7296 results for "canc*"

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• RRBS data from TRACERx non-small cell lung cancer (NSCLC) tumours and matched normal adjacent tissue.

  TRACERx (TRAcking Cancer Evolution through therapy (Rx)) is a prospective cohort study designed to investigate intratumor heterogeneity (ITH) in relation to clinical outcome, and to determine the clonal nature of driver events and evolutionary processes in early stage non-small cell lung cancer (NSCLC). This study looks at multi-region RRBS data from the TRACERx cohort selected for quantity of material available and high tumour purity

  Study EGAS00001006523

• Multi-region RNA sequencing of tumour regions and tumour-adjacent normal lung tissue

  TRACERx (TRAcking Cancer Evolution through therapy (Rx)) is a prospective cohort study designed to investigate intratumor heterogeneity (ITH) in relation to clinical outcome, and to determine the clonal nature of driver events and evolutionary processes in early stage non-small cell lung cancer (NSCLC).

  Study EGAS00001006517

• Gene signature for predicting homologous recombination deficiency in triple-negative breast cancer

  We developed a gene expression-based classifier for homologous recombination deficiency (HRD) in breast cancer patients using WES and RNA-seq data obtained from 94 TNBC samples from a Malaysian hospital-based cohort (MyBrCa). This classifier was able to predict for high levels of a mutational signature associated with HRD in an additional MyBrCa TNBC validation cohort (this EGA study) as well as in TNBCs from TCGA. We also validated the classifier on a NanoString platform with both fresh frozen and FFPE tissue.

  Study EGAS00001006518

• DERMATLAS__Tubular_adenoma

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

  Study EGAS00001006686

• The temporal mutational and immune tumour microenvironment remodelling of HER2-negative primary breast cancers

  WES and clonality characterization of different timepoints in HER2-negative primary breast cancers receiving neoadjuvant eribulin therapy.

  Study EGAS00001004953

• Characterization of MCSP+ melanoma DCC and MelDCC lines

  To dissect the sequence of genotypic and phenotypic progression during early metastatic colonization, we searched for the earliest detectable disseminated cancer cells (DCC) and identified MCSP+ melanoma cells as strong candidates for metastasis founder cells (MFC) in lymph nodes. We isolated MCSP+ DCC from various stages of metastatic colony-formation, performed scRNA-seq and unravelled their phenotypic progression. Further we performed bulk sequencing on patient-derived DCC models (MelDCC) and showed that they exhibit an immunosuppressive activity on CD8 T cells.

  Study EGAS00001006702

• The Precision Medicine in Liver Cancer across an Asia-pacific NETwork (PLANET) - Intratumoural immune heterogeneity

  The clinical relevance of immune landscape intratumoural heterogeneity (immune-ITH) and its role in tumour evolution remain largely unexplored. Here, we uncover significant spatial and phenotypic immune–ITH from multiple tumour sectors and decipher its relationship with tumour evolution and disease progression in hepatocellular carcinomas (HCC). Immune–ITH is associated with tumour transcriptomic-ITH, mutational burden, and distinct immune microenvironments. Tumours with low immune–ITH experience higher immunoselective pressure and escape via loss of heterozygosity in human leukocyte antigens and immunoediting. Instead, the tumours with high immune-ITH evolve to a more immunosuppressive/exhausted microenvironment. This gradient of immune pressure along with immune-ITH represents a hallmark of tumour evolution, which is closely linked to the transcriptome-immune networks that contributes to disease progression and immune inactivation. Remarkably, high immune-ITH and its transcriptomic signature are predictive for worse clinical outcome in HCC patients. This in-depth investigation of ITH provides evidence on tumour-immune co-evolution along HCC progression.

  Study EGAS00001003814

• cfDNA in Hereditary And High-Risk Malignancies (CHARM)

  Our goal is to improve early cancer detection by developing a blood test to predict cancer development in carriers using circulating DNA. As carriers develop cancer, they may have pre-cancerous cells which release this DNA into the blood (cell-free DNA; cfDNA), which can be detected with novel genetic technologies. We propose to use three complementary cfDNA assays:shallow whole genome sequencing (sWGS), Liquid-Biopsy Sequencing (LB-Seq) and Cell-free Methylated DNA Immunoprecipitation and High-throughput Sequencing (cfMeDip-Seq) for early cancer detection.

  Study EGAS00001006539

• Robust methylation-based classification of brain tumours using nanopore sequencing

  Background: DNA methylation-based classification of cancer provides a comprehensive molecular approach to diagnose tumours. In fact, DNA methylation profiling of human brain tumours already profoundly impacts clinical neuro-oncology. However, current implementations using hybridization microarrays are time-consuming and costly. We recently reported on shallow nanopore whole-genome sequencing for rapid and cost-effective generation of genome-wide 5-methylcytosine profiles as input to supervised classification. Here, we demonstrate that this approach allows to discriminate a wide spectrum of primary brain tumours. Results: Using public reference data of 82 distinct tumour entities, we performed nanopore genome sequencing on N=382 tissue samples covering 46 brain tumour (sub)types. Using bootstrap sampling in a cohort of N = 56 cases, we find that a minimum set of 1,000 random CpG features is sufficient for high-confidence classification by ad hoc random forests. We implemented score recalibration as confidence measure for interpretation in a clinical context and empirically determined a platform-specific threshold in a randomly sampled discovery cohort (N = 185). Applying this cut-off to an independent validation series (N = 184) yielded 148 classifiable cases (sensitivity 80.4%) and demonstrated 100 % specificity. Cross-lab validation demonstrated robustness with concordant results across four laboratories in 10/11 (90.9%) cases. In a prospective benchmarking (N = 15), median time to results was 21.1 hours. Conclusions: In conclusion, nanopore sequencing allows robust and rapid methylation-based classification across the full spectrum of brain tumours. Platform-specific confidence scores facilitate clinical implementation for which prospective evaluation is warranted and ongoing.

  Study EGAS00001006540

• The University of Hong Kong Colon Cancer GCV Study

  Background: Ganciclovir (GCV) is widely used in solid organ and hematopoietic stem cell transplant patients for prophylaxis and treatment of cytomegalovirus. It has long been considered a mutagen and carcinogen. However, the contribution of GCV to cancer incidence and other factors that influence its mutagenicity remains unknown. Methods: This retrospective cohort study analysed genomics data for 121,771 patients who had undergone targeted sequencing compiled by the Genomics Evidence Neoplasia Information Exchange (GENIE) or Foundation Medicine (FM). A statistical approach was developed to identify patients with GCV-associated mutational signature (GCVsig) from targeted sequenced data of tumour samples. Cell line exposure models were further used to quantify mutation burden and DNA damage caused by GCV and other antiviral and immunosuppressive drugs. Results: Mutational profiles from 22 of 121,771 patient samples in the GENIE and FM cohorts showed evidence of GCVsig. A diverse range of cancers was represented. All patients with detailed clinical history available had previously undergone solid organ transplantation and received GCV and mycophenolate treatment. RAS hotspot mutations associated with GCVsig¬¬ were present in 9 of the 22 samples, with all samples harbouring multiple GCV-associated protein-altering mutations in cancer driver genes. In vitro testing in cell lines showed that elevated DNA damage response and GCV¬sig are uniquely associated with GCV but not acyclovir, a structurally similar antiviral. Combination treatment of GCV with the immunosuppressant, mycophenolate mofetil (MMF), increased the misincorporation of GCV in genomic DNA and mutations attributed to GCVsig in cell lines and organoids. Conclusions: In summary, GCV can cause a diverse range of cancers. Its mutagenicity may be potentiated by other therapies, such as mycophenolate, commonly co-prescribed with GCV for post-transplant patients. Further investigation of the optimal use of these drugs could help reduce GCV-associated mutagenesis in post-transplant patients.

  Study EGAS00001006707

• Exome sequencing from cfDNA blood samples. 159 samples at 2x101bp Illumina reads in Fastq format.

  Differential presence of exons (DPE) by next generation sequencing (NGS) is a method of interpretation of whole exome sequencing. This method has been proposed to design a predictive and diagnostic algorithm with clinical value in plasma from patients bearing colorectal cancer (CRC). The aim of the present study was to determine a common exonic signature to discriminate between different clinical pictures, such as non-metastatic, metastatic and non-disease (healthy), using a sustainable and novel technology in liquid biopsy. Through DPE analysis, we determined the differences in DNA exon levels circulating in plasma between patients bearing CRC vs. healthy, patients bearing CRC metastasis vs. non-metastatic and patients bearing CRC metastasis vs. healthy comparisons. We identified a set of 510 exons (469 up and 41 down) whose differential presence in plasma allowed us to group and classify between the three cohorts. Random forest classification (machine learning) was performed and an estimated out-of-bag (OOB) error rate of 35.9% was obtained and the predictive model had an accuracy of 75% with a confidence interval (CI) of 56.6-88.5. In conclusion, the DPE analysis allowed us to discriminate between different patho-physiological status such as metastatic, non-metastatic and healthy donors. In addition, this analysis allowed us to obtain very significant values with respect to previous published results, since we increased the number of samples in our study. These results suggest that circulating DNA in patient’s plasma may be actively released by cells and may be involved in intercellular communication and, therefore, may play a pivotal role in malignant transformation (genometastasis).

  Study EGAS00001006656

• GENOMIC MUTATION LANDSCAPE OF SKIN CANCERS FROM DNA REPAIR-DEFICIENT XERODERMA PIGMENTOSUM PATIENTS

  Xeroderma pigmentosum (XP) is a genetic disorder caused by mutations in genes of the Nucleotide Excision Repair (NER) pathway (groups A-G) or in Translesion Synthesis (TLS) DNA polymerase η (group V). XP is associated with an increased skin cancer risk, reaching, for some groups, several thousand-fold compared to the general population. Here, we analyzed 38 skin cancer genomes from five XP groups. We found that the activity of NER determines heterogeneity of the mutation rates across skin cancer genomes and that transcription-coupled NER extends beyond the gene boundaries reducing the intergenic mutation rate. Mutational profile in XP-V tumors revealed the role of polymerase η in the error-free bypass of (i) rare TpG and TpA DNA lesions, (ii) 3’ nucleotides in pyrimidine dimers, and (iii) TpT photodimers. Our study unravels the genetic basis of skin cancer risk in XP and provides insights into the mechanisms reducing UV-induced mutagenesis in the general population.

  Study EGAS00001006732

• Deciphering somatic mosaic structural variation in human blood lineages using single-cell multiomics

  Somatic mosaicism (SM), referring to the presence of somatic mutations in sub-populations of cells within healthy individuals, is associated with an increased risk of a variety of diseases, including cancer. Blood is at particularly high risk of SM, given its rapid turnover and functionally- heterogeneous cell-type composition. While the roles of point mutations and large-scale rearrangements in blood SM have been scrutinised in recent years, the functional impact of mosaic structural variants (mSVs) remains poorly understood. Using haplotype-resolved single-cell multi-omics, we explored the mSV landscape of human hematopoietic stem and progenitor cells (HSPCs).

  Study EGAS00001006567

• Longitudinal monitoring of cell-free DNA methylation in ALK-positive non-small cell lung cancer patients

  Here, we performed genome-wide 5-mC profiling in plasma of metastatic ALK-rearranged non-small cell lung cancer (NSCLC) patients receiving tyrosine kinase inhibitor therapy. We established a strategy to identify ALK-specific 5-mC changes from cfDNA and demonstrated the suitability of the identified markers for cancer detection, prognosis and therapy monitoring. Longitudinal plasma samples (n = 79) of 21 ALK-positive NSCLC patients and 13 healthy donors were collected alongside 15 ALK-positive tumor tissue and 10 healthy lung tissue specimens. All plasma and tissue samples were analyzed by cell-free DNA methylation immunoprecipitation sequencing to generate genome-wide 5-mC profiles. Information on genomic alterations (i.e., somatic mutations/fusions and copy number alterations) determined in matched plasma samples were available from previous studies.

  Study EGAS00001006573

• 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

• Human pan-cancer plasma cfRNA study - raw data

  This study contains mRNA capture sequencing data from plasma of 266 different human donors. The first, pan-cancer, cohort covers 25 high-grade to metastatic cancer types (8 cancer patients per type) and a control group (8 healthy donors). The validation cohort comprises additional plasma samples from ovarian, prostate and uterine cancer patients (12 per type) as well as additional samples from controls (22 new and 8 repeated). Samples were sequenced on a NovaSeq 6000 and are provided in FASTQ format.

  Study EGAS00001006755

• SDH_deficient_renal_tumours___WGS_

  Succinate dehydrogenase (SDH) deficient renal cancers are a rare and understudied subtype of renal cancer. As such they represent an unmet need in kidney cancer research. Here, we seek to describe the genomics and transcriptomics of SDH deficient renal cancers by sequencing five such tumours. We document their mutational burden, define driver mutations, demonstrate typical patterns of structural variants, and estimate the cell of origin and cellular composition.

  Study EGAS00001004102

• 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

• PDAC organoid genomic heterogeneity

  The establishment of patient-derived pancreatic cancer organoid culture in recent years creates an exciting opportunity for researchers to perform a wide range of in vitro studies on a model that closely recapitulates the tumor. Among the outstanding questions in pancreatic cancer biology are the causes and consequences of genomic heterogeneity observed in the disease. However, to use pancreatic cancer organoids as a model to study genomic variations, we need to first understand the degree of genomic heterogeneity and its stability within organoids. Here, we used single-cell whole-genome sequencing to investigate the genomic heterogeneity of two independent pancreatic cancer organoids, as well as their genomic stability with extended culture. Clonal populations with similar copy number profiles were observed within the organoids, and the proportion of these clones was shifted with extended culture, suggesting the growth advantage of some clones. However, sub-clonal genomic heterogeneity was also observed within each clonal population, indicating the genomic instability of the pancreatic cancer cells themselves. Furthermore, our transcriptomic analysis also revealed a positive correlation between copy number alterations and gene expression regulation, suggesting the “gene dosage” effect of these copy number alterations that translates to gene expression regulation.

  Study EGAS00001006782

• The miR-185/PAK6 Axis Predicts Therapy Response and Regulates Survival of Drug-Resistant Leukemic Stem Cells in Chronic Myeloid Leukemia

  Overcoming drug resistance and targeting cancer stem cells remain challenges for curative cancer treatment. To investigate the role of miRNAs in regulating drug resistance and leukemic stem cell (LSCs) fate, we performed global transcriptome profiling in treatment-naïve chronic myeloid leukemia (CML) stem/progenitor cells and identified that miR-185 levels anticipate their response to ABL tyrosine kinase inhibitors (TKIs). miR-185 functions as a tumor suppressor; its restored expression impaired survival of drug-resistant cells, sensitized them to TKIs in vitro, and markedly eliminated long-term repopulating LSCs and infiltrating blast cells, conferring a survival advantage in pre-clinical xenotransplantation models. Integrative analysis with mRNA profiles uncovered PAK6 as a crucial target of miR-185 and pharmacological inhibition of PAK6 perturbed the RAS/MAPK pathway and mitochondrial activity, sensitizing therapy-resistant cells to TKIs. Thus, miR-185 presents as a potential predictive biomarker, and dual targeting of miR-185-mediated PAK6 activity and BCR-ABL may provide a valuable strategy for overcoming drug resistance in patients.

  Study EGAS00001004153

• The landscape of chromothripsis across adult cancer types

  Chromothripsis is a recently identified mutational phenomenon, by which a presumably single catastrophic event generates extensive genomic rearrangements of one or a few chromosome(s). Considered as an early event in tumour development, this form of genome instability plays a prominent role in tumour onset. Chromothripsis prevalence might have been underestimated when using low-resolution methods, and pan-cancer studies based on sequencing are rare. We analysed chromothripsis in 28 tumour types covering all major adult cancers (634 tumours, 316 whole-genome and 318 whole-exome sequences). We show that chromothripsis affects a substantial proportion of human cancers, with a prevalence of 49% across all cases. Chromothripsis generates entity-specific genomic alterations driving tumour development, including clinically relevant druggable fusions. Chromothripsis is linked with specific telomere patterns and univocal mutational signatures in distinct tumour entities. Longitudinal analysis of chromothriptic patterns in 24 matched tumour pairs reveals novel insights in the clonal evolution of tumours with chromothripsis. (H021)

  Study EGAS00001004250

• Treatment-mediated selection of lethal prostate cancer clones defined by copy number architectures

  Despite initial responses to hormone treatment, metastatic prostate cancer invariably evolves to a lethal state. To characterize the intra-patient relationships of metastases that evade treatment, we performed genome- wide copy number profiling and bespoke approaches targeting the androgen receptor (AR) on 142 metastatic regions from 10 organs harvested post-mortem from nine men who died from prostate cancer. We identified diverse and patient-unique alterations clustering around the AR in metastases from every patient with evidence of independent acquisition of related genomic changes within an individual and, in some patients, the co-existence of AR-neutral clones. Using the genomic boundaries of pan-autosome copy number change, we confirmed a common clone of origin across metastases and diagnostic biopsies; and identified in individual patients, clusters of metastases occupied by dominant clones with diverged autosomal copy number alterations. Autosome-defined clusters were characterized by cluster-specific AR gene architectures that in two index cases were topologically more congruent than by chance (p-values 0.03, 3.07x10-8). Integration with anatomical site suggested patterns of spread and points of genomic divergence. Copy number boundaries identified treatment-selected clones with putatively distinct lethal trajectories.

  Study EGAS00001006598

• Integrative analysis of exome-seq, RNA-seq, ATAC-seq (bulk and single-cell), and Hi-C data generated from 3-D spatially mapped samples acquired during surgical resection from 10 patients diagnosed with IDH-WT glioblastoma

  Glioblastoma (GBM), the most common primary brain cancer in adults, remains incurable with no targeted therapies approved despite decades of investigation into its molecular landscape. Treatment failure is attributed to intratumoral heterogeneity in the GBM genome and epigenome, which foster tumor evolution and selection of resistant clones. However, tumor evolution and intratumoral heterogeneity remain poorly understood on the level of the whole tumor as most studies are based on single samples per patient and lack spatial context. Here, we have used 3-D neuronavigation during surgical resection for 10 primary IDH-WT GBM patients to collect 102 samples representing maximal tumor diversity, each mapped by 3-D spatial coordinates. We have applied a strategic set of genomic and epigenomic assays spanning multiple levels of resolution to discover, orthogonally validate, and functionally assess drivers of tumor evolution and intratumoral heterogeneity. These include extrachromosomal DNA amplifications, chromothripsis events, inversions, and translocations that disrupt both the GBM genome and epigenome while generating fusion transcripts and opportunities for therapeutic intervention. We define epigenomic programs that contribute to GBM evolution and intratumoral heterogeneity, revealing their 3-D spatial patterning within whole tumors and their cell type(s) of origin in single-cell data from the same tumor samples. Notably, we distinguish neuronal, glial, and immune programs aberrantly active in tumor cells from their counterparts in normal cells and discover NEUROD1, JUN/FOS, and NF1 transcription factors as key drivers of GBM evolution and growth. Collectively, these data provide unprecedented insight into GBM evolution and intratumoral heterogeneity from single-cell to whole-tumor resolution, redefining current understanding and providing a rich resource of targets for therapeutic investigation.

  Study EGAS00001006785

• The clinical utility of genomics in childhood cancer extends beyond targetable mutations - WGS data

  We deeply sequenced 864 cancer-associated genes and the complete genomes and transcriptomes for 300 pediatric and adolescent/young adult (AYA) patients with poor prognosis or rare tumors. Using integrative somatic-germline analyses, we assessed the clinical utility of cancer genomics in this population. Clinically actionable variants were identified in 56% of patients. Improved diagnostic accuracy led to modified management in a subset. Therapeutically targetable variants, found in 54% of patients, were of unanticipated timing and type, with over 20% of these derived from the germline. Enrichment in corroborating mutational signature 3 (‘BRCAness’) in patients with germline homologous recombination defects suggests they are drivers of pediatric cancers and potential targets for PARP inhibition. Comprehensive somatic-germline cancer genomic profiling is useful at multiple points in the care trajectory for pediatric/AYA patients, supporting its integration into early clinical management. Re-biopsy at the time of relapse should be considered, and specific attention to mutational burden is indicated. Defective DNA repair genes in the germline may represent important targetable drivers.

  Study EGAS00001006610

• Hi-C analysis of metastatic prostate tumors - Part 2

  DNA strands have a complex and highly structured three-dimensional shape within the nucleus that has profound but poorly characterized impacts on transcriptional activity. Herein, we performed the first integrated deep Hi-C sequencing on 80 metastatic castration-resistant prostate cancer biopsy samples from the West Coast Dream Team consortium.

  Study EGAS00001006612

• 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

• Neoantigen Peptides derived from V(D)J-recombined Immunoglobulins Drive Outgrowth of Cytolytic CD8+ T-cells

  Study EGAS00001008229

• Persistent Mutation Burden Drives Sustained Anti-Tumor Immune Responses

  Tumor mutation burden is an imperfect proxy of tumor foreignness and has therefore failed to consistently demonstrate clinical utility in predicting responses in the context of immunotherapy. We evaluated mutations in regions of the genome that are unlikely to undergo loss and discovered that clonal mutations in single-copy regions and those present in multiple copies per cell constitute a persistent tumor mutation burden (pTMB) that is linked with therapeutic response to immune checkpoint blockade. Persistent mutations were retained in the context of tumor evolution under selective pressure of immunotherapy and tumors with a high pTMB content were characterized by a more inflamed tumor microenvironment. pTMB imposes an evolutionary bottleneck that cancer cells cannot overcome and may thus drive sustained immunologic tumor control in the context of immunotherapy.

  Study EGAS00001006660

• Identification of neoantigen from MSI-CRC patient derived organoids and its application for targeting by autologous T cells

  Targeting neoantigens expressed only by tumor cells enable tumor destruction without unexpected damages to healthy tissues. Here, we identified neoantigens from microsatellite instable (MSI) colorectal cancer (CRC) patient-derived organoids by genomics and immunopeptidomics approches. The neoantigens in this study were predicted from frame-shift mutation by whole-genome sequencing and confirmed its presentation on organoids surface class I HLA molecules by mass spectrometry. We utilized these neoantigens to isolate neoantigen-specific CD8 T cells from autologous PBMC, and proved tumor organoids killing ability of the CD8 T cells, whereas it did not attack normal organoids. This study provides a platform to identify neoantigen from patient-derived cancer organoids and a model to validate T cell recognition, which could be useful for adoptive CD8 T cell transfer treatment for MSI-CRC patient.

  Study EGAS00001006633

• The clinical utility of genomics in childhood cancer extends beyond targetable mutations - Cancer Panel data

  We deeply sequenced 864 cancer-associated genes and the complete genomes and transcriptomes for 300 pediatric and adolescent/young adult (AYA) patients with poor prognosis or rare tumors. Using integrative somatic-germline analyses, we assessed the clinical utility of cancer genomics in this population. Clinically actionable variants were identified in 56% of patients. Improved diagnostic accuracy led to modified management in a subset. Therapeutically targetable variants, found in 54% of patients, were of unanticipated timing and type, with over 20% of these derived from the germline. Enrichment in corroborating mutational signature 3 (‘BRCAness’) in patients with germline homologous recombination defects suggests they are drivers of pediatric cancers and potential targets for PARP inhibition. Comprehensive somatic-germline cancer genomic profiling is useful at multiple points in the care trajectory for pediatric/AYA patients, supporting its integration into early clinical management. Re-biopsy at the time of relapse should be considered, and specific attention to the mutational burden is indicated. Defective DNA repair genes in the germline may represent important targetable drivers.

  Study EGAS00001006642

• 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

• DNA methylation landscape of prostate cancer

  Metastases from primary prostate cancers to rare locations, such as the brain, are becoming more common due to longer life expectancy thanks to improved treatments. Epigenetic dysregulation is a feature of primary prostate cancer, and distinct DNA methylation profiles are associated with the mutually exclusive SPOP mutant or TMPRSS2-ERG fusion genetic backgrounds. Using a cohort of 42 patients with prostate cancer brain metastases (PCBM), with matched primary samples available for 17 patients, we carried out DNA methylation analysis using Illumina EPIC array. We examined the epigenetic distinction between primary PCa and PCBM, the association between epigenetic alterations and mutational background, and particular epigenetic alterations that may be associated with PCBM in particular. Multiregion sampling of PCBM revealed epigenetic heterogeneity in metastases. We found aberrant methylation in PCBM is associated with mutational background, PRC2 complex activity and upregulation of EZH2, an effect that is particularly pronounced in SPOP mutant PCBM. While we detected a hypermethylator phenotype in PCBM, we also observed hypomethylation occurring at the promoters of genes involved in neuroactive ligand-receptor interactions or the calcium signalling pathway, such as GABRB3 and GRM5, a change not observed in non-brain prostate cancer metastases.

  Study EGAS00001006670

• Recurrent DNMT3B gene rearrangements are associated with unfavorable outcome in dicentric (9;20)-positive pediatric BCP-ALL

  The dicentric chromosome dic(9;20)(p11∼13;q11), occurs in 2% of pediatric acute lymphoblastic leukemia (ALL) cases. However, the prognostic significance of the dic(9;20) alterations and the mechanism in which these alterations drive leukemogenesis remains elusive. Our study describes the demographic, clinical, prognostic, and molecular characteristics of the dic(9;20)-positive ALL in a cohort of 57 pediatric BCP-ALL patients. Targeted RNA-seq and Array CGH analysis unraveled heterogeneous breakpoints on chromosomes 9 and 20 and frequent deletions of the IKZF1 gene. Together with the intrinsic susceptibility for deletions in CDKN2A, CDKN2B, and PAX5 genes in the dic(9;20)-positive ALL, these patients are eligible for treatment escalation in the AIEOP-BFM ALL 2017 clinical study. Survival analysis revealed poor 5-year event-free survival (pEFS) of 69% in dic(9;20)-positive ALL cases, compared to BCP-ALL patients enrolled in modern treatment studies. Strikingly, we identified six dic(9;20)-positive cases with rearrangements involving the DNMT3B gene, and poor 5-year pEFS of 25% (SE = 20%), compared to 79% (SE = 9%) for the remaining cohort (P = 0.011). Despite the loss of the methyltransferase domain of the DNMT3B gene in most cases with DNMT3B rearrangements, we did not observe major changes in the global methylation patterns. Differential gene expression analysis of DNMT3B-rearranged ALL unraveled a dysregulation of genes involved in hematopoiesis, lymphocyte maturation, and the PI3K/AKT signaling pathway. After confirmation in an independent cohort, DNMT3B-rearranged ALL cases should be considered high-risk for relapse and treated accordingly. We provide clinical data sets of Array CGH, targeted RNA-seq, total RNA-seq, whole genome bisulfite (WGBS) and whole genome DNA sequencing (WGS) obtained from bone marrow (BM) or peripheral blood (PB) mononuclear cells of 57 pediatric patients with dicentric chromosome dic(9;20) positive Acute lymphocytic leukemia (ALL), from which in 6 cases DNMT3B gene rearrangement was identified. This data is complemented by total RNA-seq and WGBS of samples from 4 additional ALL patients with a t(12;21) translocation and ETV6-RUNX1 gene fusion. DNA was isolated from BM or PB lymphocytes using Qiagen QIAamp DNA Blood Midi Kit to perform i) Array CGH of 58 dic(9;20) positive samples by hybridizing 500ng DNA using a Agilent 400K SurePrint G3 Custom CGH Human Genome Microarray (e-Array design 84704) ii) WGBS of 6 DNMT3B rearrangement positive samples and 4 ETV6-RUNX1 positive samples using Tecan TrueMethyl oxBS-Seq module for library preparation and Illumina NovaSeq 6000 platform to run 2x151 cycles iii) WGS of DNMT3B rearrangement positive samples using Illumina Lotus DNA Library Prep Kit followed by sequencing running 2x160 cycles on an Illumina NovaSeq 6000 platform. RNA was isolated from PB lymphocytes using the PerkinElmer Chemagic 360 instrument, followed by i) targeted RNA-seq of 56 dic(9;20) positive samples prepared using Illumina TruSight RNA Pan-Cancer Panel and sequenced on an Illumina MiSeq platform running 2x75 cycles ii) total RNA-seq of 6 DNMT3B rearrangement positive samples and 4 ETV6-RUNX1 positive samples utilizing TruSeq Stranded Total RNA Library Prep Gold kit and running 2x100 cycles on an Illumina NovaSeq 6000 platform.

  Study EGAS00001007383

• Genomic Study of Gastric Cancer

  We perform whole exome sequencing of 50 pairs of gastric cancer and matched normal samples

  Study EGAS00001005032

• 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

• Identification of genomic aberrations in low-grade serous ovarian cancer

  Low-grade serous ovarian cancer (LGSOC) is a rare disease that occurs more frequently in younger women compared with high-grade disease. The current treatment is suboptimal, and better understanding of molecular pathogenesis of this disease is needed. In this study, we compared the whole genome sequences of LGSOCs from short-term and long-term survivors (defined as <40 and >60 months, respectively). Our goal was to identify novel genomic aberrations in LGSOC, especially in short-term survivors.

  Study EGAS00001006679

• DERMATLAS__Tubular_adenoma_RNAseq

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

  Study EGAS00001006685

• The molecular landscape of homologous recombination deficient, end-stage, high grade serous ovarian cancer

  High grade serous ovarian cancer (HGSC) is frequently characterized by homologous recombination (HR) DNA repair deficiency, and while most such tumors are sensitive to initial treatment, acquired resistance is common. We undertook a multi-omics approach to interrogating mechanisms of resistance, using multiple autopsy samples collected from 15 women with HR-deficient HGSC.

  Study EGAS00001006789

• Single-cell roadmap of immune cell responses in chronic myeloid leukemia

  To study the innate and adaptive immune responses in CML, we profiled 25 samples from CML patients including samples at diagnosis (n = 7, N = 9, where n is the number of subjects and N the number of samples if different from n) and before and after TKI-cessation with imatinib (n = 6, N = 15) with paired single-cell RNA and T cell receptor (TCR) αβ chain sequencing (scRNA+TCRαβ-seq) and compared our data to different cancers (n = 29) and healthy donors (n = 7). This dataset contains the samples from before and after TKI-cessation, please see the manuscript for info related to the other datasets.

  Study EGAS00001005044

• Pre-neoplastic liver colonization by 11p15.5 altered mosaic cells in young children with hepatoblastoma

  In children, liver tumors are a heterogeneous group representing 1-2% of all cancers with the most common diagnosis being hepatoblastoma (HB). While HBs are predominantly sporadic, around 15% of cases develop as part of predisposition syndromes such as familial adenomatous polyposis (APC mutation) or Beckwith-Wiedemann (BWS; 11p15.5 locus altered). Here, we identified a mosaic genetic alteration of 11p15.5 locus in the liver in 17% of HB patients without a clinical diagnosis of BWS syndrome. These mosaic 11p15.5 alterations were never found in children with other types of liver tumor (hepatocellular carcinoma or adenoma, fibrolamellar carcinoma). Bulk transcriptomic analysis revealed the abundance of extracellular matrix, angiogenesis, and progenitor gene signatures in mosaic livers. In situ hybridization assay RNAscope allowed for the detection of 11p15.5 altered hepatocytes mosaicism in liver FFPE sections of HB patients presenting IGF2 overexpression and H19 downregulation together with an alteration of the zonal architecture of the liver. Spatial transcriptomics analysis revealed an overexpression of the IGF2 pathway, lipogenesis, and platelet activation in 11p15.5 altered hepatocytes. These data provide insights for 11p15.5 mosaicism detection as well as functional consequences of these alterations during the early steps of carcinogenesis.

  Study EGAS00001006692

• Tissue DNA, WBC DNA and cfDNA (deep-)sequencing of mCRC patients treated with doublet chemotherapy and anti-EGFR in the CAIRO5 study

  This study assessed whether ctDNA based treatment response monitoring could be performed in a tumor tissue-independent manner by combining ultra-deep targeted sequencing analyses of cfDNA with patient-matched white blood cell (WBC) derived DNA. In total, 183 cfDNA and 49 WBC samples, along with 28 tissue samples, from 52 metastatic colorectal cancer patients participating in the prospective phase III CAIRO5 clinical trial (NCT02162563) were analyzed using the PGDx elio plasma resolve assay.

  Study EGAS00001006695

• Discovery of cancer prognostic markers based on comparison of gene expression in colorectal cancer samples.

  Here, we analyse bulk mRNA-seq data derived from normal tissues adjacent to tumors (NATs) and tumour tissues of colorectal cancer (CRC), including 80 NAT samples and 80 tumour samples.

  Study EGAS00001005068

• Characterization of chromatin accessibility in metastatic prostate cancer

  The development of resistance to second-generation AR-signaling inhibitors (ARSIs) and progression to metastatic castrate-resistant prostate cancer (mCRPC) represents a huge obstacle to the improvement of patients’ clinical outcomes. Lineage plasticity is a common mechanism that drives the development of mCRPC by changing chromatin conformation at regulatory elements affecting downstream gene activity. ATAC-seq is a popular technique that measures accessible chromatin regions. To better understand of potential epigenomic mechanisms of ARSI resistance in prostate cancer, in this study, we performed ATAC-seq on 70 mCRPC tissue biopsies from the SU2C/PCF West Coast Dream Team (WCDT) cohort.

  Study EGAS00001006698

• Subtype-associated epigenomic landscape and 3D genome structure in bladder cancer

  We determine the genome-wide transcriptome, enhancer landscape and transcription factor binding profiles of FOXA1 and GATA3 in luminal and basal subtypes of bladder cancer. Furthermore, we report the first-ever mapping of genome-wide chromatin interactions by Hi-C in both bladder cancer cell lines and primary patient tumors. We show that subtype-specific transcription is accompanied by specific open chromatin and epigenomic marks, at least partially driven by distinct transcription factor binding at distal-enhancers of luminal and basal bladder cancers. Finally, we identify a novel clinically relevant transcription factor, Neuronal PAS Domain Protein 2 (NPAS2), in luminal bladder cancers that regulates other subtype-specific genes and influences cancer cell proliferation and migration.

  Study EGAS00001005071

• single-stranded DNA study

  A ssDNA library protocol was applied to cfDNA from plasma samples obtained from different DNA extraction methods and revealed significant differences in DNA fragmentation patterns in comparison to dsDNA-based protocols. In particular, a specific combination of methods revealed a population of ultrashort fragments, organized at ~50 bp. We observed significant differences in the relative abundance of these ultrashort DNA fragments in plasma from healthy individuals and cancer patients. Through shallow whole genome sequencing (sWGS, <0.5-fold coverage) and the analysis of somatic copy number aberrations (SCNA), we determined the landscape of genetic alterations in this newly identified population of cfDNA fragments. In addition, we studied their potential link with regulatory regions by investigating the genome-wide coverage patterns at transcription start sites (TSS). Furthermore, we demonstrated that the ultrashort cfDNA fragments map to regions associated with secondary DNA structures, G-quadruplexes (G4s).

  Study EGAS00001005093

• Structural Expression of BMMF in tissues of colorectal, lung and pancreatic cancer patients

  Chronic inflammation, linked to the presence of bovine milk and meat factors (BMMF) and specific subsets of macrophages, results in oxygen radical synthesis and induction of mutations in DNA of actively replicating cells and replicating single stranded DNA (zur Hausen et al., 2017). Cancers arising from this process have been characterized as indirect carcinogenesis by infectious agents (without persistence of genes of the agent in premalignant or cancers cells). Here we investigate structural properties of pleomorphic vesicles, regularly identified by staining peritumour tissues of colorectal, lung and pancreatic cancer for expression of BMMF Rep. The latter represents a subgroup of BMMF1 proteins involved in replication of small single-stranded circular plasmids of BMMF, but most likely also contributing to pleomorphic vesicular structures found in the periphery of colorectal, lung and pancreatic cancers. Structurally dense regions are demonstrated in preselected areas of colorectal cancer, after staining with monoclonal antibodies against BMMF1 Rep. Similar structures were observed in human embryonic cells (HEK293TT) overexpressing Rep. These data suggest that Rep or Rep isoforms contribute to the structural formation of vesicles.

  Study EGAS00001006744

• Targeted therapy of advanced parathyroid carcinoma guided by genomic and transcriptomic profiling (hipo_021)

  Parathyroid carcinoma (PC) is an orphan malignancy with a high risk of recurrence after surgery. Tumor-directed systemic treatments for PC are not established. We used whole-genome and RNA sequencing in four patients with advanced PC to identify molecular alterations that could guide clinical management. In two cases, the genomic and transcriptomic profiles provided targets for experimental therapies that resulted in biochemical response and prolonged disease stabilization: (i) immune checkpoint inhibition with pembrolizumab based on high tumor mutational burden and a single-base substitution signature associated with APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) overactivation; (ii) multi-receptor tyrosine kinase inhibition with lenvatinib due to overexpression of FGFR1 and RET and, later in the course of disease, PARP inhibition with olaparib prompted by signs of defective homologous recombination DNA repair. In addition, our data provided new insights into the molecular landscape of PC with respect to the genome-wide footprints of specific mutational processes and pathogenic germline alterations. These data underscore the potential of comprehensive molecular analyses to improve care for patients with ultra-rare cancers based on insight into disease biology.

  Study EGAS00001006747

• Single-cell transcriptomics identifies pathogenic T-helper 17.1 cells and pro-inflammatory monocytes in ICI-related pneumonitis

  ICI-pneumonitis is a frequent serious adverse event of cancer immunotherapy hinging on a cell-mediated immune response, though the exact pathophysiology is currently unknown. Using single-cell transcriptomics, an enrichment of pathogenic (TBX21, RORC, IFNG, IL17A, CSF2 expressing) T-helper 17.1 cells and pro-inflammatory (TNF, IL1B, IL6, IL23A expressing) monocytes was identified in ICI-pneumonitis bronchoalveolar lavage fluid, putatively engaging in a feedforward inflammatory loop. This finding yields several novel therapeutic targets for the treatment of ICI-pneumonitis. Most notably repurposing anti-IL-23 merits further research as a potential efficacious and safe treatment for ICI-pneumonitis.

  Study EGAS00001006762