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• Genetics of 24 hour urine composition

  Genetic and environmental factors play an important role in the etiology of nephrolithiasis. This project will build on and extend our previous efforts (examining environmental risk factors for stone formation) by allowing us to study the risk of stone formation associated with specific genes and gene-environment interactions. We will take advantage of previously collected data in three large cohort studies: Nurses' Health Study I (n=121,000 women), Nurses' Health Study II (n=116,000 women), and Health Professionals Follow-up Study (n=51,000 men). Over a period of 17 to 26 years, information has been collected prospectively on important exposures including diet, family history, body size measures, past medical history, and medications. We have confirmed over 2000 incident cases of kidney stones in each cohort (DK59583, PI Curhan). Further, we have collected 24-hour urine samples from over 4100 stone formers and non-stone formers; the majority of participants have performed two collections. The primary objective of this project is to examine the association between single nucleotide polymorphisms and the 24-hour urinary excretion of stone promoters (calcium and oxalate) and a stone inhibitor (citrate). The secondary objective is to explore the impact of interactions between the genetic factors and dietary factors on 24-hour urinary excretion of relevant lithogenic factors. These findings should provide new insight into regulation of these important factors and also into novel approaches for prevention of stone formation.

  Study phs000460

• Non-coding mutations reveal cancer driver cistromes in luminal breast cancer

  Whole-genome sequencing of primary breast tumors enabled the identification of cancer driver genes and non-coding cancer driver plexuses from somatic mutations. However, differentiating between driver and passenger events among non-coding genetic variants remains a challenge to understand the etiology of cancer and inform the delivery of personalized cancer medicine. Herein, we reveal enrichment of non-coding mutations in cis-regulatory elements that cover a subset of transcription factors linked to tumor progression in luminal breast cancers. Using a cohort of 26 primary luminal ER+PR+ breast tumors, we compiled a catalogue of ~100,000 unique cis-regulatory elements from ATAC-seq data. Integrating this catalogue with somatic mutations from 350 publicly available breast tumor whole genomes, we identified four recurrently mutated individual cis-regulatory elements. By then partitioning the non-coding genome into cistromes, defined as the sum of binding sites for a transcription factor, we uncovered cancer driver cistromes for ten transcription factors, namely CTCF, ELF1, ESR1, FOSL2, FOXA1, FOXM1 GATA3, JUND, TFAP2A, and TFAP2C in luminal breast cancer. Nine of these ten transcription factors were shown to be essential for growth in breast cancer, with four exclusive to the luminal subtype. Collectively, we present a strategy to find cancer driver cistromes relying on quantifying the enrichment of non-coding mutations over cis-regulatory elements concatenated into a functional unit drawn from an accessible chromatin catalogue derived from primary cancer tissues.

  Study EGAS00001005235

• A Study of the Genetic Causes of Complex Pediatric Disorders

  The Center for Applied Genomics (CAG) at the Children's Hospital of Philadelphia (CHOP) is a high-throughput, highly automated genotyping and sequencing facility equipped with state-of-the-art genotyping and sequencing platforms. Children who are treated at the Children's Hospital Healthcare Network and their parents may be eligible to take part in a major initiative to collect more than 100,000 blood samples, covering a wide range of pediatric diseases. A large majority of participants consenting to prospective genomic analyses also consent to analysis of their de-identified electronic medical records (EMRs). EMRs are longitudinal, with a mean duration of 6.5 years. CAG has committed to releasing genotype and phenotype data for 4000 individuals diagnosed with asthma, ADHD, atopic dermatitis, GERD (1000 for each), and 1000 individuals on the upper and lower ranges of Low-Density Lipoprotein (LDL) levels to dbGaP. We will also release genotype/phenotype of 3000 controls. Relevant phenotype data includes primary diagnoses (ICD9 codes), secondary diagnoses (ICD9 codes), medical procedures/tests conducted in relation to the phenotype, and a listing of relevant medications. Further details of CAG's research programs and capacity are available at: http://www.caglab.org

  Study phs000490

• Next Generation Mendelian Genetics: Neonatal Diabetes

  The NHGRI Next Generation Mendelian Genetics project uses exome resequencing to identify variants in unsolved Mendelian diseases. Neonatal diabetes mellitus (ND) is a rare form of monogenic diabetes (90,000-260,000 live births) that is diagnosed in the first 6 months of life. The disease has been classified as transient or permanent and although it can be inherited, more frequently is sporadic as a result of 'de novo' mutations. Defects in 12 genes have been found as responsible for the disease (defects in the paternally imprinted chromosomal region 6q24, IPF1, SLCA2A, INS, EIF2AK3, GCK, FOXP3, GLIS3, PTF1A, HNF1Beta, KCNJ11 and ABCC8). The two subunits of the ATP-sensitive K channel (ABCC8 and KCNJ11) and the insulin gene (INS), account for almost half of the cases and similar to CHI, the other half, remains genetically unexplained. We became part of this study when we submitted 4 DNA samples for exome sequencing, from patients with NDM of Caucasian ancestry, which had no mutations identified in ABCC8 or KCNJ1, with the goal to identify new mutations in known genes or new mutations or genetic variants in new genes.

  Study phs000542

• Genomic Data Archive From the Network for Pancreatic Organ Donors With Diabetes

  The Network for Pancreatic Organ Donors with Diabetes (nPOD) is the largest biorepository of human pancreata from organ donors with type 1 diabetes (T1D), maturity-onset diabetes of the young (MODY), cystic fibrosis-related diabetes (CFRD), type 2 diabetes (T2D), gestational diabetes, and islet autoantibody positive (AAb+)/pre-T1D. The mission of the nPOD is to distribute biospecimens and associated de-identified data/metadata to an international researcher network, and to promote the development of new treatments for these diabetes conditions. Here, we describe the release of high-parameter genotyping data for the nPOD cohort. Specifically, 372 subjects were genotyped using a customized precision medicine single nucleotide polymorphism (SNP) microarray (UFDIchip). These data were technically validated using published algorithms to evaluate donor relatedness, ancestry, imputed HLA, and T1D genetic risk score. Additionally, 207 subjects were queried for rare known and novel coding region variants via whole exome sequencing (WES). These data are now publicly available, enabling genotype-selected sample requests and the study of novel genotype : phenotype associations, ultimately to explain diabetes heterogeneity and inform precision medicine strategies to interrupt diabetes pathogenesis.

  Study phs002861

• TDP43 proteinopathy leads to divergent cryptic splicing in the cortex and spinal cord

  Mislocalization of the nuclear TAR DNA-binding protein 43 (TDP43) is a hallmark of ALS and FTD which leads to de-repression and inclusion of cryptic exons, promising biomarkers of TDP43 pathology in a spectrum of neurodegenerative diseases. However, most cryptic exons to date have been identified from in vitro models or a single cortical FTD dataset, and little is known about cryptic splicing in the spinal cord, or within different neuronal subtypes. We meta-analyzed published bulk RNAseq datasets representing 1,778 RNAseq profiles of ALS and FTD post-mortem tissue, and in vitro models with experimentally depleted TDP43. We identified 142 cryptic splices, including 76 novel events. We found a novel pattern of spinal cord cryptic splicing, validated in an independent cohort by qPCR, which differed significantly from cortical and in vitro splicing. Finally, leveraging multiple public single-nucleus RNAseq datasets of ALS and FTD motor and frontal cortex, we confirmed the elevation of cortical-enriched splices in disease and localized them to layer-specific neuronal populations. This catalog of cryptic splices could inform efforts to develop biomarkers for tissue-specific and cell type-specific TDP43 pathology.

  Study EGAS50000000575

• MATISSE WES and bulk RNA-sequencing data

  High-risk cutaneous squamous cell carcinoma is frequently seen in frail, elderly patients and often requires mutilating surgical treatment and adjuvant radiotherapy (RT). The MATISSE trial (NCT04620200) was conducted to improve clinical prospects in CSCC patients eligible for extensive curative surgery, and evaluated early treatment response and immune dynamics following ultra-short neoadjuvant immunotherapy prior to standard of care surgery with or without radiotherapy. Fifty patients were randomized to receive two courses of nivolumab 3 mg/kg (NIVO, weeks 0&2) or nivolumab 3 mg/kg (weeks 0&2) and one course of ipilimumab 1 mg/kg (week 0 only, NIVO/IPI before surgery at week 4, with the primary objective being histopathological response based on residual viable tumor cells in the surgical specimen. Ten patients choose not to undergo surgery, of whom nine reached a clinical complete response during follow up, and were disease-free at median 34 months follow up. Serial tumor and blood samples at baseline, week 1, week 2 and week 4, enabled to investigate dynamical changes through bulk WES and RNA sequencing to potentially aid future de-escalation trials.

  Study EGAS50000001003

• Integrative_genome_profiling_in_AML

  AML emerges as a consequence of accumulating independent genetic aberrations that direct regulation and/or dysfunction of genes resulting in aberrant activation of signalling pathways, resistance to apoptosis and uncontrolled proliferation. Given the significant heterogeneity of AML genomes, AML patients demonstrate a highly variable response rate and poor median survival in response to current chemotherapy regimens. For the past 4 years we have conducted gene expression profiling on purified bone marrow populations equating to normal haematopoietic stem and progenitor cells from healthy subjects and patients with de novo AML in order to identify AML signatures of aberrantly expressed genes in cancer versus normal. We are now applying a series of bioinformatic methodologies combined with clinical and conventional diagnostic data to establish novel genomics strategies for improved prognostication of AML. Additionally, we use our AML signatures to unravel oncogenic signalling pathway activities in AML patients and test inhibitory drugs for these pathways inn preclinical therapeutic programmes. We consider that superimposing GEP and clinical data for our AML patient cohort with additional data on their mutational status will significantly improve the prognostic power of the study as well as unravel yet unknown mutations associated with aberrant signalling activities of oncogenic pathways.

  Study EGAS00001000858

• Transgenerational transmission of reproductive and metabolic dysfunction in the male progeny of polycystic ovary syndrome

  The transgenerational maternal effects of PCOS in female progeny have been revealed. As there are evidence that a male equivalent of PCOS may exist, we asked whether sons born to mother with PCOS (PCOS-sons) transmit reproductive and metabolic phenotypes to their male progeny. Here, in a Swedish nationwide register-based cohort and a clinical case-control study from Chile we found that PCOS-sons are more often obese and dyslipidemic. Their serum miRNAs are found to potentially regulate PCOS-risk genes. Our prenatal androgenized PCOS-like mouse model with or without diet-induced obesity confirmed that reproductive and metabolic dysfunctions in F1 male offspring are passed down to F3. Small non-coding RNAs (sncRNAs) sequencing of F1-F3 sperm revealed distinct differentially expressed (DE) sncRNAs across generations in the androgenized, obese, and obese and androgenized lineages, respectively. Notably, common targets between transgenerational DEsncRNAs in mouse sperm and in PCOS-sons serum indicate similar effects of maternal hyperandrogenism. These findings strengthen the translational relevance highlighting a previously underappreciated risk of reproductive and metabolic dysfunction via the male germline transmission and potential molecular markers to study in future generations.

  Study EGAS00001007079

• Global Anaplastic Thyroid Cancer Initiative

  Thyroid cancer is the most common endocrine malignancy. Most thyroid cancers are of the well-differentiated (non-aggressive) phenotype, and are almost always cured with standard treatments. In contrast, anaplastic thyroid cancer (ATC) is rare, accounting for only 1% of thyroid cancers, however it is perhaps the most lethal human malignancy with an average survival of 3 to 6 months. ATC presents with dramatic and rapid onset of airway and esophageal blockage with frequent spread to the lungs. Interestingly, 21–79% of ATCs have coexisting areas or a previous history of well-differentiated cancers. Although this suggests a progression from well-differentiated cancers to ATC, to date there is little molecular conformation that such a progression exists versus de novo generation of ATC. As ATC is extremely rare and most cases are inoperable, there are a paucity of tissue samples for study at any one center. The Global Anaplastic Thyroid Cancer Initiative (GATCI) aims to unite international institutions in order to pool samples (ATC with or without a paired well-differentiated component) for a comprehensive analysis of the genomic landscape of this disease.

  Study EGAS00001002234

• Germline mutations in the transcription factor IKZF5 cause thrombocytopenia.

  To identify novel causes of hereditary thrombocytopenia, we performed a genetic association analysis of whole-genome sequencing data from 13,037 individuals enrolled in the NIHR BioResource, including 233 cases with isolated thrombocytopenia. We found an association between rare variants in the transcription factor encoding gene IKZF5 and thrombocytopenia. We report five causal missense variants in or near IKZF5 zinc fingers (Znfs), of which two occurred de novo and three co-segregated in three pedigrees. A canonical DNA-Znf binding model predicts that three of the variants alter DNA recognition. Expression studies showed that chromatin binding was disrupted in mutant compared to wild-type (WT) IKZF5 and electron microscopy revealed a reduced quantity of alpha granules in normally sized platelets. Proplatelet formation (PPF) was reduced in megakaryocytes (MKs) from seven cases relative to six controls. Comparison of RNA-seq data from platelets, monocytes, neutrophils and CD4 T-cells from three cases and 14 healthy controls showed 1,194 differentially expressed genes in platelets but only four DEGs in each of the other blood cell types. In conclusion, IKZF5 is a novel transcriptional regulator of megakaryopoiesis and the eighth transcription factor associated with dominant thrombocytopenia in humans.

  Study EGAS00001003736

• Clonal relationships of ductal carcinoma in situ and recurrent invasive breast cancers defined by genomic analysis

  Ductal Carcinoma In Situ (DCIS) is the most common form of pre-invasive breast cancer and despite treatment a small fraction (5-10%) of DCIS patients present with invasive disease many years later. A fundamental biologic question is whether the invasive disease recurring in the same breast is established by tumor cells in the initial DCIS or represents new unrelated disease. To address this question, we performed genomic analyses on the initial pure DCIS lesion and paired invasive recurrent tumors in 95 patients together with single cell DNA sequencing in a subset of cases. Our data shows that in 75% the invasive recurrence was clonally related to the initial DCIS, suggesting that the tumor cells were not eliminated during the initial treatment with surgery +/- radiotherapy. Surprisingly however, 18% were clonally unrelated to the DCIS, representing new independent lineages, and 7% of cases were ambiguous. Our findings show that although DCIS is often the precursor of invasive recurrence, a significant fraction of invasive recurrences are unrelated to the initial DCIS. This knowledge is essential for accurate risk evaluation of DCIS treatment de-escalation strategies and the identification of predictive biomarkers.

  Study EGAS00001005784

• The proliferative history shapes the DNA methylome of B-cell tumor and predicts clinical outcome

  Here, we provide access to CLL and DLBCL DNA methylation and gene expression data in the context of a systematic analysis of the DNA methylation variability in 1,595 samples of normal cell subpopulations and 14 tumor subtypes spanning the entire human B-cell lineage. This approach showed that differential methylation among tumor entities relates to differences in cellular origin and to de novo epigenetic alterations, which allowed us to build an accurate machine learning-based diagnostic algorithm. We identify extensive patient-specific methylation variability in silenced chromatin associated with the proliferative history of normal and neoplastic B cells. Mitotic activity generally leaves both hyper- and hypomethylation imprints, but some B-cell neoplasms preferentially gain or lose DNA methylation. Subsequently, we construct a DNA methylation-based mitotic clock called epiCMIT, whose lapse magnitude represents a strong independent prognostic variable in B-cell tumors and is associated with particular driver genetic alterations. Our findings reveal DNA methylation as a holistic tracer of B-cell tumor developmental history, with implications in the differential diagnosis and prediction of clinical outcome.

  Study EGAS00001004640

• Clonal relationships of ductal carcinoma in situ and recurrent invasive breast cancers defined by genomic analysis

  Ductal Carcinoma In Situ (DCIS) is the most common form of pre-invasive breast cancer and despite treatment a small fraction (5-10%) of DCIS patients present with invasive disease many years later. A fundamental biologic question is whether the invasive disease recurring in the same breast is established by tumor cells in the initial DCIS or represents new unrelated disease. To address this question, we performed genomic analyses on the initial pure DCIS lesion and paired invasive recurrent tumors in 95 patients together with single cell DNA sequencing in a subset of cases. Our data shows that in 75% the invasive recurrence was clonally related to the initial DCIS, suggesting that the tumor cells were not eliminated during the initial treatment with surgery +/- radiotherapy. Surprisingly however, 18% were clonally unrelated to the DCIS, representing new independent lineages, and 7% of cases were ambiguous. Our findings show that although DCIS is often the precursor of invasive recurrence, a significant fraction of invasive recurrences are unrelated to the initial DCIS. This knowledge is essential for accurate risk evaluation of DCIS treatment de-escalation strategies and the identification of predictive biomarkers.

  Study EGAS00001006306

• Evolutionary origin and methylation status of human intronic CpG islands that are not present in mouse

  Imprinting of the human RB1 gene is due to the presence of a differentially methylated CpG island (CGI) in intron 2, which is part of a retrogene derived from the PPP1R26 gene on chromosome 9. The murine Rb1 gene does not have this retrogene and is not imprinted. We have investigated whether the RB1/Rb1 locus is unique with respect to these differences. For this we have compared the CGIs from human and mouse by in silico analyses and found out that there are at least 2033 human intronic CGIs that are not present in the mouse. Among these CGIs, 104 show sequences similarities elsewhere in the human genome, which suggests that they arose by retrotransposition. We could narrow down the time points when most of these CGIs appeared during evolution. Their methylation status was analysed in two monocyte methylome datasets from whole genome bisulfite sequencing and in 18 published methylomes. Five CGIs appear to be differentially methylated, which suggests that they are subject of genomic imprinting. They are located in introns of the following genes: RB1, ASRGL1, PARP11, PDXDC1 and MYO1D. Four of these CGIs are parts of retrogenes. Our study supports the notion that imprinting builds on host defence mechanisms by which the genome protects itself against retrotransposed and foreign DNA and that the epigenetic fate of the retrotransposed DNA depends on selective forces at the integration site.

  Study EGAS00001000719

• Integration of genomics and histology reveals diagnosis and effective therapy of refractory cancer of unknown primary with PDL1 amplification (H021)

  Identification of the tissue of origin in cancer of unknown primary (CUP) poses a diagnostic challenge and is critical for directing site-specific therapy. Currently, clinical decision making in patients with CUP primarily relies on histopathology and clinical features. Comprehensive molecular profiling has the potential to contribute to diagnostic categorization and, most importantly, guide CUP therapy through identification of actionable lesions. We here report the case of an advanced-stage malignancy initially mimicking poorly differentiated soft-tissue sarcoma that did not respond to multi-agent chemotherapy. Molecular profiling within a clinical whole-exome and transcriptome sequencing program revealed a heterozygous, highly amplified KRAS G12S mutation, compound-heterozygous TP53 mutation/deletion, high mutational load, and focal amplification of chromosomes 9p (including PDL1 [CD274] and JAK2) and 10p (including GATA3). Integrated analysis of molecular data and conventional histopathology suggested a diagnosis of triple-negative breast cancer (TNBC) and provided a rationale for immune checkpoint inhibitor therapy with pembrolizumab, which resulted in rapid clinical improvement and a lasting partial remission. Analysis of 157 TNBC samples from The Cancer Genome Atlas revealed focal, high-level PDL1 amplification coinciding with excessive PDL1 mRNA expression in 24% of cases. Collectively, these results illustrate the diagnostic utility of multidimensional tumor profiling in cases with non-descript histology and immune phenotype, demonstrate the predictive power of genomic PDL1 amplification for immune checkpoint inhibition, and suggest a targeted therapeutic strategy in chromosome 9p24.1/PDL1-amplified cancers.H021

  Study EGAS00001001846

• Whole exome sequencing of an invasive diffuse intrinsic pontine glioma sampled from different sites

  The lateral ventricle subventricular zone (SVZ) is a frequent site of high-grade glioma (HGG) spread and tumor invasion of the SVZ is a predictor of a worse clinical prognosis. A range of HGG types invade the stem cell niche of the SVZ, including both adult glioblastoma and pediatric high-grade gliomas such as diffuse intrinsic pontine glioma (DIPG). The cellular and molecular mechanisms mediating this frequent invasion of the SVZ are poorly understood. Here we demonstrate that neural precursor cell (NPC):glioma cell communication underpins the propensity of glioma to colonize the SVZ. SVZ NPCs secrete chemoattractant signals toward which glioma cells home. Biochemical and proteomic analyses of factors secreted by SVZ NPCs revealed a discrete list of candidate proteins. Necessity and sufficiency testing implicated the neurite outgrowth-promoting factor pleiotrophin, along with three required binding partners (secreted protein acidic and rich in cysteine (SPARC), SPARC-like protein 1, and heat shock protein 90B), as key mediators of this chemoattractant effect. Pleiotrophin protein expression is strongly enriched in the SVZ, and knockdown of pleiotrophin expression starkly reduced glioma invasion of the SVZ in the adult murine brain. Pleiotrophin, in complex with the three binding partners, activated the Rho/ROCK pathway in DIPG cells, and inhibition of ROCK resulted in decreased DIPG invasion toward SVZ neural precursor cell-secreted factors. These findings demonstrate a pathogenic role for neural precursor cell – glioma interactions and potential therapeutic targets to limit glioma invasion.

  Study EGAS00001002326

• Copy number profiling of putative cancer stem from pleural effusion aspirates from breast cancer patients

  A common symptom during late stage breast cancer disease is pleural effusion, which is related to poor prognosis. In pleural effusions malignant cells can be detected, which indicates a metastatic spread from the primary tumor site. Beside the usefulness for investigation of the metastatic process, it has been a source to isolate cells with putative cancer stem cell (CSC) properties. For this study, pleural effusion aspirate from 25 metastatic breast cancer patients were processed to establish in vitro culture. Patient-derived aspirates were cultured under sphere forming conditions and isolated primary cultures were sorted for cancer stem cell populations ALDH1+ and CD44+CD24-/low and sphere forming efficiency of CSC and non-CSC subpopulation was determined. Unsorted cells had a higher potential to form spheres compared to CSC subpopulations. Subsequently, DNA was isolated from pleural effusions before and after cell sorting, to compare their copy number profiles generated by low-coverage whole genome sequencing to DNA from FFPE primary tumors or bone metastasis. Unbalanced profiles could be detected in four pleural samples before sorting, in two ALDH1+ sorted samples, in one CD44+CD24-/low and in all control samples. Additionally, spheroid culture from one pleural sample could be passaged on and was characterized. Therefore, pleural effusions are an appropriate media for enrichment of putative CSC. However, low-coverage sequencing is difficult due to low quantities of abnormal cells compared to normal cells.

  Study EGAS00001002343

• Defining the metastasome in colorectal cancer: Implications for hypotheses on metastasis evolution and personalized therapy (HIPO-032)

  Personalized cancer therapy aims at individual genetic changes characterizing primary cancers. Still, however, metastasis is the major clinically unmet problem, also due to an incomplete understanding of its molecular evolution.This study is the first to define the metastasis-specific whole genome landscape of human colorectal primary vs. matched metastatic lesions.Protein coding, ncRNA genes and 3’UTRs harbored about a third each of single nucleotide variations (SNVs)/indels, 19% of them being metastasis-specific. We found novel mutational hills among ncRNAs and 3’UTRs, copy number changes able to explain changes in microRNA expression in metastases, and novel metastasis-specific mutations in the 3’UTRs on important cancer signalling genes. Some metastatic lesions showed targetable mutations not detected in the primaries. Analysis of mutual exclusivity patterns supported a model that has progressive alterations in important colorectal cancer genes and revealed new partners. Metastatic lesions were enriched in SNVs, specific structural variations, and alterations in genes affecting cell adhesion and extracellular matrix interaction.Furthermore, a hepatic stellate activation cascade was enriched in metastases, suggesting genetic programs for site-specific colonization. Allele frequency distribution and mutational signature analysis suggests a common ancestor clone to both the primary tumor and the metastasis, with additional mutagenesis ongoing in both sites independently. Taken together, our results significantly add to hypothesis generation on metastasis evolution, and suggest novel metastasis-specific genomic changes which would be missed by current personalized therapy concepts. (HIPO-032)

  Study EGAS00001002717

• Conserved features of TERT promoter duplications reveal an activation mechanism that mimics hotspot mutations in cancer

  Mutations in the TERT promoter are the single most common non-coding mutation in cancer and represent the genetic underpinnings of tumor cell immortality. Beyond the two most common point mutations, G228A and G250A, which selectively recruit the ETS factor GABP to activate TERT, the significance of other variants in the TERT promoter are unknown. We identified duplications of wildtype sequence within the core promoter region of TERT in 7 different cancer types that have strikingly similar features including size, insertion position, and inclusion of one of the native ETS motifs. Each duplication activates the TERT promoter to a similar level as G228A and G250A and is critically dependent on the insertion site. The GABP tetramer binds to the TERT duplicated promoter sequence by virtue of the native ETS motif and its duplicated version with precise spacing, and it is necessary for the transcriptional activation by all duplications tested. Spatiotemporal analysis in a multifocal glioblastoma shows the duplication is clonal and its activation of TERT is readily detectable at the single cell level and in bulk tumor tissue. We conclude that recurrent TERT promoter duplications of the native ETS sequence are functionally and mechanistically equivalent to the hotspot mutations that confer tumor cell immortality. The shared mechanism of these divergent somatic genetic alterations suggests a strong selective pressure for recruitment of the GABP tetramer to activate TERT.

  Study EGAS00001006118

• National Institute on Aging (NIA) Long Life Family Study (LLFS)

  The Long Life Family Study (LLFS) is an international collaborative study of the genetics and familial components of exceptional survival, longevity, and healthy aging. Families were recruited through elderly probands (generally in their 90s) who self-reported on the survival history of their parents and siblings, and on the basis of this information, families which showed clustering of exceptional survival were recruited. [Specifically, a Family Longevity Selection Score (FLOSS) ≥7 was required. The FLOSS measures the average excess Observed lifespan over that Expected based upon lifetables, while adding a bonus term for still-living individuals. Thus FLOSS is a useful tool for scoring and selecting families for inclusion in a research study of exceptional survival (Sebastiani et al., 2009, PMID: 19910380)]. Probands resided in the catchment areas of four Field Centers (Boston University, Columbia University, University of Pittsburgh, and University of Southern Denmark). Recruited family members were phenotyped through extensive in-home visits by teams of technicians who traveled all over the USA and Denmark. Blood assays were centrally processed at a Laboratory Core (University of Minnesota) and protocols were standardized, monitored and coordinated through a Data Management Coordinating Center (Washington University). We examined and extensively phenotyped in all major domains of healthy aging, 4,953 individuals in 539 families through comprehensive in-home visits. Of these, 4,815 gave dbGaP sharing permission and had sufficient quantity/quality of DNA for GWAS genotyping. This large collection of families, selected on the basis of clustering for exceptional survival, is a unique resource for the study of human longevity and healthy aging. We estimate that less than 1% of the Framingham Heart Study (FHS) families (a roughly random population family sample) would meet the minimal entrance criteria for exceptional survival required in the LLFS (Sebastiani et al., 2009, PMID: 19910380). Thus, the least exceptional LLFS families show more clustering for exceptional longevity than 99% of the FHS families. Although the LLFS pedigrees were selected on the basis of longevity per se in the upper generation (and the generation above that), the children's generation have significantly lower rates of many major diseases and have better healthy aging profiles for many disease phenotypes (Newman et al., 2011, PMID: 21258136). The participants had their first in-person visit between 2006 and 2009. After that visit, they were contacted annually by telephone to update vital status, medical history, and general health. Between 2014 and 2017, willing participants completed a second in-person visit. The second visit followed the same protocols and centralized training as the first visit. During the second visit, a portable carotid ultrasound exam was added. Again, participants were continuously contacted annually for telephone follow-up during the period of the second in-person visit and after that. Annual telephone follow-ups currently ongoing, and plans for a third in-person visit are in progress.

  Study phs000397

• SC_DDD-G-4

  Post-QC (pre-imputation) genotype data for N=6,983 DDD probands included in the neurodevelopmental disorder discovery GWAS (Niemi et al., Nature 2018). Consists of filtered set of samples and variants from EGAD00010001598 and EGAD00010001600. Includes patient HPO phenotype terms and GWAS summary statistics (including imputed variants). Samples were genotyped on the Illumina HumanCoreExome BeadChip and Illumina InfiniumCoreExome Beadchip

  Dataset EGAD00010001604

• Bulk RNA-seq of human muscle-invasive bladder cancer tissue samples before and after platinum-based chemotherapy (Chelushkin, van Dorp, et al., 2024)

  The current dataset represents bulk RNA-Seq gene expression profiling (with an exome library preparation kit) of muscle-invasive bladder cancer tissue samples obtained before and after platinum-based chemotherapy. 89 samples are pre-treatment transurethral resection of the bladder tumor (TUR-BT) tissue at diagnosis (baseline), 86 are post-treatment cystectomy tissue (resected tumor bulk), comprising 76 pairs of samples from the same patients. FASTQ files contain gene expression data.

  Dataset EGAD50000000446

• Admixture histories of São Tomé e Príncipe.

  Genotyping datasets used in the article "Nested admixture during and after the Trans-Atlantic Slave Trade in the island of Sao Tome" by Ciccarella M et al. 2025 The genotype data corresponds to 2,104,148 autosomal SNPs genotyped from the IlluminaOmni 2.5 Million BeadChip for 97 volunteer participants sampled on São Tomé e Príncipe, family unrelated at the 2nd degree based on population genetics analyses. In particular, the dataset is composed of 95 individual samples collected on São Tomé and 2 collected on Príncipe. SNP rsID, Chromosome position and genetic position in (bp) are in Build GRCh38.

  Dataset EGAD50000001348

• WGS data of conditional knockout mouse model mammary tumours

  Deposited here are 56 whole-genome sequencing BAM files from 15 Trp53f/w, 12 Trp53f/f, 14 Brca1f/f Trp53f/w, and 15 Brca1f/f Trp53f/f mouse mammary tumor samples sequenced on Illumina NovaSeq PE150. An additional 6 whole genome sequencing BAM files from corresponding normal tissues of mice are also included as controls (BPC_D666, B1PC_D840, BPTC_D992, PC_D503, PC_D720_Kid, PTC_H531). All samples were used in the study “Insights into BRCA1 and TP53 associated breast cancer development from integrated whole genome analysis of mouse model mammary tumors, Huo et al., 2026.”

  Dataset EGAD50000002036

• small RNA-sequencing and RNA-sequencing of human brain tissue with temporal lobe epilepsy

  This data set contains the raw .fastq files from two RNA-sequencing experiments and two small RNA-sequencing experiments. Both control brain tissue and tissue from sufferers of mesial temporal lobe epilepsy were sequenced. Two different brain regions were sequenced; the cortex and the hippocampus. For more details please see: Mills, James D., et al. "Coding and non-coding transcriptome of mesial temporal lobe epilepsy: Critical role of small non-coding RNAs." Neurobiology of disease 134 (2020): 104612.

  Dataset EGAD00001005735

• SCLC study George et al. - RNA-sequencing data set

  RNA-sequencing (RNA-seq) was performed with RNA extracted from fresh-frozen human tumor tissue samples. cDNA libraries were prepared from poly-A selected RNA applying the Illumina TruSeq protocol for mRNA. The libraries were then sequenced with a 2 x 100bp paired-end protocol to a minimum mean coverage of 30x of the annotated transcriptome.

  Dataset EGAD00001001244

• ICGC Prostate Cancer Whole Genome Sequencing

  Whole Genome Sequencing Illumina HiSeq data from 20 men with prostate cancer. 20 samples were taken from primary tissue obtained at prostatectomy (target sequencing depth 50X) with matched blood control (target sequencing depth 30X). These were submitted for use in the ICGC Pan-Cancer Analysis of Whole Genomes project. Same raw data submitted in EGAD00001001116. As of September 2020, some of the studies using these data include: Wedge et al, Nature Genetics 2018 (PMID: 29662167) Pan-Cancer Analysis of Whole Genomes, Nature 2020 (PMID: 32025007)

  Dataset EGAD00001000892

• RNA-seq analysis of CCO+/CCO- hepatocytes in normal human liver

  RNAseq data from Passman et al 2023. Clonal CCO-deficient hepatocyte patches and nearby CCO-proficient hepatocytes were identified in morphologically normal human livers and sampled at varying distances along the PT-CV axis. Samples are characterised according to their location within the liver lobule, with "PT" denoting samples abutting the portal triad, "CV" denoting samples abutting the central hepatic vein, and "Mid" sampled acquired midway between these structures. Analysis was performed on an Illumina Nextseq using a high output kit and 100 single-end cycles.

  Dataset EGAD00001010033

• TK-EPN862 - Patient-derived xenograft model of Posterior Fossa A Ependymoma - RNAseq

  In Vivo Loss of Tumorigenicity in a Patient-Derived Orthotopic Xenograft Mouse Model of Ependymoma. Whitehouse et al. 2023 Frontiers in Oncology. We describe the establishment of a patient-derived orthotopic xenograft (PDOX) model of posterior fossa A (PFA) EPN, derived from a metastatic cranial lesion. Patient and PDOX tumors were analyzed using RNA sequencing. RNAseq data (paired end) provided here correspond to Primary tumour, two metastatic lesions (one spinal, one cranial), and a patient-derived xenograft derived from the patient.

  Dataset EGAD00001009870

• Ghana Breast Health Study

  The Ghana Breast Health Study (GBHS) was a multi-disciplinary, population-based case-control study conducted in Accra and Kumasi, Ghana that was designed to investigate breast cancer etiology in the West Africa region. The study enrolled 1,126 invasive breast cancer cases and 2,106 frequency matched population-based controls using census-based sampling. GHBS participants were between the ages of 18 to 74 years of age. Breast cancer cases were recruited at the time they presented with lesions suspicious of breast cancer at three hospitals: Korle Bu Teaching Hospital (Accra), Komfo Anoyke Teaching Hospital (Kumasi) and Peace and Love Hospital (Kumasi). These hospitals are the primary providers of treatment for breast cancer in Ghana, allowing for cases in our study to represent most breast cancers diagnosed in these areas during the study period. The following publications describe the GBHS in detail: 1) Brinton LA et al. Design considerations for identifying breast cancer risk factors in a population-based study in Africa. Int J Cancer 2017;140:2667-2677 (PMID:28295287). 2) Nyante SJ et al. Recruiting population controls for case-control studies in sub-Saharan Africa: The Ghana Breast Health Study. PloS one 2019;14:e0215347 (PMID:30990841)Among subjects with an available source of germline DNA genotyping was performed using the Infinium Global Screening Array-24 per the manufacturer’s guidelines using the Infinium automated protocol. We excluded probable duplicates and close relatives, and samples with a call rate < 95% or samples with extreme heterozygosity. Female sex was verified by Identifiler using X chromosome heterozygosity and the X chromosome inbreeding coefficient F statistics. The GLU genetics’ ld.tagzilla module was used to confirm African ancestry. To resolve more detailed population substructure, principal components analysis was conducted among all unrelated subjects using the EIGENSOFT v7.2.1. Imputation was performed using the Michigan imputation server Minimac3 with 1K genomes phase3 as reference panel.

  Study phs002387

• NINDS-Genome-Wide Genotyping in Parkinson's Disease: First Stage Analysis and Public Release of Data

  Epidemiological studies have estimated a cumulative prevalence of PD of greater than 1 per thousand. When prevalence is limited to senior populations, this proportion increases nearly 10-fold. The estimated genetic risk ratio for PD is approximately 1.7 (70% increased risk for PD if a sibling has PD) for all ages, and increases over 7-fold for those under age 66 years. The role for genes contributing to the risk of PD is therefore significant. This study utilized the well characterized collection of North American Caucasians with Parkinson's disease, and neurologically normal controls from the sample population which are banked in the National Institute of Neurological Disorders and Stroke (NINDS Repository) collection for a first stage whole genome analysis. Genome-wide, single nucleotide polymorphism (SNP) genotyping of these publicly available samples was originally done in 267 Parkinson's disease patients and 270 controls, and this has been extended to include genome wide genotyping in 939 Parkinson's disease cases and 802 controls. The NINDS repository was established in 10-2001 towards the goal of developing standardized, broadly useful diagnostic and other clinical data and a collection of DNA and cell line samples to further advances in gene discovery of neurological disorders. All samples, phenotypic, and genotypic data are available to the research community including to academics and industry scientists. In addition, well characterized neurologically normal control subjects are a part of the collection. This collection formed the basis of this first stage study by Fung et al., and the expanded study by Simon-Sanchez et al. The genotyping data was generated and provided by the laboratory of Dr. Andrew Singleton NIA, and Dr. John Hardy NIA (NIH Intramural, funding from NIA and NINDS). Important links to apply for individual-level data Data Use Certification Requirements (DUC) Apply here for controlled access to individual level data Participant Protection Policy FAQ

  Study phs000089

• RNAseq data to study PRPF6 regulated splice forms in colon cancer cell lines

  Alternative splicing plays critical roles in differentiation, development, and cancer (Pettigrew et al., 2008; Chen and Manley, 2009). The recent identification of specific spliceosome inhibitors has generated interest in the therapeutic potential of targeting this cellular process (van Alphen et al., 2009). Using an integrated genomic approach, we have identified PRPF6, an RNA binding component of the pre-mRNA spliceosome, as an essential driver of oncogenesis in colon cancer. Importantly, PRPF6 is both amplified and overexpressed in colon cancer, and only colon cancer cells with high PRPF6 levels are sensitive to its loss. Our data clearly point to an important role for PRPF6 in colon cancer growth and suggest that a better understanding of its role in alternative splicing in colon cancer is warranted. To determine the specific alternative splice forms that PRPF6 regulates in colon cancer, we plan three experiments: 1. The first involves knocking down expression of PRPF6 in two different cancer cell lines with 3 different siRNAs, and then completing RNA-seq to determine the gene expression changes that occur relative to a non-targeting control siRNA. Because of the role for PRPF6 in pre-mRNA splicing, we especially want to quantify the changes in splice-specific forms of all genes genome-wide to identify genes whose splicing is altered upon PRPF6 knockdown. 2. The second involves immunoprecipitating PRPF6 from two different cancer cell lines and isolating any RNA that is bound to PRPF6, since PRPF6 is an RNA-binding protein. We then want to carry out RNA-seq to identify which RNA molecules co-immunoprecipitated with PRPF6. This will help us determine possible functions for PRPF6 in regulating colon cancer growth. 3. The third involves overexpressing PRPF6 in cell lines and then carrying out RNA-seq to identify any changes in splice-specific gene expression. This will allow us to determine whether increased PRPF6 expression is sufficient to drive alternative splicing changes.

  Study EGAS00001000761

• Single Cell Sequencing of Sperm (scSperm)

  The aim of this project is to genotype and sequence single spermatozoa from two men, one in his twenties and the other in his seventies. The resulting data is used to quantify the mutations that have arisen in the gametes of both individuals in order to better understand the effect of aging on mutation rates and modes.Project Outline. In order to quantify mutations, semen from two individuals are sequenced. 48 single sperm cells are isolated from each individual, and their DNA is extracted. The resulting genomes are amplified using PicoPlex, GenomiPhi MDA, Repli-G MDA, and MALBAC. QC step is applied to check the quality of WGA DNA using standard Sequenom plex (26 SNPs). A subset of 32 amplification products which pass the intiall QC, are genotyped using Affymetrix SNP6 chips. 12 of the genotyped amplification products are also sequenced. In addition, one multi-cell sample per individual is sequenced as a reference and for validation purposes.Altogether, 12 single cell sperm genomes and two multi-cell genomes are sequenced, coming to a total of 14 genomes. Of the single cell sperm genomes, 2 are sequenced to 50x coverage, and the other 10 to 25x coverage. Both multi-cell genomes are sequenced to 25x coverage.

  Dataset EGAD00001001216

• Cell-free DNA Methylome Analysis Enables Early Preeclampsia Prediction

  This dataset contains in solution target-enrichment bisulfite sequencing of placental tissue, buffy coat and plasma DNA from pregnant women. Blood samples were taken for cell-free DNA (cfDNA) DNA extraction from 64 women at the time of early-onset preeclampsia (PE) diagnosis, or from 38 controls (uncomplicated pregnancies) at a similar gestational age that did not develop preeclampsia subsequently. Among these subjects, plasma samples from 7 PE patients and 6 controls were also subjected to oxidative bisulfite sequencing. Placental tissues from 11 PE and 26 control subjects after delivery, and buffy coat from 16 PE and 16 control subjects at the same time of cfDNA sampling were profiled. A discovery cohort for early PE assessment in the first trimester was collected. In this cohort, cfDNA from 75 pregnancies that went on to develop early-onset PE and from 124 matched controls were collected and methylome sequencing were carried out. An independent validation cohort to validate early PE assessment with methylome profiling was collected as well. This validation cohort includes cfDNA samples from 61 PE and 136 control pregnancies.

  Dataset EGAD00001010159

• Partner independent fusion gene detection by multiplexed CRISPR Cas9 enrichment and long read Nanopore sequencing (FUDGE)

  Targeted long-read nanopore sequencing. Abstract: Fusion genes are hallmarks of various cancer types and important determinants for diagnosis, prognosis and treatment. Fusion gene partner choice and breakpoint-position promiscuity restricts diagnostic detection, even for known and recurrent configurations. To accurately and impartially identify fusions, we developed FUDGE: FUsion Detection from Gene Enrichment. FUDGE couples target-selected and strand-specific CRISPR/Cas9 activity for fusion gene driver enrichment - without prior knowledge of fusion partner or breakpoint-location – to long-read Nanopore sequencing with the bioinformatics pipeline NanoFG. FUDGE has flexible target-loci choices and enables multiplexed enrichment for simultaneous analysis of several genes in multiple samples in one sequencing run. We observe on-average 665 fold breakpoint-site enrichment and identify nucleotide resolution fusion breakpoints - within two days. The assay identifies cancer cell line and tumor sample fusions irrespective of partner gene or breakpoint-position. FUDGE is a rapid and versatile fusion detection assay, providing unparalleled opportunity for diagnostic pan-cancer fusion detection.

  Dataset EGAD00001006111

• International Collaboration of Incident HIV and HCV in Injecting Cohorts (InC3)

  This study represents a merged international multi-cohort project of pooled biological and behavioral data from ten prospective cohorts of injection drug users (Grebely J, Morris MD, Rice TM, Bruneau J, Cox AL, Kim AY, et al., 2012, PMID: 23203695). Of the 10 cohorts, six provided data and samples for the genome wide association study (GWAS) entitled “Genetic Analysis of Opioid Addiction in People Who Inject Drugs”. The InC3 cohorts included in the GWAS were: i) Australian Trial in Acute Hepatitis C (ATAHC-I, Sydney); ii) Hepatitis C Incidence and Transmission Study in Prison (HITS-p) (Sydney); iii) Hepatitis C Incidence and Transmission Study in Community (HITS-c) (Sydney); iv) HepCo Study (Montreal); v) SuperMIX Study (combining the Networks II & MIX studies, Melbourne); and vi) the UFO Study (San Francisco).

  Study phs002310

• African American Breast Cancer GWAS

  The GWAS includes African American participants from 9 epidemiological studies of breast cancer, comprising a total of 3,153 cases and 2,831 controls (cases/controls: The Multiethnic Cohort Study (MEC), 734/1,003; The Los Angeles component of The Women's Contraceptive and Reproductive Experiences (CARE) Study, 380/224; The Women's Circle of Health Study (WCHS), 272/240; The San Francisco Bay Area Breast Cancer Study (SFBCS), 172/231; The Northern California Breast Cancer Family Registry (NC-BCFR), 440/53;The Carolina Breast Cancer Study (CBCS), 656/608; The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) Cohort, 64/133; The Nashville Breast Health Study (NBHS), 310/186; and, The Wake Forest University Breast Cancer Study (WFBC), 125/153). Quality control of the GWAS data and additional details can be found in Chen et al. Hum Genet. 2013 (PMID: 22923054)

  Study phs000851

• A Single Cell Atlas of MMRd and MMRp Colorectal Cancer

  Immune responses to cancer vary across cancer types and patients. Colorectal cancer tumors with mismatch repair-deficiency (MMRd) show an elevated immune cell activity as compared to mismatch repair proficient (MMRp) tumors. To understand the immune response patterns in these two types of colorectal cancer, we transcriptionally profiled 371,223 tumor and adjacent normal cells from 28 MMRp and 34 MMRd patients. Unsupervised analysis identified 88 cell subsets, from 7 distinct cell clusters (that contain epithelial, malignant, stromal and immune cell lineages), and an associated compendium of 204 gene expression programs. Examination of these cell subsets and programs revealed extensive transcriptional and spatial remodeling of malignant, stromal and immune cells in MMRd and MMRp tumors. This dataset was generated as part of a published study (Pelka, Hofree, Chen, et al., Cell 2021 Sep 2;184(18):4734-4752; PMID: 34450029).

  Study phs002407

• HCI-PDX Trial Center for Breast Cancer Therapy

  The HCI-PDX Trial Center for Breast Cancer Therapy study is a collection of patient-tumor samples that are serially established as patient-derived tumor xenografts (human tumor in mouse) and matching organoids. For this study, we describe valuable methods and resources to generate organoids and use them as cost-effective models for precision drug screens. This study leveraged whole-exome sequencing, RNAseq, and SNP-array data to illustrate how the heterogeneity of tumors is preserved in xenograft and organoid models. Sequencing files are provided for whole-exome and RNAseq data. Processed copy number variant calls from the SNP arrays are also available. A full description of the study can be found in the article entitled, "A human breast cancer-derived xenograft and organoid platform for drug discovery and precision oncology," written by Guillen et al., 2022 in Nature Cancer (PMID: 35221336).

  Study phs002479

• Recurrent CLTC::SYK fusions and CSF1R mutations in juvenile xanthogranuloma of soft tissue

  In this study, the genomic landscape of extracutaneous juvenile xanthogranuloma (JXG) was analyzed. By leveraging the Dutch Nationwide Pathology Databank (Palga), tumor samples were obtained from different academic medical centers in the Netherlands. The study was approved by the Palga Scientific Council and Privacy Committee (LZV-2016-183) and the Institutional Review Board of Leiden University Medical Center (B19.074). In addition, the study was approved by the Biobank and Data Access Committee of the Princess Máxima Center for Pediatric Oncology (PMCLAB2024.0512). Provided are whole transcriptome sequencing (WTS) data of 3 histiocytic tumors with CLTC::SYK fusions. WTS was performed in the routine workflow of the Princess Máxima Center for Pediatric Oncology (as described in Hehir-Kwa, et al. JCO Precis Oncol 2022). RNA was derived from formalin-fixed paraffin-embedded tumor tissue (n=1) or from frozen tumor tissue (n=2).

  Study EGAS50000000584

• Beta-Blocker Evaluation in Survival Trial (BEST-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Objectives The Beta-Blocker Evaluation of Survival Trial was designed to determine whether bucindolol hydrochloride- a nonselective beta-adrenergic blocker and mild vasodilator- would reduce the rate of death from any cause among patients with advanced heart failure and to assess its effects in various subgroups defined by ethnic background and demographic criteria- specifically women and members of minority groups. Background Although beta-adrenergic-receptor antagonists reduce morbidity and Mortality in participants with mild-to-moderate chronic heart failure, their effort on survival in participants with more advanced heart failure is unknown. Participants There were 2,708 participants. Conclusions Bucindolol resulted in no significant overall survival benefit. (Krause-Steinrauf et al., 2001, PMID: 11386264).

  Study phs003730

• APOL1 Risk Variants Induce Metabolic Reprogramming of Podocytes in Patient-Derived Kidney Organoids

  Apolipoprotein L1 (APOL1) high-risk genotypes G1 and G2 are responsible for the increased risk of chronic kidney disease (CKD) in the African-American population, especially in the presence of interferon gamma (IFN-γ). Here, we applied single cell transcriptomics on kidney organoids generated from patient-derived induced pluripotent stem cells (iPSCs) to model human APOL1 nephropathy. iPSCs were generated from fibroblasts of two patients with APOL1 nephropathy homozygous for G1 or G2 risk variants, and an isogenic control (G0) was created by gene correction. Kidney organoids were generated according to previously published protocol (Takasato M et al. Nat. Protoc. 2016) and treated with IFN-γ for two days to induce APOL1. Twenty-four hours after IFN-γ removal, treated organoids from all three lines that were cultured in parallel were harvested for single cell transcriptomics.

  Study EGAS50000001223

• Colorectal advanced adenomas NKI-AvL TGO COCOS series

  Colorectal cancer (CRC) develops from normal epithelium, through a benign precursor lesion called adenoma, by accumulation of genetic alterations affecting oncogenes and tumour suppressor genes. About 5% of colorectal adenomas are estimated to progress to CRC. However, it is important to identify which adenomas actually carry a high-risk of progression, because these serve as intermediate endpoints for e.g. screening programs. In clinical practice, adenomas with a size of ≥10 mm, villous component and/or high-grade dysplasia, called advanced adenomas, are considered high-risk, although solid evidence for this classification is lacking. Specific DNA copy number changes are associated with adenoma-to-carcinoma progression.For this tissue dataset, we applied low-pass whole genome sequencing to 96 advanced adenomas. Advanced adenomas were classified as lesions with low-risk or high-risk of progression, according to the presence of specific DNA copy number changes (Carvalho et al, CancerPrevRes, 2018).

  Study EGAS00001002952

• single nuclei RNASeq of 5 regions of the human prenatal brain

  Data generated through single nuclei RNA sequencing on 5 regions of the brain (frontal cortex, ganglionic eminence, hippocampus, thalamus and cerebellum) from 3 fetuses (two of 14 and one of 15 post-conception weeks, all female). Tissue was acquired from the MRC-Wellcome Trust Human Developmental Biology Resource (HDBR) with ethical approval. snRNA-seq libraries were prepared from ∼10,000 nuclei from each sample using Chromium Single Cell 3ʹ (v3) reagents (10X Genomics). Quality control of libraries was performed using the Agilent 5200 Fragment Analyzer before sequencing on an Illumina NovaSeq 6000 to a depth of at least 865 million (median = 1.01 billion) read pairs per library. Raw sequencing data were converted into FASTQ files. For a full description of data generation, please see Cameron et al, Biological Psychiatry 2022, https://doi.org/10.1016/j.biopsych.2022.06.033.

  Study EGAS00001006537

• Analysis of a cohort of familial ademomatous polyposis patients bearing APC gene mutation

  large number of colorectal adenomas with high risk of evolving into colorectal tumors. Mutations of the Adenomatous polyposis coli (APC) gene is often at the origin of this disease, as well as of a high percentage of spontaneous colorectal tumors. APC is therefore considered a tumor suppressor gene. While the role of APC in intestinal epithelium homeostasis is well characterized, its importance in immune responses remains ill defined. We investigated an array of immune cell features in FAP subjects carrying APC mutations. A group of 12 FAP subjects and age and sex-matched healthy controls were studied. In particular, the expression of 579 immune response genes was analyzed in whole blood cells using the Nanostring nCounter Human Immunology kit v2. (Cuche C. et al. Frontiers in Immunology, 2023, in press)

  Study EGAS00001007237

• Whole exome and targeted DNA sequencing data for formalin-fixed paraffin embedded tissue from de novo small cell prostatic carcinoma cases

  This dataset consists of 44 compressed paired fastq files, 15 of which are generated from whole exome sequencing, and 29 of which are generated from DNA sequencing using a targeted gene panel capturing the exonic regions of 73 prostate cancer driver genes. Targeted DNA sequencing was performed on an Illumina MiSeq (v3 600 cycle kit), and exome sequencing was done using an Illumina HiSeq 2500 (v4 250 cycle kit) machine. The fastq files are named in accordance with the sample aliases provided, which reflect the pathology of interest to this study (small cell prostatic carcinoma--SCPC), whether it was sequenced using an exome or targeted gene panel, whether the FFPE sample was sourced from tumor or benign tissue (labeled T or B, respectively), and whether there exists multiple samples belonging to a single patient.

  Dataset EGAD00001004139

• Single-cell RNA-seq of immune cells from human tumor fragments after 48 hour culture ex vivo (Kaptein et al., 2024)

  Single-cell RNA-seq profiling of immune cells from human ovarian carcinoma, renal carcinoma and melanoma samples after 48h of ex vivo culture using the patient-derived tumor fragment platform (5 samples total). Samples were cultured in various conditions, including: untreated, CD8-IL2v-treated, CD8-IL2v + LCKi -treated, aPD1-treated, CD8-IL2v + aPD1 -treated, Untargeted IL2-treated, aCD3-treated and aCD3 + CD8-IL2-treated . FASTQ files contain gene expression data, feature barcode antibody capture or TCR data on immune cells from all conditions combined per patient.

  Dataset EGAD50000000377

• scRNAseq: Human liver cholangiocyte organoids capture the heterogeneity of in vivo human liver ductal epithelium

  Liver ductal organoids expanded in either conventional (Huch et al., 2015) or refined medium were split and seeded either in the same medium or in DM+. They were sequenced on day 10 after splitting. Droplet-based scRNA-seq was performed using the 10x Genomics Chromium Single Cell Kit v3, and libraries were sequenced on an Illumina NovaSeq 6000 S4. Raw sequencing data were processed using Cell Ranger software (v6.0.1) with the human genome reference (hg38) and gene annotation (Ensembl 98). Dataset integration and downstream analysis were mainly performed using Seurat (v4.3.0.1) with R v4.1.3 “One Push-up”.

  Dataset EGAD50000001464

• Single MII oocyte mRNA expression from women

  This dataset contains 14 paired-end FASTQ sequences from mRNA-Seq on single human M-II stage oocytes that were collected from ovarian tissue from unstimulated patients undergoing fertility preservation treatments due to cancer diagnoses, which did not influence ovarian function. Cumulus-oocyte-complexes were matured in vitro according Gruhn et al (Science 365: 1466-1469) and short term flash frozen prior to lysis, RNA extraction, full length cDNA preparation and amplification using the Ultra-low-input SMART-Seq2 v4 kit from Takara Clonetech. Further, these cDNA were used to prepare libraries for sequencing according the Nextera XT DNA library preparation kit from Illumina

  Dataset EGAD00001005971