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• Complement C1s deficiency in a male Caucasian patient with systemic lupus erythematosus: A case report

  This study involves whole genome sequencing of a 34-year-old male with a rare deficiency in complement component C1s, linked to systemic lupus erythematosus (SLE). Genomic analysis revealed two novel mutations in the C1S gene, resulting in absent C1s protein and impaired classical complement pathway function. The goal was to confirm the C1s deficiency and identify the specific mutations causing this condition.

  Study EGAS50000000707

• Germline WES of serrated polyposis syndrome

  The serrated polyposis syndrome (SPS) is a disease with a mainly unknown inherited genetic basis characterized by the presence of multiple and/or large serrated polyps in the colon and a higher associated risk for colorectal cancer (CRC). The objective of the present study was to identify new SPS/CRC germline predisposition genes by using whole-exome sequencing in two affected SPS patients from the same family.

  Study EGAS50000000765

• Analysis of tumor periphery and center-specific mutations in renal cell carcinoma

  Renal cell carcinoma (RCC) is a genomically heterogeneous tumor. In the present project, the question whether intratumoral heterogeneity follows a zonal pattern indicating spatial niches was addressed. Whole exome sequencing of 16 paired samples from tumor periphery and center revealed a number of region-specific functional SNVs and Indels. Therefore, RCCs are not composed of evenly admixed tumor cells but show topological differences in their clonal composition.

  Study EGAS00001001784

• Molecular characterization of hepatocellular carcinoma in patients with non-alcoholic steatohepatitis

  Patients with hepatocellular carcinoma (HCC) associated to non-alcoholic steatohepatitis (NASH) are increasing globally, but their molecular traits are not well characterized. Our molecular characterization revealed higher rates of ACVR2A mutations (10%) – a potential tumour suppressor, presence of a novel mutational signature (MutSig-NASH-HCC), a more relevant role of Wnt/TGF-β proliferation subclass in tumours (42%) and immunosuppressive traits in the adjacent non-tumoral tissue.

  Study EGAS00001005222

• Discriminating Th17.1 cell driven sarcoidosis-like inflammation from relapse after anti-BCMA CAR T cells in multiple myeloma

  We present a case study on sarcoidosis-like flare-up after Idecabtagen Vicleucel (Ide-cel), a BCMA targeting CAR T cell therapy, and identified a Th17.1 driven autoimmune mechanism as the biological underpinning of this phenomenon using single-cell RNA-seq analysis. Furthermore, single-cell RNA-seq allowed to discriminate between immune-mediated changes and true relapse after CAR T cell treatment.

  Study EGAS00001006133

• Study the genetic susceptibility of esophagus squamous cell carcinomas (ESCC) in high-risk area Henan Chinese

  This study utilized a genetically-enriched cohort of patients with familial ESCC from the high-risk Henan region, located near the Tai-Hang Mountain region in Northern China, to identify high penetrance ESCC predisposition genes using a comprehensive unbiased whole-exome sequencing (WES) strategy. Subsequent validate the prevalence of rare damage variants by targeted gene sequencing in a large sample size.

  Study EGAS00001003423

• Vitamin C boosts DNA demethylation in TET2 germline mutation carriers

  We recently identified a family with lymphoma predisposition where a heterozygous truncating germline mutation in TET2 segregated with nodular lymphocyte predominant Hodgkin lymphoma. In a clinical trial of one year, we investigated the effects of oral 1 g/day vitamin C supplementation on DNA methylation by analyzing genome-wide DNA methylation and gene expression patterns from the family members.

  Study EGAS00001006916

• 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

• A Microwell Platform for High-Throughput Longitudinal Phenotyping and Selective Retrieval of Organoids

  In traditional bulk culture, organoids tend to overlap, hindering the analysis of individual organoid characteristics in a high-throughput manner. Additionally, variations in the local spatial properties of the bulk matrix make it challenging to distinguish whether phenotypic differences between organoids stem from inherent cellular disparities or disparities in the microenvironment. To address these challenges, we have developed a microwell-based technique that facilitates the quantification of image-based parameters for organoids grown from single cells. Furthermore, these organoids can be easily retrieved from their respective microwells for molecular profiling. By employing a deep-learning image processing pipeline, we conducted a comprehensive assessment of various phenotypic traits in two CRISPR-engineered human gastric organoid models. This analysis encompassed growth rates, cellular movement, and apical-basal polarity. Through our investigation, we successfully identified genomic alterations associated with increased growth rate, as well as changes in accessibility and expression patterns correlated with apical-basal polarity. This novel methodology offers a valuable tool for studying organoid behavior at a single-cell level, enabling researchers to gain deeper insights into organoid biology and associated genetic modifications.

  Study phs003315

• Development of a diagnostic gene panel for Gorlin syndrome and its application to liquid biopsy

  Gorlin syndrome is an autosomal dominant, rare disease caused by mutations in PTCH1, PTCH2, and SUFU with various symptoms in multiple organs making early diagnosis challenging. In this study, we generated a Gorlin syndrome gene panel that could help to overcome the difficulties in diagnosing Gorlin syndrome using a single test. This gene panel is time- and cost-efficient and highly reliable with a high-quality score of 30, on-target ratio, and coverage depth, and could detect more mutations than whole-exome sequencing of the same patient. Although the current in silico prediction tools have a limited genetic database of gene mutations in rare hereditary diseases, five prediction tools were used to identify pathological mutations. Pathogenic gene mutations were detected not only in PTCH1 but also in PTCH2 in five out of 12 patients with Gorlin syndrome diagnosed based on clinical symptoms. Using this gene panel, we showed the same gene mutation in the patients and their asymptomatic relatives; hence, it has enabled a highly reliable genetic diagnosis of Gorlin syndrome at a low cost requiring only blood sample.

  Study JGAS000308

• Reference Exome Data for a Northern Brazilian population

  Whole exome sequencing (WES) is a popular technology widely used in the diagnosis of rare genetic diseases and provides useful variant data for analysis of complex diseases. However, there is not always adequate population-specific reference data available to assist clinical geneticists in assigning a diagnostic variant to a specific clinical condition. Here we provide a catalogue of variants called after sequencing the exomes of 45 babies from the State of Rio Grande do Nord in Brazil. Sequence data were processed using an ‘intersect-then-combine’ (ITC) approach, using GATK and SAMtools to call variants. A total of 612,761 variants were identified in at least one individual in this Brazilian Cohort, including 559,448 single nucleotide variants (SNVs) and 53,313 insertion/deletions. Of these, 58,111 overlapped with nonsynonymous (nsSNVs) or splice site (ssSNVs) SNVs in dbNSFP. As an aid to clinical diagnosis of rare diseases, we used the American College of Medicine Genetics and Genomics (ACMG) guidelines to assign pathogenic/likely pathogenic status to 439 (0.755%) of the 58,111 nsSNVs and ssSNVs. Our data set provides a useful reference point for diagnosis of rare diseases in Brazil.

  Study EGAS00001004112

• Discovery of a highly widespread bacteriophage family and its associations to metabolic syndrome gut microbiomes

  There is significant interest in altering the course of cardiometabolic disease development via the gut microbiome. Nevertheless, the highly abundant phage members of the complex gut ecosystem -which impact gut bacteria- remain understudied. Here, we characterized gut virome changes associated with metabolic syndrome (MetS), a highly prevalent clinical condition preceding cardiometabolic disease, in 196 participants with a combination of whole genome shotgun and virus like particle sequencing. MetS gut virome populations exhibited decreased richness and diversity, but larger inter-individual variation. These populations were enriched in phages infecting Bacteroidaceae and depleted in those infecting Ruminococcaeae. Differential abundance analysis identified eighteen viral clusters (VCs) as significantly associated with either MetS or healthy viromes. Among these are a MetS-associated Roseburia VC that is related to healthy control-associated Faecalibacterium and Oscillibacter VCs. Further analysis of these VCs revealed the Candidatus Heliusviridae, a highly widespread gut phage lineage found in 90+% of the participants. The identification of the temperate Ca. Heliusviridae provides a novel starting point to a better understanding of the effect that phages have on their bacterial hosts and the role that this plays in MetS

  Study EGAS00001006260

• Circulating Tumor Cell Heterogeneity in Neuroendocrine Prostate Cancer by Single Cell Copy Number Analysis

  Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that may arise de novo or develop from pre-existing prostate adenocarcinoma as a mechanism of treatment resistance. Combined loss of tumor suppressors RB1, TP53, PTEN are frequent in NEPC but also present in a subset of prostate adenocarcinomas. Most clinical and preclinical studies support a trans-differentiation process, whereby NEPC arises clonally from a prostate adenocarcinoma precursor during the course of treatment resistance. Here we highlight a case of NEPC with significant intra-patient heterogeneity observed across metastases. We further demonstrate how single-cell genomic analysis of circulating tumor cells combined with phenotypic evaluation of cellular diversity can be considered as a window into tumor heterogeneity in patients with advanced prostate cancer. We performed whole genome sequencing of circulating tumor cells (CTCs) from patients with castration resistant adenocarcinoma (n=4) and neuroendocrine prostate cancer (n=8). CTCs were collected via Epic Sciences platform and single CTC genomic data (n=215) generated via Illumina NextSeq500. 

  Study phs002462

• Discovering the Genetic Basis of Cleft Palate: CIDR

  Cleft palate (CP) is a common craniofacial structural birth defect caused by the incomplete closure of the palate (the structure separating the oral and nasal cavities), resulting in feeding, speech, and hearing problems. CP accounts for 33% of all orofacial clefts (OFCs) or approximately 1 in 1500 babies born worldwide. Although CP is commonly grouped with other types of orofacial clefts (e.g. cleft lip or cleft with cleft palate), CP is embryologically and epidemiologically distinct, suggesting a unique etiology. The risk of CP recurrence in first degree relatives is over 50-fold higher than the population risk, suggesting a strong genetic component. However, there have been a dearth of genetic studies for CP. Three well-powered genome-wide association studies and meta-analysis have revealed only two associated loci, neither of which account for a large portion of the genetic heritability in any population. The goal of this study is to elucidate the genetic architecture of CP by performing whole genome sequencing of case-parent trios in a well-phenotyped, multi-ethnic cohort. 

  Study phs002220

• CSER: Incorporating Genomics into the Clinical Care of Diverse NYC Children (NYCKidSeq)

  The NYCKidSeq program will significantly advance the implementation of genomic medicine, particularly for children, young adults and their families in Harlem and the Bronx. The study will assess the clinical utility of genomic medicine in three broad areas of pediatric disorders, while engaging a range of providers and community advisors to overcome the well-documented barriers to inclusion of underserved and underrepresented populations in genomic research. The study will also include testing, analyzing, and implementing a novel communication tool, Genomic Understanding, Information and Awareness (GUÍA), to facilitate the return of genomic test results. The use of GUÍA will enhance the understanding of these genomic testing results by families, patients, and care providers at all levels of expertise, in two health systems. Healthcare system leadership will be engaged to provide insights into their readiness for genomic implementation. Overall, the NYCKidSeq program will inform the genomics and clinical communities about how to implement genomic medicine in a diverse population in a clinically useful, technologically savvy, culturally sensitive, and ethically sound manner.

  Study phs002337

• ARRA - NHLBI Lung Cohorts Sequencing Project: Genetic modifiers of

  The major goal of this project is to apply second generation resequencing technology to identify disease causing variants influencing pediatric and adult lung diseases in a collection of two longitudinal population cohorts of cystic fibrosis patients that have been well characterized for a comprehensive set of clinical traits. In Phase I, exome sequencing was performed on 43 cystic fibrosis patients with early Pa infection and 48 cystic fibrosis patients with late Pa infection to identify variants influencing the time to onset of Pa infection. In Phase II, additional exomes were added to the study, to reach a total of 91 individuals with early Pa infection and 96 with late Pa infection. The majority of the 340 subjects of Phase II do not have a Pa infection phenotype, but instead have a pulmonary function phenotype (121 severe vs. 124 mild impairment) as determined by the survival corrected Kulich FEV percentile of Corey et al. A small minority have intermediate phenotypes and/or show severe decline in lung function during childhood.

  Study phs000254

• The Cardiopulmonary Effects of Particulate Exposure

  The study was initially designed as a longitudinal cohort study of cardiovascular effects of particulate exposure. Participants were boilermaker construction workers who were exposed to particulate matter (PM) component (e.g. a focus on metal constituents) while performing welding, grinding or cutting work in the welding plants. Participants were followed up approximately half a year for a non-work day and a work day from 1999 to 2012, and blood, urine, blood pressure, as well as real-time PM2.5 samples were collected from each participant. In this specific study, we conducted epigenome-wide DNA methylation profiling through Center for Inherited Disease Research (CIDR) services using Illumina Infinium HumanMethylation450, which will give us more compete epigenome-wide coverage. Genome-wide DNA methylation was carried out on paired samples pre- and post-work shift at a welding apprentice school. With transcriptomic and metabolomic data already generated from the same panel study, we will be able to conduct integrative analysis to gain insights into mechanisms of gene-metal interactions and maximize the probability of finding genes functionally relevant to PM-induced adverse cardiovascular outcomes.

  Study phs000968

• Study of Tumor Recurrence Related to the Expression of the PAX3-FOXO1 Oncogenic Transcription Factor in Fusion-Positive Rhabdomyosarcoma

  Alveolar rhabdomyosarcoma (ARMS) is a highly aggressive pediatric soft tissue cancer characterized by a recurrent 2;13 chromosome translocation. This translocation generates a PAX3-FOXO1 (P3F) fusion gene, which encodes a chimeric transcription factor with oncogenic activity. Using a human myoblast system that models targeted therapy directed against P3F, we demonstrated that the expression of the fibroblast growth factor 8 (FGF8), a direct transcriptional target of P3F, is necessary and sufficient for PAX3-FOXO1-independent tumor recurrence in addition to be required for the tumorigenic activity of primary tumors expressing P3F. In addition, we showed that FGF8 is expressed in human rhabdomyosarcoma cell lines that express P3F. We also demonstrated that FGF8 contributes to their proliferation and transformation in vitro, and is sufficient to maintain their oncogenicity after the loss of P3F expression. We suggest that targeting the expression of the PAX3-FOXO1 transcription factor can generate resistance and recommend that additional anticipated therapeutic approaches, such as targeting FGF8 pathway, may avoid this resistance mechanism.

  Study phs002344

• Investigating Genetics in Suspected Congenital Syndromes

  We employed forward and reverse genetics to identify individuals with heterozygous JAK1 variants associated with autoimmune and inflammatory diseases. We first recruited six unrelated probands and seven affected family members presenting with a range of autoimmune and inflammatory conditions. Whole exome sequencing revealed 4 different variants spanning all domains of the JAK1 protein: FERM domain (chr1: 64873438-G>A; c.415C>T; p.E139K), SH2 domain (chr1: 64855641-G>A; c.1516C>T; p.R506C), pseudokinase domain (chr1: 64845529-C>T; c.2099G>A; p.S700N, and kinase domain (chr1: 64838479-C>T; c.2953G>A; p.V985I). We then performed a systematic review of electronic health records of the BioME BioBank database and identified 43 additional individuals with at least one of these JAK1 variants. Comparing variant-positive and variant-negative individuals, our study revealed increased occurrences of autoimmunity, atopy, colitis, and dermatitis in patients harboring these JAK1 gain-of-function variants. We have deposited in dbGaP the whole exome sequencing files of the 43 patients identified in the BioME biobank, as well as their phenotype information.

  Study phs003453

• SNP array files, IDAT files, from 34 members of a Family with a high prevalence of psychosis

  We investigated the genetic causes of major mental disorders (MMDs) including schizophrenia, bipolar disorder I, major depressive disorder, and attention deficit hyperactive disorder, in a large family pedigree from Alpujarras, South of Spain, a region with a high prevalence of psychotic disorders. We applied a systematic genomic approach based on karyotyping (N=4), genotyping by genome-wide SNP array (N=33), whole-exome sequencing (N=4), and whole-genome sequencing (N=12). We performed genome-wide linkage analysis, family-based association analysis, and polygenic risk score estimates. Significant linkage was obtained at chromosome 9 (9q33.1-33.2, LOD score= 4.11), a suggestive region that contains five candidate genes ASTN2, BRINP1, C5, TLR4, and TRIM32, previously associated to MMDs. Comprehensive analysis associated the MMD phenotype with genes of the immune system with dual brain functions. Moreover, the psychotic phenotype was enriched for genes involved in synapsis. These results should be considered once studying the genetics of psychiatric disorders in other families, especially the ones from the same region, since founder effects may be related to the high prevalence.

  Study EGAS00001004592

• Long-read sequencing of diagnosis and post-therapy medulloblastoma reveals complex rearrangement patterns and epigenetic signatures

  Cancer genomes harbor a broad spectrum of structural variants (SV) driving tumorigenesis, a relevant subset of which are likely to escape discovery in short reads. We employed Oxford Nanopore Technologies (ONT) sequencing in a paired diagnostic and post-therapy medulloblastoma to unravel the haplotype-resolved somatic genetic and epigenetic landscape. We assemble complex rearrangements and such associated with telomeric sequences, including a 1.55 Megabasepair chromothripsis event. We uncover a complex SV pattern termed "templated insertion thread", characterized by short (mostly less than 1kb) insertions showing prevalent self-concatenation into highly amplified structures of up to 50kbp in size. Templated insertion threads occur in 3% of cancers, with a prevalence ranging to 74% in liposarcoma, and frequent colocalization with chromothripsis. We also perform long-read based methylome profiling and discover allele-specific methylation (ASM) effects, complex rearrangements exhibiting differential methylation, and differential promoter methylation in seven cancer-driver genes. Our study shows the potential of long-read sequencing in cancer.

  Study EGAS00001006576

• Uveal melanoma patient with germline MBD4 nonsense mutation

  There is currently no effective treatment for metastasised uveal melanoma (UM). Recently, it was reported that a UM patient was responsive to checkpoint inhibitor (CI) treatment, due to a high tumour mutation burden correlated with a germline loss-of-function MBD4 mutation. Here, we report on another UM patient who carried an MBD4 germline nonsense variant (p.Leu563Ter) and her tumour showed a 5-fold higher than average mutation burden. We confirmed the association between germline loss-of-function variant in MBD4 and CI response. The patient experienced stable disease (10 months) and survived two years with metastatic disease, which is twice as long as median survival. Additionally, the frequency of MBD4 loss-of-function variants in reported UM cohorts was >20 times higher than in an aggregated population genome database (P < 5x10-5), implying a potential role as UM predisposition gene. These findings provide a strong basis for the inclusion of MBD4 in screening of potential UM-prone families as well as stratification of immunotherapy.

  Study EGAS00001003362

• Genetic_mechanisms_of_resistance_to_chemotherapy_in_breast_cancer

  Resistance towards chemotherapy is one of the main causes of treatment failure and deathamong breast cancer patients.The main objective of this project is to identify genetic mechanisms causing some breastcancer patients not to respond to a particluar type of chemotherapy (epirubicin) while otherpatients respond very well to the same treatment.In the project we will perform genome / exome sequencing of a selection of breast cancerpatients (n=30). These patients are drawn from a cohort where all patients have recievedtreatment with epirubicin monotherapy before surgical removal of a locally advanced breasttumour, and where all patients have been subjected to objective evaluation of the response tothe therapy.Subsequent to sequencing, we will analyse the data and compare with the clinical data foreach patient (object response to therapy). The main aim being to identify mutations that areassociated with resistance to epirubicin.Identification of mutations with strong predictive value, may have a direct impact on cancertreatment since it opens the possibility for genetic testing of a tumour, and desicion on whichdrug is likely to work best, prior to treatment start.

  Study EGAS00001000276

• Reference exome data for Australian Aboriginal populations to support health-based research

  Whole exome sequencing (WES) is a popular and successful technology which is widely used in both research and clinical settings. However, there is a paucity of reference data for Aboriginal Australians to underpin the translation of health-based genomic research. Here we provide a catalogue of variants called after sequencing the exomes of 50 Aboriginal individuals from the Northern Territory (NT) of Australia and compare these to 72 previously published exomes from a Western Australian (WA) population of Martu origin. Sequence data for both NT and WA samples were processed using an ‘intersect-then-combine’ (ITC) approach, using GATK and SAMtools to call variants. A total of 289,829 variants were identified in at least one individual in the NT cohort and 248,374 variants in at least one individual in the WA cohort. Of these, 166,719 variants were present in both cohorts, whilst 123,110 variants were private to the NT cohort and 81,655 were private to the WA cohort. Our data set provides a useful reference point for genomic studies on Aboriginal Australians.

  Study EGAS00001003745

• Long-read sequencing of diagnosis and post-therapy medulloblastoma reveals complex rearrangement patterns and epigenetic signatures (Hipo_021)

  Cancer genomes harbor a broad spectrum of structural variants (SV) driving tumorigenesis, a relevant subset of which escape discovery using short-read sequencing. We employed Oxford Nanopore Technologies (ONT) long-read sequencing in a paired diagnostic and post- therapy medulloblastoma to unravel the haplotype-resolved somatic genetic and epigenetic landscape. We assemble complex rearrangements and such associated with telomeric sequences, including a 1.55 Megabasepair chromothripsis event. We uncover a complex SV pattern termed ‘templated insertion thread’ (TI thread), characterized by short (mostly <1kb) insertions showing prevalent self-concatenation into highly amplified structures of up to 50kbp in size. TI threads occur in 3% of cancers, with a prevalence ranging to 74% in liposarcoma, and frequent colocalization with chromothripsis. We also perform long-read based methylome profiling and discover allele-specific methylation (ASM) effects, complex rearrangements exhibiting differential methylation, and differential promoter methylation in cancer-driver genes. Our study shows the advantage of long-read sequencing in the discovery and characterization of complex somatic rearrangements.

  Study EGAS00001006629

• Synthetic - FEGA Sweden Heilsa synthetic dataset December 2023

  Synthetic - This submission contains a subset of a synthetic dataset derived from the project Heilsa Tryggvedottir - a Nordic collaboration on sharing sensitive human data. Heilsa Tryggvedottir is funded by the Nordic e-Infrastructure Collaboration (NeIC), the ELIXIR nodes of Finland, Norway, and Sweden, Computerome in Denmark, and the Estonian Scientific Computing Infrastructure (ETAIS). In the synthetic data creation process, it was attempted to strike a fine balance between the usability of the datasets (e.g. technical FEGA development, testing, user training, and basic bioinformatics) and compliance with GDPR. File names and file content (e.g. headers in fastq) are anonymized. Moreover, the X, Y, and mitochondrial sequences have been discarded from the original data since these data can be used for maternal, paternal, or ethnic origin tracing. The dataset does not follow natural haplotype distribution (inherent to imputation panels). The only inputs derived from real sequence data are variant distribution density per chromosome and learning sequencing error models. The synthetic dataset consists of two fastq files, a cram file, a vcf file, and two index files.

  Study EGAS50000000086

• A Phase II Clinical Trial of the PARP Inhibitor Talazoparib in BRCA1 and BRCA2 Wild-Type Patients

  The Talazoparib Beyond BRCA (TBB), a phase II proof-of-concept clinical trial, was designed to test the efficacy of talazoparib, a potent, orally bioavailable PARP inhibitor, with an established Phase II recommended dose, in the treatment of advanced BRCA wildtype (WT), HER2-negative breast cancer and other solid tumors with homologous recombination (HR) deficiency. Eligible patients had advanced HER2-negative breast cancer or other solid tumors with a germline or somatic mutation in a gene linked to the HR pathway. Patients identified as harboring a deleterious or suspected deleterious germline or somatic mutation in the HR pathway were treated with single agent talazoparib until disease progression. Primary and metastatic tumor samples were sequenced with panel sequencing and exome sequencing to detect commonly mutated genes and those associated with DNA repair deficiency. In addition, ctDNA was sequenced at baseline and progression. Fastq files for tumor and ctDNA sequencing are deposited. 

  Study phs002803

• Transcriptome sequencing across a prostate cancer cohort identifies PCAT-1, an unannotated lincRNA implicated in disease progression

  Noncoding RNAs (ncRNAs) are emerging as key molecules in human cancer, with the potential to serve as novel markers of disease and to reveal uncharacterized aspects of tumor biology. Here we discover 121 unannotated prostate cancer-associated ncRNA transcripts (PCATs) by ab initio assembly of high-throughput sequencing of polyA+ RNA (RNA-Seq) from a cohort of 102 prostate tissues and cells lines. We characterized one ncRNA, PCAT-1, as a prostate-specific regulator of cell proliferation and show that it is a target of the polycomb repressive complex 2 (PRC2). We further found that patterns of PCAT-1 and PRC2 expression stratified patient tissues into molecular subtypes distinguished by expression signatures of PCAT-1-repressed target genes. Taken together, our findings suggest that PCAT-1 is a transcriptional repressor implicated in a subset of prostate cancer patients. These findings establish the utility of RNA-Seq to identify disease-associated ncRNAs that may improve the stratification of cancer subtypes.

  Study phs000443

• A Translational, Pharmacodynamic and Pharmacokinetic Phase IB Clinical Study of Everolimus in Resectable Non-Small Cell Lung Cancer

  This phase IB clinical trial studied the pharmacodynamic changes induced by everolimus in patients with previously untreated, resectable non small cell lung cancer. Using a combination of in vivo and ex vivo assessments with FDG PET, immunohistochemistry and genomic assays, evidence of mTOR pathway perturbation was assessed in patients treated with everolimus, an allosteric mTOR inhibitor. Untreated patients served as controls for comparison. Key results from this work include a dose-dependent biologic effect of everolimus, signal of activity in RAS mutant tumors as well as near complete metabolic and pathologic response in a case of sarcomatoid lung cancer. These findings represent novel translational insights that can guide future development of mTOR inhibitors in lung cancer and other tumor types. Additionally, metabolic response and anatomic tumor shrinkage observed in a significant proportion of patients following a short of duration of therapy with everolimus suggests potential clinical utility of this agent in carefully-selected lung cancer patients.

  Study phs000829

• Kbtbd13 knock-down restores muscle function in a human-based mouse model of nemaline myopathy type 6

  Nemaline myopathy type 6 (NEM6) is caused by pathogenic variants in KBTBD13. Patients experience muscle weakness, excessive fatigue and impaired muscle relaxation which significantly impact their daily activities. NEM6 pathophysiology consist of abnormal protein aggregation in muscle cells and a predominance of slow-twitch myofibers, and most patients carry the Dutch founder variant in KBTBD13 (NP_001094832.1: p.Arg408Cys, referred to as KBTBD13R408C). Currently, no specific therapy is available. Here, we used a KBTBD13R408C knock-in mouse model and aimed to identify the molecular changes driving disease pathogenesis and to define a therapeutic window to test a therapeutic intervention. We revealed that the mouse model closely phenocopies the human phenotype at a morphological, functional, and transcriptional level and that the p.Arg408Cys variant causes mis-localization of KBTBD13 within the muscle sarcomere. Our natural history data in the Kbtbd13(R408C) mouse model showed that disease onset occurs between 1-3 months and plateaus by 9 months with little progression at 18 months.

  Study EGAS50000001678

• DONSON encodes a novel replication fork protection factor mutated in microcephalic dwarfism.

  To ensure efficient genome duplication, cells have evolved a multitude of factors that promote unperturbed DNA replication, and protect, repair and restart damaged forks. Here we identify DONSON as a novel fork protection factor, and report biallelic DONSON mutations in 29 individuals with microcephalic dwarfism. We demonstrate that DONSON is a component of the replisome that stabilises forks during normal genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATR-dependent signalling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity, and potentiating chromosomal instability. Hypomorphic mutations substantially reduce DONSON protein levels and impair fork stability in patient cells, consistent with defective DNA replication underlying the disease phenotype. In summary, we identify mutations in DONSON as a common cause of microcephalic dwarfism, and establish DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability.

  Study EGAS00001002224

• Human induced pluripotent stem cells display a similar mutation burden as embryonic pluripotent cells in vivo

  Induced pluripotent stem cells (iPSCs) hold great promise for regenerative medicine, but genetic instability is a major concern. Embryonic pluripotent cells also accumulate mutations during early development, but how this relates to the mutation burden in iPSCs remains unknown. Here, we directly compared the mutation burden of cultured iPSCs with their isogenic embryonic cells during human embryogenesis. We generated developmental lineage trees of human fetuses by phylogenetic inference from somatic mutations in the genomes of multiple stem cells, which were derived from different germ layers. Using this approach, we characterized the mutations acquired pre-gastrulation and found a rate of 1.65 mutations per cell division. When cultured in hypoxic conditions, iPSCs generated from fetal stem cells of the assessed fetuses displayed a similar mutation rate and spectrum. Our results show that iPSCs maintain a genomic integrity during culture at a similar degree as their pluripotent counterparts do in vivo.

  Study EGAS00001005939

• Systematic kinase inhibitor profiling identifies CDK9 as a synthetic lethal target in NUT midline carcinoma

  Kinase inhibitors represent the backbone of targeted cancer therapy, yet only a limited number of oncogenic drivers are directly druggable. By interrogating the activity of 1,505 kinase inhibitors we found that BRD4-NUT-rearranged NUT midline carcinoma (NMC) cells are specifically killed by CDK9 inhibition (CDK9i) and exhibit a unique dependency on CDK9 and Cyclin-T1 expression. We show that CDK9i leads to robust induction of apoptosis and of markers of DNA damage response in NMC cells. While both CDK9i and bromodomain inhibition over time result in reduced Myc protein expression, only bromodomain inhibition induces cell differentiation and a p21-induced cell cycle arrest in these cells. Finally, RNA-Seq and ChIP-based analyses reveal a BRD4-NUT specific CDK9i-induced perturbation of transcriptional elongation. Thus, our data provide a mechanistic basis for the genotype-dependent vulnerability of NUT midline carcinoma cells to CDK9i that may be of relevance for the development of targeted therapies for NMC patients.

  Study EGAS00001002588

• The genomic landscape of cutaneous squamous cell carcinoma from immunosuppressed and immunocompetent patients reveals common drivers and a novel mutational signature associated with chronic azathioprine exposure

  Cutaneous squamous cell carcinoma (cSCC) has a high tumour mutational burden (50 mutations per megabase DNA pair). Combining whole exome analyses from 40 primary cSCC tumours, comprising 20 well differentiated and 20 moderately/poorly differentiated tumours, with accompanying clinical data from a longitudinal study of immunosuppressed and immunocompetent patients, coupled with integration of independent gene expression studies has allowed the identification of commonly mutated genes and altered pathways and processes. Mutational signature analysis revealed the presence of a novel signature (signature 32), which was found exclusively in the tumours from immunosuppressed patients who had been exposed to azathioprine. Characterisation of a panel of 15 keratinocyte cancer cell lines derived from tumours from immunocompetent and immunosuppressed patients reveals that they accurately reflect the mutational signatures and genomic alterations of primary tumours and provide a resource for the validation of tumour drivers and therapeutic targets.

  Study EGAS00001002612

• Hereditary Cancer Diagnostics with I2HCP gene panel

  Germline blood DNA sequencing data generated in routine diagnostics of hereditary cancer using the I2HCP gene panel (~135 genes). There are 130 samples sequenced in a MiSeq machine and 108 sequenced in a HiSeq machine. There is a partial overlap between those two sets, meaning that some samples were sequenced in both machines. There is a strong enrichment in samples with copy-number variants (CNV), both single- and multi-exon, since this dataset was compiled for a benchmarking effort of CNV calling tools for genetic diagnostics.

  Dataset EGAD00001006171

• Single-Cell DNA Methylation Profiling via scTAMseq

  This dataset comprises single-cell DNA methylation and nuclear genotyping profiles of 7 total bone marrow aspirates (donors A.1-A.7) and 5 CD34+-enriched bone marrow samples (donors B.1-B.5) generated using the scTAMseq protocol. Sequencing was performed on the Mission Bio Tapestri platform, targeting a panel of 448 CpGs to assess epigenetic patterns and We also included 147 genomic regions commonly mutated in clonal hematopoiesis and 20 regions targeting chromosome Y. Samples B.1 & B.5, B.2 & B.4 and A.2 & A.5 were, in pairs, multiplexed into single tapestri lanes.

  Dataset EGAD00001015498

• SU2C-MARK Lung Cancer Consortium - Checkpoint Blockade Response Project

  Immune checkpoint inhibitors have become a critical part of the armamentarium against advanced Non-Small Cell Lung Cancer (NSCLC). While early studies have identified Tumor Mutation Burden (TMB) and PD-L1 staining as important biomarkers of response, they remain imperfect predictors. Here we describe a multi-institutional effort as part of the SU2C-MARK Lung Cancer Consortium in which Whole Exome Sequencing (WES) - and in select cases, RNA sequencing – was performed on a large collection of NSCLC samples prior to immune checkpoint blockade therapy, along with matched clinical response data following therapy. (Profiling of a small number of on- or post-treatment samples was also performed.) We anticipate this dataset to be of high value for the development of a deep understanding of the molecular determinants of immune checkpoint blockade response as well as the discovery of novel biomarkers.

  Study phs002822

• Transcriptome of 2-Hydroxypropyl-Beta-Cyclodextrin Treatment in Niemann-Pick Disease Type C1

  Niemann-Pick type C (NPC) disease is a rare and fatal lysosomal storage disorder. Classically, children with NPC demonstrate neurological dysfunction with cerebellar ataxia, dysarthria, seizures, vertical gaze palsy, motor impairment, dysphagia, psychotic episodes, and progressive dementia. In general, adolescent and adult onset forms have a more insidious onset and slower progression. As part of a multi-omics approach to address the genetic architecture of NPC1 disease, we have recently completed a transcriptome analysis using 43 primary NPC1 patient-derived fibroblasts from an NIH-cohort study (NCT00344331) where extensive clinical data has been obtained regarding the natural history of the disease. Initial transcriptome analysis of this dataset demonstrated a set of 485 genes that are significantly upregulated in patient samples and subsequently downregulated in response to 2-hydroxypropyl-beta-cyclodextrin treatment. 

  Study phs002392

• Validation of Gene Array to Predict Bacterial Co-infection In Adults Hospitalized with Viral Lower Respiratory Tract Infections (LRTI)

  Accurate tests for microbiologic diagnosis of lower respiratory tract infections (LRTI) are needed. Gene expression profiling of whole blood represents a powerful new approach for analysis of the host response during respiratory infection that can be used to supplement pathogen detection testing. Using qPCR, we prospectively validated the differential expression of 10 genes previously shown to discriminate bacterial and non-bacterial LRTI confirming the utility of this approach. In addition, a novel approach using RNAseq analysis identified 141 genes differentially expressed in LRTI subjects with bacterial infection. Using "pathway-informed" dimension reduction, we identified a novel 11 gene set (selected from lymphocyte, α-linoleic acid metabolism, and IGF regulation pathways) and demonstrated a predictive accuracy for bacterial LRTI (nested CV-AUC=0.87). RNAseq represents a new and an unbiased tool to evaluate host gene expression for the diagnosis of LRTI.

  Study phs001248

• The Nurses' Health Study (NHS) GWAS of Mammographic Density

  The Nurses' Health Study is an on-going prospective cohort study of women that was initiated in 1976. This specific study was part of a larger study to advance our knowledge of breast cancer etiology, expand the current knowledge of mammographic density, and clarify the relationship between mammographic density and breast cancer risk. We conducted a nested case control study of breast cancer among women who provided a blood sample. We then targeted our mammogram collection to participants that were selected as part of this nested case-control study (i.e. those who had provided a blood sample). The mammogram closest to the date of blood draw (~1989-1990) was used. We assessed mammographic breast density from digitized film images using a computer assisted thresholding method (Cumulus). The women in this study were genotyped using the Illumina Omni Express Platform.

  Study phs000975

• Methylation Profiles of Cell-Free DNA Using Nanopore Sequencing

  Epigenetic characterization of cell-free DNA (cfDNA) is an emerging approach for detecting and characterizing diseases such as cancer. We developed a strategy using nanopore-based single-molecule sequencing to measure cfDNA methylomes. This approach generated up to hundreds of millions of reads for a single cfDNA sample from cancer patients, an order of magnitude improvement over existing nanopore sequencing methods. We developed a single-molecule classifier to determine whether individual reads originated from a tumor or immune cells. Leveraging methylomes of matched tumors and immune cells, we characterized cfDNA methylomes of cancer patients for longitudinal monitoring during treatment.Control subjects consist of healthy individuals without a positive diagnosis of cancer. cfDNA was obtained through purification of plasma from blood draws. Genomic DNA (gDNA) was derived from extraction of primary tumor tissue or from leukocytes from blood draws.

  Study phs002950

• Whole Genome and Exon Capture Sequencing of Bladder Cancers

  One primary bladder cancer and paired peripheral blood sample were subjected to whole genome sequencing on an Illumina HiSeq 2000 platform. This technology was utilized to investigate the genetic basis of a durable remission of metastatic bladder cancer in a patient treated with everolimus, a drug that inhibits the mTOR (mammalian target of rapamycin) signaling pathway. Among the somatic mutations found was a loss-of-function mutation in TSC1 (Tuberous Sclerosis Complex 1), a regulator of mTOR pathway activation. Targeted sequencing using an exon capture and sequencing assay was performed on 13 tumors derived from patients on the same everolimus trial as the index patient and the sequencing data from these tumors is included. TSC1 mutation status was correlated with response to everolimus. The index patient responder tumor and peripheral blood DNA were also subjected to exon capture and sequencing.

  Study phs000535

• Efficacy of Ustekinumab Followed by Abatacept for the Treatment of Psoriasis Vulgaris (PAUSE)

  Psoriasis is a chronic immune disease of the skin and joints that affects about 2% of the population. The most common form of psoriasis is plaque psoriasis, also called psoriasis vulgaris. A variety of drugs, including biologics, are available for treatment of moderate to severe psoriasis. When biologic agents are stopped, psoriasis can return (relapse) and often requires the biologic to be restarted and continued. No treatment program has been identified to prevent relapse of psoriasis. The study design has a lead-in period of weight-based ustekinumab treatment, with all participants receiving either 45 mg ustekinumab ( 100 kg) administered subcutaneously at weeks 0 and 4. At week 12, participants will be assessed for a Psoriasis Area and Severity Index (PASI) 75 response to ustekinumab. Participants who do not achieve a PASI 75 score will be discontinued from the investigation and permitted to seek standard therapy.

  Study phs003395

• The Prostate, Lung, Colon, Ovary Screening Trial (PLCO)

  The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial is a large population-based randomized trial designed and sponsored by the National Cancer Institute (NCI) to determine the effects of screening on cancer-related mortality and secondary endpoints in over 150,000 men and women aged 55 to 74. The screening component of the trial was completed in 2006. However, participants have been under follow-up for cancer incidence and mortality since that time. In addition, PLCO included a large biological sample biorepository which has served as a unique resource for cancer research, particularly for etiologic and early-marker studies. As part of these efforts, PLCO has been used for a large number of genome-wide association and exome sequencing studies for different types of cancer. Recently, a blood DNA methylation analysis was conducted in annexes case-controls study of breast cancer.

  Study phs001286

• A Comprehensive Catalogue of Somatic Mutations from a Human Cancer Genome

  We have carried out complete sequencing of the genome of the human male maligant melanoma cell line COLO-829 using the Illumina Genome Analyzer II. We generated a sequencing library with a median insert size of ~200 bp following random fragmentation and gel fractionation of the genomic DNA. We sequenced 75 bases from both ends of these templates to cover the COLO-829 genome to an average depth of more than 40x. We have carried out purity-filtering (PF) to remove mixed reads, where two or more different template molecules are close enough on the surface of the flow-cell to form a mixed or overlapping cluster. No other filtering of the data has been carried out prior to submission. We have also submitted sequence data for a lymphoblastoid control cell line COLO-829BL from the same individual.

  Study EGAS00000000052

• RNAseq_of_healthy_mesothelial_cells_and_primary_mesothelioma_cell_lines

  Mesothelioma is a rare and aggressive cancer associated with previous exposure to asbestos. Currently there are no effective treatments for mesothelioma and majority of patients will die within a year after diagnosis. Although a large number of preclinical and clinical trials assessed the efficacy of various therapuetic modes, including anti-angiogenic therapies, immunotherapy, antibody-drug conjugates and oncolytic viruses, none of the tested molecules entered the clinic. Thus, to better understand what drives mesothelioma carcinogenesis and to identify novel targets for therapy, in this project we aim at performing a comprehensive transcriptomic analysis of heathy mesothelial cells and a panel of mesothelioma cells lines. Primary mesothelial cell lines were established in prof. Marciniak lab from human pleural specimens, while primary mesothelioma cell lines were obtained from MesobanK. Both models constitute low passage cell lines and therefore should closely represent genetics of the original tissue.

  Study EGAS00001005728

• CD49f single-cell methylomes

  Single-cell DNA methylation has emerged as a powerful tool to study molecular heterogeneity within cellular populations. We report the development of a bisulfite based whole genome protocol suitable for use on single index sorted primary mammalian cells. Application of this protocol to human hematopoietic stem cells provided quantitative DNA methylation measurements of up to 5.7 million CpGs in a single cell. Analysis of cis CpG methylation states in single cells revealed a loss of concordance beyond 2kb, which supported the development of a new analytical framework (PDclust) for single-cell DNA methylation datasets that considers heterogeneity of methylation states at single CpG resolution. PDclust identified epigenetically distinct subpopulations within highly purified and functionally defined human stem cell populations. In silico merging of the methylation states from the single cells allowed us to ascribe function to these epigenetically distinct subpopulations on the basis of their epigenetic states.

  Study EGAS00001002789

• Molecular and Clonal Evolution in Recurrent Metastatic Gliosarcoma

  We present a rare case of a 37-year-old woman who was initially diagnosed with IDH wild-type gliosarcoma in the frontal lobe and later developed two local recurrences and extracranial metastases to the vertebral and pelvic bones. In order to understand the clonal relationships between the four tumor instances and the origin of metastasis, we performed whole genome sequencing of the intracranial tumors and the tumor located in the right iliac bone. Mutational and copy number profile comparisons of the metastatic to intracranial tumors highlighted a high similarity in molecular profile, but contrasting evidence regarding the origin of the metastasis. Subclonal reconstruction suggested a parallel evolution of the recurrent tumors, and that the metastatic tumor was largely derived from the first recurrence. We conclude that metastasis in glioma can be a late event in tumorigenesis.

  Study EGAS00001004076

• Germline MBD4 Mutations and Predisposition to Uveal Melanoma

  Uveal melanoma (UM) arises from malignant transformation of melanocytes from the uveal tract. This rare tumor has a poor outcome with frequent liver metastases and primary resistance to treatment1. The only strong predisposing condition for UM is the BAP1 tumor predisposition syndrome due to germline BAP1 deleterious mutations. UMs are generally characterized by a very low tumor mutation burden (TMB). However, some UMs display a high level of CpG to TpG mutations associated with MBD4 inactivation. Here, we explored the incidence of germline MBD4 variants in a consecutive series of 1, 099 primary UMs, and identified 8 deleterious MBD4 mutations, an aprox 10-fold increased incidence compared with the general population. These mutations were associated with a high TMB in tested UMs. We thus demonstrated that MBD4 is the second major predisposing gene for UM.

  Study EGAS00001003941

• Identification of four new susceptibility loci for testicular germ cell tumour, including variants near GAB2, GSPT1 and ZFPM1

  Genome wide association studies (GWAS) have identified multiple risk loci for testicular germ cell tumour (TGCT), revealing a polygenic model of disease susceptibility strongly influenced by common variation. To identify further SNPs associated with TGCT we conducted a multistage GWAS with a combined dataset of >25,000 individuals (6,059 cases and 19,094 controls). We identified new risk loci for TGCT at 3q23 (rs11705932, TFDP2, P = 1.5 x 10-9), 11q14.1 (rs7107174, GAB2, P = 9.7 x 10-11), 16p13.13 (rs4561483, GSPT1, P = 1.6 x 10-8) and 16q24.2 (rs55637647, ZFPM1, P = 3.4 x 10-9). We additionally present detailed functional analysis of these loci, identifying a statistically significant relationship between rs4561483 risk genotype and increased GSPT1 expression in TGCT patient samples. These findings provide additional support for a polygenic model of TGCT risk and further insight into the biological basis of disease development.

  Study EGAS00001001302