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• The preterm infant microbiome: biological, behavioral and health outcomes at 2 and 4 years of age

  This project follows a cohort of 78 Very Low Birth Weight (VLBW) previously enrolled infants in a R21 grant plus additional 25 infants through their Neonatal Intensive Care Unit (NICU) stay until they reach the age of 4 years. The data, gathered over 6 weeks of the NICU stay, includes multiple factors, such as prenatal and postnatal events and illnesses, received human milk amount, weekly means of cytokines, chemokines, growth factors, and secretory Immunoglobulin A in the milk, and weekly levels of fecal calprotectin. These factors could potentially alter the gut microbiome. Microbiome species and diversities will be measured in the laboratory of Dr. Jack Gilbert at Argonne National Laboratory using state of the science deep sequencing and amplification of microbial sRNA genes. The microbiome will again be measured in stool samples from those children at the ages of 2 and 4 years. Relationship between the prenatal and postnatal factors, human milk volume and immunobiology, fecal calprotectin levels, and the very early microbiome will be analyzed. The predictive power of the VLBW infant gut microbiome for determining later childhood microbiomes will be analyzed prospectively. The relationships between microbiomes across time and later growth, development and health will be determined. VLBW infants are at risk for both early and later health effects, and the role of the microbiome in these effects will be measured in this prospective study.

  Study phs001578

• ICR96 exon CNV validation series

  A resource for assessment of exon CNV calling methods in targeted NGS data, we here present the ICR96 exon CNV validation series. The dataset includes high-quality sequencing data from a targeted NGS assay (the TruSight Cancer Panel) together with Multiplex Ligation-dependent Probe Amplification (MLPA) results for 96 independent samples. 66 samples contain at least one validated exon CNV and 30 samples have validated negative results for exon CNVs in 26 genes. The dataset includes 46 exon CNVs in BRCA1, BRCA2, TP53, MLH1, MSH2, MSH6, PMS2, EPCAM and PTEN, giving excellent representation of the cancer predisposition genes most frequently tested in clinical practice. Moreover, the validated exon CNVs include 25 single exon CNVs the most difficult exon CNV to detect.

  Dataset EGAD00001003335

• Deletion of FUNDC2 and CMC4 on chromosome Xq28 is sufficient to cause hypergonadotropic hypogonadism in men

  Hypergonadotropic hypogonadism (HH) is characterized by low sex steroid levels and secondarily elevated gonadotropin levels with either congenital or acquired etiology. Genetic factors leading to HH have yet to be fully elucidated. We submit genome and transcriptome data analyses from a male patient with HH and history of growth delay who has an inherited deletion of chromosome Xq28. Expression analyses were done for this patient and his unaffected family members, and compared to normal controls to identify dysregulated genes due to this deletion. Our patient's Xq28 deletion is 44,806 bp and contains only two genes, FUNDC2 and CMC4. Expressions of both FUNDC2 and CMC4 are completely abolished in the patient. Gene ontology analyses of differentially expressed genes in the patient in comparison to controls show that significantly up-regulated genes in the patient are enriched in Sertoli cell barrier regulation, apoptosis, inflammatory response and gonadotropin-releasing regulation. Indeed, our patient has an elevated FSH level, which regulates Sertoli cell proliferation and spermatogenesis. In his mother and sister, who are heterozygous for this deletion, X-chromosome inactivation is skewed towards the deleted X, suggesting a mechanism to avoid FSH dysregulation. Compared to the previously reported men with variable sized Xq28 deletions, our study suggests that the loss of function of FUNDC2 and/or CMC4 results in dysregulation of apoptosis, inflammation and FSH, and is sufficient to cause Xq28-associated HH.

  Study phs002234

• GBM-Space: Spatial Transcriptomic Profiling of Glioblastoma (10x Genomics - Visium)

  Cancer cells display heterogeneous and dynamic states in glioblastoma, but how these malignant states arise and whether they follow a tractable cellular trajectory across tumours is poorly understood. Here, we generate a deep single cell and spatial multi-region atlas of 12 isocitrate dehydrogenase wild-type (IDH-wt) primary glioblastomas that integrates transcriptomic, epigenomic and genomic analysis to comprehensively characterise their tumour heterogeneity. The datasets in this study include sequencing data from Visium spatial transcriptomic (10x Genomics) profiling of these tumours. Note: 2 new samples were added to the dataset on 2026-05-19.

  Dataset EGAD00001015527

• Normal Pressure Hydrocephalus

  Idiopathic normal pressure hydrocephalus (iNPH) is a neurological disorder of aging that is characterized by enlarged cerebral ventricles, gait difficulty, incontinence and dementia. It is a common disorder that occurs almost exclusively after the age of 60. About 1.3% of patients over the age of 65 and 9-14% of nursing home residents are thought to have iNPH. Unfortunately, more than 90% of these patients remain misdiagnosed or undiagnosed, in part because the symptoms of iNPH resemble the symptoms of other neurodegenerative diseases, and in part because many health care practitioners are unfamiliar with this disorder. The etiology of iNPH is not known. Scattered reports of familial cases of iNPH suggest a genetic origin, but the genes involved are unknown. To investigate this matter, we have used exome sequencing to look for genetic factors associated with iNPH. We find recurrent heterozygous mutations in 10 genes, nearly all of which show increased expression in the ciliated ventricular epithelium and/or choroid plexus. Many have previously been associated with the function of cilia. 

  Study phs002296

• Childhood Cancer Data Initiative (CCDI): Molecular Characterization across Pediatric Brain Tumors and Other Solid and Hematologic Malignancies for Research, Diagnostic, and Precision Medicine

  This study contains tumor and germline WGS, RNA-Seq, Clinical Panel Sequencing, and other omics and molecular data for patients with pediatric brain tumors and other solid and hematologic malignancies. This data has been collected from multiple organizations including the multi-institute Children's Brain Tumor Network (CBTN), the Pacific Pediatric Neuro-Oncology Consortium (PNOC), and the Children's Hospital of Philadelphia Division for Genomic Diagnostics (CHOP DGD). In addition to being available pre-publication and without embargo via dbGaP and the NCI Cancer Research Data Commons, this data is made available via Cavatica, PedcBioPortal and the Kids First Data Resource Portal. Collectively, this availability strives to accelerate the research process and enable members of the scientific and patient communities to partner and make discoveries faster than ever before.In 2019, the CBTN launched the Pediatric Brain Tumor Atlas, which now comprises the largest collection of childhood brain tumor data in the world. This resource is helping accelerate not only brain tumor research, but is also empowering discovery for other rare childhood conditions. Brain tumors are the most common form of cancer in children aged 0-19 in the United States, and are the largest cause of cancer-related deaths. The estimated number of new cases in 2019 is nearly 3,800, and thus brain tumors are a rare disease. Despite their relative rarity, the years of potential life lost due to brain tumors in 2009 was estimated at 47,631 years for children and adolescents aged 0-19 in the United States; this is a disproportionate amount of life lost compared to adult cancers and represents an unrecognized societal threat. There is an urgent need to improve therapies for these children. This sequencing cohort defines the largest, clinically annotated pediatric brain tumor cohort study to date and seeks to define the intersection of germline and somatic underpinnings of pediatric brain tumors across a shared developmental context of cancer and structural birth defects.

  Study phs002517

• GenomeDenmark Phase 2 - MHC haplotypes

  The MHC vcf call set was generated using a modified AsmVar and BayesTyper pipeline. In contrast to the original pipeline, where variant calling is performed using alignment of collapsed assemblies to a reference genome, the MHC call set was produced using alignment of phased MHC haplotypes. Two iterations of BayesTyper was run, a first iteration for each haplotype seperately and a second iteration performing joint variant calling on all haplotypes. The sample IDs for the fathers and mothers are TrioID-01 and TrioID-02, respectively, and the IDs for the children are TrioID-0x, where x is a number between 3 and 7.

  Dataset EGAD00001003455

• Long-read sequencing identifies a common transposition haplotype predisposing for CLCNKB deletions

  Long-read whole genome sequencing, long-read long-range PCR sequencing, targetted long fragment long-read sequencing data of the CLCNKA/CLCNKB locus in 27 Bartter syndrome patients. Multiple different deletion alleles are identified and a new common transposition haplotype predisposing for CLCNKB deletions is described.

  Study EGAS00001007339

• Japanese Reference Genome JG1

  The complete human genome sequence is used as a reference for next-generation sequencing analyses. However, some ethnic ancestries are under-represented in the reference genome (e.g., GRCh37) due to its bias toward European and African ancestries. Here, we perform de novo assembly of three Japanese male genomes using >100�� Pacific Biosciences long reads and Bionano Genomics optical maps per sample. We integrate the genomes using the major allele for consensus and anchor the scaffolds using genetic and radiation hybrid maps to reconstruct each chromosome. The resulting genome sequence, JG1, is contiguous, accurate, and carries the major allele for a Japanese population.

  Study JGAS000259

• Kids First: Genomics of Orofacial Clefts in the Philippines

  Orofacial clefts (OFCs) are the most common craniofacial structural birth defect in humans caused by incomplete formation of the upper lip and/or the palate. Over 4,000 children in the Philippines are born with an OFC every year, and the Filipino OFC birth prevalence rate of 1 in 500 live births is one of the highest in the world. Genome-wide association studies support a multifactorial etiology for OFCs, but common variants only account for up to ~25% of the heritable risk in any one population. Sequencing studies in diverse populations is essential to fully understand the genetic architecture of OFCs. The study goals of the Kids First project are to sequence a collection of case-parent trios from the Philippines, in order to identify de novo mutations and inherited rare variants, and understand the population differences in common variant signals in the Philippines versus other populations. Approximately 373 trios from the Philippines were selected for whole genome sequencing (WGS) as part of this Gabriella Miller Kids First project.

  Study phs002595

• Mapping the lineage-retained antigen landscape in neuroblastoma

  Neuroblastoma is among the deadliest pediatric solid tumors, and relapse is frequently driven by lineage plasticity between adrenergic (ADRN) and mesenchymal (MES) cell states that escape conventional and targeted therapies. This project aims to identify tumor antigens that are retained across both lineage states and are therefore suitable for T-cell–based immunotherapy resistant to lineage switching, including non-canonical antigens derived from the "dark proteome." To support this aim, we generated paired RNA-sequencing and ribosome profiling (Ribo-seq) data from neuroblastoma cell lines, patient-derived tumor organoids, and primary patient tumors spanning ADRN and MES states. The RNA-seq data enable custom transcriptome assembly to recover non-reference and non-canonical transcripts, while Ribo-seq maps actively translated canonical and non-canonical open reading frames at codon resolution. Together these data provide the molecular substrate for systematic discovery of lineage-retained, translation-supported neuroblastoma antigens.

  Study EGAS00001008445

• Providing access to COVID-19 data: one year later

  response efforts On 11 March 2020 the World Health Organization declared the novel coronavirus outbreak a global pandemic. Four months later, the European Genome-phenome Archive (EGA) released its first COVID-19 dataset. This dataset – single cell RNA and VDJ sequencing of B cells from 60 COVID-19 patients – showed that neutralizing antibodies could be identified by high-throughput sequencing in response to SARS-CoV-2 infection. That was one year ago. Today, the EGA provides access to fifteen COVID-19 datasets from researchers across seven countries in Asia, Europe, and North America. These studies represent almost 17,000 individuals and have resulted in at least sixteen publications and preprints. Researchers deposit controlled access COVID-19 data at EGA The global research community has come together rapidly to investigate the SARS-CoV-2 coronavirus and better understand the related disease, COVID-19. These research efforts generate valuable genetic and phenotypic data from patients and research participants that can be shared with approved researchers. The EGA enables sharing of this research data by providing a service for archiving and controlled distribution of sensitive data. Over the past year, the EGA has worked with researchers to archive and distribute COVID-19 data from high-throughput sequencing experiments, genotyping studies, and phenotypic information. These datasets investigate the immune system, blood, and cells and tissues of the lung, which are relevant for studying a contagious respiratory illness caused by a viral infection. *Study Spotlight. In January 2021, Ancestry.com demonstrated the utility of deep phenotyping based on self-reported outcomes from a large population of mild and asymptomatic COVID-19 cases. They identified genetic associations with eight COVID-19 phenotypes and showed distinct patterns of association, most notably related to the chr3/SLC6A20/LZTFL1 and chr9/ABO regions. The supporting data is available at the EGA to approved researchers and includes both genotype and phenotype data for 15,000 individuals. EGA collaborates with global COVID-19 community Since the coronavirus outbreak, the EGA has collaborated with other life science resources to support discovery and access to COVID-19 datasets. COVID-19 Host Genetics Initiative. With the NHGRI’s Genomic Data Science Analysis, Visualization, and Informatics Lab-space (AnVIL) platform, the EGA enables sharing of individual-level genetic and phenotypic data from the COVID-19 Host Genetics Initiative (HGI). This initiative aims to generate, share, and analyze data from COVID-19 host genetics research projects to better understand the genetic determinants of COVID-19 susceptibility, severity, and outcomes. In response to COVID-19, the EGA actively supports COVID-19 data submissions and integration of data access and flow into the COVID-19-HGI analysis platform. *Study Spotlight. The COVID-19 HGI has combined individual-level data for 13,868 COVID-19 positive patients (N=7,167 hospitalized) from 17 cohorts in nine countries. The data were used to assess the association of the major common COVID-19 genetic risk factor (chromosome 3 locus tagged by rs10490770) with mortality, COVID-19-related complications, and laboratory values. The genotype and phenotype data for 10 of these cohorts is available at the EGA to approved researchers under accession EGAS00001005304. Fig 1: EGA COVID-19 studies are searchable in the European COVID-19 Data Portal alongside other COVID-19 and SARS-CoV-2 public datasets. European COVID-19 Data Portal. EGA-archived COVID-19 data are discoverable via the European COVID-19 Data Portal (Fig. 1), which brings together public and controlled access data to accelerate coronavirus research for the international community. By indexing all COVID-19-related data in one place, researchers can more easily discover relevant datasets of interest, thus increasing the “FAIRness” (Findability, Accessibility, Interoperability, Reusability) of this valuable data. Fig 2: SARS-CoV-2 viral sequences are imported from ENA and analysed in Galaxy to detect variants. Results are accessible to researchers through the COVID-19 Viral Beacon. COVID-19 Viral Beacon. The COVID-19 Viral Beacon tool was developed in collaboration with the European Nucleotide Archive and Galaxy to enable near real-time browsing of SARS-CoV-2 variability at genomic, amino acid, and motif levels (Fig. 2). The COVID-19 Viral Beacon allows researchers to (i) perform detailed searches about genomic variants, (ii) filter queries and find unique cases, (iii) filter data based on strain-specific variants, and (iv) explore associated metadata. It uses the Global Alliance for Genomics and Health (GA4GH) Beacon standard including new Beacon v2 features. With this tool, researchers can study intra-host mutations on genomic regions of interest, or trace any variant frequency over time using raw read data. More than 200,000 SARS-CoV-2 analysed genomic data files are now available to researchers for further exploration. Ongoing COVID-19 efforts at EGA Addressing the COVID-19 pandemic is a global effort. Federated resources are necessary to support transnational deposition, access, and analysis of sensitive COVID-19 host genetics and other related data. At the same time, many countries now have emerging personalized medicine programmes which are generating data from national or regional healthcare initiatives. These data are subject to more stringent information governance than research data and often must comply with national data protection legislation. To address this need, the Federated EGA was established to serve as the primary global resource for discovery and access of sensitive human omics and associated data consented for secondary use. The Federated EGA will comprise a network of national human data repositories and will implement community standards and common interfaces. Launching Federated EGA promises to accelerate not only global research efforts to understand, diagnose, and treat COVID-19, but also to foster data reuse, enable reproducibility, and accelerate biomedical and disease research to ultimately improve human health.

  Blog providing-access-to-covid-19

• a cohort-scale multi-omic atlas of human colon organoids and matched primary tissue biopsies.

  As part of the Human Cell Atlas, we present a cohort-scale multi-omic atlas of human colon organoids and matched primary tissue biopsies. Using single-nucleus RNA and ATAC-seq, we provide a systematic assessment of inter-individual variability and organoid fidelity. We benchmark organoid quality, discovering that while organoids adapt to a regenerative state and lack specific stromal signals, they robustly preserve donor-specific properties and cellular architecture. This resource and benchmarking method facilitate the use of high-fidelity organoids for large-scale studies of human biology, population heterogeneity, and precision medicine.

  Study EGAS00001008434

• Anaplastic meingioma methylation

  Methylation of anaplastic meningiona samples

  Dataset EGAD00010001629

• Genetic Epidemiology Network of Arteriopathy (GENOA)

  The Genetic Epidemiology Network of Arteriopathy (GENOA) is one of four networks in the NHLBI Family-Blood Pressure Program (FBPP). GENOA's long-term objective is to elucidate the genetics of target organ complications of hypertension, including both atherosclerotic and arteriolosclerotic complications involving the heart, brain, kidneys, and peripheral arteries. The longitudinal GENOA Study recruited European-American and African-American sibships with at least 2 individuals with clinically diagnosed essential hypertension before age 60 years. All other members of the sibship were invited to participate regardless of their hypertension status. Participants were diagnosed with hypertension if they had either 1) a previous clinical diagnosis of hypertension by a physician with current anti-hypertensive treatment, or 2) an average systolic blood pressure ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm Hg based on the second and third readings at the time of their clinic visit. The Family Blood Pressure Program (FBPP), GENOA's parent program, 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 created a single confederation with program-wide and network-specific goals.

  Study phs001238

• Profiling the genomic landscape and evolutionary history of polyploid giant cancer cells in undifferentiated pleomorphic sarcomas

  In this study, we characterise PGCCs in ten pleomorphic sarcomas and use topographic single-cell DNA sequencing (scDNA-seq) to investigate their genomic landscape. We selected PGCCs based on their nuclear morphology, including mononucleated or multinucleated bizarre, misshapen nuclei, and analysed them at single-cell resolution. Histopathological analysis showed that PGCCs were often randomly distributed throughout the tumour and did not appear in clusters, suggesting that they arise de novo rather than through clonal expansion. scDNA-seq revealed that PGCCs originate from the dominant tumour population and exhibit extensive copy number heterogeneity, either due to subsequent or ongoing chromosomal instability. Both clonal and subclonal chromothripsis-like events were identified in PGCCs, indicating that chromothripsis is a key driver of heterogeneity in these cells and is linked to multinucleation rather than mononuclear PGCC formation.

  Dataset EGAD50000002084

• Genomics of Opioid Pharmacogenomics and Acute/Chronic Postsurgical Pain after Major Surgery in Children

  Pain management after surgery is not optimal, partly due to great interindividual variability in pain perception and coping. This can lead to persistent pain beyond the healing period and disability. Up to two-thirds of the inter-individual variability results from genetic variations in pain perception as well as response to the pain medicine. The investigators aim to identify genomic (genetic/epigenetic), psychological and drug profiles contributing to this variability. Opioids are the mainstay for treatment of postoperative pain in children. Experience dictates that opioids have narrow therapeutic indices and large inter-patient variability in response. This leads to serious side effects like respiratory depression in up to 50% of children undergoing invasive surgery, which can be fatal. It is evident that there are particular children who are more susceptible to suffering side effects and having inadequate pain relief from opioids.It is hypothesized that much of the genetic variability can be explained by gene function which is modulated by a) Single Nucleotide Polymorphisms (SNPs) in genes that encode proteins involved in pain perception, opioid transport/metabolism (pharmacokinetics), and opioid receptor signaling (pharmacodynamics); b) epigenetics which modify gene expression without structural changes to the DNA, and c) genes that influence psychological factors.The purpose of this research study is to identify factors and genes that may be associated with acute and chronic post-surgical pain, and to develop pharmacometric models for response to opioids, like morphine and hydromorphone. While children undergoing different surgeries will be recruited for acute outcomes, children undergoing spine fusion will be followed for 10-12 months for evaluation of psychological and genomic factors affecting chronic post-surgical pain, with a goal of identifying genetic and epigenetic risk models for prediction of acute and chronic post-surgical pain. Although opioids are used every day, some children have bad reactions from their use, like breathing problems, sedation, etc. The investigators want to study factors that may be associated with pain sensitivity, opioid requirements after surgery, their metabolism, efficacy and their side-effects. The investigators expect that the information obtained in this research study will help to develop effective, safer, and tailored treatment options in the future.

  Study phs002105

• The Landscape of Genetic Alterations in Hepatocellular Carcinoma, 88 matched HCC tumour/normal pairs WGS belongs to ICGC LICA-CN project

  Hepatocellular carcinoma (HCC) is the most common malignancy of the liver. Genomic analysis is conducted to identify genetic alterations in driver genes which are all druggable targets for cancer therapy. Whole genome shotgun sequencing (WGS) and the landscaple of somatic mutations in 88 paired samples from HCC patients including tumors and matched adjacent normal tissues using Illumina HiSeq 2000 platform were performed.

  Study EGAS00001002218

• Elucidation of factors involved in the progression of diabetic kidney disease

  A new concept of diabetic kidney disease has been proposed as a more comprehensive disease concept for chronic kidney disease associated with diabetes.The factors and molecular mechanisms that determine the course of diabetic nephropathy, whether it is the classic diabetic nephropathy or the rapid decliner, are unknown.In order to develop effective diagnostic and therapeutic methods for individual cases and conditions of diabetic nephropathy patients, it is necessary to elucidate the molecular mechanisms.We performed single-cell RNA sequencing and analyzed the characteristics of 3 cases of rapid decline in diabetic kidney disease.

  Study JGAS000802

• Neuroblastoma Genome-Wide Association Study (NBL-GWAS)

  Neuroblastoma is a malignancy of the developing sympathetic nervous system that most commonly affects young children and is often lethal. The etiology of this embryonal cancer is not known. We have performed a whole genome scan for association of neuroblastoma with SNP genotypes and copy number variation to discover predisposition loci. We therefore initiated a genome-wide association study (GWAS) in 2007 focused on neuroblastoma patients identified through the Children's Oncology Group (COG; 238 member institutions). Control patients for this study are children cared for at the Children's Hospital of Philadelphia (CHOP) without a diagnosis of cancer. The study was designed to collect up to 5000 neuroblastoma cases and 10,000 controls and is powered to detect common susceptibility variants in Caucasian and African American patients. Whole genome genotyping is being performed on the Illumina HH550 SNP array.

  Study phs000124

• Reliable assessment of telomere maintenance mechanisms in neuroblastoma

  Telomere maintenance mechanisms (TMM) are a hallmark of high-risk neuroblastoma, and are conferred by activation of telomerase or alternative lengthening of telomeres (ALT). However, detection of TMM is not yet part of the clinical routine, and consensus on TMM detection, especially on ALT assessment, remains to be achieved. We here propose a workflow to reliably detect TMM in neuroblastoma. We show that unambiguous classification is feasible following a stepwise approach that determines both, activation of telomerase and ALT. The workflow proposed in this study can be used in clinical routine and provides a framework to systematically and reliably determine telomere maintenance mechanisms for risk stratification and treatment allocation of neuroblastoma patients.

  Study EGAS00001006510

• WES data of central nervous system neoplasm patients

  Dataset containing 2068 WES tumor and control samples of central nervous system neoplasm patients. The data was sequenced on a Illumina NextSeq 500 using a NPHD2015A kit. The sequencing was always paired.

  Dataset EGAD00001009855

• Gabriella Miller Kids First Pediatric Research Program for Infantile Hemangiomas Associated with Multi-Organ Structural Birth Defects

  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. Infantile hemangiomas are the most common benign vascular tumor in infants, affecting 4-5% of children. Thirty percent of segmental infantile hemangiomas on the face and scalp are associated with birth defects of multiple organs. This condition is known as PHACE, an acronym for posterior fossa brain malformations, segmental facial hemangiomas, arterial anomalies, cardiac defects, eye anomalies, and sternal clefting. Genomic analysis of PHACE will inform treatment and expand knowledge about the causes of birth defects affecting the brain, arteries, heart, eye, midline development and hearing. The knowledge gained in this study will be used to drive strategies for prevention and provide critical targets for treatments for a range of birth defects and infantile hemangiomas.

  Study phs001785

• Whole genome sequencing of retinoblastoma reveals the diversity of rearrangements disrupting RB1 and uncovers a treatment related mutational signature

  Background: The development of retinoblastoma is thought to require pathological genetic changes in both alleles of the RB1 gene. However, cases exist where RB1 mutations are undetectable suggesting alternative pathways to malignancy. Methods: We applied comprehensive whole genome sequencing (WGS) and transcriptomics to sporadic retinoblastomas derived from twenty patients attending our clinic, contrasting these results to that obtained through customary clinical testing. We sought RB1 and other driver mutations, investigated mutation burden, mutational signatures and phylogenetic relatedness in one case of bilateral retinoblastoma. Results: At least one RB1 mutation was identified in all retinoblastomas. We confirmed RB1 mutations previously identified by clinical screening, identified three new RB1 mutations and provided clarity to the mechanism behind a further six mutations. Eight tumours carried structural rearrangements involving RB1 ranging from relatively simple to extremely complex rearrangement patterns, including a chromothripsis-like pattern in one tumour. Potential driver mutations included mutations in BCOR (5/20) and amplification of MYCN (2/20) and MDM4 (1/20). We show that RB1 mutations are not mutually exclusive of MYCN amplifications, and further reveal that all tumours demonstrate increased MYCN expression suggesting a universal role in retinoblastoma tumorigenesis.  Bilateral tumours obtained from one patient harboured conserved germline but divergent somatic RB1 mutations, indicating independent evolution. In-keeping with previous WGS of paediatric cancers, the mutation burden in retinoblastomas was extremely low. Mutational signature analysis showed a predominance of signatures associated with cell division and an absence of ultraviolet-related DNA damage. In a tumour exposed to chemotherapy prior to enucleation, a profound platinum-related mutational signature was observed. Conclusions: WGS provides a complete picture of the genomic landscape of retinoblastomas, allowing the discovery of mutations otherwise undetected by conventional clinical screening approaches. The presence of at least one RB1 mutation in all retinoblastomas and the relative paucity of driver mutations in other genes suggests mutations beyond RB1, MYCN and BCOR are rare. Whilst most RB1 mutations are identifiable by clinical screening, the increased resolution and ability to detect otherwise elusive rearrangements of RB1 by WGS, confirming whether they are somatic or germline, has important repercussions on clinical management and advice on recurrence risks.

  Dataset EGAD00001006431

• Dynamics of Tumor Heterogeneity from Primary to Metastatic Dissemination in Prostate Cancer

  PRO-SPeCT: PROstate cancer heterogeneity deconvolution through Single cell Profiling of Chromatin accessibility and Transcriptomic output Identifying drivers of cancer progression to guide treatment selection is hindered by limited abilities to understand tumor heterogeneity’s impact on evolution. Here, we delineated the phenotypic variability across ~300,000 prostate tumor cells collected from multiple loci in primary and matched locoregional metastases. We found inter-patient heterogeneity to be confined to malignant populations. While malignant cell populations exhibit intra-locus heterogeneity, they maintain inter-loci phenotypic similarity within a patient’s prostate gland. In addition, the intra-locus heterogeneity between malignant cell populations is paired with a common clonal architecture. Lastly, we show that malignant cell populations disseminating to locoregional lymph nodes mirror the clonal architecture and phenotypic heterogeneity observed across primary tumor loci while showcasing cell state transition toward inflammatory phenotypes. These findings provide insights into distinct measures of tumor heterogeneity, revealing diverse evolutionary paths across patients converging to common phenotypic adaptations in early prostate cancer progression.

  Study EGAS50000000524