9296 results for "cancer rna-seq"

in 69.19 milliseconds.

• BCL3-rearrangements in B-cell lymphoid neoplasms occur in two breakpoint clusters associated with different diseases

  Study EGAS00001007465

• Methylation_cfDNA_cancer

  Genome-wide CpG methylation information of cell-free DNA samples from cancer patients

  Dataset EGAD00010002587

• NanoString Cancer

  RCC files of 17 Cartridges from metastatic melanoma

  Dataset EGAD00010002432

• A capture-based next-generation sequencing panel for the molecular characterization of chronic lymphocytic leukemia

  Study EGAS00001006975

• Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma

  Study EGAS00001000226

• Surgery in combination with immune checkpoint therapy as an effective treatment for patients with metastatic cancer.

  Study EGAS00001005667

• Transcriptomic profiling of prostate cancer metastasis xenograft models reveals conservation of bone microenvironment signatures

  Study EGAS00001004770

• Vento_Placental_Cell_Atlas

  The Human Cell Atlas initiative is an ambitious global research effort which aims to describe every cell in the human body across all developmental stages to generate a reference map to accelerate progress in science and medicine particularly relating to human development and disease. The initiative is led by investigators based at the Wellcome Sanger Institute and the Broad Institute of MIT and Harvard and funding support from the Wellcome and NIH. This specific project will assess human development. We aim to interrogate the cellular composition and molecular regulators underpinning development and maturation through single cell RNA-sequencing/spatial transcriptomics and computational algorithms to predict cellular developmental trajectories and cell-cell interactions. We will subsequent validate these findings in situ using allied imaging technologies e.g. immunohistochemistry and RNAscope and in vitro culture of human intestinal organoids (HIOs).

  Study EGAS00001004187

• Targeting AXL Kinase Uniquely Sensitizes Therapy-Insensitive Leukemic Stem and Progenitor Cells to Venetoclax Treatment in Acute Myeloid Leukemia

  The abundance of genetic abnormalities and phenotypic heterogeneities in AML pose significant challenges to developing improved treatments. Here we demonstrated that a key GAS6/AXL axis is highly activated in AML patient cells, particularly in leukemic stem cells. We developed a potent, selective AXL inhibitor that has excellent pharmaceutical properties and efficacy against preclinical patient-derived xenotransplantation models of AML. Importantly, inhibition of AXL sensitized AML stem/progenitor cells to venetoclax treatment, with strong synergistic effects in vitro and in vivo. Mechanistically, single-cell RNA-sequencing and functional validation studies uncovered that AXL inhibition or in combination with venetoclax potentially targets intrinsic metabolic vulnerabilities of AML stem/progenitor cells, which shows a distinct transcriptomic profile and inhibits mitochondrial oxidative phosphorylation. These findings have direct translational impact on the treatment of AML and other cancers with high AXL activity.

  Study EGAS00001004663

• Molecular dissection of germline chromothripsis in a developmental context

  Complex germline genomic rearrangements can affect many genes and regulatory elements, but the precise mechanisms that caused the phenotype of patients with such rearrangements are often unknown. To dissect the impact of germline chromothripsis in a relevant developmental context, we performed trio-based RNA expression analysis on blood cells,induced pluripotent stem (iPS) cells and iPS-cell derived neuronal cells from a patient with de novo germline chromothripsis and both healthy parents. In addition, we performed Hi-C on iPS cell-derived neural progenitors of the patient and the father to study the effects of the chromothripsis rearrangements on the architecture of the derivative chromosomes. We demonstrate that a combination of patient-derived iPS cell differentiation and trio-based molecular profiling is a powerful approach to improve the interpretation of pathogenic complex genomic rearrangements.

  Study EGAS00001001896

• Assessment_of_genetic_and_epigenetic_variation_in_human_IPS_cells_RNA

  In order to progress human induced pluripotent stem cells (hiPSCs) towards the clinic, several outstanding questions must be addressed. It is possible to reprogram different somatic cell types into hiPSCs and from studies in the mouse, it appears that an epigenetic memory of the starting cell type is carried over to hiPSCs. However a comprehensive comparative study of the characteristics of these hiPSCs has been missing from the literature. Importantly studies which aimed to address these aspects of hiPSCs have used cells from different patients. In order to avoid this important confounding variable and to keep the genetic background constant, tissue samples were procured from the patients and reprogrammed to iPS cells. The transcriptomes of these iPS cells will be compared. Protocol: primary cultures of cells were reprogrammed to iPS cells. RNA was extracted using a standard column extraction kit.

  Study EGAS00001000367

• Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML

  This study assessed molecular determinants of response in a cohort of patients with AML that were treated with venetoclax in combination with either DNA methyltransferase inhibitors or low dose cytarabine. RNA sequencing was performed on 31 patients from three different response classes [10 Group A - Durable remission (n=10), Group B - Relapsed (n=10) and Group C - Refractory (n=11)]. Library preparation and sequencing was performed at the Australian Genome Research Facility, using the Truseq Stranded mRNA library kit. Technical and batch replicate samples are included, and these replicates are designated in the sample name. Gene count data are provided with the original publication. The use of the sequencing data is subject to a data transfer agreement and is restricted to ethically approved research into blood cell malignancies and cannot be used to assess germline variants.

  Study EGAS00001003820

• Genomic and transcriptional landscape of P2RY8-CRLF2-positive childhood acute lymphoblastic leukemia

  The mutational and transcriptional landscape of P2RY8-CRLF2-positive ALL was defined in 41 major clone fusion-positive cases including 19 matched diagnosis and relapse pairs by an integrated analysis of whole-exome and RNA sequencing. We detected a variety of frequently subclonal and highly unstable JAK/STAT but also RTK/Ras pathway activating mutations in 76% of cases at diagnosis and virtually all relapses. Unlike P2RAY8-CRLF2 that was lost in 32% of relapses, all other genomic deletions affecting lymphoid development and cell cycle remained stable. Only IKZF1 alterations predominated in relapsing cases and increased from initially 36 to 58% in matched cases. IKZF1¹s transcriptional signature revealed compromised stem cell features with signs of impaired lymphoid differentiation, enhanced focal adhesion, activated hypoxia pathway, deregulated cell cycle and increased drug resistance.

  Study EGAS00001001847

• Measuring the level of relatedness between NGS datasets

  Sequencing technologies are providing increasingly detailed insight in genetic makeup are paving their way into molecular diagnostics. The field will benefit from rigorous and bias-free measures for the quality of sequence data and for the proper representation of the complexity of the original samples. While current methodologies rely on the availability of a well-characterized reference genome, we propose kMer profiling for alignment-free assessment of the quality, comparability, and complexity of sequencing datasets. We show that kMer detects technical artefacts such as high duplication rates, library chimaeras, and differences in library preparation protocols in whole-genome, whole-exome, and RNA sequencing data. Additionally, it successfully captures the complexity and diversity of microbiomes. Thus, kMer allows for a robust evaluation of the quality and complexity of sequencing data without relying on any prior information and opens the way to a more reliable biological reasoning.

  Study EGAS00001000600

• Pilot study for Illumina TST170 NGS panel on cutaneous T cell lymphoma samples

  A number of genomic studies using next generation sequencing (NGS) techniques have attempted to understand the underlying genetic basis of cutaneous T-cell lymphoma and found alterations in genes that are involved in T-cell activation, NF-kB and JAK-signal transducer and activator of transcription (STAT) pathways. 8 diagnostic skin biopsy samples (2xplaque, 6xtumour) on FFPE blocks were selected from 8 MF patients (stage IB:n=1, IIB:n=6, IVA2:n=1). An H&E was performed in order to assess percentage of tumor cells, viable cells, necrosis and immune infiltration, to determine the number of slides required for NGS. Freshly cut unstained slides were manually macrodissected prior to DNA and RNA extraction. Targeted deep sequencing was performed using panel of 170 genes associated with common solid tumours (Illumina TruSight Tumour 170 NGS panel). VCF files generated via the Illumina’s Basespace platform.

  Study EGAS00001002567

• mRNA and T cell receptor sequencing of patients with Pandemrix-associated narcolepsy type 1

  Increased risk of Narcolepsy type 1 (NT1) was reported among children and adolescents vaccinated with AS03-adjuvanted pandemic influenza A vaccine (H1N1; Pandemrix®). We hypothesized that viral T cell epitope(s) in Pandemrix mimicked self-epitope(s), and that recognition of these cross-reactive epitopes contributed to disease-specific autoimmunity. We demonstrate that pediatric, Pandemrix-associated NT1 patients had enhanced T-cell immunity against dominant T-cell epitopes of Pandemrix vaccine viral proteins neuraminidase (NA) and nucleoprotein (NP), and also responded against a self-epitope in brain-expressed protein-O-mannosyltransferase 1 (POMT1). Here, the gene expression profiles and TCR repertoire of PBMC from patients and healthy controls were compared. PBMC samples were stimulated with peptides NA-175-189 or POMT1-675-589, and bulk RNA isolated and sequenced (RNAseq and TCRseq).

  Study EGAS00001004886

• Multi-omic single-cell profiling of peripheral blood immune cells from COVID-19 patients and controls.

  The COVID-19 pandemic, caused by SARS coronavirus 2 (SARS-CoV-2), has resulted in excess morbidity and mortality as well as economic decline. To characterise the systemic host immune response to SARS-CoV-2, we performed single-cell RNA-sequencing coupled with analysis of cell surface proteins, providing molecular profiling of over 800,000 peripheral blood mononuclear cells from a cohort of 130 patients with COVID-19. Our cohort, from three UK centres, spans the spectrum of clinical presentations and disease severities ranging from asymptomatic to critical. Three control groups were included: healthy volunteers, patients suffering from a non-COVID-19 severe respiratory illness and healthy individuals administered with intravenous lipopolysaccharide to model an acute inflammatory response. Full single cell transcriptomes are coupled with quantification of 188 cell surface proteins, and T and B lymphocyte antigen receptor repertoires.

  Study EGAS00001005465

• Transcriptome Changes in ASD (NRXN1α+/-) iPSC-derived neurons

  NRXN1 deletions are identified as one of major rare risk factors for autism spectrum disorder (ASD) and other neurodevelopmental disorders. ASD has 30% co-morbidity with epilepsy and the latter is associated with excessive neuronal firing. NRXN1 encodes hundreds of presynaptic neuro-adhesion proteins categorized as NRXN1α/β/γ. Previous studies on cultured cells show that the short NRXN1β primarily exerts excitation effect, whereas the long NRXN1α which is more commonly deleted in patients involves in both excitation and inhibition. However, patient-derived models are essential for understanding functional consequences of NRXN1α deletions in human neurons Quantitative RNA sequencing was performed by BGI using 50bp single-end strategy with BGI-SEQ500 sequencing device on iPSC-derived cortical neurons from 6 control lines; (2VC1, 3VCX1, 3VC2, 4C3, 4CX1, NCRM-1) of 4 healthy donors, and 4 NRXN1α+/- lines; (ND1C1, ND2C11, ND2CX1, ND4-1C2) from 3 ASD patients.

  Study EGAS00001005536

• SPECTA RP-1759-AYA Sarcoma cohort

  EORTC-SPECTA RP1759 study focuses on cancers in adolescent and young adult (AYA), age 12 to 29 years. This study explicitly recruited AYA patients and therefore collected empirical data to bridge the molecular gap between pediatric and adult oncology. The initial pilot study, activated in February 2019 across Europe, aimed to recruit 100 AYA patients (aged 12-29 years) with newly diagnosed or relapsed high-grade gliomas and high-grade bone and soft tissue sarcomas. The primary objective of the pilot is to determine feasibility and recruitment rates. Here we submit the data from patients with newly diagnosed, recurrent intermediate or high-grade sarcoma that were collected and analyzed during the study. More specifically, we submit raw FASTQ files obtained from whole exome sequencing (WES) of matching tumor and blood samples, tumor RNA sequencing and DNA methylation profiling.

  Study EGAS00001005840

• COPD and neutrophils

  Chronic obstructive pulmonary disease (COPD) is a major respiratory disease characterized by small airway inflammation, emphysema and severe breathing difficulties. Low-grade systemic inflammation is an established hallmark of severe disease, however, the molecular changes in peripheral immune cells remain far from understood. We combined multi-color flow cytometry with single-cell RNA sequencing and showed that blood neutrophil numbers are significantly increased in COPD and they are a heterogeneous population. A transcriptomic state that expressed interferon response genes correlated with alveolar damage and acute exacerbations. Furthermore, bronchoalveolar neutrophils expressed gene signatures corresponding to certain blood neutrophil states. Last, our data in a murine model of cigarette smoke exposure demonstrated that bone marrow neutrophil progenitors are expanded in smoke-treated animals and display signs of immune activation. Our study provides evidence that COPD systemic inflammation may derive from an activated haematopoietic precursor compartment.

  Study EGAS00001006281

• COPD and neutrophils sc

  Chronic obstructive pulmonary disease (COPD) is a major respiratory disease characterized by small airway inflammation, emphysema and severe breathing difficulties. Low-grade systemic inflammation is an established hallmark of severe disease, however, the molecular changes in peripheral immune cells remain far from understood. We combined multi-color flow cytometry with single-cell RNA sequencing and showed that blood neutrophil numbers are significantly increased in COPD and they are a heterogeneous population. A transcriptomic state that expressed interferon response genes correlated with alveolar damage and acute exacerbations. Furthermore, bronchoalveolar neutrophils expressed gene signatures corresponding to certain blood neutrophil states. Last, our data in a murine model of cigarette smoke exposure demonstrated that bone marrow neutrophil progenitors are expanded in smoke-treated animals and display signs of immune activation. Our study provides evidence that COPD systemic inflammation may derive from an activated haematopoietic precursor compartment.

  Study EGAS00001006322

• COPD and neutrophils sc rhapsody

  Chronic obstructive pulmonary disease (COPD) is a major respiratory disease characterized by small airway inflammation, emphysema and severe breathing difficulties. Low-grade systemic inflammation is an established hallmark of severe disease, however, the molecular changes in peripheral immune cells remain far from understood. We combined multi-color flow cytometry with single-cell RNA sequencing and showed that blood neutrophil numbers are significantly increased in COPD and they are a heterogeneous population. A transcriptomic state that expressed interferon response genes correlated with alveolar damage and acute exacerbations. Furthermore, bronchoalveolar neutrophils expressed gene signatures corresponding to certain blood neutrophil states. Last, our data in a murine model of cigarette smoke exposure demonstrated that bone marrow neutrophil progenitors are expanded in smoke-treated animals and display signs of immune activation. Our study provides evidence that COPD systemic inflammation may derive from an activated haematopoietic precursor compartment.

  Study EGAS00001006323

• Genetic and transcriptional landscape of plasma cells in POEMS syndrome

  POEMS syndrome is a rare paraneoplastic disease, associated with monoclonal plasma cells whose pathogenic importance remains unclear. We performed comprehensive genetic analyses of plasma cells in 20 patients with POEMS syndrome. Whole exome sequencing and targeted sequencing identified 7 recurrently mutated genes: KLHL6, LTB, EHD1, EML4, HEPHL1, HIPK1, and PCDH10. None of the driver gene mutations frequently found in multiple myeloma (MM) such as NRAS, KRAS, BRAF, and TP53 was detected. Copy number analysis showed chromosomal abnormalities shared with monoclonal gammopathy of undetermined significance (MGUS). RNA sequencing revealed a transcription profile specific to POEMS syndrome, especially in terms of tumorigenesis. Unexpectedly, disease-specific VEGFA expression was not increased in POEMS syndrome. Our study illustrates that the genetic and transcriptional profiles of plasma cells in POEMS syndrome are distinct from MM and MGUS, indicating its unique pathogenesis.

  Study JGAS000150

• Analysis of IDHwt-glioblastoma samples from paired primary and recurrent tumor samples

  IDHwt-glioblastomas rapidly recur after initial treatment. To study genetic evolution in glioblastoma, we analyzed whole genomes of 21 pairs of primary and recurrent tumor samples using next generation sequencing. In addition we sequenced RNA from 16 tumor pairs and a panel of 50 glioma-associated genes in tumor pairs from 43 patients (including 14 of the 21 patients included in the WGS discovery set). Glioblastoma subtypes were determined using 450k/EPIC methylation arrays. This study was supported within the e:med program of the German Ministry of Education and Research (BMBF) by the collaborative research project ‘SYS-GLIO - Systems-based prediction of the biological and clinical behavior of gliomas’ (https://www.sys-med.de/de/demonstratoren/sys-glio/) This study is part of the Heidelberg Center for Personalized Oncology - HIPO-043

  Study EGAS00001003184

• Characterization of X Chromosome Inactivation Using Integrated Analysis of Whole-Exome and mRNA Sequencing

  This study of DNA and RNA sequencing of 5 parent-offspring trios is a single center study. The goal of this study is to characterize X chromosome inactivation (XCI) ratio in females using phased genomic variations obtained through whole genome or exome sequencing in trios, followed by allele-specific expression analysis of the phased, heterozygous alleles in the mRNA of the female offspring, and to apply this method to clinical diagnosis. The distribution of allele ratios across X obtained from mRNA sequencing allows for the estimation of X inactivation status of inherited X chromosomes, and the parameters of each parental allele distributions in the offspring's mRNA data can be used as determinants for XCI ratio. This approach was used to evaluate the contribution of skewed XCI ratio to phenotypic heterogeneity in an undiagnosed, mild neurological condition.

  Study phs000816

• University of Texas at Austin (UTA) Histone Modification and Gene Expression Profiling in 9 Primary Glioblastoma Multiforme, 2 Anaplastic Astrocytomas and Two Meningiomas

  The primary goal of this study was to collect and analyze genomic data from primary glioblastoma multiforme tumors. Our collaborators at St David's Medical Center (SDMC) obtained informed consent from patients undergoing surgery to remove a tumor in the brain. After consent was obtained, specimens were removed from the operating suite and flash frozen in liquid nitrogen. Tumors were analyzed if they were a grade III (anaplastic astrocytoma) or grade IV glioma (glioblastoma multiforme). Tumors were transported from SDMC to UT Austin, then weighed and homogenized. Chromatin immunoprecipitation was performed for 7 proteins in each tumor (histone modifications H3K4me3, H3K4me1, H3K9ac, H3K9me3, H3K27ac, H3K27me3, and the multifunctional insulator binding protein CTCF) and no-antibody input was also sequenced. An aliquot of tumor material was set aside for isolation of total RNA.

  Study phs001389

• Pediatric Preclinical Testing Consortium (PPTC)

  The Pediatric Preclinical Testing Consortium (PPTC) is addressing the unmet need of streamlining the development of new therapies for childhood cancers. The PPTC seeks to develop robust biomarkers of anticancer drug activity, and the majority of these are predicted to be genetic mutations that can be detected in tumor DNA and/or RNA. In order to design the most impactful experiments that can be rapidly translated to the clinic, PPTC investigators require a complete genomic characterization of the patient-derived xenograft tumor models that are utilized across the consortium. This will not only allow for the most robust experimental design, but also will increase the engagement of industry partners who seek collaborators poised to provide the proof-of-concept necessary for drugs in their development pipelines. All data and models will be made available to academically qualified investigators.

  Study phs001437

• University of Washington Developmental Single Cell Atlas

  We set out to generate a human cell atlas of both gene expression and chromatin accessibility using tissues obtained during development. In this study, we applied an assay for single cell profiling of gene expression based on three-level combinatorial indexing (sci-RNA-seq3) to 121 fetal tissue samples representing 15 organs, altogether profiling transcription in over 4 million single cells. In parallel, we devised an improved assay for single cell profiling of chromatin accessibility also based on three-level combinatorial indexing (sci-ATAC-seq3). We applied this method to 53 fetal tissue samples representing 15 organs, altogether profiling on the order of one million single cells. From these data, we identify and characterize diverse human cell types and annotate them with respect to marker genes, expression and regulatory modules. These data comprise a rich resource for the exploration of human biology.

  Study phs002003

• HuBMAP: KULMAP - Human Kidney, Urinary Tract, and Lung Mapping Center

  The major goal of the Human Kidney, Urinary Tract, and Lung Mapping Center (KULMAP) is to generate multi-omic and spatially resolved molecular anatomical maps of the human bladder, ureter and kidneys (BUKMAP) and the lung airways and parenchyma (LAPMAP) at a single cell resolution. This entails sequencing of the transcriptomes and epigenomes of dissociated single cells in a massively parallel manner. These profiles will then inform on highly multiplexed RNA in situ imaging for spatial mapping of hundreds of molecular targets in the tissue sections, at a subcellular resolution. These spatial molecular maps will serve as scaffolds for computational registration of cell types and the associated transcriptome/chromatin maps to the tissue space. The combination of sequencing single dissociated cells and multiplexed in situ mapping will allow the construction of detailed spatial maps for these large organs.

  Study phs002249

• Modeling Malignant Progression in Glioma

  Gliomas are the most common primary brain tumor in humans. Low-grade gliomas (WHO grade II) invariably progress to high-grade gliomas (WHO grade III or IV). Although malignant progression may take many years, the survival rate after transformation to a high-grade glioma is poor, often only 12-15 months. In this data set, we have identified low-grade gliomas that have progressed to high-grade gliomas or high-grade gliomas that have progressed from low-grade gliomas. Some cases are matched pairs (meaning we have both the original low-grade tumor and the subsequent high-grade tumor). The samples deposited have been analyzed with bulk-RNA sequencing. They are also de-identified but are clinically annotated. When available, genetic information including IDH mutation status, 1p/19q deletion and histological subtype are also included.

  Study phs002607

• A Human Lymphoma Organoid Model for Evaluating and Targeting the Follicular Lymphoma Tumor Immune Microenvironment

  Heterogeneity in the tumor microenvironment (TME) of follicular lymphoma (FL) can affect clinical outcomes. We developed a new organoid culture method for cultivating patient-derived lymphoma organoids (PDLOs), which include cells from the native FL TME. We generated organoids from 12 FL patients at diagnosis, clinical progression, or relapse. These organoids were profiled with targeted DNA sequencing and mRNA sequencing. We evaluated the stability of organoids in culture at serial weekly timepoints (D0, D7, D14, D21). We treated organoids with CD19:CD3 or CD20:CD3 bispecific antibodies or unconjugated anti-CD20, anti-CD19, and anti-CD3 as a control, and profiled DNA/RNA at D11 to evaluate treatment response. This system is intended as a platform for advancing precision medicine efforts in FL through patient-specific modeling, high-throughput screening, TME signature identification, and treatment response evaluation.

  Study phs003410

• LLDeep DAG2+: scRNA-seq in PBMCs

  Single cell transcriptomics of PBMCs of 47 donors from the Lifelines Deep cohort (general population, Northern part of the Netherlands). Cells of five or six different donors were pooled together in one sample pool, resulting in eight different sample pools. In total, 28.855 cells were captured and their transcriptomes were sequenced to an average depth of 74k. Genotype data was available for each donor, which allowed us to use the Demuxlet method that uses variable SNPs between the pooled individuals to determine which cell belongs to which individual. Since genotype information is lacking of 2 individuals, the transcriptome of only 45 individuals could be retrieved.

  Dataset EGAD00001003459

• Whole Genome Sequencing of Asian Lung Cancers: Second Hand Smoke is Not Responsible for Higher Incidence of Lung Cancer Among Asian Never-Smokers

  Background Asian nonsmoking populations have a higher incidence of lung cancer compared to their European counterparts. There is a long-standing hypothesis that the increase of lung cancer in Asian never-smokers is due to environmental factors such as second-hand smoke. Results We analyzed whole-genome sequencing of 30 Asian lung cancers. Unsupervised clustering of mutational signatures separated the patients into two categories: i) all of the never-smokers, and ii) only smokers or ex-smokers. Half of the ex-smokers / smokers were in the never-smoker-like cluster. The overall somatic variant profiles of Asian lung cancers were similar to that of European origin with G.C>T.A being predominant in smokers. We found EGFR and TP53 are the most frequently mutated genes with mutations in 50% and 27% of individuals, respectively. Among these Asian never-smokers, 71% had an EGFR mutation compared to 20% of the smokers in the smoking cluster. Other frequently mutated genes include RYR2, SATB2, C1orf88, FERMT1 and CTNNB1. Somatic alterations occurred in WNT signaling pathway genes, suggesting this pathway plays a role in both Western and Asian lung cancers. Conclusions Asian never-smokers have lung cancer signatures distinct from the smoker signature and their mutation profiles are similar to that of European never-smokers. The profiles of Asian and European smokers are also similar. This suggests that the same mutational mechanisms underlie the etiology for both ethnic groups, and the high incidence of lung cancer in Asian never-smokers might not be due to second hand smoke or other carcinogens that cause oxidative DNA damage. Half of the ex-smokers/smokers have a molecular phenotype similar to never-smokers; of which, 50% had EGFR mutations. This suggests that routine EGFR testing is warranted in the Asian population, regardless of smoking status.

  Study EGAS00001000621

• Childhood Cancer Data Initiative (CCDI): Genomic Analysis in Pediatric Malignancies

  Pediatric solid tumors are highly heterogeneous, encompassing a large number of histotypes. The genomic landscape of these diseases is characterized by few single-nucleotide variants (SNVs) compared to adult cancers. In contrast, many exhibit a high prevalence of structural or epigenetic changes that alter gene expression, underlining the need for comprehensive genomic approaches such as whole-genome sequencing (WGS). Several studies have specifically addressed the clinical utility of genomic analysis in the pediatric and AYA cancer setting. Review of these studies point to key challenges that must be addressed in order to advance the routine use of genomics in this population. We have established a large collection of solid tumor tissue samples through our biobanking efforts. Where possible, we obtain longitudinal samples from the same patient. These primary patient samples and their corresponding germline have been analyzed using whole genome and whole transcriptome sequencing methods and have been linked to clinical metadata using both manual curation and robust methods for automatic extraction from the electronic health record (EHR). Importantly, research-grade genomic analysis is performed in parallel to our CLIA-grade sequencing (“UCSF500”) efforts for some of the patients in this study cohort and have been submitted as part of the American Association for Cancer Research's project GENIE and/or the National Childhood Cancer Registry. For our sequenced tumor samples, we have retrospective clinical data and ongoing efforts to prospectively record key events throughout the patient's cancer journey. In our solid tumor program, we have developed many patient-derived xenograft models and a number of PDX-derived cell lines. These unique models have been evaluated using genomic and functional approaches including (in some cases) treatment with conventional chemotherapy or investigational agents. Lastly, these samples were collected from a population that is among the most diverse in the nation and includes significant numbers of Asian, Latino, Indigenous and African-American patients, groups that are traditionally underrepresented in many banking efforts.

  Study phs002430

• Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA

  These data relate to Abbosh et al 2023 'Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA'. Some patients were included in this work that were excluded from the other TRACERx 421 papers (Frankell et al and Al-bakir et al) often due to exclusion criteria in the TRACERx clinical trial. Reasons include partial contamination with C>A artefact mutational signature (CRUK0480 ,0490) which were included for ctDNA detection analyses using high confidence clonal mutations but not clonality analyses, incomplete resection at primary surgery (CRUK0291, 0234, 0230, 0387, 0622) and a concurrent oesophageal second primary cancer (CRUK0498). The primary tissue exome sequencing for these patients that were used in this study are included in this repository. Deep targeted sequencing of (median 200) tumour specific mutations in plasma for 1069 samples from 198 TRACERx patients are also included. Additional details related to these patients and samples can be found in the supplementary or data repositories from Frankell et al and Abbosh et al.

  Study EGAS00001006923

• The immunopeptidome landscape associated with T cell infiltration, inflammation and immune-editing in lung cancer

  One key barrier for improving efficacy of cancer immunotherapy remains patient stratification. While patients with CD3+CD8+ T cell inflamed ‘hot’ tumors typically show better response to immune checkpoint inhibitors, it is still unknown if the repertoire of HLA bound peptides (HLAp) presented in ‘hot’ and ‘cold’ tumors is substantially different. We surveyed 61 tumor regions and adjacent non-malignant lung tissues from eight lung cancer patients and performed deep antigen discovery combining immunopeptidomics, genomics, bulk and spatial transcriptomics and explored the heterogenic expression and presentation of tumor (neo)antigens. We associated diverse immune cell populations with the immunopeptidome in CD3+CD8+ T cell excluded, infiltrated, hot and cold tumors and found evidence for lack of immune-editing and higher presentation efficiency of tumor antigens in cold and CD3+CD8+ T cell excluded tumors. This could have implications for the choice of combination therapies tailored to the patient’s mutanome and microenvironment.

  Study EGAS00001006298

• Contribution of allelic imbalance to colorectal cancer

  Point mutations in cancer have been extensively studied but chromosomal gains and losses have been more challenging to interpret due to their unspecific nature. Here we examine high-resolution allelic imbalance (AI) landscape in 1699 colorectal cancers, 256 of which have been whole genome sequenced (WGSed). The imbalances pinpoint 38 genes as plausible AI targets based on previous knowledge, and unbiased CRISPR-Cas9 knockout and activation screens identified altogether 79 genes within AI peaks regulating cell growth. Genetic and functional data implicates loss of TP53 as a sufficient driver of AI. The WGS highlights an influence of copy number aberrations on the rate of detected somatic point mutations. Importantly, the data reveal several associations between AI target genes, suggesting a role for a network of lineage-determining transcription factors in colorectal tumorigenesis. Overall, the results unravel the contribution of AI in colorectal cancer and provide a plausible explanation why so few genes are commonly affected by point mutations in cancers.

  Study EGAS00001002966

• Clinical Implications of Genomic Alterations in the Tumor and Circulation of Pancreatic Cancer Patients

  Pancreatic adenocarcinoma has the worst mortality of any solid cancer. To evaluate the clinical implications of genomic alterations in this tumor type, we performed whole-exome analyses of 24 tumors, targeted genomic analyses of 77 tumors, and used non-invasive approaches to examine tumor-specific mutations in the circulation of these patients. These analyses reveal somatic mutations in chromatin regulating genes MLL, MLL2, MLL3, and ARID1A in 20% of patients that were associated with improved survival. We observe alterations in genes with potential clinical utility in over a third of cases. Liquid biopsy analyses demonstrate that 43% of patients with localized disease have detectable circulating tumor DNA (ctDNA) at diagnosis. Detection of ctDNA after resection predicts clinical relapse and poor outcome, and recurrence by ctDNA is detected 6.5 months earlier than with CT imaging. These observations provide genetic predictors of outcome in pancreatic cancer and have implications for new avenues of therapeutic intervention.

  Study EGAS00001001257

• Data from the paper Context-specific Effects of TGFβ/SMAD3 in Cancer Are Modulated by the Epigenome. Tufegdzic et al, Cell Reports 2015

  The transforming growth factor beta (TGFβ) signalling pathway exerts opposing effects on cancer cells, acting either as a tumor-promoter or as a tumor-suppressor. Here we show these opposing effects are a result of the synergy between SMAD3, a downstream effector of TGFβ signalling, and the distinct epigenomes of breast tumor initiating cells (BTICs). These effects of TGFβ are associated with distinct gene expression programs, but genomic SMAD3 binding patterns are highly similar in the BTIC-promoting and BTIC- suppressing contexts. Our data show cell type-specific epigenetic configurations provide a modulatory layer by determining accessibility of genes to regulation by TGFβ/SMAD3. LBH, one such context-specific target gene, is regulated according to its DNA methylation status, and is crucial for TGFβ-dependent promotion of BTICs. Overall, these results reveal that the epigenome plays a central and previously overlooked role in shaping the context-specific effects of TGFβ in cancer.

  Study EGAS00001001570

• Rare disruptive mutations in ciliary function genes contribute to testicular cancer susceptibility

  Testicular germ cell tumor (TGCT) is the most common cancer in young men1,2. Here we aimed to identify novel risk factors for TGCT using whole-exome sequencing, which was performed on 328 affected individuals from 153 families, 634 sporadic cases and 1,644 controls. We searched for genes that were recurrently affected by rare variants (minor allele frequency <0.01) with potentially damaging effects and evidence of segregation in families. 8.7% of families carried rare disruptive mutations in the cilia-microtubule genes (CMG) as compared to 0.5% of controls3 (P=2.1x10-8). The most significantly mutated CMG was DNAAF1 with biallelic inactivation and loss of DNAAF1 expression shown in tumors from carriers. DNAAF1 as a cause of TGCT was supported by a DNAAF1Hu255h(+/-) zebrafish model with 94% penetrance for TGCT compared to 14% in wildtype fish. These data implicate cilia-microtubule inactivation as a cause of TGCT development and are the first evidence for CMGs as cancer susceptibility genes.

  Study EGAS00001001789

• Sensitive and Frequent Identification of High Avidity Neo-epitope Specific CD8 + T-cells in Immunotherapy-naïve Ovarian Cancer

  Immunotherapy directed against private tumor neo-antigens derived from non-synonymous somatic mutations is a promising strategy of personalized cancer immunotherapy. However, feasibility in low mutational load tumor types remains unknown. Comprehensive and deep analysis of circulating and tumor-infiltrating lymphocytes (TILs) for neo-epitope specific CD8 + T cells allowed prompt identification of oligoclonal and polyfunctional such cells from most immunotherapy-naïve patients with advanced epithelial ovarian cancer studied. Neo-epitope recognition was discordant between circulating T cells and TILs, and was more likely to be found among TILs, which displayed higher functionalavidity and unique TCRs with higher predicted affinity than their blood counterparts. Our results imply that identification of neo-epitope specific CD8 + T cells is achievable even in tumors with relatively low number of somatic mutations, and neo-epitope validation in TILs extends opportunities for mutanome-based personalized immunotherapies to such tumors.

  Study EGAS00001002803

• Real-time response profiling through serial plasma analyses during FOLFOX treatment in patients with colorectal cancer

  Response evaluation of cancer therapeutics relies on the assessment of the change in tumor burden, which is performed in accordance with defined criteria every 8-12 weeks. However, predictive factors for response are not available for the majority of patients with advanced stage colorectal cancer. Here we show that measurement of circulating tumor DNA (ctDNA) levels during one of the most commonly administered drug regimens, i.e. FOLFOX, allows an early, real-time assessment of treatment response. During the 48-hour FOLFOX application, we serially assessed plasma DNA and observed that ctDNA levels initially decreased during the first 23 hours. In patients with stable disease or partial response, ctDNA levels remained low, whereas in patients with progressive disease, ctDNA levels increased at the end of the treatment cycle predicting clinical and radiologic response correctly. Hence, ctDNA monitoring during treatment may contribute to an early outcome prediction with significant implications for the management of patients.

  Study EGAS00001004213

• Early on-treatment changes in circulating tumor DNA fraction and response to enzalutamide or abiraterone in metastatic castration-resistant prostate cancer

  On-treatment circulating tumor DNA (ctDNA) quantification is touted as a surrogate biomarker for understanding metastatic cancer response to systemic therapy, but there is relatively little supporting data from standardized patient cohorts. Here, in a prospective observational cohort, we demonstrate that 4-week on-treatment changes in plasma ctDNA levels can accurately identify metastatic castration-resistant prostate cancer that will progress within 6 months of initiating first-line abiraterone or enzalutamide treatment. On-treatment ctDNA measurements outperformed existing clinical variables for predicting disease response and were also closely associated with differential overall survival. Although optimal timing of blood collections and thresholds for ctDNA detection will require further testing, our data highlights the potential for sequential ctDNA measurements to provide an early and reliable read-out for therapy response. The high accuracy of this information suggests that ctDNA could be useful for guiding clinical trials of therapy changes in initially non-responsive metastatic cancers.

  Study EGAS00001006856

• ZNF703 is a common Luminal B breast cancer oncogene that differentially regulates luminal and basal progenitors in human mammary epithelium.

  The telomeric amplicon at 8p12 is common in oestrogen receptor-positive (ER+) breast cancers. Array-CGH and expression analyses of 1172 primary breast tumours revealed that ZNF703 was the single gene within the minimal amplicon and was amplified predominantly in the Luminal B subtype. Amplification was shown to correlate with increased gene and protein expression and was associated with a distinct expression signature and poor clinical outcome. ZNF703 transformed NIH 3T3 fibroblasts, behaving as a classical oncogene, and regulated proliferation in human luminal breast cancer cell lines and immortalized human mammary epithelial cells. Manipulation of ZNF703 expression in the luminal MCF7 cell line modified the effects of TGFβ on proliferation. Overexpression of ZNF703 in normal human breast epithelial cells enhanced the frequency of in vitro colony-forming cells from luminal progenitors. Taken together, these data strongly point to ZNF703 as a novel oncogene in Luminal B breast cancer.

  Study EGAS00000000082

• A living biobank of breast cancer organoids captures disease heterogeneity

  Breast Cancer (BC) comprises multiple distinct subtypes that differ genetically, pathologically, and clinically. Xeno-transplantation and direct culturing of tumor tissue are increasingly used in drug development and personalized medicine strategies. Here, we describe a robust protocol for long-term culturing of human mammary epithelial organoids. Using this protocol, 101 BC organoid lines were generated, broadly recapitulating the diversity of the disease. BC organoid morphologies typically matched the histopathology, hormone receptor-, and HER2 status of the original tumor. DNA copy number variations as well as sequence changes were consistent within tumor-organoid pairs and largely retained even after extended passaging. BC organoids furthermore populated all major gene expression-based classification groups and allowed drug screens in vitro and upon xenotransplantation. This study describes a representative collection of well-characterized BC organoids available for cancer research and drug development, as well as a strategy to assess in vitro drug response in a personalized fashion.

  Study EGAS00001002158

• Genetic and immune landscape evolution defines subtypes of MMR deficient colorectal cancer

  Mismatch repair deficient colorectal cancers have high mutation loads and many respond to immune checkpoint-inhibitors. We investigated how genetic and immune landscapes co-evolve in these tumors. All cases had high truncal mutation loads. Driver aberrations showed a clear hierarchy despite pervasive intratumor heterogeneity: Those in WNT/βCatenin, mitogen-activated protein kinase and TGFβ receptor family genes were almost always truncal. Immune evasion drivers were predominantly subclonal and showed parallel evolution. Pan-tumor evolution, subclonal evolution, and evolutionary stasis of genetic immune evasion drivers defined three MMRd CRC subtypes with distinct T-cell infiltrates. These immune evasion drivers have been implicated in checkpoint-inhibitor resistance. Clonality and subtype assessments are hence critical for predictive immunotherapy biomarker development. Cancer cell PD-L1 expression was conditional on loss of the intestinal homeobox transcription factor CDX2. This explains infrequent PD-L1 expression by cancer cells and likely contributes to the high recurrence risk of MMRd CRCs with impaired CDX2 expression.

  Study EGAS00001005769

• WES of Colorectal cancer organoid-stroma biobank cohort

  In colorectal cancers (CRC) the tumor microenvironment plays a key role for prognosis and therapy efficacy. Patient-derived tumor organoids (PDTOs) show enormous potential for preclinical testing, however, in purely epithelial cultures features including the ‘consensus molecular subtypes’ (CMS) are largely eradicated. To better reflect cell heterogeneity, we established the CRC organoid-stroma biobank of matched PDTOs and cancer-associated fibroblasts (CAFs) from 30 patients. Context-specific phenotyping showed that xenotransplantation or co-culture with CAFs restores the individual transcriptomic status and instructs subtype-specific stromal gene expression. Furthermore, co-culture exposed CMS4-specific resistance to Gefitinib and SN-38 and revealed prognostic gene expression signatures. Chemogenomic library screening identified patient- and therapy-dependent mechanisms of stromal resistance including MET as common target. Our results demonstrate that CRC phenotypes are encrypted in the cancer epithelium in a plastic fashion that strongly depends on the context. Consequently, CAFs are essential for faithful representation of molecular subtypes and therapy responses ex vivo.

  Study EGAS00001007301

• RNAseq of Colorectal cancer organoid-stroma biobank cohort

  In colorectal cancers (CRC) the tumor microenvironment plays a key role for prognosis and therapy efficacy. Patient-derived tumor organoids (PDTOs) show enormous potential for preclinical testing, however, in purely epithelial cultures features including the ‘consensus molecular subtypes’ (CMS) are largely eradicated. To better reflect cell heterogeneity, we established the CRC organoid-stroma biobank of matched PDTOs and cancer-associated fibroblasts (CAFs) from 30 patients. Context-specific phenotyping showed that xenotransplantation or co-culture with CAFs restores the individual transcriptomic status and instructs subtype-specific stromal gene expression. Furthermore, co-culture exposed CMS4-specific resistance to Gefitinib and SN-38 and revealed prognostic gene expression signatures. Chemogenomic library screening identified patient- and therapy-dependent mechanisms of stromal resistance including MET as common target. Our results demonstrate that CRC phenotypes are encrypted in the cancer epithelium in a plastic fashion that strongly depends on the context. Consequently, CAFs are essential for faithful representation of molecular subtypes and therapy responses ex vivo.

  Study EGAS00001007300

• Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer

  Tumour heterogeneity in primary prostate cancer is a well-established phenomenon. However, how the subclonal diversity of tumours changes during metastasis and progression to lethality is poorly understood. Here we reveal the precise direction of metastatic spread across four lethal prostate cancer patients using whole-genome and ultra-deep targeted sequencing of longitudinally collected primary and metastatic tumours. We find one case of metastatic spread to the surgical bed causing local recurrence, and another case of cross-metastatic site seeding combining with dynamic remoulding of subclonal mixtures in response to therapy. By ultra-deep sequencing end-stage blood, we detect both metastatic and primary tumour clones, even years after removal of the prostate. Analysis of mutations associated with metastasis reveals an enrichment of TP53 mutations, and additional sequencing of metastases from 19 patients demonstrates that acquisition of TP53 mutations is linked with the expansion of subclones with metastatic potential which we can detect in the blood.

  Study EGAS00001000942

• Molecular Subtype-specific Biomarkers Improves Colorectal Cancer Prognostication

  Colorectal cancer (CRC) is characterized by major inter-tumor diversity that complicates the prediction of disease and treatment outcomes. Recent efforts help resolve this by sub-classification of CRC according to natural molecular subtypes, however, this strategy is not yet able to provide clinicians with improved tools for decision-making. We here present an extended framework for CRC stratification that specifically aims to improve patient prognostication. Using transcriptional profiles from 1,100 CRCs, including a novel set of >300 samples, we identify novel cancer cell and tumor archetypes and suggest the tumor microenvironment as a major prognostic determinant that can be influenced by the microbiome. Notably, our subtyping strategy allowed identification of novel archetype-specific prognostic biomarkers that provided information beyond and independent of UICC-TNM staging, MSI-status and consensus molecular subtyping. The results illustrate that our extended subtyping framework, combining subtyping and subtype-specific biomarkers, could contribute to improved patient prognostication and may form a strong basis for future studies.

  Study EGAS00001002376

• The interface of malignant and immunologic clonal dynamics in high-grade serous ovarian cancer

  High-grade serous ovarian cancer exhibits extensive intratumoral heterogeneity coupled with widespread intraperitoneal disease. Despite this, metastatic spread of tumor clones is non-random, implying the existence of local microenvironmental factors that shape tumor progression. We interrogated the molecular interface between tumorinfiltrating lymphocytes (TIL) and cancer cells in 143 samples from 21 patients using whole-genome sequencing, immunohistochemistry, histologic image analysis, gene expression profiling, and T- and B-cell receptor sequencing. We identify 3 immunologic response categories, which frequently co-exist within individual patients. Furthermore, epithelial CD8+ TIL were inversely associated with malignant cell diversity, evidenced by subclonal neoepitope elimination and spatial tracking between tumor and T-cell clones. Intersecting mutational signatures and immune analysis showed that foldback inversion genomic aberrations lead to worse outcomes even in the presence of cytotoxic TIL (n=433). Thus, regional variation in immune contexture mirrors the pattern of intraperitoneal malignant spread, provoking new perspectives for treatment of this challenging disease.

  Study EGAS00001002839

• Combined gene expression and digital pathology identifies molecular mediators of T cell exclusion and immune suppression in ovarian cancer

  Close proximity between cytotoxic T lymphocytes and tumour cells is required for effective immunotherapy. However, what determines the spatial distribution of T cells in the tumour microenvironment is not well understood. Coupling digital pathology and transcriptome analysis on a large ovarian tumour cohort, we develop a machine learning approach to molecularly classify and characterize tumour-immune phenotypes. Our study identifies two important hallmarks characterizing T cell excluded tumours: 1) loss of antigen presentation on tumour cells and 2) upregulation of TGFb and activated stroma. Furthermore, we identify TGFb as a key mediator of T cell exclusion. TGFb reduces MHC-I expression in ovarian cancer cells in vitro; TGFb also activates fibroblasts and induced extracellular matrix (ECM) production as a potential physical barrier to hinder T cell infiltration. Our findings indicate that targeting TGFb may represent a promising strategy to overcome T cell exclusion and improve clinical benefits of cancer immunotherapy.

  Study EGAS00001003487

• Genome-wide cell-free DNA mutational integration enables ultra-sensitive cancer monitoring

  In many areas of oncology, we lack sensitive tools to track low burden disease. While cell-free DNA (cfDNA) shows promise in detecting cancer mutations, we found that the combination of low tumor fraction (TF) and limited number of DNA fragments restricts low disease burden monitoring through the prevailing deep targeted sequencing paradigm. We reasoned that breadth may supplant depth of sequencing to overcome the barrier of cfDNA abundance. Whole genome sequencing (WGS) of cfDNA allowed ultra-sensitive detection, capitalizing on the cumulative signal of thousands of somatic mutations observed in solid malignancies, with TF detection sensitivity as low as 10-5. The WGS approach enabled dynamic tumor burden tracking and post-operative residual disease detection, associated with adverse outcome. Thus, we present an orthogonal framework for cfDNA cancer monitoring via genome wide mutational integration, enabling ultra-sensitive detection, overcoming the limitation of cfDNA abundance, and empowering treatment optimization in low-disease burden oncology care

  Study EGAS00001004406

• Genomic Analysis of Paired Endometrial Cancer Primaries and Metastases

  Formation of metastases is the major cause of cancer related deaths. Recent studies have sequenced primary endometrial carcinomas yielding data for a single entity in the progression from the birth of a progenitor tumor cell to metastatic disease. However, the progression of these tumors to metastases has not been characterized. We performed whole-exome sequencing of 98 tumor biopsies including complex atypical hyperplasias, primary tumors and paired abdominopelvic metastases to survey the evolutionary landscape of endometrial cancer. We expanded and reanalyzed TCGA-data, identifying novel recurrent alterations in primary tumors, including mutations in the estrogen receptor cofactor NRIP1 in 12% of patients. We found that likely driver events tended to be shared by primary and metastatic tissue-samples, with notable exceptions such as ARID1A mutations. Phylogenetic analyses in cases with multiple metastases indicated these metastases typically arose from one lineage of the primary tumor. These data indicate extensive genetic heterogeneity within endometrial cancers and relative homogeneity across metastatic sites.

  Study phs001127

• Analysis of AR Gene Rearrangements in Prostate Cancer

  Molecularly-targeted therapies for advanced prostate cancer include castration modalities that suppress ligand-dependent transcriptional activity of the androgen receptor (AR). However, persistent AR signaling undermines therapeutic efficacy and promotes progression to lethal castration-resistant prostate cancer (CRPC), even when patients are treated with potent second-generation AR-targeted therapies abiraterone and enzalutamide. Here we define diverse AR genomic structural rearrangements (AR-GSRs) as a class of molecular alterations occurring in one third of CRPC-stage tumors. AR-GSRs occur in the context of copy-neutral and amplified AR and display heterogeneity in breakpoint location, rearrangement class, and sub-clonal enrichment in tumors within and between patients. Despite this heterogeneity, one common outcome in tumors with high sub-clonal enrichment of AR-GSRs is outlier expression of diverse AR variant species lacking the ligand binding domain and possessing ligand-independent transcriptional activity. Collectively, these findings reveal AR-GSRs as important drivers of persistent AR signaling in CRPC.

  Study phs001223

• Prospective Analysis of Genotypes in Adults Undergoing Therapy for Lung Cancer (Paclitaxel Cohort)

  Lung cancer is frequently treated with paclitaxel in combination with several other agents; however, paclitaxel treatment is often ineffective or limited by treatment-related toxicities. Heritable variants in genes associated with absorption, distribution, metabolism, and elimination may predict paclitaxel clinical outcome and toxicity. We designed a prospective multi-institutional study that recruited 546 patients receiving therapy with a 5-year follow up. All patients were genotyped using the Drug Metabolizing Enzymes and Transporters (DMET) platform, which ascertains 1931 genotypes in 235 genes. Genotypes were compared to the progression-free survival of paclitaxel therapy and clinically-significant paclitaxel toxicities. Seven genetic variants were associated with paclitaxel PFS (in ABCB11, ABCC3, ABCG1, CYP8B1, NR3C1, FMO6P, and GSTM3), whereas four genetic variants (in VKORC1, SLC22A14, GSTA2, and DCK) were associated with paclitaxel toxicities. The present SNPs have limited clinical utility but suggest that certain genes are related to important paclitaxel pathways in lung cancer.

  Study phs001660

• Genomics and Methylation of Neuroendocrine Prostate Cancer from cfDNA (Cornell/Trento 2019)

  A subset of castration resistant prostate cancers develop small cell neuroendocrine prostate cancer (NEPC) as a mechanism of treatment resistance. Metastatic tissue biopsies to evaluate for NEPC transformation are invasive and challenging to perform serially. We performed whole exome and whole genome bisulfite sequencing of plasma cfDNA and matched tumor biopsy samples from 62 patients with metastatic prostate cancer along the disease spectrum to evaluate for NEPC associated genomic and epigenomic features. Multiple tissue biopsies and/or plasma time points were included for a subset of patients to characterize disease heterogeneity and dynamic changes. Computational analysis of clonality and allele specific quantification allowed for detailed comparison of matched tumor tissue and cfDNA data (CLONET v2). Methylation profiles detected from tissue and plasma data were compared and NEPC specific alterations were evaluated in cfDNA. The study supports the feasibility of a plasma based assay for the detection of NEPC.

  Study phs001752

• International Cancer Proteogenome Consortium (ICPC): proteogenomics of early stage lung adenocarcinoma in Taiwan

  Lung cancer in East Asia is characterized by high percentage of never-smokers, early-onset and predominant EGFR mutations. To provide an insight into the molecular phenotype of this demographically distinct disease, we have performed a proteogenomics study on a prospectively collected cohort representing early stage lung adenocarcinomas in Taiwan. The distinct mutational profile revealed high prevalence of the APOBEC mutational signature in early-onset females implicating differential regulation of APOBEC enzymes and DNA damage pathways, as well as enrichment of mutational signatures congruent with environmental carcinogens over-represented in the genomic location of EGFR. We delineate the proteogenomic hallmarks of tumor progression and propose a proteomics-informed classification that resolves the EGFR mutation heterogeneity associated with survival within the early stages. Functional annotation of the molecular subtypes by protein network analysis highlights candidate biomarkers for patient stratification. Our integrative analysis reveals the molecular architecture of lung cancer in East Asia and enables the path for precision medicine.

  Study phs001954

• Genetic Analysis of Latin American Cervical Cancer

  HPV16 is the most oncogenic type of human papillomaviruses (HPV). Integration of HPV into the human genome is an important mechanism of carcinogenesis but is absent in at least 30% of HPV16+ tumors. We applied long-read whole-genome sequencing (WGS) to cervical cancer cell lines and tumors to characterize HPV16 carcinogenesis in the absence of integration. WGS of HPV16+ cervical tumor samples from Latin America revealed that 11/20 tumors with only episomal HPV (EP) had intact monomer episomes. The remaining 9 EP tumors had multimer and rearranged HPV genomes. The majority (80%) of the HPV rearrangements and deletions disrupted the E1 and E2 genes, and EP tumors overexpressed the E6 and E7 viral oncogenes, a similar profile to tumors with HPV integration. Tumors with putative multimer HPV integrations display HPV multimers and concatemers of human and viral sequences. Our data uncovered a novel mechanism for HPV16 to cause cancer without integration through aberrant episomal replication, and forming rearranged, mutated, and multimer episomes.

  Study phs002810

• A Phase III Randomized Study of Nivolumab Plus Ipilimumab Versus Nivolumab in Stage IV Squamous Cell Lung Cancer

  Lung-MAP (S1400, NCT02785952) was a multicenter, open-label, phase III randomized clinical trial. The Lung-MAP-I substudy (S1400I) was conducted from December 2015 to April 2018, through the National Clinical Trials Network and led by the SWOG Cancer Research Network. The trial compared nivolumab plus ipilimumab (nivo+ipi) with nivolumab monotherapy (nivo) in patients with chemotherapy-pretreated, immunotherapy-naïve, advanced squamous non-small cell lung carcinoma (sqNSCLC). Two hundred fifty-two patients were randomly assigned to receive nivo+ipi (n = 125) or nivo (n = 127). The clinical efficacy endpoints were overall survival, progression free survival, duration of response, and best objective response by RECIST 1.1. Multi-omic translational analysis was performed in collaboration with the the CIMAC–Cancer Immunologic Data Commons (CIDC) Network using available tumor tissue samples and blood samples (n = 160) submitted for Lung-MAP screening and provided by the SWOG tissue bank.

  Study phs003412

• Subclonal diversification of primary breast cancer

  Cancers are ecosystems of genetically related clones, competing across space and time for limited resources. To understand the clonal structure of primary breast cancer, we applied genome and targeted sequencing to 295 samples from 49 patients’ tumors. The extent of subclonal diversification varied considerably among patients and encompassed many spatial patterns, including local growth, intraductal dissemination and clonal intermixture. Landmarks of disease progression, such as acquiring invasive or metastatic potential, arose within detectable subclones of antecedent lesions, suggesting that subclonal mutations could be relevant if actionable. No defined temporal order of mutation was evident, with the commonest genes, including PIK3CA, TP53, BRCA2, PTEN and MYC, mutated early in some, late in others, often exhibiting parallel evolution across subclones. Signatures of homologous recombination deficiency correlated with response to neoadjuvant chemotherapy. Thus, the interplay of mutation, growth and competition drives clonal structures of breast cancer that are complex, variable across patients and clinically relevant.

  Dataset EGAD00001000898

• Subclonal diversification of primary breast cancer

  Cancers are ecosystems of genetically related clones, competing across space and time for limited resources. To understand the clonal structure of primary breast cancer, we applied genome and targeted sequencing to 295 samples from 49 patients’ tumors. The extent of subclonal diversification varied considerably among patients and encompassed many spatial patterns, including local growth, intraductal dissemination and clonal intermixture. Landmarks of disease progression, such as acquiring invasive or metastatic potential, arose within detectable subclones of antecedent lesions, suggesting that subclonal mutations could be relevant if actionable. No defined temporal order of mutation was evident, with the commonest genes, including PIK3CA, TP53, BRCA2, PTEN and MYC, mutated early in some, late in others, often exhibiting parallel evolution across subclones. Signatures of homologous recombination deficiency correlated with response to neoadjuvant chemotherapy. Thus, the interplay of mutation, growth and competition drives clonal structures of breast cancer that are complex, variable across patients and clinically relevant.

  Dataset EGAD00001000965

• The evolving mutational landscape of normal human esophagus

  The extent to which cells in normal tissues accumulate mutations during life is poorly understood. Some mutant cells expand into clones that can be detected by genome sequencing. We mapped mutant clones in normal esophageal epithelium from nine donors aged 20-75. Somatic mutations accumulate with age and are mainly caused by intrinsic mutational processes. We found strong Darwinian selection of clones carrying mutations in 14 cancer genes, with tens to hundreds of such clones per square centimeter. By middle age, clones with cancer-associated mutations cover most of the epithelium, with NOTCH1 and TP53 mutations affecting 40% and 10% of all cells, respectively. Remarkably, the prevalence of NOTCH1 mutations in normal esophagus is several times higher than in esophageal cancers. The esophagus emerges as an evolving patchwork of mutant clones that colonize the majority of the epithelium, with implications for our understanding of cancer and ageing.

  Dataset EGAD00001004158

• The evolving mutational landscape of normal human esophagus

  The extent to which cells in normal tissues accumulate mutations during life is poorly understood. Some mutant cells expand into clones that can be detected by genome sequencing. We mapped mutant clones in normal esophageal epithelium from nine donors aged 20-75. Somatic mutations accumulate with age and are mainly caused by intrinsic mutational processes. We found strong Darwinian selection of clones carrying mutations in 14 cancer genes, with tens to hundreds of such clones per square centimeter. By middle age, clones with cancer-associated mutations cover most of the epithelium, with NOTCH1 and TP53 mutations affecting 40% and 10% of all cells, respectively. Remarkably, the prevalence of NOTCH1 mutations in normal esophagus is several times higher than in esophageal cancers. The esophagus emerges as an evolving patchwork of mutant clones that colonize the majority of the epithelium, with implications for our understanding of cancer and ageing.

  Dataset EGAD00001004159

• MutWP5__CRUK_Mutographs_of_Cancer__Breast__Cancer_Mastectomy__Exome_

  Sequencing of LCM-derived microbiopsies from 30 women who underwent mastectomies due to a breast cancer diagnosis. Goal to assess the mutational burden, spectrum, and clonal dynamics within the tissue. Exome data will be used as a driver and clonality screen, highly clonal or driver-containing samples will subsequently be sent for whole-genome sequencing. Results from this portion of the study will be compared to women who had cosmetic breast reduction surgeries and those with germline BRCA 1/2 mutations.

  Study EGAS00001003319

• Clonal_expansion_of_mutated_cell_population_in_bladder_urothelium_

  1cm biospies of from patients undergoing bladder cystectomy will be collected. The underlying muscle and stroma will be removed and the remaining epithelia dissected into small sequential areas which will be sent for ultra-deep exome sequencing using a panel of known cancer and viral genes. Sequence analysis using similar methods to Martincorena I et al (Science 2015, 348:880) will provide an idea of the somatic mutational landscape in these patient samples. Individual patient muscle samples will also be sequenced as a reference.

  Study EGAS00001001687

• AML_targeted_resequencing_study

  Genomic libraries will be generated from whole genome amplified genomic DNA derived from 3,000 myeloid neoplasms. Targeted capture will be performed by multiplexing 16 barcoded samples in each library. Pools of 96 DNA samples will be subjected to 1-2 lanes of HiSeq 75bp sequencing. Reads will be mapped to the current build of the human reference genome to facilitate the generation of a comprehensive catalog of somatic mutations associated with 116 known myeloid and cancer driver genes.

  Study EGAS00001000275

• Genomic Signatures Reveal DNA Damage Response Deficiency in Brain Metastases of Colorectal Cancer

  Brain metastasis (BM) of colorectal cancer (CRC) is rare but lethal, and lacks effective therapies or a good understanding of its genomic landscapes. We conduct an analysis of whole-exome sequencing (WES) and whole-genome sequencing (WGS) data on 19 trios of patient-matched BMs, primary CRC tumors, and adjacent normal tissue to (1) document genomic signatures during the evolution of CRC BM; (2) identify clinically actionable targets for the BM treatment; and (3) identify potential drivers in CRC BM.

  Study EGAS00001003659

• Bulk RNAseq gene expression of baseline tumors from metastatic urothelial bladder cancer patients (IMvigor210) and metastatic renal cell carcinoma (IMmotion150)

  We examined tumors from a large cohort of patients with metastatic urothelial bladder cancer (mUC) and metastatic renal cell carcinoma (mRCC) treated with an anti-PD-L1 agent (atezolizumab) and found that high tumor IL8 gene expression was associated with worse overall survival (OS). We further identified the tumoral immune presence based on Teff signature. We found that high tumor IL8 expression continued to be associated with worse OS even in inflamed tumors in mUC and mRCC.

  Study EGAS00001004386

• PELICAN33 longitudinal clinical and autopsy phenomic assessment in lethal metastatic prostate cancer

  Objective: To identify novel phenotypes and features associated with metastatic prostate cancer (mPC) outcome, and to identify biomarker and data requirements to be tested in future precision oncology trials. Design, Setting, and Participants: We analyzed deep longitudinal clinical, neuroendocrine expression, and autopsy data of 33 men who died from mPC between 1995 and 2004 (PELICAN33), and related findings to mPC biomarkers reported in the literature. Intervention: 33 men prospectively consented to participate in an integrated clinical-molecular rapid autopsy study of mPC.

  Study EGAS00001005399

• Genomic characterization of co-existing biliary tract intraepithelial neoplasia and carcinoma lesions reveals distinct evolutionary paths of gallbladder cancer

  Gallbladder carcinoma is the most common cancer of the biliary tract with dismal survival largely due to delayed diagnosis. Biliary tract intraepithelial neoplasia (BilIN) is the common benign tumor that is suspected to be precancerous lesions. However, the genetic and evolutionary relationships between BilIN and carcinoma remain unclear. Here we performed whole-exome sequencing of coexisting low-grade BilIN (adenoma), high-grade BilIN, and carcinoma lesions, and normal tissues from the same patients.

  Study EGAS00001005402

• Genotyping by OncoArray and Global Screening Array for colorectal cancer risk prediction

  The study was conducted to build a Polygenic risk scores (PRS) based on a reported set of 140 single nucleotide polymorphisms that were identified to be associated with a higher risk of colorectal cancer (CRC). Genotyping by OncoArray and Global Screening Array was performed using DNA extracted from blood samples collected at baseline of 187 participants who develop CRC and 176 randomly selected controls without diagnosis of CRC identified within 14 years of follow-up.

  Study EGAS00001005411

• 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

• Tumour evolvability metrics predict recurrence in advanced localised prostate cancer (tumour data)

  There is a need for quantitative measurements of evolutionary metrics in controlled clinical trials with long term follow-up information. This is particularly true in advanced localised prostate cancer, which can recur more than a decade after diagnosis. Here we mapped genomic intra-tumour heterogeneity in 642 tumour samples from 114 patients who took part in the IMRT and DELINEATE clinical trials, for which full clinical information and 12y median follow-up was available. We concomitantly assessed phenotypic (morphological) heterogeneity using Deep Learning in 1,923 histological sections from 250 IMRT patients (fully overlapping with the genetic set). This study shows that combining genomics with AI-aided histopathology in clinical trials leads to novel clinical biomarkers. This EGA repository contains data produced from tumour samples using low coverage whole genome sequencing and a prostate cancer specific gene panel data following compression of unique molecular identifiers.

  Dataset EGAD00001010274

• Tumour evolvability metrics predict recurrence in advanced localised prostate cancer (normal data)

  There is a need for quantitative measurements of evolutionary metrics in controlled clinical trials with long term follow-up information. This is particularly true in advanced localised prostate cancer, which can recur more than a decade after diagnosis. Here we mapped genomic intra-tumour heterogeneity in 642 tumour samples from 114 patients who took part in the IMRT and DELINEATE clinical trials, for which full clinical information and 12y median follow-up was available. We concomitantly assessed phenotypic (morphological) heterogeneity using Deep Learning in 1,923 histological sections from 250 IMRT patients (fully overlapping with the genetic set). This study shows that combining genomics with AI-aided histopathology in clinical trials leads to novel clinical biomarkers. This EGA repository contains data produced from tumour samples using low coverage whole genome sequencing and a prostate cancer specific gene panel data following compression of unique molecular identifiers.

  Dataset EGAD00001010295

• Melanoma_Til_Study_RNAseq

  In this study, mutations present in a series of human melanomas (stage IV disease) will be determined, using autologous blood cells to obtain a reference genome. From each of the samples that are analyzed, tumour-infiltrating T lymphocytes have also been isolated. This offers a unique opportunity to determine which (fraction of) mutations in human cancer leads to epitopes that are recognized by T cells. The resulting information is likely to be of value to understand how T cell activating drugs exert their action.

  Study EGAS00001000251

• Targeted_sequencing_of_genes_recurrently_mutated_in_AML___part2

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

  Study EGAS00001000570

• Whole Exome Sequencing for Colorectal Cancer

  This project was designed to use next generation sequencing technology to screen the protein coding regions of the genome for low frequency variants in a panel of high-risk colorectal adenocarcinoma cases. Blood and cell-line DNA for colorectal cancer patients and a subset of quality control samples that had existing whole exome sequence data were analyzed using Illumina HiSeq sequencers. Samples from this project were from participants in the Women's Health Initiative (WHI) and the Diet, Activity, and Lifestyle Study (DALS).

  Study phs000410

• Comprehensive Analysis of Structural Variants in Breast Cancer Genomes Using Single Molecule Sequencing

  This study used the SKBR3 breast cell line and tumor/normal organoids derived from breast tissue to explore the utility of long read sequencing for detecting structural variants in complex samples. Three technologies were used to characterize the samples: Illumina/10X, Pacific Biosciences, and Oxford Nanopore. Methylation results were derived from the Oxford Nanopore data. It is hoped that this resource will better help researchers better understand the utility of long read sequencing in cancer samples.

  Study phs002210

• A National Translational Science Network of Precision-Based Immunotherapy for Primary Liver Cancer (PLC)

  The primary objective of the NCI-CLARITY study is to establish a biospecimen repository for genomic, genetic and epigenetic analysis to study the biology of primary liver cancer (PLC) development and progression. Secondary objectives include predicting overall and progression-free survival following immunotherapy. In the retrospective phase, anonymous archival tissue from PLC patients was obtained from five participating sites. Whole exome and transcriptome sequencing was generated and used to predict overall survival in response to immunotherapy.

  Study phs003074

• Metastatic Prostate Follow Up 2

  Validation/deeper sequencing for metastatic prostate cancer samples

  Dataset EGAD00001000989

• CPC-GENE Prostate Cancer Heterogeneity Study

  Aligned Sequence (bam format), Duplicates removed

  Dataset EGAD00001001329

• Global Anaplastic Thyroid Cancer Initiative

  Raw exome sequence data(fastq) for the GATCI project

  Dataset EGAD00001003235

• Pancreatic Cancer OICR

  ICGC DCC Release 24, PACA-CA Exome sequence

  Dataset EGAD00001003264

• Transcriptome sequencing of Gingivo-buccal Cancer : ICGC-India Project_Batch05

  Dataset EGAD00001004430

• Tumor dataset - Case

  tumor-based gene expression from breast cancer cases

  Dataset EGAD00010001064

• Sharc-ovarian

  Low coverage nanopore sequencing of ovarian cancer tumors

  Dataset EGAD00001005472

• : Centromeric cohesion failure invokes a conserved choreography of chromosomal mis-segregations in pancreatic neuroendocrine tumours

  Study EGAS00001004239

• Bisulphite_MPN_colonies

  Swift kit whole genome bisulphite of MPN colonies

  Study EGAS00001003094

• Identifying_Novel_Fusion_Genes_in_Myeloma

  To identify novel fusion genes in Myeloma samples

  Study EGAS00001000220

• Children's Cancer Therapy Institute DAC

  Dac EGAC00001001828

• DNA methylation and Panel sequencing for pancreatic neuroendocrine carcinomas (PanNECs) and pancreatic neuroendocrine tumors (PanNETs)

  Study EGAS00001005731

• Single cell sequencing of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis

  Study EGAS00001002845

• Polyomavirus-positive Merkel cell carcinoma derived from a trichoblastoma suggests an epithelial origin of Merkel cell carcinoma

  Study EGAS00001003784

• Molecular profiling reclassifies adult astroblastoma into known and clinically distinct tumor entities with frequent MAPK pathway alterations

  Study EGAS00001003798

• Genetic characterization of a Unique Neuroendocrine Transdifferentiation Prostate Circulating Tumor Cell - Derived eXplant (CDX) Model

  Study EGAS00001004272

• The data access committee for Evolution of neoantigen landscape during immune checkpoint blockade in non-small cell lung cancer.

  Dac EGAC00001000757

• Data Access Committee for the study "Somatic chronology of treatment-resistant prostate cancer via deep whole-genome ctDNA sequencing"

  Dac EGAC00001002479

• This DAC takes care of requests for data for the Swiss epigenetic colorectal cancer cohort study, SWEPIC

  Dac EGAC00001003471

• Molecular analysis of CRC in patients with Primary Sclerosing Cholangitis (PSC) and Inflammatory Bowel Disease (IBD)

  Study EGAS00001004497