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• MutWP1__CRUK_Grand_Challenge_Mutographs_of_Cancer__clear_cell_renal_cell_carcinoma

  The Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Different patterns of somatic mutation are generated by the different environmental, lifestyle and genetic factors that cause cancer, many of them are still unknown. Within Mutographs, the International Agency for Research on Cancer is coordinating the recruitment of 5000 individuals with cancer (colorectal, renal, pancreatic, oesophageal adenocarcinoma or oesophageal squamous cancers) across 5 continents to explore whether different mutational signatures explain marked variation in incidence. In brief, through an international network of collaborators around the world, biological materials are collected, along with demographic, histological, clinical and questionnaire data. Whole genome sequences of tumour-germline DNA pairs are generated at the Wellcome Trust Sanger Institute. Somatic mutational signatures are subsequently extracted by non-negative matrix factorisation methods and correlated with risk factors data. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development.

  Study EGAS00001002608

• Stratifying and Targeting Pediatric Medulloblastoma through Genomics

  In this project, genomic analyses of pediatric medulloblastoma samples, obtained through the international medulloblastoma consortium, will be performed. RNA and miRNA expression profiles of 1000 samples, representing all four subgroups (Wnt, Shh, Group C, and D), will be studied to identify novel subtypes within each subgroup. The resulting subtype-specific expression profiles will support the development of reliable and robust biomarkers to more accurately and reliably classify medulloblastomas for treatment in clinical trials. For that purpose, two assays will be developed: an antibody-based immunohistochemical assay and an orthogonal nucleic acid-based hybridization assay. Additional genomic DNA analysis of the 300 high risk subgroup cases will support the discovery of subgroup specific somatic mutations in order to inform current clinical trials of targeted therapies, and to identify genes and pathways already targeted in other diseases. Such therapies could be rapidly transitioned to Phase II trials in medulloblastoma. Furthermore, the discovery of somatic mutations could be used for developing as well as validating specific biomarkers. The project team will also try to identify risk factors that predispose children to this type of cancer.

  Study EGAS00001000273

• MutWP1__CRUK_Grand_Challenge_Mutographs_of_Cancer__Colorectal_LCM

  The Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Different patterns of somatic mutation are generated by the different environmental, lifestyle and genetic factors that cause cancer, many of them are still unknown. Within Mutographs, the International Agency for Research on Cancer is coordinating the recruitment of 5000 individuals with cancer (colorectal, renal, pancreatic, oesophageal adenocarcinoma or oesophageal squamous cancers) across 5 continents to explore whether different mutational signatures explain marked variation in incidence. In brief, through an international network of collaborators around the world, biological materials are collected, along with demographic, histological, clinical and questionnaire data. Whole genome sequences of tumour-germline DNA pairs are generated at the Wellcome Trust Sanger Institute. Somatic mutational signatures are subsequently extracted by non-negative matrix factorisation methods and correlated with risk factors data. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development.

  Study EGAS00001003455

• The evolutionary steps from primary to metastatic prostate cancer are largely uncharted, and the ability to use DNA present in body fluids as correlates of aggregate metastatic status is under-examined. We reconstructed phylogenies in ten prostate cancer patients with fatal disease using deep targeted sequencing of the prostate, adjacent and distant organs, as well as plasma, serum, and cerebrospinal fluid at various time points. A total of 163 samples are studied.

  The evolutionary steps from primary tumor to metastasis in prostate cancer are largely uncharted, and the ability to use serum, plasma, and cerebrospinal fluid as a correlate of aggregate metastatic tumor genomic status has not been tested. We used deep targeted sequencing to reconstruct tumor evolution in ten prostate cancer patients with fatal disease encompassing examination of the prostate and adjacent and distant organs, as well as plasma, serum, and cerebrospinal fluid at various time points. We show that there is substantial evolution from a common ancestor within the prostate that results in branching to multiple lineages which form an intermixed multi-clonal primary tumor mass. After the occurrence of key driver aberrations, one of these lineages will metastasize to multiple sites in a sequential fashion. These metastatic sites are then susceptible to being populated by cells from other intra-prostatic lineages or from other metastases. Genomic representation of metastases in body fluids is not uniform. Cerebrospinal fluid analysis can detect lineages not detected in circulating DNA, suggesting possible clinical utility.

  Study EGAS00001003848

• A system-wide approach to monitor responses to synergistic BRAF and EGFR inhibition in colorectal cancer cells

  Molecular heterogeneity of tumors, epigenetic changes and a diverse range of molecular mechanisms are main contributors to drug resistance, which represents one of the great challenges in cancer treatment. A deeper understanding of the molecular biology of cancer has resulted in better targeted therapies, where one or multiple drugs are adopted in novel therapies to tackle resistance. This beneficial effect of using combination treatments has to some extent also been observed in colorectal cancer (CRC) patients harboring the BRAF(V600E) mutation, whereby dual inhibition of BRAF(V600E) and EGFR increases antitumor activity. Notwithstanding this success, it is not clear whether this combination treatment is the only or most effective treatment to block resistance. Here, we investigate molecular responses upon single and multi-target treatments, over time, using BRAF(V600E) mutant CRC cells as a well-define model system. Through integration of transcriptomic, proteomic and phosphoproteomics data we obtain a comprehensive overview, revealing both well-known and novel responses. We primarily observe widespread upregulation of tyrosine kinases (RTKs) and and metabolic pathways. This points to by which the treated cells switch energy sources as a defensive response entering a quiescent like state, while activating signalling to re-activate the MAPK pathway.

  Study EGAS00001002654

• THE GENOMIC LANDSCAPE OF ACTINIC KERATOSIS

  Actinic keratoses (AK) are lesions of epidermal keratinocyte dysplasia and are pre-cursor lesions to invasive cutaneous squamous cell carcinoma (cSCC). Identifying the specific genomic alterations driving the progression of normal skin to AK and invasive cSCC is challenging due to the massive, ultraviolet radiation-induced mutational burden characteristic to these lesions. Here, we present the largest whole exome sequencing study to date on AK with matched cSCC and demonstrate that AK and cSCC are almost indistinguishable at the genomic level, in terms of mutational burden, patterns of driver gene mutations and copy number alterations. We identified 44 significantly mutated AK driver genes through our established bioinformatics pipeline and demonstrate these genes are similarly mutated in cSCC. We also identified mutational signature-32 exclusively in AK from patients exposed to azathioprine, providing further, compelling evidence for this drug’s role in keratinocyte carcinogenesis, likely through its blocking of transcription coupled repair. We demonstrated that cSCC had higher levels of intra-sample heterogeneity than AK and that several signaling pathways, including immune-related signaling and TGF-beta signaling were significantly more mutated in cSCC. Integrating our findings with independent gene expression data confirms that dysregulated TGF-beta signaling may represent the critical pathway in the progression from AK to cSCC.

  Study EGAS00001004243

• MutWP1__CRUK_Grand_Challenge_Mutographs_of_Cancer__clear_cell_renal_cell_carcinoma___2

  The Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Different patterns of somatic mutation are generated by the different environmental, lifestyle and genetic factors that cause cancer, many of them are still unknown. Within Mutographs, the International Agency for Research on Cancer is coordinating the recruitment of 5000 individuals with cancer (colorectal, renal, pancreatic, oesophageal adenocarcinoma or oesophageal squamous cancers) across 5 continents to explore whether different mutational signatures explain marked variation in incidence. In brief, through an international network of collaborators around the world, biological materials are collected, along with demographic, histological, clinical and questionnaire data. Whole genome sequences of tumour-germline DNA pairs are generated at the Wellcome Trust Sanger Institute. Somatic mutational signatures are subsequently extracted by non-negative matrix factorisation methods and correlated with risk factors data. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development.

  Study EGAS00001003542

• Long-term organoid culture of a small intestinal neuroendocrine tumor

  Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare and highly heterogeneous neoplasms whose incidence has markedly increased over the last decades. A grading system based on the tumor cells' proliferation index predicts high-risk for G3 NETs. However, low-to-intermediate grade (G1/G2) NETs have an unpredictable clinical course that varies from indolent to highly malignant. Cultures of human cancer cells enable to perform functional perturbation analyses that are instrumental to enhance our understanding of cancer biology. To date, no tractable and reliable long-term culture of G1/G2 NET has been reported to permit disease modeling and pharmacological screens. Here, we report of the first long-term culture of a G2 metastatic small intestinal NET that preserves the main genetic drivers of the tumor and retains expression patterns of the endocrine cell lineage. Replicating the tissue, this long-term culture showed a low proliferation index, and yet it could be propagated continuously without dramatic changes in the karyotype. The model was readily available for pharmacological screens using targeted agents and as expected, showed low tumorigenic capacity in vivo. Overall, this is the first long-term culture of NETs to faithfully recapitulate many aspects of the original neuroendocrine tumor.

  Study EGAS00001007093

• Transcriptomics identifies blunted immunomodulatory effects of vitamin D in people with multiple sclerosis

  Vitamin D deficiency is a risk factor for developing multiple sclerosis (MS). However, the immune effects of vitamin D in people with MS are not well understood. We analyzed transcriptomic datasets generated by RNA sequencing of immune cell subsets (CD4+, CD8+ T cells, B cells, monocytes) from 33 healthy controls and 33 untreated MS cases. We utilized a traditional bioinformatic pipeline and weighted gene co-expression network analysis (WGCNA) to determine genes and pathways correlated with endogenous vitamin D. In controls, CD4+ and CD8+ T cells had 1079 and 1188 genes, respectively, whose expressions were correlated with plasma 25-hydroxyvitamin D level (P<0.05). Functional enrichment analysis identified association with TNF-alpha and MAPK signaling. In CD4+ T cells of controls, vitamin D level was associated with expression levels of several genes proximal to multiple sclerosis risk loci (P=0.01). Genes differentially associated with endogenous vitamin D by case-control status were enriched in TNF-alpha signaling via NF-κB. WGCNA suggested a blunted response to vitamin D in cases relative to controls. Collectively, our findings provide further evidence for the immune effects of vitamin D, and demonstrate a differential immune response to vitamin D in cases relative to controls, highlighting a possible mechanism contributing to MS pathophysiology.

  Study EGAS00001007254

• Adipocytes Regulate Fibroblast Function and Their Loss Contributes to Fibroblast Dysfunction in Inflammatory Diseases

  We profiled live synovial cells from 16 individuals with no diagnosed arthritis using single-cell RNA sequencing. Our study was designed to provide a reference single cell RNA sequencing dataset for researchers interested in studying arthritic synovium, providing sequencing data on healthy synovial cells for comparison to cells from diseased synovial tissues. Synovial tissue was collected post-mortem from three different sources between 2019-2021: the National Disease Research Interchange, a collaboration with Rush University and the Gift of Hope, and the Brigham and Women's Hospital Autopsy Department. To be included in the study, patients had to be between the ages of 18 to 72 and have no diagnosed arthritis or autoimmune diseases. Additionally, this study includes bulk RNA sequencing data of cultured primary synovial fibroblasts isolated from three rheumatoid arthritis patents. Cells were stimulated with either cortisol, fat conditioned media, TGFβ, TNFα, fat conditioned media with mifepristone, TGFβ with fat conditioned media, or TNFα with fat conditioned media. Cells were harvested 4 or 22 hours later and lysates collected for sequencing. Data from this study submitted to the Gene Expression Omnibus (GEO) may be accessed via accession number GSE233504.

  Study phs003304

• Development of cell lines and mouse models of bone and soft tissue sarcoma to establish novel treatment

  Malignant giant-cell tumors are extremely rare bone sarcomas that transform from conventional giant-cell tumors during long periods of treatment. We have applied the culture methods and succeeded in establishing patient-derived organoids (PDO) of rare sarcomas. This study aimed to investigate the genomic characteristics of our established novel organoids from human malignant giant-cell tumors. The developed tumors with xenograft were genomically analyzed to compare their characteristics with those of the original tumors. Genetic changes over time throughout treatment were analyzed, and the genomic status of the established organoid was confirmed. Next generation sequencing revealed that the established organoids lacked the H3-3A G34W mutation. The xenografted organoids of the malignant giant-cell tumor had phenotypes genetically similar to those of the original tumor. The established organoids were confirmed to be derived from human malignant giant-cell tumors. In summary, the present study demonstrated a novel organoid model of a malignant giant-cell tumor that was genetically confirmed to be a malignant transformed tumor. Our organoid model could be used to elucidate the molecular pathogenesis of a malignant giant-cell tumor and develop novel treatment modalities.

  Study JGAS000618

• Adaptive Therapy Exploits Fitness Deficits in Chemotherapy-Resistant Ovarian Cancer to Achieve Long-Term Tumor Control Open Access

  Drug resistance results in poor outcomes for cancer patients. Adaptive therapy is a potential strategy to address drug resistance that exploits competitive interactions between sensitive and resistant subclones. Here, we showed that adapting carboplatin dose according to tumor response (adaptive therapy) significantly prolonged survival of murine ovarian cancer models compared to standard carboplatin dosing, without increasing mean daily drug dose or toxicity. Platinum resistant ovarian cancer cells exhibited diminished fitness when drug was absent in vitro and in vivo, which caused selective decline of resistant populations due to reduced proliferation and increased apoptosis. Conversely fitter, sensitive cells re-grew when drug was withdrawn. Using a bioinformatics pipeline that exploits copy number changes to quantify the emergence of treatment resistance, analysis of cell‐free DNA obtained longitudinally from ovarian cancer patients during treatment showed subclonal selection through therapy, and measurements of resistant population growth correlated strongly with disease burden. These preclinical findings pave the way for future clinical testing of personalized adaptive therapy regimens tailored to the evolution of carboplatin resistance in individual ovarian cancer patients.

  Study EGAS50000001142

• Dissection of the molecular complexity of colorectal cancer in pre-clinical models identifies predictive signatures of sensitivity to EGFR inhibitors

  Colorectal carcinoma (CRC) is a heterogeneous tumour entity, with only a fraction of the tumours responding to currently available therapies. A detailed understanding of the biology and genetics of CRC is a prerequisite for precision medicine. To address this challenge in clinical oncology, the OncoTrack consortium recruited 106 CRC patients (stages I-IV) and developed an integrated pre-clinical platform analysing drug sensitivity in the established matched patient-derived in vivo and in vitro models, 46 three-dimensional cell cultures and 59 xenografts, recapitulating many of the molecular features of the donor tumours. We generated extensive omics information on patient tumours and their derived models used to generate a compendium of drug sensitivity data. We could distinguish tumour molecular sub-groups responding differently to therapy and identified a novel independent predictor of sensitivity to the EGFR inhibitor cetuximab. The findings reported here will advance our understanding of CRC and its response to therapy.

  Study EGAS00001001752

• Identification of ALS Associated Genes Using Whole Genome Sequencing

  The overall aim of this study is to discover of novel genetic elements associated with amyotrophic lateral sclerosis (ALS). Towards this goal, we have performed exome and whole genome sequencing for over 2000 samples. This data will be process and harmonized to yield high quality variant calling. These variants will be combined with control cohorts to identify novel genetic elements associated with ALS through case: control analyses.

  Study phs001585

• Laser Capture Microscopy (LCM)-RNAseq for Topological Mapping of Synovial Pathology during Rheumatoid Arthritis

  Synovial tissue from the hip or knee was collected from rheumatoid arthritis (RA) and osteoarthritis (OA) patients at the time of joint replacement surgery. Samples were analyzed using laser capture microdissection (LCM) followed by RNA-seq to evaluate the transcriptome in distinct synovial compartments. Results indicated that synovial compartments have both shared and distinct transcriptional signatures that correspond to key pathways relevant to RA pathogenesis.

  Study phs003587

• Cellular Heterogeneity in Early Human Development at Stage CS16

  In this study, we applied 10x Genomics Multiome assays for single-nucleus profiling of gene expression and chromatin accessibility simultaneously to a Carnegie stage 16 (37-42 days) specimen. These data can be used to 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 phs003532

• Childhood Cancer Data Initiative (CCDI): Texas Pediatric Patient Derived Xenograft 

  The DNA/RNA samples of patients for which PDX models were developed were from a population of children, adolescents, and young adults from South Texas. Consent was obtained for collection of malignant and non-malignant tissue samples for genetic analysis and for the development of models to study new ways to treat cancer. For additional details, please refer to these publications: PMID: 37915590; PMID: 37990009.

  Study phs003215

• Osteosarcoma_Sequencing

  Genomic libraries (500 bps) will be generated from total genomic DNA derived from 25 osetocarcinoma samples and subjected to total of three lanes of 37 bp paired end sequencing on the llumina GA per sample. Paired reads will be mapped to build 37 of the human reference genome to facilitate the generation of genome wide copy number information, and the identification of novel rearranged cancer genes and gene fusions.

  Study EGAS00001000013

• ADCC_Rearrangement_Screen

  Genomic libraries (500 bps) will be generated from total genomic DNA derived from 25 adenoid cystic carcinoma samples and subjected to total of eight lanes of 37 bp, paired end sequencing on the llumina GA. Paired reads will be mapped to build 37 of the human reference genome to facilitate the generation of genome wide copy number information, and the identification of novel rearranged cancer genes and gene fusions.

  Study EGAS00001000030

• Non_Hodgkin_lymphoma_project___mutational_burden_of_chemotherapy_in_normal_blood

  his study aims to further investigate the mutational burden induced by chemotherapy in the normal stem and progenitor cell of individuals treated for Non -hodgkins lymphoma. Single cell derived progenitor colonies have been grown and DNA extracted. 5-10 colonies from a number of individuals exposed to chemotherapeutic regimens for lymphoma will undergo whole genome sequencing to address the question of the extent of mutational impact of these different regimens.

  Study EGAS00001006733

• Study of the role of aneuploidy in cB-ALL

  We modeled two proposed routes to hyperdiploidy, chromosome missegregation and cytokinesis failure, by transiently exposing human fetal liver–derived HSPCs to reversine or cytochalasin-D. Induced hyperdiploidy impaired fitness and delayed differentiation in vitro, causing hyperdiploid cells to be rapidly outcompeted by euploid counterparts. Nonetheless, hyperdiploid cells engrafted immunodeficient mice, where rare clones persisted long-term and acquired non-random chromosomal gains frequently observed in cB-ALL.

  Study EGAS50000001613

• Various_Cancer_Fusion_Gene_Sequencing

  Genomic libraries (500 bps) will be generated from total genomic DNA derived from 50 commomon epithelial cancer samples and subjected to total of eight lanes of 37 bp, paired end sequencing on the llumina GA. Paired reads will be mapped to build 37 of the human reference genome to facilitate the generation of genome wide copy number information, and the identification of novel rearranged cancer genes and gene fusions.

  Study EGAS00001000012

• Molecular profiles in early onset prostate cancer

  Paired germline (blood) and tumour samples were collected from prostate cancer cases <65 years at diagnosis to identify genetic changes in early onset prostate cancer.  Whole exome sequencing was performed on these samples. The aim was to determine if these changes are associated with more aggressive disease and to identify targets for treatment and screening by identifying associations with family history, DNA repair germline mutations, and clinical features.

  Study EGAS50000001467

• Benchmarking V(D)J Repertoire Reconstruction: Bulk RNA-Seq vs PCR-Based RepSeq Validated by SMRT Sequencing

  The aim of this study is to benchmark methods for immunoglobulin repertoire profiling using human B-cell samples. We compare targeted VDJ mRNA sequencing and repertoire reconstruction from bulk RNA-seq data to PCR-independent full-length transcript sequencing using Single-Molecule Real-Time technology. The objective is to assess methodological biases and establish a robust reference framework for immunoglobulin repertoire analysis.

  Study EGAS50000001541

• Mate-pair sequencing of 12q-amplified osteosarcomas

  Mate-pair sequencing of 12q-amplified osteosarcomas for the detection of structural variants. This was carried out in order to study the structure of the chromosome 12q-amplicons and whether material from other chromosomes is also intertwined and amplified in a bid to further characterise these tumours beyond CDK4 and MDM2 amplification. Mate-pair data was also used to verify gene fusions detected with RNA-seq.

  Study EGAS50000000493