overexpressing stem cell and DNA repair genes, proliferate faster after neo-adjuvant chemotherapy. These results highlight how the interplay of clonal evolution and epigenetic plasticity shapes the potential of HB subclones to respond to chemotherapy.

  Study EGAS00001006932

• Whole-Transcriptomic Profiling of Sorted Human Renal Cell Carcinoma Immune Populations

  It is poorly understood how the tumor immune micro-environment influences disease progression in renal cell carcinoma (RCC). Here we performed whole-transcriptomic profiling of immune cell populations which were derived from RCC patients representing distinct flow-sorted immune lineages.

  Study EGAS00001006593

• Genomic_characterisation_of_MGUS__

  he hematological malignancy multiple myeloma (MM), also called Kahler’s disease or plasma cell (PC) myeloma, is characterized by a clonal expansion of PCs originating in the bone marrow (BM). The expansion of these cells leads to an overproduction of antibodies and results in typical symptoms such as anemia, renal failure and bone lesions. All cases of MM are preceded by the asymptomatic, non-malignant pre-stage monoclonal gammopathy of undetermined significance (MGUS). Of all MGUS patients, only 1% per year will progress to MM. Despite efforts to elucidate the molecular mechanisms underlying the MGUS-to-MM progression, its pathogenesis still remains largely unknown. Additionally, the genetic profiles of MGUS patients have only been limitedly investigated due to the only incidental finding of MGUS, the difficulties in BM sampling and isolating a sufficient number of aberrant PCs from the BM aspirates of MGUS patients. Consequently, reliable biomarkers to individually predict which MGUS patients will progress to MM and which will not, are lacking. Therefore, it is highly required to study the molecular pathogenesis of MGUS and the role of genetic events in relation to the malignant transformation to MM.

  Study EGAS00001004124

• Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell RCC-- CA209-025

  Immune checkpoint inhibitors targeting the PD-1 pathway have transformed the management of many advanced malignancies, including clear cell renal cell carcinoma (ccRCC), but the drivers and resistors of PD-1 response remain incompletely elucidated. Here, we analyzed 592 tumors collected from advanced ccRCC patients enrolled in prospective clinical trials of treatment with PD-1 blockade (or mTOR inhibition as control arm) by whole-exome and RNA-sequencing, integrated with immunofluorescence analysis, to define the somatic alteration landscape of late-stage ccRCC and to uncover the immunogenomic determinants of therapeutic response. While conventional genomic markers (tumor mutation burden, neoantigen load) and degree of CD8+ T cell infiltration were not associated with clinical response, we discovered numerous chromosomal alterations in advanced ccRCC associated with response or resistance to PD-1 blockade. These advanced tumors were highly CD8+ T cell infiltrated, with only 22% and 5% with an immune desert and immune excluded phenotype, respectively. Our analysis revealed that CD8+ infiltrated tumors are depleted of favorable PBRM1 mutations and are enriched for unfavorable chromosomal losses of 9p21.3 when compared to non-infiltrated tumors. These data demonstrate how the interplay of somatic alterations and immunophenotypes impacts therapeutic efficacy.

  Study EGAS00001004292

• Cell-free DNA fragmentation patterns and personalized sequencing reveal circulating tumor DNA in urine and plasma of glioma patients

  Glioma-derived cell-free DNA (cfDNA) is challenging to detect using liquid biopsy as levels in body fluids are low. We determined the glioma-derived DNA fractions in tumor biopsies, in cerebrospinal fluid (CSF), plasma and urine samples, using deep sequencing of personalized capture panels. By sequencing cfDNA across thousands of mutations identified individually in each patient’s matched tumor we detected tumor-derived DNA in plasma (10/12) and urine samples (8/11). The median tumor fraction was 6.4x10-3 in CSF, 3.1x10-5 in plasma and 4.7x10-5 in urine. We identified a shift in the size distribution for mutant cfDNA fragments in these body fluids. Next, we analyzed cfDNA fragment sizes with paired-end shallow whole genome sequencing (WGS) in urine samples from 35 patients with gliomas, 8 individuals with non-malignant brain disorders, and 26 controls (n=69 individuals, 96 samples). cfDNA in urine of glioma patients was significantly more fragmented compared to urine from patients with non-malignant brain disorders (t-test, p=1.7x10-2) and compared to urine of controls (t-test, p=5.2x10-9). The proportion of DNA fragments <60 bp was higher in glioma patients urine and could be used for classification (AUC=0.93). Machine learning models integrating fragment lengths could identify urine samples from glioma patients (AUC=0.97 in cross-validation).

  Study EGAS00001004355

• Whole exome sequencing identifies clinically relevant mutational signatures in resected hepatocellular carcinoma

  We conducted a multicentre pilot study on patients with localized HCC following complete radiological response to surgical resection. Patients received 250 mg oral gefitinib once daily as adjuvant therapy, up to a maximum of 6 months. The clinical endpoints included recurrence-free survival (RFS) and overall survival (OS), and correlative genetic analyses were conducted from whole exome sequencing data (n=33). All statistical analyses were carried out on an intention-to-treat basis. The study is registered with ClinicalTrials.gov (NCT00282100).

  Study EGAS00001004371

• Tumorigenic role of Musashi-2 in aggressive mantle cell lymphoma

  SOX11 is overexpressed in the highly aggressive conventional mantle cell lymphoma (MCL) but rarely in the indolent non-nodal MCL subtype. We performed RNA-seq of SOX11+ and SOX11- MCLs to search for SOX11-regulated genes that contributed to MCL clinical evolution, identifying Musashi-2 (MSI2) stem cell-related gene. By performing RNA-seq upon MSI2 knockdown or inhibition in MCL, we identified MSI2 as a potential target to inhibit drug resistance in aggressive MCLs.

  Study EGAS00001006613

• Long-read sequencing of diagnosis and post-therapy medulloblastoma reveals complex rearrangement patterns and epigenetic signatures (Hipo_021)

  Cancer genomes harbor a broad spectrum of structural variants (SV) driving tumorigenesis, a relevant subset of which escape discovery using short-read sequencing. We employed Oxford Nanopore Technologies (ONT) long-read sequencing in a paired diagnostic and post- therapy medulloblastoma to unravel the haplotype-resolved somatic genetic and epigenetic landscape. We assemble complex rearrangements and such associated with telomeric sequences, including a 1.55 Megabasepair chromothripsis event. We uncover a complex SV pattern termed ‘templated insertion thread’ (TI thread), characterized by short (mostly <1kb) insertions showing prevalent self-concatenation into highly amplified structures of up to 50kbp in size. TI threads occur in 3% of cancers, with a prevalence ranging to 74% in liposarcoma, and frequent colocalization with chromothripsis. We also perform long-read based methylome profiling and discover allele-specific methylation (ASM) effects, complex rearrangements exhibiting differential methylation, and differential promoter methylation in cancer-driver genes. Our study shows the advantage of long-read sequencing in the discovery and characterization of complex somatic rearrangements.

  Study EGAS00001006629

• The Genetic Landscape of Ocular Adnexa MALT Lymphoma Reveals Frequent Aberrations in NFAT and MEF2B Signaling Pathways

  A comprehensive constellation of somatic non-silent mutations and copy number (CN) variations in ocular adnexa marginal zone lymphoma (OAMZL) is unknown. By utilizing whole-exome sequencing in 69 tumors we define the genetic landscape of OAMZL. Mutations and CN changes in CABIN1 (30%), RHOA (26%), TBL1XR1 (22%), and CREBBP (17%) and inactivation of TNFAIP3 (26%) were among the most common aberrations. Candidate cancer driver genes cluster in the B-cell receptor (BCR), NFkB, NOTCH and NFAT signaling pathways. One of the most commonly altered genes is CABIN1, a calcineurin inhibitor acting as a negative regulator of the NFAT and MEF2B transcriptional activity. CABIN1 deletions enhance BCR-stimulated NFAT and MEF2B transcriptional activity, while CABIN1 mutations enhance only MEF2B transcriptional activity by impairing binding of mSin3a to CABIN1. Our data provide an unbiased identification of genetically altered genes that may play a role in the molecular pathogenesis of OAMZL and serve as therapeutic targets.

  Study EGAS00001006631

• Whole genome analysis of pediatric patients with medulloblastoma

  Cancer genomes often contain structural variations (SVs) in non-coding regions, while its impact on tumorigenesis is still unclear. Our goal is to discover genome folding changes resulted from SVs using InfoGenomeR and InfoHiC frameworks, which may reveal novel therapeutic targets. We applied our frameworks to five pediatric patients with medulloblastoma, revealing 3D genome changes of medulloblastoma driver genes.

  Study EGAS00001006653

• Single cell RNAseq of lung adenocarcinoma

  Little is known of the geospatial architecture of individual cell populations in lung adenocarcinoma (LUAD) evolution. Here, we perform single-cell RNA sequencing as well as single-cell BCR sequencing of cells from 16 LUADs and 47 multi-region normal lung tissues of defined spatial proximities from the tumors. Our multi-region single-cell sequencing analyses unravel cell populations, states, and phenotypes in the spatial and ecological evolution LUAD from the lung that comprise high-potential targets for early interception.

  Study EGAS00001005021

• Follicular lymphoma at diagnosis, treated in first line with immunochemotherapy

  We performed targeted NGS in Follicular lymphoma samples at diagnosis. Explored clinico-genetic correlations and assessed four clinical or clinicogenetic risk models (FLIPI, FLIPI-2, PRIMA-IP or m7-FLIPI-molecular score) in patients with symptomatic FL who received frontline immunochemotherapy. Out of 191 patients with FL grade 1-3a, 109 were successfully genotyped. Treatment consisted on rituximab (R) plus CVP/CHOP (72.5%) or R-bendamustine (R-B) (27.5%).

  Study EGAS00001006674

• Longitudinal evaluation of serum microRNAs as biomarkers for neuroblastoma burden and therapeutic p53 reactivation

  Accurate assessment of treatment response and residual disease is indispensable for the evaluation of cancer treatment efficacy. However, performing tissue biopsies for longitudinal follow-up poses a major challenge in the management of solid tumours like neuroblastoma. In the present study, we evaluated whether circulating miRNAs are suitable to monitor neuroblastoma tumour burden and whether treatment-induced changes of miRNA abundance in the tumour are detectable in serum. We performed small RNA sequencing on longitudinally collected serum samples from mice carrying orthotopic neuroblastoma xenografts that were exposed to treatment with idasanutlin or temsirolimus. We identified 57 serum miRNAs to be differentially expressed upon xenograft tumour manifestation, out of which 21 were also found specifically expressed in the serum of human high-risk neuroblastoma patients. The murine serum levels of these 57 miRNAs correlated with tumour tissue expression and tumour volume, suggesting potential utility for monitoring tumour burden. In addition, we describe serum miRNAs that dynamically respond to p53 activation following treatment of engrafted mice with idasanutlin. We identified idasanutlin-induced serum miRNA expression changes upon one day and 11 days of treatment. By limiting to miRNAs with a tumour-related induction, we put forward hsa-miR-34a-5p as a potential pharmacodynamic biomarker of p53 activation in serum.

  Study EGAS00001006678