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• Advancing Precision Oncology in a Humanized, Fully Autologous Mouse Model

  Progress in the early detection and treatment of cancer requires accurate model systems to further evaluate new, promising discoveries. Small animal and, in particular, mouse model systems are attractive to researchers for numerous reasons, including their ease of use and well-described platforms. The ability to grow human tumors in immune-deficient mice (so-called patient-derived xenografts, or PDXs) allows researchers to work directly with human cancer tissue in a controlled setting. However, PDX models are limited by their lack of an intact immune system. Immunotherapy has revolutionized clinical oncology, but lacks pre-clinical models of the human immune system and human cancer to investigate new modalities and limitations/toxicities of treatment regimens. The broad objective of this study is to validate an in vivo model to evaluate human tumors in the context of a complete and intact human immune system in a completely personalized and autologous fashion to study cancer immunotherapy. Herein, we will: (1) validate the ability of our humanized system to serve as a model for cancer immunotherapy treatment response and toxicity in patients with melanoma, including immunotherapy checkpoint blockade and vaccine strategies, and (2) extend our current work in melanoma by validating the ability to establish humanized mice and evaluate tumor growth and leukocyte development in autologous human pancreatic and colorectal tumors established in humanized mice. In each of these areas, we will leverage our multi-institutional team's individual expertise along with our institutional infrastructure to maximize the success of the experimental aims. The results from this project will be widely available to the general research community for future, hypothesis-driven research. Taken together, our study will meet multiple goals and address several unmet needs in cancer immunotherapy, thus significantly enhancing the applicability of a fully autologous and immunocompetent precision model system for use in translational oncology research.

  Study phs003090

• Genetic Epidemiology Network of Arteriopathy (GENOA)

  The Genetic Epidemiology Network of Arteriopathy (GENOA): GENOA is one of four research networks that form the NHLBI Family Blood Pressure Program (FBPP). From its inception in 1995, GENOA's long-term objective was to elucidate the genetics of hypertension and its arteriosclerotic target-organ damage, including both atherosclerotic (macrovascular) and arteriolosclerotic (microvascular) complications involving the heart, brain, kidneys, and peripheral arteries. Two GENOA cohorts were originally ascertained (1995-2000) through sibships in which at least 2 siblings had essential hypertension diagnosed prior to age 60 years. All siblings in the sibship were invited to participate, both normotensive and hypertensive. These include non-Hispanic White Americans from Rochester, MN (n =1583 at the 1st exam) and African Americans from Jackson, MS (N=1854 at the 1st exam). During the second exam (2000-2005), approximately 80% of participants were re-recruited. The GENOA data consists of biological samples (DNA, serum, urine) as well as demographic, anthropometric, environmental, clinical, biochemical, physiological, and genetic data for understanding the genetic predictors of diseases of the heart, brain, kidney, and peripheral arteries. Family Blood Pressure Program (FBPP): GENOA's parent program, the FBPP, is an unprecedented collaboration to identify genes influencing blood pressure (BP) levels, hypertension, and its target-organ damage. This program has conducted over 21,000 physical examinations, assembled a shared database of several hundred BP and hypertension-related phenotypic measurements, completed genome-wide linkage analyses for BP, hypertension, and hypertension associated risk factors and complications, and published over 130 manuscripts on program findings. The FBPP emerged from what was initially funded as four independent networks of investigators (HyperGEN, GenNet, SAPPHIRe and GENOA) competing to identify genetic determinants of hypertension in multiple ethnic groups. Realizing the greater likelihood of success through collaboration, the investigators began working together during the first funding cycle (1995-2000) and formalized this arrangement in the second cycle (2000-2005), creating a single confederation with program-wide and network-specific goals.

  Study phs000379

• UK10K COHORT ALSPAC

  The UK10K project proposes a series of complementary genetic approaches to find new low-frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome-wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein-coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will directly analyse quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches. The Avon Longitudinal Study of Parents and Children (ALSPAC) is a two-generation prospective study. Pregnant women living in one of three health districts in the former county of Avon with an expected delivery date between April 1991 and December 1992 were eligible to be enrolled in the study, and this formed the initial point of contact for the development of a large, family based resource. Information has been collected on the children and the mothers through retrieval of biological materials (e.g. antenatal blood samples, placentas), biological sampling (e.g. collection of cord blood, umbilical cord, milk teeth, hair, toenails, blood and urine), self-administered questionnaires, data extraction from medical notes, linkage to routine information systems and at repeat research clinics.

  Study EGAS00001000090

• Childhood Cancer Survivor Study (CCSS)

  Background and Rationale for the Childhood Cancer Survivor Study (CCSS) Over the last several decades, advances in treatments for childhood and adolescent cancer have substantially improved survival following diagnosis. These improvements gave rise to the responsibility for investigating long-term treatment-associated morbidity and mortality. Early efforts to describe late effects were largely conducted through single-institution and limited consortia studies. However, by the mid-1980s, it became increasingly clear that these approaches had inherent limitations, including small sample size, convenience sampling, incompletely characterized populations, and limited length of follow-up. To overcome these limitations, the CCSS was proposed and funded by the National Cancer Institute (NCI) as a U01 grant in 1994. Subsequently, the strengths of the CCSS, including an efficient and extensive infrastructure, plus expanding database and biorepository, were recognized and appreciated. Thus, in consultation with the NCI, the CCSS was converted to a U24 (resource grant) funding mechanism to serve the scientific community in 2000. The overarching goal of the CCSS resource is to increase the conduct of innovative and high impact research related to pediatric cancer survivorship. CCSS has been used extensively by researchers from a wide range of disciplines to address a broad spectrum of topics. Strengths of the resource include its large size, comprehensive annotation of treatment exposures, ongoing longitudinal follow-up with characterization of a wide array of participant characteristics and outcomes, and an established biorepository. Design of the Childhood Cancer Survivor Study The Childhood Cancer Survivor Study (CCSS) is a multi-institutional, multi-disciplinary collaborative research resource comprised of a retrospective hospital-based cohort of survivors of childhood cancer and a comparison sibling cohort. Eligible survivors from 31 participating institutions were diagnosed between 1970 and 1999, prior to age 21 years, with selected common pediatric cancers (leukemia, central nervous system tumors, Hodgkin lymphoma, non-Hodgkin lymphoma, kidney tumors, neuroblastoma, soft tissue sarcoma, or bone tumors). All patients who survived five years from the date of diagnosis were eligible, regardless of disease or treatment status. The baseline questionnaire was completed by 24,368 survivors and 5,039 siblings recruited to serve as a comparison group. To date, participants have completed three general follow-up surveys, as well as a number of specialized surveys on specific topics (e.g. health care, insurance, screening practices, men's and women's health issues, adolescent health, sleep and fatigue). In addition, biological samples (buccal cells, saliva and/or blood) have been collected for over 11,000 participants. Full descriptions of the design and characteristics of the CCSS have been previously published (Robison et al; Leisenring et al.), and available data and samples are described at https://ccss.stjude.org/develop-a-study/gwas-data-resource.html. Treatment Data in the Childhood Cancer Survivor Study A key feature of CCSS is the availability of detailed treatment data, which were collected by abstraction of medical records for each individual member of the cohort. Detailed abstraction included dates of therapy, protocol information, and specific details regarding surgery, chemotherapy and radiation. Quantitative dose details were collected for 22 specific chemotherapeutic agents, including alkylating agents, anthracyclines, platinum compounds and epipodophyllotoxins. In addition to individual agent doses, algorithms have been created to calculate cumulative doses of all drugs in a specific class, such as anthracyclines (doxorubicin, daunomycin and idarubicin) or platinum agents (cisplatinum and carboplatinum). Data abstracted for surgeries included dates and both the names and corresponding International Classification of Diseases (9th revision) code. For radiation treatment data, all relevant records were sent to the Radiation Physics Center at M.D. Anderson Cancer Center for detailed abstraction and dosimetry. Initial body region dosimetry was performed for all participants, followed by more detailed dosimetry as needed for specific studies. Genomics Data in the Childhood Cancer Survivor StudyThe NCI's Division of Cancer Epidemiology and Genetics and CCSS investigators collaborated to conduct genomics studies (SNP array genotyping and whole exome sequencing) using samples from the CCSS Biorepository. Studies included all cohort participants with available DNA regardless of sex or ancestry when the genomics studies were initiated. Phenotype Data in the Childhood Cancer Survivor Study Vital status and cause of death for both participants and non-participants is determined via linkage with the National Death Index (NDI). Identification of subsequent neoplasms is based on self-report, followed by validation using medical records, or via NDI. A wide array of additional health outcomes have been ascertained via a comprehensive set of questions on the CCSS questionnaires, covering potential adverse events across a range of organ systems (hearing/vision/speech, urinary, hormonal, heart and circulatory, respiratory, digestive, brain and nervous systems). In addition to health outcomes, longitudinal data have been collected on demographics, health behaviors, family history, screening practices, insurance status, and a range of psychosocial and neurocognitive factors. A full listing of available variables and copies of the CCSS questionnaires are available at http://ccss.stjude.org. Research Areas in the Childhood Cancer Survivor Study Extensive use by the research community has resulted in over 265 published manuscripts on a wide range of topics, including associations between treatment factors and mortality, subsequent neoplasms, chronic health conditions, cardiac events, neurocognitive sequelae, psychosocial factors, fertility, and health status. Additional topics have included health behaviors, screening practices, health care access and utilization, statistical and exposure assessment methodology, and development of risk prediction models. A full listing of published manuscripts using CCSS data is available on the CCSS website at https://ccss.stjude.org/published-research/publications.html. The Childhood Cancer Survivor Study as a Resource for Investigators The CCSS is an NCI-funded resource (U24 CA55727) to promote and facilitate research among long-term survivors of cancer diagnosed during childhood and adolescence. Interested investigators are encouraged to develop research ideas and propose projects within CCSS, whether or not they are from a participating CCSS institution. The CCSS is now accepting proposals to collaborate with CCSS and NCI investigators in the use of genomics data and corresponding outcomes-related data to address innovative research questions relating to potential genetic contributions to risk for treatment-related outcomes. Any researcher, or group of researchers, qualified to conduct genetic research can submit a proposal. There are no restrictions relative to country, institution, or prior involvement in CCSS. A full description of the process for developing a proposal for genetic research in CCSS can be found at https://ccss.stjude.org/develop-a-study/gwas-data-resource.html, along with listings of approved proposals.

  Study phs001327

• Diabetes Control and Complications Trial (DCCT) and Epidemiology of Diabetes Interventions and Complications Study (EDIC)

  The Diabetes Control and Complications Trial (DCCT, 1982-93) and the Epidemiology of Diabetes Interventions and Complications follow-up study (EDIC, 1994-2016) have been ongoing for more than twenty years. After a mean follow-up of approximately 16 years, the DCCT-EDIC cohort of 1,441 Type 1 diabetics had remained remarkably complete with more than 90% of the original cohort being actively followed. Taken together, the DCCT clinical trial and subsequent EDIC longitudinal follow-up provide a uniquely rich source of information on the impact of intensive therapy on glycemia and the its long-term complications for persons with Type 1 diabetes. The DCCT was a multicenter, randomized clinical trial (1, 2) designed to compare intensive with conventional diabetes therapy with regard to their effects on the development and progression of the early complications of Type 1 diabetes. The DCCT trial found that "intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy" in patients with Type 1 diabetes (1). The goal of the EDIC follow-up was to examine the longer term effects of the original DCCT interventions, especially as they apply to late-occurring complications, such as cardiovascular disease and more advanced stages of retinal and renal disease (3). The EDIC study has been remarkably fruitful in discovering the long term "imprinting" effects (metabolic memory) of the previous intensive therapy, and in delineating the interactions among risk factors with regard to microvascular complications (4-6). In addition, EDIC established, for the first time, the role of intensive therapy and chronic glycemia on atherosclerosis (7-9). Note: This study description has been prepared using materials authored by the DCCT-EDIC Data Coordinating Center. DETAILED DESCRIPTION OF STUDY

  Study phs000086

• Gene-Environment Interactions (GxE) and Complex Traits

  Functional variants associated with complex traits tend to fall in non-coding regions and affect regulatory mechanisms that are not yet well characterized. Furthermore, it is generally difficult to determine in which tissues and conditions they may have a functional impact. This is because the effect of a genetic variant on a molecular pathway, and ultimately on the individual's phenotype, may be modulated by "environmental" factors. We denominate such variants "gene-expression environment-specific quantitative trait nucleotides" GxE-QTNs. Achieving a better understanding of the mechanisms underlying GxE is a critical step in understanding the link between genotype and complex phenotype. It is also crucial to develop computationally efficient and statistically sound methods capable to integrate tissue/condition-specific functional genomics data to predict and validate when a sequence variant is functional. In this study we developed novel experimental and computational approaches to screen, analyze and functionally characterize genetic variants for complex traits modulated by environmental exposures. To identify and characterize genes with GxE, we analyzed allele specific gene expression in a panel of five relevant tissues (e.g. the vascular endothelium for cardiovascular diseases) under 50 controlled environmental conditions (e.g. glucocorticoids treatment, as a proxy for stress exposure). These data should be useful to develop computational tools that integrate different sources of evidence including data collected by ENCODE, RoadMap Epigenome and GTEx projects to functionally annotate GWAS variants. The experimental and computational tools developed by this project have widespread applicability, for example, can be used to tackle the functional basis of complex traits in other environmental contexts (e.g. other types of stress and hormonal levels) and genetic backgrounds. This resource represents the first comprehensive catalog of genetic variants that interact with environmental exposure in determining human complex traits.

  Study phs001176

• Effects of Metformin on Transcriptomic and Metabolomic Profiles in Breast Cancer Survivors Enrolled in the Randomized Placebo-Controlled MetBreCS Trial

  Metformin reduces the incidence of breast cancer in patients with obesity and type 2 diabetes. However, our knowledge of the effects of metformin on breast cancer recurrence is limited. Within the randomized double-blind placebo-controlled phase II trial MetBreCS, we examined changes in breast tissue from breast cancer survivors with BMI >25 kg/m2 after treatment with metformin. To identify metformin-regulated signaling pathways, we integrated the transcriptomic, metabolomic and steroid hormone profiles using bivariate and functional analyses. We identified MS4A1, HBA2, MT-RNR1 and MT-RNR2 expression to be differentially expressed in breast tissues from metformin-treated women. We also found metformin-associated down-regulation of EGFL6 and FDCSP in postmenopausal women. The integration of transcriptomic and metabolomic profiles revealed down-regulation of immune response genes associated with reduced levels of arginine and citrulline in the metformin-treated group. The integration of transcriptomic and steroid hormone profiles showed an enrichment of steroid hormone biosynthesis and metabolism pathways with highly negatively correlated CYP11A1 and CYP1B1 expression in breast tissue from postmenopausal metformin-treated women. Our results indicate that breast cancer survivors treated with metformin have specific changes in breast tissue gene expression that may prevent the development of new tumors. Within the randomized double-blind placebo-controlled phase II trial MetBreCS, we examined changes in breast tissue from breast cancer survivors with BMI >25 kg/m2 after treatment with metformin using bulk RNAseq (total mRNA sequencing), that is deposited in Federated EGA. The steroid hormones, and metabolomics and the insulin sensitivity serum biomarker data underlying this article may be shared upon reasonable request to the PI of the MetBreCS study (Dr. Bernardo Bonanni), following approval by the Data and Safety Monitoring Board at IEO, Milan.

  Study EGAS50000000874

• 1 Intratumoral genetic heterogeneity and clonal evolution following neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal tumors.

  Purpose: Neoadjuvant chemoradiotherapy (nCRT) is the standard treatment forpatients with locally advanced rectal cancer. However, little is known about the effect of nCRT in the mutational landscape and intratumoral genetic heterogeneity (ITGH) of rectal tumors. Moreover, response to nCRT vary substantially among patients and the genetic determinants of treatment response are not fully understood. Here, we sought to determine the impact of nCRT in the mutational landscape and ITGH of rectal tumors and to identify putative drivers of therapeutic resistance. Patients and Methods: We analyzed whole-exome sequencing (WES) and clinical data from 79 primary non-treated rectal cancers obtained from The Cancer Genome Atlas (TCGA). We also compared the mutational landscape of a matched set of peripheral blood cells, irradiated tumor-adjacent colonic mucosa and pre and post-treatment tumor samples to determine the iatrogenic effects of nCRT and its impact in tissue genetic heterogeneity. Finally, we performed WES of 7 matched pre and post-treatment tumor samples to examine how nCRT affects the clonal architecture of rectal tumors. Results: We show that rectal tumors exhibit remarkable ITGH, which increases with disease progression. We also show that nCRT, per se, does not introduce novel somatic mutations, nor alters the clonal architecture of the irradiated colonic mucosa. Instead, we show that it acts as a potent selective pressure, favoring the expansion of tumor cell subpopulations more prone to resist therapy and increasing ITGH in the residual tumor. Conclusion: Our results reveal the highly heterogeneous and dynamic clonal architecture of rectal tumors undergoing nCRT. Our results also uncover putative genetic determinants of response to nCRT and a possible role for ITGH in predicting treatment outcome.

  Study EGAS00001003250

• The Immune Microenvironment, Genome–Wide Copy Number Aberrations and Survival in Mesothelioma

  IntroductionResults of recent clinical studies of immune checkpoint inhibitors in malignant pleural mesothelioma (MPM) have dampened initial enthusiasm. However, the immune environment and targets of these treatments such as program cell death protein 1 (PD-1) and its ligand PD-L1 have not been well characterised in MPM. Using a large cohort of patients, we investigated PD-L1 expression, immune infiltrates and genome-wide copy number status and correlated them to clinicopathological features.Patients and methodsTissue microarrays were constructed and stained with PD-L1(clone E1L3N, CST), CD4, CD8 and FOXP3 antibodies. PD-L1 positivity was defined as ≥5% membranous staining regardless of intensity and PD-L1+hi as ≥50%. Genomic DNA from a representative subset of 113 patients was used for genome-wide copy number analysis. The percent genome alteration (PGA) was computed as a proxy for genomic instability, and statistical analyses were used to relate copy number aberrations (CNA) to other variables.ResultsAmongst 329 patients evaluated, PD-L1+ was detected in 130/311 (41.7%), but PD-L1+hi was only seen in 30/311 (9.6%). PD-L1+ correlated with non–epithelioid histology and increased infiltration with CD4+, CD8+ and FOXP3+ lymphocytes. PD-L1+hi expression correlated with worse prognosis (HR = 2.37; 95%CI= 1.57-3.56; P < 0.001) on univariate analysis, but not in multivariate analysis. Higher PGA was associated with epithelioid histology and poorer survival (HR = 1.59; 95%CI= 1.01-2.5; P = 0.04), but not PD-L1 expression.ConclusionPD-L1 expression was associated with non-epithelioid MPM, poor clinical outcome and increased immunological infiltrates. Increased genomic instability did not correlate with PD-L1 expression, but was associated with poorer survival.

  Study EGAS00001002323

• Comprehensive characterization of pre- and post-treatment samples of breast cancer reveal potential mechanisms of chemotherapy resistance

  When locally advanced breast cancer is treated with neoadjuvant chemotherapy, the recurrence risk is significantly higher if no complete pathologic response is achieved. Identification of the underlying resistance mechanisms is essential to select treatments with maximal efficacy and minimal toxicity. Here we employed gene expression profiles derived from 317 HER2-negative treatment-naïve breast cancer biopsies of patients who underwent neoadjuvant chemotherapy, deep whole exome and RNA-sequencing profiles of 22 matched pre- and post-treatment tumors, and treatment outcome data to identify biomarkers of response and resistance mechanisms. Molecular profiling of treatment-naïve breast cancer samples revealed that expression levels of proliferation, immune response and extracellular matrix (ECM) organization combined predict response to chemotherapy. Triple negative patients with high proliferation, high immune response and low ECM expression had a significantly better treatment response and survival benefit (HR 0.29, 95% CI 0.10-0.85; p=0.02), while in ER+ patients the opposite was seen (HR 4.73, 95% CI 1.51-14.8; 0=0.008). The characterization of paired pre-and post-treatment samples revealed that aberrations of known cancer genes were either only present in the pre-treatment sample (CDKN1B) or in the post-treatment sample(TP53, APC, CTNNB1). Proliferation-associated genes were frequently down-regulated in post-treatment ER+ tumors, but not in triple negative tumors. Genes involved in ECM were upregulated in the majority of post-chemotherapy samples. Genomic and transcriptomic differences between pre- and post-chemotherapy samples are common and may reveal potential mechanisms of therapy resistance. Our results show a wide range of distinct, but related mechanisms, with a prominent role for proliferation- and ECM-related genes.

  Study EGAS00001005876

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

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

  Study EGAS00001006502

• Gabriella Miller Kids First Pediatric Research Program in Craniofacial Microsomia

  The Gabriella Miller Kids First Pediatric Research Program (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in pediatric cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource). All of the WGS and phenotypic data from this study are accessible through dbGaP and kidsfirstdrc.org, where other Kids First datasets can also be accessed. Craniofacial microsomia (CFM), also termed hemifacial microsomia or oculo-auricular-vertebral spectrum, is the third most common congenital craniofacial condition. CFM comprises a variable phenotype and the most common features include malformations of the ear (i.e. microtia) and lower jaw (i.e. mandibular hypoplasia) on one or both sides. Microtia in the absence of other anomalies is believed to represent the mildest form of CFM. The cause of CFM is unknown for most affected individuals. We have established a cohort through previous studies and collected DNA to identify the genetic contributions to CFM, which could facilitate diagnosis, tailored treatments and guide prevention strategies. Successful completion of this proposal will advance knowledge in the genetic architecture of susceptibility to CFM and will provide insight about the biological mechanisms underlying craniofacial development. The results from this study have the potential to further research on the etiology of other craniofacial conditions, and the pathogenesis of typical and atypical craniofacial development.

  Study phs002130

• Medulloblastoma exome sequence analysis

  Medulloblastomas are the most common malignant brain tumors in children. Identifying and understanding the genetic events that drive these tumors is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma based on transcriptional and copy number profiles. Here, we utilized whole exome hybrid capture and Illumina sequencing to identify somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs. Overall, medulloblastomas exhibit low mutation rates consistent with other pediatric tumors, with a median of 0.35 non-silent mutations per megabase. We identified twelve genes mutated at statistically significant frequencies, including previously known mutated genes in medulloblastoma such as CTNNB1, PTCH1, MLL2, SMARCA4 and TP53. Recurrent somatic mutations were identified in an RNA helicase gene, DDX3X, often concurrent with CTNNB1 mutations, and in the nuclear co-repressor (N-CoR) complex genes GPS2, BCOR, and LDB1, to our knowledge novel findings in medulloblastoma and all cancer. We show that mutant DDX3X potentiates transactivation of a TCF promoter and enhances cell viability in combination with mutant but not wild type beta-catenin. Together, our study reveals the alteration of Wnt, Hedgehog, histone methyltransferase and now N-CoR pathways across medulloblastomas and nominates the RNA helicase DDX3X as a component of pathogenic beta-catenin signaling in medulloblastoma. "Reprinted from 'MEDULLOBLASTOMA EXOME SEQUENCING UNCOVERS SUBTYPE-SPECIFIC SOMATIC MUTATION', with permission from Nature"

  Study phs000504

• METABRIC miRNA landscape

  MicroRNAs (miRNAs) are key players in cancer pathogenesis1. They display differential expression across breast cancer subtypes, and play oncogenic and tumor-suppressive roles2-6. A systematic study of the global miRNA landscape in breast cancer and the factors shaping it has not been undertaken. Here we report the results of profiling miRNA expression in 1,302 breast tumors with detailed clinical annotation and long-term follow-up, and for which matching genomic and mRNA expression data were available7. This provides a comprehensive view of the quantity, distribution and variation of the miRNA population and dissects how much genomic, transcriptional and post-transcriptional events contribute to miRNA expression architecture. The key clinical parameters and cellular pathways related to the miRNA landscape are identified, exemplified by context-dependent interaction with cell adhesion and Wnt signaling. Strikingly, in breast cancer miRNAs appear to act as modulators of mRNA-mRNA interactions rather than molecular switches. We demonstrate an important modulatory role for miRNAs in the biology of breast tumors devoid of somatic copy number aberrations, a common subtype where immune response is prominent. Remarkably, prognostic miRNA signatures derived in this subtype are consistently prognostic across several other subtypes and validate in external cohorts. These findings represent a new framework to study the biology of miRNA in human cancer.

  Study EGAS00000000122

• Enhanced Adjuvanticity of a Personal Neoantigen Vaccine Generates Potent Neoantigen-Specific Immunity

  Personalized neoantigen-targeting vaccines can induce durable and diverse T cell responses and have been associated with improved outcomes. To augment immunogenicity, we tested a synthetic long peptide vaccine formulated with the adjuvants Montanide and poly-ICLC in 10 patients with melanoma. The vaccines, co-administered locally with ipilimumab and systemically with nivolumab, generated de novo ex vivo T cell responses against the majority of immunizing neoepitopes in all 9 fully vaccinated patients, and ex vivo CD8+ T cell responses in 6 of 9. Hundreds of circulating and intratumoral T cell receptor (TCR) clonotypes emerged following vaccination that were distinct from those arising after PD-1 inhibition. By linking vaccine-specificity and cellular phenotype of TCRs in post-treatment tumors at single cell resolution, we demonstrate remodeling of the intratumoral T cell repertoire following vaccination. These observations demonstrate the impact of multi-pronged immune adjuvanticity on the T cell repertoire in the context of neoantigen-targeting vaccines. We are submitting WES data from whole blood samples and tumor FFPE samples, and RNA-seq data from tumor FFPE samples. We are also submitting RNA-seq data from purified tumor samples. scRNA-seq data will also be submitted for skin samples (pre and post neoantigen vaccine dose #3), and tumor samples before starting treatment, before starting neoantigen vaccine Dose #1, and before neoantigen vaccine dose #4. Bulk TCR-seq data will be submitted for blood samples.

  Study phs003919

• Identification of a Fumarate-Hydratase Deficient-like RCC Subtype with Convergent Pathway Alterations

  The development of molecularly targeted therapies builds upon the identification of tumor clades with shared molecular abnormalities. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a familial syndrome resulting from germline mutation of the two-hit tumor suppressor gene, Fumarate Hydratase (FH). HLRCC renal tumors present often in young adults, exhibit unique histological features and are particularly aggressive. HLRCC is uncommon and poorly understood, and whether there are sporadic renal tumors with similar characteristics, is unclear. Notably, FH can also be inactivated somatically in RCC, and should be included among FH-deficient (FHD) kidney tumors. We identified a tumor clade without FH mutations but with similar morphological and molecular characteristics as well as aggressive clinical behavior, which we name FHDL (FHD-like). We show that FHD/FHDL tumors represent a unique subtype of CIMP (CpG Island Methylator Phenotype) with the highest levels of overall genome methylation and CDKN2A silencing. FHD/FHDL tumors are characterized by convergent activation of the Hippo pathway as determined by frequent and mutually exclusive mutations in NF2 and PTPN14. AKR1B10, an NRF2 target, was upregulated in FHD/FHDL tumors as well as GATA3, which suggests a shared origin in the renal medulla and is consistent with topological studies. There is loss of 5-hydroxymethylcytosine in both FHD and FHDL tumors. These data define a group of particularly aggressive renal cancers with shared molecular features and potential targets for therapeutic intervention.

  Study EGAS00001002646

• Genomic Alterations in Gingivo-buccal Cancer: ICGC-India Project_YR01

  As a part of the ICGC, India has undertaken genomic studies on gingivobuccal cancer of the oral cavity, which is the most prevalent form of cancer among men in India. There are various known environmental (life-style) correlates of this cancer, the most important of which are tobacco chewing and HPV infection. Paired DNA samples – isolated from the tumor tissue and from the blood of fifty patients – have been analyzed to catalog germline and somatic mutations. Association between each observed genomic alteration and exposure to environmental risk factors is being explored.Detailed clinical characterization of the patients, collection of data on demographic and environmental exposures, and isolation of DNA samples from blood and tumor tissues collected from each patient are being done at the Advanced Centre for Research, Treatment and Education on Cancer, Mumbai. Exome capture and deep resequencing are being performed at the National Institute of Biomedical Genomics, Kalyani. We have analyzed the exomes of paired blood and tumor DNA samples using two orthogonal platforms – exome capture by Roche-Nimblegen SeqCap Ez kit followed by sequencing on Roche-454 GS FLX, and exome capture by Illumina TrueSeq Exome Enrichment kit followed by sequencing on Illumina HiSeq-2000. Each exome is being sequenced at a mean depth of 30x. In addition, we have used Illumina Omni Quad SNP-chips to generate genotype data at 1.14 million genomic markers. The average concordance between SNP-chip and sequence data is 99.8%.

  Study EGAS00001000249

• Renal_habitat_WXS

  This project aims at correlating genetic diversity (as well as transcriptomic, metabolic and immune diversity) observed in multiple targeted tumour biopsies and circulating tumour DNA with heterogeneity on multiparametric MRI. To this end, 20 patients with RCC (15 patients with localised/locally advanced disease and 5 with mRCC) will undergo multiparametric MRI including metabolic assessment by 13C-MRSI as well as measurements of tumour perfusion, oxygenation and water diffusion. Based on unique combinations of these imaging parameters, tumour habitats will be defined through cluster mapping. Intra-operative biopsy and immediate freezing of tumour cores from different imaging habitats will be performed. Multiregional ex-vivo tumour biopsies will be spatially registered to the MR data by using 3D printed tumour moulds generated from high-resolution volumetric sequences. These moulds allow slicing tumour specimens in identical planes to the MR acquisition and increase the accuracy of tissue sampling. The biopsies will then undergo molecular profiling such as metabolomic and RNA sequencing (including mRNA immune profiling), as well as DNA sequencing to assess driver and clonal mutations in different tumour habitats and guide design of appropriate cfDNA probes. The targeted cfDNA capture panel will be employed to determine the ability of cfDNA to capture the full genetic diversity observed in the primary tumour and to relate cfDNA to various imaging habitats in both renal and pancreatic cancer. Data integration will be undertaken between imaging habitats and molecular profiles for each region.

  Study EGAS00001003703

• A novel orthotopic patient-derived xenograft model of radiation-induced glioma following medulloblastoma

  Radiation-induced glioma (RIG) is a highly aggressive brain cancer arising as a consequence of radiation therapy. We report a case of RIG that arose in the brain stem following treatment for paediatric medulloblastoma, and the development and characterisation of a matched orthotopic patient-derived xenograft (PDX) model (TK-RIG915). Patient and PDX tumours were analysed using DNA methylation profiling, whole genome sequencing (WGS) and RNA sequencing. While initially thought to be a diffuse intrinsic pontine glioma (DIPG) based on disease location, results from methylation profiling and WGS were not consistent with this diagnosis. Furthermore, clustering analyses based on RNA expression suggested the tumours were distinct from primary DIPG. Additional gene expression analysis demonstrated concordance with a published RIG expression profile. Multiple genetic alterations that enhance PI3K/AKT and Ras/Raf/MEK/ERK signalling were discovered in TK-RIG915 including an activating mutation in PIK3CA, upregulation of PDGFRA and AKT2, inactivating mutations in NF1, and a gain-of-function mutation in PTPN11. Additionally, deletion of CDKN2A/B, increased IDH1 expression, and decreased ARID1A expression were observed. Detection of phospho-S6, -4EBP1 and -ERK via immunohistochemistry confirmed PI3K pathway and ERK activation. Here, we report one of the first PDX models for RIG, which recapitulates the patient disease and is molecularly distinct from primary brain stem glioma. Genetic interrogation of this model has enabled the identification of potential therapeutic vulnerabilities in this currently incurable disease.

  Study EGAS00001004709

• Exploring_the_landscape_of_somatic_mutations_in_normal_tissue___GI___WGS

  The aim of this project is to investiagte somatic mutations, including rates of mutations and signatures, and clonal dynamics in normal (non-cancerous) human tissues from the gastrointestinal tract. The project will involve the studyof normal tissues from healthy individuals and those with specific candidate diseases. We are utilising laser capture microscopy to idnetifiy and isolate specific cell populations which are then subjected to whole genome sequencing to estimate mutational burdens and begin to understand clonal structures across the normal tissues.

  Study EGAS00001003012

• Exploring_the_landscape_of_somatic_mutations_in_normal_tissue___UGI___WGS

  The aim of this project is to investiagte somatic mutations, including rates of mutations and signatures, and clonal dynamics in normal (non-cancerous) human tissues from the gastrointestinal tract. The project will involve the studyof normal tissues from healthy individuals and those with specific candidate diseases. We are utilising laser capture microscopy to idnetifiy and isolate specific cell populations which are then subjected to whole genome sequencing to estimate mutational burdens and begin to understand clonal structures across the normal tissues.

  Study EGAS00001003541

• Immune Profiling in Patients with High-Risk Smoldering Myeloma

  Single-cell RNA-sequencing identifies immune biomarkers of response to immunotherapy in patients with high-risk Smoldering Multiple Myeloma (SMM). We conducted a Phase II trial of the immunotherapeutic anti-SLAMF7 antibody, Elotuzumab, in combination with Lenalidomide and Dexamethasone (E-PRISM study), to determine the utility and safety of early immunotherapy in patients with high-risk SMM and develop biomarkers for optimal patient selection and monitoring of response to treatment.There is an overlap in subjects between this study and dbGaP accession phs001323.

  Study phs002476

• The Nephrotic Syndrome Study Network (NEPTUNE)

  The Nephrotic Syndrome Study Network (NEPTUNE) is a collaborative investigational infrastructure of 40 North American sites for conducting clinical and translational research in Focal Segmental Glomerulosclerosis (FSGS), Membranous Nephropathy (MN), and Minimal Change Disease (MCD). NEPTUNE provides prospective, un-blinded, standardized evaluation of clinical and molecular outcomes in two cohorts: A) adults and children with incident or prevalent, biopsy-proven FSGS, MN, or MCD, recruited at the time of first biopsy, and B) children with incident Nephrotic Syndrome without a diagnostic kidney biopsy.

  Study phs003210

• C9ORF72 Hexanucleotide Repeat Sequence Genotyping Project

  This study reports long-range and high-resolution repeat sizing of the C9orf72 repeat region for 2095 samples from the National Institute of Neurological Disorders and Stroke (NINDS) repository's ALS collection. Genomic DNA samples were analyzed with a PCR assay (AmplideX® PCR/CE C9orf72 Kit) and resolved on capillary electrophoresis. Expanded samples were also analyzed using a gene-specific assay and resolved by capillary electrophoresis (up to 145 GGGGCC hexanucleotide repeats) and AGE agarose gel electrophoresis (up to 950 hexanucleotide repeats, respectively).

  Study phs001718

• Genomic Characterization of African-American Prostate Cancer

  African-American men have the highest incidence and mortality rate from prostate cancer. This study represents a whole exome sequencing study of prostate cancer samples from African-American men. We performed exome sequencing and analysis of prostate tumors and matched normal tissues to identify somatic mutations and insertion/deletions across this cohort. All sequencing was performed at the Broad Institute. This study has the potential to identify novel recurrently mutated genes in prostate cancer and improve our understanding of prostate cancer in African-Americans.

  Study phs000945

• Evolution of Chronic Lymphocytic Leukemia to Richter's Syndrome (RS)

  Richter's syndrome arising from chronic lymphocytic leukemia is a striking example of an aggressive malignant histology that emerges from indolent cancer. To understand this process, we reconstructed phylogenies based on whole exome sequencing of matched normal, CLL and RS samples. We computationally deconvoluted CLL and RS clones and identified drivers of transformation. We additionally performed whole genome sequencing, whole transcriptome sequencing and single-cell transcriptome sequencing to understand the mutational signatures, genome-wide events and gene expression changes associated with transformation.

  Study phs002458

• Characterization of copy number quiet oral cancer

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

  Study EGAS50000000558

• CARE idiopathic subglottic stenosis bulk transcriptomics.

  Idiopathic subglottic stenosis (iSGS) is a severe chronic orphan disease characterised by recurrent scarring of the subglottis, predominantly affecting Caucasian females in their fourth to sixth decade of life. Due to its rarity, understanding the clinical trajectory and molecular factors involved in iSGS disease development and prognosis has been challenging. In this study, we prospectively enrolled patients with iSGS, trauma-induced subglottic stenosis, and controls to investigate the clinical, transcriptional, and genetic features that may be associated with disease pathogenesis and treatment outcomes.

  Study EGAS50000000879

• Childhood Cancer Data Initiative (CCDI): Comprehensive Genomic Sequencing of Pediatric Cancer Cases (CMRI/KUCC)

  This study provides paired tumor normal genomic sequencing data from ~ 200 children with cancer, including both solid tumors and leukemias, done by the Children's Mercy Research Institute (CMRI) and University of Kansas Cancer Center (KUCC). These data include whole genome sequencing (generally, ~20x), whole exome sequencing (generally, ~300x), bulk RNA sequencing (generally, ~80 million reads), and single-cell RNA and ATAC sequencing (>50,000 reads/cell). Additional phenotypic, pathologic, and genetic data, gathered clinically for these samples, are also provided.

  Study phs002529

• INCLUDE: Human Trisome Project

  The INCLUDE (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE) Project is an NIH-wide collaboration that seeks to improve health and quality-of-life for people with Down syndrome. The INCLUDE Project Data Coordinating Center and partners created the INCLUDE Data Hub, a centralized data resource that allows access to large-scale clinical and multi-omics datasets specific to Down syndrome and supports collaborative, cloud-based analysis to accelerate scientific discoveries related to Down syndrome and its co-occurring conditions.

  Study phs002981

• Activation-Induced Marker (AIM) Sequencing of Healthy Human T Cells

  T cells from five healthy human donors were stimulated with a peptide pool (CEFX, JPT) and anti-CD28/CD49d co-stimulation. Cells were then sorted based on activation (OX40 and PD-L1 for CD4s, CD137 for CD8s) and labeled with corresponding hashing antibodies prior to sequencing. In total, this dataset encompasses 42,370 cells (12,743 activation-induced marker (AIM)-positive, 15,369 AIM-negative, 14,258 Mock) for CITE-sequencing and TCR-sequencing of sorted activated, unactivated, and mock T cells derived from blood.

  Study phs004043

• Transcriptome and epigenomic landscape of cytotrophoblasts from normal and HDP placentas

  Hypertensive isorders of pregnancy (HDP) is a severe pregnancy-related disorder that poses significant risks to both maternal and fetal health. Dysfunctional placental development is one of the major contributors to the onset of HDP. In this study, we investigated the gene expression and epigenomic modifications in cytotrophoblasts from normal and HDP placentas. The information obtained in this study contributes to the growing body of knowledge aimed at improving the diagnosis, management, and treatment of HDP.

  Study JGAS000667

• Multi-modal single-cell analysis of salivary glands from patients with Sjogren's syndrome collaboration

  Sjogren's syndrome (SS) is an autoimmune disease that causes salivary gland dysfunction due to immune-mediated destruction. While autoantibodies such as anti-SSA and anti-centromere (CENT) are associated with distinct clinical manifestations, the underlying mechanisms remain to be elucidated. In this study, we apply multi-modal single-cell technologies-single-cell RNA sequencing, T- and B-cell receptor sequencing, and spatial transcriptomics-to salivary gland lesions, aiming to uncover common and unique cellular and transcriptional signatures linked to different autoantibody profiles.

  Study JGAS000773

• Genome-wide methylation profiling by high-throughput sequencing of tissue (resident) versus blood circulating memory T lymphocyte populations

  This study contains RRBS data generated from 54 ex vivo samples, including CD4+ Trm (2x intestine, 2x lung, and 3x skin), CD4+CD69- tissue cells (2x bone marrow, 2x spleen, 2x intestine, 2x lung, and 3x skin), CD8+ Trm (2x bone marrow, 2x spleen, 2x intestine, 2x lung, and 3x skin), CD8+CD69- tissue cells (2x bone marrow, 2x spleen, 2x intestine, 2x lung, and 2x skin), blood CD4+ (7x) and CD8+ (8x) memory T cells.

  Study EGAS50000000085

• Comprehensive molecular profiling of pulmonary pleomorphic carcinoma

  Information regarding the molecular features of pulmonary pleomorphic carcinoma (PPC) is insufficient. Here, we performed next-generation sequencing to determine the genomic and transcriptomic profiles of PPC. Whole exome sequencing (WES) of fresh-frozen tissue samples and target-capture sequencing of formalin-fixed-paraffin-embedded (FFPE) samples were performed. Fresh-frozen tissue samples and FFPE samples were subjected to WES and target-capture sequencing as normal control, respectively. Fresh-frozen tissue samples and 56 FFPE samples were subjected to RNA-seq.

  Study JGAS000297

• Tools

  EGA Tools This page provides details of the applications available at the EGA. Submission Tool Description EgaCryptor Encrypt and create md5sum values. Crypt4gh Encrypt, decrypt or re-encrypt files. INBOX Upload your files once encrypted. FTP Upload your files once encrypted. Submitter Portal Submit and manage your submission metadata online (SEQUENCING AND PHENOTYPE ONLY) Submitter Portal API Submit and manage your submission metadata programmatically. Webin Submit and manage your submission metadata online (array data) Webin API Submit metadata using XML files. Aimed to array-based submissions. Star2xml Format conversion tool to transform tabular formats (e.g. spreadsheets) into EGA's XMLs. Used for large programmatic submissions. Data Access Tool Description DAC Portal Manage and control data access request. Download Tool Description PyEGA3 Download and decrypt datasets requested through your EGA web account. Live Outbox Download and decrypt datasets requested through your EGA web account. Fuse Client A quick and convenient way to browse through EGA files without the need for complete downloads. EGA QuickView A quick and convenient way to browse through EGA files without the need for complete downloads.

  Documentation tools

• Jeju Genome Project

  The Jeju Genome Project (JGP) is a multi-omics resource for precision medicine in a geographically distinct South Korean population. It comprises 5,309 participants (3,001 community-based; 2,308 hospital-based) with data spanning Whole-Genome Sequencing (WGS) and genotyping arrays. The hospital cohort is specifically enriched for neurological and rheumatic diseases and malignancies. By providing a population-specific reference panel, JGP enables high-resolution genetic architecture analysis, risk stratification, and the discovery of rare variants relevant to Jeju and broader East Asian populations.

  Study EGAS50000001706

• Genome-wide SNP data of Fulani populations from the Sahel belt

  This project seeks to uncover the genetic structure and ancestry of the Fulani populations across the Sahel/Savannah Belt. The study includes two datasets (''WGA_Fulani_Database'' and ''Saliva_Fulani_Ddatabase''), and SNP-genotyping data was generated using the Illumina Infinium H3Africa Consortium array (BeadChip type: H3Africa_2019_20037295_B1) in two genotyping batches (TE-2559_201029 and TE-2559_201020). In total, 419 were genotyped for this study and the key results were presented in Fortes-Lima et al. 2024 (doi: 10.1101/2024.06.22.600206).

  Study EGAS50000000451

• RNAseq___Discovery_of_resistance_mechanisms_to_the_BRAF_inhibitor_vemurafenib_in_metastatic_BRAF_mutant_melanoma

  We propose to biopsy 20 consented BRAF mutant melanoma patients at Addenbrooke's Hospital pre-treatment with vemurafenib and also upon the development of resistant disease, with the aim of using exome sequence and SNP6 data to identify novel sequence variants and copy number alterations that can be used to validate observed resistance mechanisms in our cell line models and also to use these models to inform as to likely candidate small molecule inhibitors to overcome resistance and that could be tested in the clinical trial setting.

  Study EGAS00001000813

• Discovery_of_resistance_mechanisms_to_the_BRAF_inhibitor_vemurafenib_in_metastatic_BRAF_mutant_melanoma

  We propose to biopsy 20 consented BRAF mutant melanoma patients at Addenbrooke's Hospital pre-treatment with vemurafenib and also upon the development of resistant disease, with the aim of using exome sequence and SNP6 data to identify novel sequence variants and copy number alterations that can be used to validate observed resistance mechanisms in our cell line models and also to use these models to inform as to likely candidate small molecule inhibitors to overcome resistance and that could be tested in the clinical trial setting.

  Study EGAS00001000812

• Genomic_landscape_of_liver_cirrhosis

  We are interested in the genomic landscape of liver cirrhosis and its potential manifestations for liver physiology and risk for hepatocellular carcinoma. Previous work in CASM has shown that there is a strong element of clonality within cirrhotic nodules and that some recurring mutations have been identified. However how this relates to the overall liver is not known and therefore by taking geographically disparate biospies, we aim to correlate our findings and make conclusions as to the characteristics of the overall genomic landscape.

  Study EGAS00001004329

• Genetic ancestry contributes to somatic mutations in lung cancers from admixed Latin American populations

  Inherited lung cancer risk, particularly in non-smokers, is poorly understood. Genomic and ancestry analysis of 1,153 lung cancers from Latin America revealed striking associations between Native American ancestry and their somatic landscape, including tumor mutational burden (TMB), and specific driver mutations in EGFR, KRAS, and STK11. A local Native American ancestry risk score predicted EGFR and KRAS mutation frequency more strongly than global ancestry, suggesting that germline genetics (rather than environmental exposure) underlie these disparities.

  Study EGAS00001004752

• A GWAS for cutaneous leishmaniasis in Brazil

  Our goal was to identify genetic risk factors for cutaneous leishmaniasis (CL) caused by Leishmania braziliensis. Genotyping 2066 CL cases and 2046 controls using Illumina HumanCoreExomeBeadChips provided data for 4,498,586 imputed single nucleotide variants (SNVs). Genome-wide association testing using linear mixed models took account of genetic diversity/ethnicity/admixture. Post-GWAS positional, expression quantitative trait locus (eQTL), and chromatin interaction mapping was performed in FUMA. Transcriptional data were compared between lesions and normal skin, and cytokines measured using flow cytometry and Bioplex assay.

  Study EGAS00001004596

• Mutational Landscape of Plasmablastic Lymphoma

  Plasmablastic lymphoma (PBL) represents a clinically heterogeneous subtype of aggressive B-cell non-Hodgkin lymphoma. Although targeted sequencing studies and a single center whole exome sequencing (WES) study in HIV+ patients recently revealed several genes, associated with PBL pathogenesis, the global mutational landscape and transcriptional profile of PBL remain elusive. To inform on disease-associated mutational drivers, mutational patterns and perturbed pathways in HIV+ and HIV- PBL we performed WES and RNA-sequencing (RNA-seq) of 34 PBL tumors.

  Study EGAS00001004906

• Exploring_the_landscape_of_somatic_mutations_in_normal_tissue___BD___WGS

  The aim of this project is to investiagte somatic mutations, including rates of mutations and signatures, and clonal dynamics in normal (non-cancerous) human tissues from the biliary tree. The project will involve the studyof normal tissues from healthy individuals and those with specific candidate diseases. We are utilising laser capture microscopy to idnetifiy and isolate specific cell populations which are then subjected to whole genome sequencing to estimate mutational burdens and begin to understand clonal structures across the normal tissues.

  Study EGAS00001003014

• Exploring_the_landscape_of_somatic_mutations_in_normal_tissue___GI___TPS___WGS

  The aim of this project is to investigate somatic mutations, including rates of mutations and signatures, and clonal dynamics in normal (non-cancerous) human tissues from the gastrointestinal tract. The project will involve the study of normal tissues from healthy individuals and those with specific candidate diseases. We are utilising laser capture microscopy to identify and isolate specific cell populations which are then subjected to whole genome sequencing to estimate mutational burdens and begin to understand clonal structures across the normal tissues.

  Study EGAS00001003089

• 46 CLL Whole Genome Sequencing Study

  Chronic lymphocytic leukaemia (CLL) consists of two biologically and clinically distinct subtypes defined by the abundance of somatic hypermutation (SHM) affecting the Ig variable heavy-chain locus (IgHV). The molecular mechanisms underlying these subtypes are incompletely understood. Here, we present a comprehensive whole-genome sequencing analysis of somatically acquired genetic events from 46 CLL patients, including a systematic comparison of coding and non-coding single nucleotide variants, copy number variants and structural variants, regions of kataegis and mutation signatures between IgHVmut and IgHVunmut subtypes.

  Study EGAS00001003254

• Single cell RNA sequencing of normal endometrial derived organoids uncovers novel cell type markers for prognostication

  Endometrial carcinoma, the most common gynecologic cancer, develops from endometrial epithelium which is composed of secretory and ciliated cells. Pathologic classification is unreliable and there is a need for prognostic tools. We used single cell sequencing to study organoid model systems derived from normal endometrial endometrium to discover novel markers specific for endometrial ciliated or secretory cells. We performed single cell sequencing on endometrial and ovarian tumors and found both secretory-like and ciliated-like tumor cells.

  Study EGAS00001004466

• Illumina RNA sequencing for HLA expression qauntification

  In this study, we quantified mRNA expression levels of HLA class I and II genes from peripheral blood samples of 50 healthy individuals. The gene- and allele-specific mRNA expression was assessed using unique molecular identifiers, which enabled PCR bias removal and calculation of the number of original mRNA transcripts. We identified differences in mRNA expression between different HLA genes and alleles. Our results suggest that HLA alleles are differentially expressed and these differences in expression levels are quantifiable using RNA sequencing technology.

  Study EGAS00001004931

• Multiomic profiling of pleomorphic rhabdomyosarcoma

  Rhabdomyosarcoma (RMS) describes rare soft-tissue tumors that exhibit features of skeletal muscle differentiation. The most common subtypes in children are alveolar and embryonal rhabdomyosarcoma, with the alveolar subtype characterized by PAX3/7 fusions. A lesser known and rarer subtype, pleomorphic rhabdomyosarcoma (PRMS), occurs most frequently in adults vetween the ages of 40 and 50. This pleomorphic subtype is often misdiagnosed and little is known about its molecular characterization. Here, we conducted comprehensive genomic, transcriptomic, and methylation profiling of these tumors.

  Study EGAS00001007230