12277 results for ""statistically+reactive"+taxa+in+microbial+community"

in 34.72 milliseconds.

• Genome-wide discovery of somatic coding and regulatory variants in Diffuse Large B-cell Lymphoma

  Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer originating from mature B-cells. Prognosis is strongly associated with molecular subgroup, although the driver mutations that distinguish the two main subgroups remain poorly defined. Through an integrative analysis of whole genomes, exomes, and transcriptomes, we have uncovered genes and non-coding loci that are commonly mutated in DLBCL. Our analysis has identified novel cis-regulatory sites, and implicates recurrent mutations in the 3'UTR of NFKBIZ as a novel mechanism of oncogene deregulation and NFκB pathway activation in the activated B-cell (ABC) subgroup. Small amplifications associated with over-expression of FCGR2B (the Fcγ receptor protein IIB), primarily in the germinal centre B-cell (GCB) subgroup, correlate with poor patient outcomes suggestive of a novel oncogene. These results expand the list of subgroup driver mutations that may facilitate implementation of improved diagnostic assays and could offer new avenues for the development of targeted therapeutics.

  Study EGAS00001002936

• A molecular signature for IL-10-producing Th1 cells in protozoan parasitic diseases

  Control of the intracellular parasites that cause malaria and visceral leishmaniasis (VL) is dependent on the generation of pro-inflammatory, IFNγ+ Tbet+ CD4+ T (Th1) cells by infected hosts. Immunoregulatory IL-10 produced by Th1 cells serves to mitigate subsequent inflammation and related disease pathology. However, these IL-10-producing Th1 (Tr1) cells can also not only promote parasite persistence, but may impair immunity to re-infection and potential vaccine efficacy. Here, we identify molecular and phenotypic signatures that distinguish Th1 cells from Tr1 cells in both experimental VL, caused by infection of C57BL/6 mice with the human parasite Leishmania donovani, and in Plasmodium falciparum-infected humans participating in controlled human malaria infection (CHMI) studies. Such characterisations allow for the better understanding of Tr1 cell development and function in the context of these parasitic diseases, and for the identification of targets for immune modulation to improve anti-parasitic immunity.

  Study EGAS00001004454

• Dissecting features of epigenetic variants underlying cardiometabolic risk using full-resolution epigenome profiling in regulatory elements

  Sparse profiling of CpG methylation in blood by microarrays have identified epigenetic links to common diseases. We apply methylC-capture sequencing (MCC-Seq) in a clinical population of ~200 adipose tissue and matched blood samples (Ntotal ~400), providing high-resolution methylation profiling (>1.3M CpGs) at regulatory elements. We link methylation to cardiometabolic risk through associations to circulating plasma lipid levels and identify lipid-associated CpGs with unique localization patterns in regulatory elements. We show distinct features of tissue-specific versus tissue-independent lipid-linked regulatory regions by contrasting with parallel assessments in ~800 independent adipose tissue and blood samples from the general population. We follow-up on adipose-specific regulatory regions under (1) genetic and (2) epigenetic (environmental) regulation via integrational studies. Overall, the comprehensive sequencing of regulatory element methylomes reveals a rich landscape of functional variants linked genetically as well as epigenetically to plasma lipid traits.

  Study EGAS00001003415

• Somatic mutation and selection at epidemiological scale - TwinsUK_TargetedNanoSeq_Buccal

  Targeted NanoSeq in buccal epithelium obtained longitudinally from a number of donors. A custom-designed panel of ~200 genes will be used to achieve high depth coverage (aiming for ~1000X at panel sites).As we age, many tissues become colonised by microscopic clones carrying somatic driver mutations. Some of these clones represent a first step towards cancer whereas others may contribute to ageing and other diseases. However, our understanding of the clonal landscapes of human tissues, and their impact on cancer risk, ageing and disease, remains limited due to the challenge of detecting somatic mutations present in small numbers of cells. Here, we introduce a new version of nanorate sequencing (NanoSeq), a duplex sequencing method with error rates of less than 55 per billion base pairs, which is compatible with whole-exome and targeted gene sequencing. Deep sequencing of polyclonal samples with single-molecule sensitivity enables the simultaneous detection of mutations in large numbers of clones, yielding accurate somatic mutation rates, mutational signatures and driver mutation frequencies in any tissue. Applying targeted NanoSeq to 1,042 non-invasive samples of oral epithelium and 371 samples of blood from a twin cohort, we found an unprecedentedly rich landscape of selection, with 46 genes under positive selection driving clonal expansions in the oral epithelium, over 62,000 driver mutations, and evidence of negative selection in some genes. The high number of positively selected mutations in multiple genes provides high-resolution maps of selection across coding and non-coding sites, a form of in vivo saturation mutagenesis. Multivariate regression models enable mutational epidemiology studies on how carcinogenic exposures and cancer risk factors, such as age, tobacco or alcohol, alter the acquisition and selection of somatic mutations. Accurate single-molecule sequencing has the potential to unveil the polyclonal landscape of any tissue, providing a powerful tool to study early carcinogenesis, cancer prevention and the role of somatic mutations in ageing and disease.

  Dataset EGAD00001015618

• Somatic mutation and selection at epidemiological scale - TwinsUK_ExomeNanoSeq_Buccal

  Exome NanoSeq in buccal swab samples obtained from patients with a wide range of clinical phenotypes. As we age, many tissues become colonised by microscopic clones carrying somatic driver mutations. Some of these clones represent a first step towards cancer whereas others may contribute to ageing and other diseases. However, our understanding of the clonal landscapes of human tissues, and their impact on cancer risk, ageing and disease, remains limited due to the challenge of detecting somatic mutations present in small numbers of cells. Here, we introduce a new version of nanorate sequencing (NanoSeq), a duplex sequencing method with error rates of less than 5 per billion base pairs, which is compatible with whole-exome and targeted gene sequencing. Deep sequencing of polyclonal samples with single-molecule sensitivity enables the simultaneous detection of mutations in large numbers of clones, yielding accurate somatic mutation rates, mutational signatures and driver mutation frequencies in any tissue. Applying targeted NanoSeq to 1,042 non-invasive samples of oral epithelium and 371 samples of blood from a twin cohort, we found an unprecedentedly rich landscape of selection, with 46 genes under positive selection driving clonal expansions in the oral epithelium, over 62,000 driver mutations, and evidence of negative selection in some genes. The high number of positively selected mutations in multiple genes provides high-resolution maps of selection across coding and non-coding sites, a form of in vivo saturation mutagenesis. Multivariate regression models enable mutational epidemiology studies on how carcinogenic exposures and cancer risk factors, such as age, tobacco or alcohol, alter the acquisition and selection of somatic mutations. Accurate single-molecule sequencing has the potential to unveil the polyclonal landscape of any tissue, providing a powerful tool to study early carcinogenesis, cancer prevention and the role of somatic mutations in ageing and disease.

  Dataset EGAD00001015620

• Ancestry and somatic profile predict acral melanoma origin and prognosis – WXS

  Acral melanoma, which is not ultraviolet (UV)-associated, is the most common type of melanoma in several low- and middle-income countries including Mexico. Latin American samples are significantly underrepresented in global cancer genomics studies, which directly affects patients in these regions as it is known that cancer risk and incidence may be influenced by ancestry and environmental exposures. To address this, we characterise the genome and transcriptome of 123 acral melanoma tumours from 92 Mexican patients, a population notable because of its genetic admixture. Compared with other studies of melanoma, we found fewer frequent mutations in classical driver genes such as BRAF, NRAS or NF1. While most patients had predominantly Amerindian genetic ancestry, those with higher European ancestry had increased frequency of BRAF mutations and a lower median number of structural variants. The tumours with activating BRAF mutations have a transcriptional profile more similar to cutaneous non-volar melanocytes, suggesting that acral melanomas in these patients may arise from a distinct cell of origin compared to other tumours arising in these locations. KIT mutations were found in a subset of these tumours, and quadruple wild-type samples (non BRAF/NRAS/NF1/KIT) differed from mutated samples in their structural genomic profile and overall and recurrence-free survival patterns. Transcriptional profiling defined three expression clusters; these characteristics were associated with recurrence-free and overall survival. We highlight potential novel low-frequency drivers, such as PTPRJ, NF2 and RDH5. Our study enhances knowledge of this understudied disease and underscores the importance of including samples from diverse ancestries in cancer genomics studies.

  Dataset EGAD00001015755

• Molecular diagnosis of albinism (2018-03-14)

  Albinism is genetically heterogeneous rare genetic condition affecting 1:17000 in the Western world (but more frequent in Africa) whose main feature is a profound visual impairment, characterised by foveal hypoplasia, abnormal chiasmatic connections, nystagmus and photofobia. All these features result in severly altered visual acuity (<0,1), absent depth perception and poor night vision. People with albinism are primarily visually handicapped. In addition, for some types of albinism, the visual phenotype can be presented with partial or total hypopigmentation, hence resulting in a secondary phenotype which can lead to skin cancer if skin is not adequately protected. Recently a new syndrome has been described, FHONDA, with the same visual abnormalities of albinism but without pigment alteration. The traditional classification differentiates Oculoculatenous albinism (OCA), where hypopigmentation involves hair, skin and eyes versus Ocular Albinism (OA), where hypopigmentation only affects the eyes. These are non-sydrimic types of albinism. Some syndromic forms (Hermansky-Pudlak=HPS, Chediak-Higashi=CHS) affect cells beyond pigment cells, present in the lungs, immune system, platelets and intestines, resulting in more severe phenotypes that can be fatal. Mutations in at least 19 genes are assocaited with the corresponding types of albinism. Most hospitals will only diagnose the most frequent cases using traditional Sanger, MLPA approaches. Some will use CGH arrays. We aim to diagnose all cases of albinism through the Albinochip proposal, which combines a Sequenom first step of known mutations combined with subsequent NGS approaches. In some cases we fail to find a second mutation, these are good candidates for further full exome analyses. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/ . This dataset contains all the data available for this study on 2018-03-14.

  Dataset EGAD00001004039

• Comprehensive cancer predisposition gene testing in an adult multiple primary tumor series shows a broad range of deleterious variants and atypical tumor phenotypes

  Multiple primary tumors (MPT) affect a substantial proportion of cancer survivors and may result from various causes including inherited predisposition. Currently, germline genetic testing of MPT cases for cancer predisposition gene (CPG) variants is mostly targeted by tumor type. We ascertained pre-assessed MPT cases from genetics centers (defined as ≥2 primaries by age 60 years or ≥3 by 70) and performed whole genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment/molecular investigations, pathogenic variants in moderate and high-risk CPGs were detected in 67/440 (15.2%) of probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies including structural variants at low frequency (6/440 (1.4%) of probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant) the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice site CPG variants and at least one discordant tumor type was significantly higher than a control population (χ2=43.642 P=<0.0001). 2/67 (3%) of probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Summing together variant detection rates from a similarly ascertained previous MPT case series, the present results suggest that first-line comprehensive CPG analysis in a clinical genetics referral-based MPT cohort would detect a deleterious variant in about a third of cases.

  Dataset EGAD00001004088

• Clinical Outcomes by Tumor Mutational Burden and Inflammatory Gene Expression With Combined Nivolumab and Ipilimumab or Monotherapy in Advanced Melanoma_CM67-RNASeq

  Purpose Exploratory analyses of CheckMate 066 and 067 trials were conducted to investigate associations of tumor mutational burden (TMB), a 4-gene inflammatory gene expression signature, and BRAF mutation status with tumor response, progression-free survival (PFS), and overall survival (OS) in patients with advanced melanoma. Patients and Methods Patients with known programmed death ligand 1 (PD-L1) expression and BRAF mutation status received nivolumab (NIVO) or dacarbazine in CheckMate 066 and either NIVO, ipilimumab (IPI), or NIVO+IPI in CheckMate 067. Whole exome sequencing and RNA sequencing were used to determine TMB and inflammatory gene expression signature scores, respectively. These biomarkers were evaluated in terms of their association with PFS and OS. Results In the NIVO, NIVO+IPI, and IPI arms of CheckMate 067, longer survival was associated with high (> median) versus low (≤ median) TMB with hazard ratios (HRs) (95% confidence interval [CI]) for PFS of 0.45 (0.30–0.65), 0.55 (0.38–0.81), and 0.60 (0.43–0.82), and for OS of 0.46 (0.30–0.71), 0.53 (0.34–0.82), and 0.52 (0.36–0.74), respectively. For NIVO-treated patients, these results were confirmed in CheckMate 066. A survival benefit was observed with high TMB and absence of BRAF mutation. Survival was associated with high versus low inflammatory signature scores with HRs (95% CI) for PFS of 0.56 (0.34–0.94), 0.40 (0.23–0.72), and 0.43 (0.27–0.70), and for OS of 0.37 (0.20–0.66), 0.38 (0.19–0.74), and 0.46 (0.27–0.79), in the NIVO, NIVO+IPI, and IPI arms, respectively. Weak correlations were observed between PD-L1, TMB, and the inflammatory signature. Conclusions Combined assessment of TMB, inflammatory gene expression signature, and BRAF mutation status may be predictive for response to immunotherapy in advanced melanoma.

  Dataset EGAD00001006306

• Clinical Outcomes by Tumor Mutational Burden and Inflammatory Gene Expression With Combined Nivolumab and Ipilimumab or Monotherapy in Advanced Melanoma - CM066-WES

  Purpose Exploratory analyses of CheckMate 066 and 067 trials were conducted to investigate associations of tumor mutational burden (TMB), a 4-gene inflammatory gene expression signature, and BRAF mutation status with tumor response, progression-free survival (PFS), and overall survival (OS) in patients with advanced melanoma. Patients and Methods Patients with known programmed death ligand 1 (PD-L1) expression and BRAF mutation status received nivolumab (NIVO) or dacarbazine in CheckMate 066 and either NIVO, ipilimumab (IPI), or NIVO+IPI in CheckMate 067. Whole exome sequencing and RNA sequencing were used to determine TMB and inflammatory gene expression signature scores, respectively. These biomarkers were evaluated in terms of their association with PFS and OS. Results In the NIVO, NIVO+IPI, and IPI arms of CheckMate 067, longer survival was associated with high (> median) versus low (≤ median) TMB with hazard ratios (HRs) (95% confidence interval [CI]) for PFS of 0.45 (0.30–0.65), 0.55 (0.38–0.81), and 0.60 (0.43–0.82), and for OS of 0.46 (0.30–0.71), 0.53 (0.34–0.82), and 0.52 (0.36–0.74), respectively. For NIVO-treated patients, these results were confirmed in CheckMate 066. A survival benefit was observed with high TMB and absence of BRAF mutation. Survival was associated with high versus low inflammatory signature scores with HRs (95% CI) for PFS of 0.56 (0.34–0.94), 0.40 (0.23–0.72), and 0.43 (0.27–0.70), and for OS of 0.37 (0.20–0.66), 0.38 (0.19–0.74), and 0.46 (0.27–0.79), in the NIVO, NIVO+IPI, and IPI arms, respectively. Weak correlations were observed between PD-L1, TMB, and the inflammatory signature. Conclusions Combined assessment of TMB, inflammatory gene expression signature, and BRAF mutation status may be predictive for response to immunotherapy in advanced melanoma.

  Dataset EGAD00001006309

• A longitudinal single-cell atlas of treatment response in pediatric AML

  Pediatric acute myeloid leukemia (pAML) is a disease characterized by heterogeneous cellular composition, driver alterations and prognosis. Characterization of this heterogeneity and how it affects treatment response remains relatively understudied in pediatric patients. We therefore used single-cell RNA sequencing and single-cell ATAC sequencing to profile 684,031 diagnosis, remission and relapse cells from 28 patients representing different pAML subtypes. Analysis revealed that at diagnosis, cellular compositions differed between distinct subgroups. Upon relapse, cellular hierarchies transitioned towards a more primitive state regardless of subtype. These primitive cells were distinct compared to cells at diagnosis, having underrepresentation of transcriptional programs involved in myeloid differentiation while programs commonly found in other lineages were overrepresented. In a subset of patients, this appeared to accompany the appearance of a B-lymphoid-like hierarchy. Together, our data reveal the emergence of apparent subtype-specific plasticity upon treatment and inform on potential novel therapeutic angles to target these cell populations.

  Study EGAS00001007323

• Chemotherapy induces canalization of cell state in childhood B-cell precursor acute lymphoblastic leukemia

  Comparison of intratumor genetic heterogeneity in cancer at diagnosis and relapse suggests that chemotherapy induces bottleneck selection of subclonal genotypes. However, evolutionary events subsequent to chemotherapy could also explain changes in clonal dominance seen at relapse. We therefore investigated the mechanisms of selection in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) during induction chemotherapy where maximal cytoreduction occurs. To distinguish stochastic versus deterministic events, individual leukemias were transplanted into multiple xenografts and chemotherapy administered. Analyses of the immediate post-treatment leukemic residuum at single-cell resolution revealed that chemotherapy has little impact on genetic heterogeneity. Rather, it acts on extensive, previously unappreciated, transcriptional and epigenetic heterogeneity in BCP-ALL, dramatically reducing the spectrum of cell states represented, leaving a genetically polyclonal but phenotypically uniform population, with hallmark signatures relating to developmental stage, cell cycle and metabolism. Hence, canalization of the cell state accounts for a significant component of bottleneck selection during induction chemotherapy.

  Study EGAS00001004407

• Genome-wide cell-free DNA termini in patients with cancer

  The structure, fragmentation patterns and terminal sequences of cell-free DNA (cfDNA) are altered by nucleases and biological mechanisms in the blood of cancer patients. The cfDNA fragment-end composition recovered from low coverage WGS (<1 fold coverage) using a bespoke software (FrEIA) is aberrant in the plasma from cancer patient (n = 418, 655 samples) compared to controls (n = 117). As a standalone test FrEIA allows detection down to ~0.2% tumor fraction in vitro and in silico at 95% specificity, leading to a sensitivity of ~71% for detecting lung cancer (14/22 stage I-II, 27/38 stage III, 92/127 stage IV) and ~68% for detecting esophageal adenocarcinoma (26/44 stage II, 46/62 stage III). Additional cfDNA biological patterns can be combined with FrEIA increasing the diagnostic potential of low coverage WGS at minimal cost (mean AUROC = 0.96). Integrating multiple cfDNA biological signal augments the diagnostic performance of liquid biopsy.

  Study EGAS00001006142

• An IL-1β driven neutrophil-stromal cell axis fosters a BAFF-rich microenvironment in multiple myeloma

  The bone marrow is continuously occupied by high numbers of neutrophils, and a tumor-supportive bias of these cells could significantly impact bone marrow-confined malignancies. In multiple myeloma, the bone marrow is characterized by inflammatory stromal cells with the potential to influence neutrophils. Here, we investigated myeloma-associated alterations in marrow neutrophils and the impact of stromal inflammation on neutrophil function. Mature neutrophils in myeloma marrow are activated and tumor-supportive, transcribing increased levels of pro-inflammatory cytokines, including IL-1β, and myeloma cell survival factors, such as the BCMA-ligand BAFF. Neutrophils were re-activated after first-line treatment, while this regimen reduced, but did not normalize, stromal inflammation. Interactions with inflammatory stroma induced neutrophil activation, including BAFF secretion, in a STAT3-dependent manner and once activated, neutrophils gained the ability to reciprocally induce stromal activation. Combined, our data define the presence of a neutrophil-stromal cell feed-forward loop driving tumor-supportive inflammation that could impact disease recurrence.

  Study EGAS00001007038

• Identifying Novel Fusion Genes in Myeloma

  Identifying Novel Fusion Genes in Myeloma

  Dataset EGAD00001000112

• KIR imputation panel

  Construction of the KIR variant imputation panel in the Japanese population

  Study JGAS000314

• Analysis mechanism of CD19- relapse in CARPALL study

  Whole exome sequencing of CD19- relapses in CARPALL study

  Dataset EGAD00001005195

• Genotype of C3 SNPs in LOTx donors and recipients

  Genotype of C3 SNPs in 140 LOTx donors and recipients pairs.

  Dataset EGAD00001006889

• Alcohol Dependence GWAS in European- and African Americans

  This study includes SSADDA (Semi Structured Assessment for Drug Dependence and Alcoholism) assessed subjects (mostly unrelated, but including some affected sibling pairs) recruited in the course of several substance dependence genetics projects. The sample includes 1889 African-American (AA) subjects and 1020 European-American (EA) subjects. Among the AAs, 1397 meet DSM-IV criteria for alcohol dependence and 491 are controls. Among the EAs, 1010 meet the criteria for alcohol dependence and 9 are controls. (One in each population meets criteria for alcohol abuse and not dependence, and is therefore counted in neither category.) Although alcohol dependence is the major focus, the sample is informative also for cocaine, nicotine, and opioid dependence.

  Study phs000425

• Developing Biomarkers Incorporating High Throughput RNA, DNA, Small RNA Sequencing and Protein Expression in Inflammatory Bowel Disease Using Formalin-Fixed, Paraffin-Embedded (FFPE) Tissue Samples

  This study included pediatric patients with suspected inflammatory bowel disease (IBD) who underwent endoscopy between 2008 and 2012. This included 101 colonic tissue samples and 100 ileal tissue samples. Biopsies were obtained at the time of diagnosis, and patients were followed for a mean of 6 years to record clinical characteristics. These included baseline characteristics, such as age of diagnosis and initial Montreal classification, as well as outcomes, such as stricturing or fistulizing complications, disease remission, or progression to surgery.Genes with significant results in the non-IBD vs CD comparison in colonic tissue are listed in the "Links to Related Genes" section of this page.

  Study phs003156

• Human periportal liver assembloids recapitulate periportal liver tissue in vitro

  In vitro expansion of human hepatocytes from fresh patient tissues has not yet been achieved, limiting the possibility of modelling liver composite structures in vitro. Here, we developed human hepatocyte organoids from patient-donors that sustain the long-term expansion of hepatocytes in vitro. We profiled them using RNAseq to determine their gene expression pattern and compared this with the original native fresh isolated liver cell. Then, we used them to generate periportal liver assembloids by combining them with portal mesenchyme and cholangiocyte organoids. By increasing the number of mesenchymal cells we obtained structures with a fibrotic ratio of portal mesenchyme and we performed scRNAseq analysis to determine their gene expression and cell-cell interactions.

  Study EGAS50000000994

• Star2xml: metadata converter into XML

  Star2xml: metadata converter into XML Welcome to the landing page for star2xml - a tool developed by the European Genome-phenome Archive (EGA) that enables users to convert metadata into XML format that is compliant with EGA's programmatic submission system. For starters, if you are not sure what metadata is in this context, you may want to explore our brief metadata introduction. . Star2xml is useful for users who have already submitted their data to the EGA and want to also submit their metadata programmatically without having to create the XML files manually. The need for these XMLs containing metadata is explained in the EGA's metadata schemas and programmatic submission guidelines. In summary, star2xml allows for users to deposit metadata in a tabular format (e.g. excel spreadsheet) and transform it into a compliant XML format. This saves time in large submissions, where the sheer size of metadata makes it difficult to manage. For smaller submissions, it is recommended to use EGA's Submitter Portal (SP) instead. The installation of the tool is straightforward, and it contains detailed documentation on how to use it in its GitHub repository . While star2xml can help users convert metadata formats, it does not validate the resulting metadata against EGA's schemas. Therefore, after creating your XMLs, you should still validate your metadata before submitting it to EGA, as described in the documentation for programmatic metadata validation.

  Documentation tools/star2xml

• Identification of novel fusion genes in lung cancer using breakpoint assembly of transcriptome sequencing data

  Genomic translocation events frequently underlie cancer development through generation of gene fusions with oncogenic properties. Identification of such fusion transcripts by transcriptome sequencing might help to discover new potential therapeutic targets. We developed TRUP (Tumor-specimen suited RNA-seq Unified Pipeline (https://github.com/ruping/TRUP), a computational approach that combines split-read and read-pair analysis with de-novo assembly for the identification of chimeric transcripts in cancer specimens. We apply TRUP to RNA-seq data of different tumor types, and find it to be more sensitive than alternative tools in detecting chimeric transcripts, such as secondaryrearrangements in EML4-ALK-positive lung tumors, or recurrent inactivating rearrangements affecting RASSF8.

  Study EGAS00001000659

• Case Report: Precision medicine target revealed by in-vitro modelling of relapsed, refractory ALL from a child with neurofibromatosis

  Children with neurofibromatosis have a higher risk of developing juvenile myelomonocytic leukaemia and acute myeloid leukaemia, but rarely develop B-cell acute lymphoblastic leukaemia (B-ALL). Through in-vitro modelling, a novel NF1 p.L2467 frameshift (fs) mutation identified in a relapsed/refractory Ph-like B-ALL patient with neurofibromatosis demonstrated cytokine independence and increased RAS signalling, indicative of leukaemic transformation. Furthermore, these cells were sensitive to the MEK inhibitors trametinib and mirdametinib. Bi-allelic NF1 loss of function may be a contributing factor to relapse and with sensitivity to MEK inhibitors, suggests a novel precision medicine target in the setting of neurofibromatosis patients with B-ALL.

  Study EGAS00001006187

• 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

• Subtype-associated epigenomic landscape and 3D genome structure in bladder cancer

  We determine the genome-wide transcriptome, enhancer landscape and transcription factor binding profiles of FOXA1 and GATA3 in luminal and basal subtypes of bladder cancer. Furthermore, we report the first-ever mapping of genome-wide chromatin interactions by Hi-C in both bladder cancer cell lines and primary patient tumors. We show that subtype-specific transcription is accompanied by specific open chromatin and epigenomic marks, at least partially driven by distinct transcription factor binding at distal-enhancers of luminal and basal bladder cancers. Finally, we identify a novel clinically relevant transcription factor, Neuronal PAS Domain Protein 2 (NPAS2), in luminal bladder cancers that regulates other subtype-specific genes and influences cancer cell proliferation and migration.

  Study EGAS00001005071

• Somatic mutation rates scale with lifespan across mammals

  The rates and patterns of somatic mutation in normal tissues are largely unknown outside of humans. Comparative analyses can shed light on the diversity of mutagenesis across species and on long-standing hypotheses regarding the evolution of somatic mutation rates and their role in cancer and ageing. Here, we used whole-genome sequencing of 208 intestinal crypts from 56 individuals to study the landscape of somatic mutation across 16 mammalian species. We found somatic mutagenesis to be dominated by seemingly endogenous mutational processes in all species, including 5-methylcytosine deamination and oxidative damage. With some differences, mutational signatures in other species resembled those described in humans, although the relative contribution of each signature varied across species. Remarkably, the somatic mutation rate per year varied greatly across species and exhibited a strong inverse relationship with species lifespan, with no other life-history trait studied displaying a comparable association. Despite widely different life histories among the species surveyed, including ~30-fold variation in lifespan and ~40,000-fold variation in body mass, the somatic mutation burden at the end of lifespan varied only by a factor of ~3. These data unveil common mutational processes across mammals and suggest that somatic mutation rates are evolutionarily constrained and may be a determinant of lifespan.

  Dataset EGAD00001008032

• Targeted replication of LVOTO genes

  Non-syndromic cases of congenital heart defects (CHD) exhibit variable modes of inheritance (Mendelian and non-Mendelian). Several studies have identified strong candidates in humans by taking a candidate gene approach as well as by using whole exome next generation sequencing (NGS). So far these studies could only explain a minor fraction of the observed phenotype in humans, most of them in syndromic cases and no single study has focused on the subset of cases with left ventricular outflow tract obstruction (LVOTO). To discover novel disease-causing genes a large cohort of patients with LVOTO, approximately 100 cases, 25 families and 100 trios have been exome sequenced. This study based on NGS sequencing data yielded several known and novel compelling candidate genes, such as MYH6, NR2F2 and MYH11, but also novel ones, such as ITGB4. To evaluate the significance of our findings in a replication cohort we assembled another 1614 cases with an LVOTO phenotype from our collaborators in Toronto, Berlin and Amsterdam. Targeted resequencing in this additional cohort will help to find additional cases with mutations in the identified candidate genes to strengthen genotype-phenotype association. We will use control data from the INTERVAL project for case/control analyses The pulldowns will be performed as 24-plex ISC with 192 or greater indexes, and the sequencing will be performed with 192 samples per lane, requiring 9 lanes of sequencing.

  Dataset EGAD00001002212

• 33 patients with Monoclonal Gammopathy of Undetermined Significance (MGUS)

  Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant precursor of multiple myeloma (MM) with a 1% risk of progression per year. Although targeted analyses have shown the presence of specific genetic abnormalities such as IGH translocations, RB1 deletion, 1q gain, hyperdiploidy or RAS genes mutations, little is known about molecular mechanism of malignant transformation. We have performed whole exome sequencing together with SNP array analysis in 33 flow-cytometry separated abnormal PC samples of MGUS patients to describe somatic gene mutations and chromosome changes at the genome-wide level. Non-synonymous mutations (NS-SNVs) and copy number alterations (CNAs) were present in 97.0% and in 63.6% of cases, respectively. Importantly, the number of somatic mutations was significantly lower in MGUS compared to MM (p<10-4) and we have identified 6 myeloma significantly mutated genes which are KRAS, NRAS, DIS3, HIST1H1E, EGR1 and LTB in the MGUS dataset. We also found a positive correlation with increasing chromosome changes and somatic mutations. IGH translocations were present in 27.3% of cases comprising t(4;14), t(11;14), t(14;16) or t(14;20) and were in a similar frequency to MM, which corresponded with primary lesion hypothesis. Data from this study showed MGUS is a genetically comprehensive disease, however overall genetic instability is significantly lower compared to MM.

  Dataset EGAD00001001901

• An exome sequencing study of the HIV elite-long term non progressors and rapid progressors (CASCADE cohorts)

  Background: A rare subgroup of HIV infected individuals naturally controls infection without treatment. These ?elite controllers? constitute an important model for the natural control of HIV infection. Indeed, the study of these individuals may provide insights into strategies for the development of HIV vaccines. Although several HLA and chemokine alleles are known to be over-represented in elite controllers, only a small portion of HIV phenotypic variation is explained by known genetic variants. The elite controller phenotype is rare and distinct, representing the extreme of an infectious disease trait. As such, this phenotype may be partly explained by variation in host immune control, which may be characterized by differences in rare functional genetic variants. Genomic regions underlying elite control can be potentially identified by comparing the presence or frequency of variants in this group to that representing the opposite extreme. In this context, ?rapid progressors? is a group defined by its rapid immunological and clinical disease progression. Aim: To extend an existing study, in order to identify DNA sequence variants involved in the control of HIV infection with greater statistical resolution. Specifically, we aim to sequence up to 200 exomes from multiple cohort studies within the EuroCoord CASCADE collaboration (a collaboration of 25 HIV seroconversion cohort studies across Europe).

  Dataset EGAD00001002179

• The mutational landscape of skin tumours in CYLD cutaneous syndrome determined

  Patients with germline mutations in CYLD can develop hundreds of benign skin tumours called cylindromas. The development of multiple tumours within a single patient at sun-protected and sun-exposed sites, varying tumour histological patterns and grades of malignancy allow for the testing of several genetic hypothesis in relation to cutaneous carcinogenesis. By adopting the unprecedented approach of whole genome sequencing of multiple benign skin tumours within individuals in multigenerational families, we set out to study the impact of mutational diversity on models such as multistep carcinogenesis as well as non-sequential carcinogenesis. Using non-negative matrix factorisation (NMF) to discover mutational signatures, we found distinct mutational signatures in identical benign tumours (N=2 patients; n=11 tumours) at sun exposed and sun protected skin tumours within a mother and her daughter. We found recurrent mutations in epigenetic modifying genes in CCS tumours which are known to have an oncogenic dependency on Wnt signalling. We also demonstrate that cutaneous tumours that metastasize to the lung carry a a UV signature, supporting the origin from the skin. Distinct malignant tumours, such as BCC and malignant spiradenocarcinoma carried unique driver mutations. These findings add new dimensions to the existing paradigms of UV-induced skin cancer and highlight the utility of studying rare disease to gain novel insights into genetic mechanisms of tumour formation.

  Dataset EGAD00001004573

• Clonal selection after gene therapy in sickle cell disease

  While gene therapy (GT) provides a potentially curative treatment option for patients with sickle cell disease (SCD), the occurrence of myeloid malignancies in clinical trials has prompted concern. To interrogate potential mechanisms underlying increased cancer risk, we used hematopoietic stem cell (HSC) clonal tracking by whole genome sequencing (WGS) to map the somatic mutation and clonal landscape of 2,592 gene modified as well as unmodified single stem and progenitor cells from six SCD patients undergoing gene therapy (7-26 years old, average 12.7× depth). Pre-GT phylogenetic trees in SCD were highly polyclonal and mutation burdens per cell were elevated in some, but not all, patients. Post-GT, no clonal expansions were identified. However, an increased frequency of driver mutations associated with myeloid neoplasms or clonal hematopoiesis (DNMT3A- and EZH2-mutated clones in particular) were seen in both genetically modified and unmodified cells suggested positive selection of mutant clones during gene therapy. This work sheds light on the mutation landscape and HSC clonal dynamics in gene therapy for SCD and highlights enhanced fitness of some HSCs harboring pre-existing driver mutations following gene therapy. Future studies should define the long-term fate of mutant clones including any contribution to expansions associated with myeloid neoplasms.

  Dataset EGAD00001010914

• Smith-Lemli-Opitz Syndrome: A Longitudinal Clinical Study of Patients Receiving Cholesterol Supplementation

  Smith-Lemli-Opitz syndrome (SLOS) is a disorder of cholesterol production by the body. It is caused by changes in the DHCR7 gene, which is the blueprint for an enzyme called 7-dehydrocholesterol- delta7-reductase. This enzyme is necessary for the production of cholesterol by all cells in the body. People with SLOS often have malformations of major organs, slow growth, feeding difficulties and intellectual disability or learning problems. Because patients with SLOS cannot make enough cholesterol, it has been proposed that cholesterol supplementation (either with egg yolk or liquid suspensions of cholesterol) could help improve the symptoms of the disease. However, despite the widespread use of cholesterol supplementation, it is still not known whether it works or not. The study will try to provide an answer to this question by studying the disease and its progression while patients are receiving cholesterol. The clinical features of SLOS are thought to be related to low cholesterol and buildup of toxic cholesterol precursors (substances from which cholesterol is formed). But how exactly low cholesterol and toxic precursors contribute to the disease is poorly understood. This knowledge is critically important because it should help discover new therapeutic targets and develop treatments of the disease in the long run. The study will try to fill this gap with a comprehensive clinical and biochemical testing of the study participants over the course of several years. Last, a limitation of previous SLOS research studies has been their low number of participants. This is understandable because SLOS is a rare diseases and few research groups are working on it. However, in order to fully understand the disease, researchers need to study as many patients as possible. This study is unique in that it is run by a network of several highly specialized clinical research sites across the country. Having several sites involved increases the researcher's ability to recruit and study large number of patients, and centralize patients' information in a comprehensive SLOS clinical registry. This registry will be key to identify markers for diagnostic testing, screening and measuring outcomes in future studies of treatment. The purpose of this study is to learn as much as possible about Smith-Lemli-Opitz Syndrome (SLOS) by following a large group of affected children and adults over time. In this study, we will measure cholesterol and other similar chemicals in blood and urine, evaluate development and behavior, do limited medical evaluation, and carry out brain imaging studies.This study will help researchers: learn more about what causes SLOS and how SLOS changes with age, note differences in features of SLOS among those affected, evaluate the effect of giving extra cholesterol in this condition, and develop ways to evaluate whether treatments developed in the future will be helpful.

  Study phs001430

• Capturing sex-specific and infertility-linked effects of assisted reproductive technologies on the cord blood DNA methylome

  Background: Children conceived through assisted reproduction are at an increased risk for growth and genomic imprinting disorders, often linked to DNA methylation defects. It has been suggested that assisted reproductive technologies (ART) and the underlying parental infertility can induce epigenetic instability, specifically interfering with DNA methylation reprogramming events during germ cell and preimplantation development. To date, human studies exploring the association between ART and DNA methylation defects report inconsistent or inconclusive results, likely due to population heterogeneity and the use of technologies with limited coverage of the epigenome. In our study, we explore the epigenetic risk of ART by comprehensively profiling the DNA methylome of 73 human cord blood samples from singleton pregnancies (n=36 control group, n=37 ART/infertility group) from a human prospective longitudinal birth cohort, the Design, Develop, Discover (3D) Study using a high resolution sequencing based custom capture panel that interrogates over 2.4 million autosomal CpGs in the genome. Results: the main findings We identified striking sex-specific effects of ART on cord blood DNA methylation patterning both genome-wide and for imprinted genes. When compared to less invasive procedures such as in utero insemination, more invasive ARTs (IVF, ICSI, embryo culture) resulted in more marked and distinct effects on the cord blood DNA methylome, including targeting of loci involved in development. Background: Children conceived through assisted reproduction are at an increased risk for growth and genomic imprinting disorders, often linked to DNA methylation defects. It has been suggested that assisted reproductive technologies (ART) and the underlying parental infertility can induce epigenetic instability, specifically interfering with DNA methylation reprogramming events during germ cell and preimplantation development. To date, human studies exploring the association between ART and DNA methylation defects report inconsistent or inconclusive results, likely due to population heterogeneity and the use of technologies with limited coverage of the epigenome. In our study, we explore the epigenetic risk of ART by comprehensively profiling the DNA methylome of 73 human cord blood samples from singleton pregnancies (n=36 control group, n=37 ART/infertility group) from a human prospective longitudinal birth cohort, the Design, Develop, Discover (3D) Study, using a high resolution sequencing based custom capture panel that interrogates over 2.4 million autosomal CpGs in the genome. Results: We identified striking sex-specific effects of ART on cord blood DNA methylation patterning both genome-wide and for imprinted genes. When compared to less invasive procedures such as in utero insemination, more invasive ARTs (in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), embryo culture) resulted in more marked and distinct effects on the cord blood DNA methylome, including targeting of loci involved in development. Conclusions: Our study highlights the ability of a sensitive, targeted, sequencing based approach to uncover DNA methylation perturbations in cord blood associated with infertility and ART and influenced by offspring sex and ART technique invasiveness.

  Study EGAS00001006643

• The complex SNP and CNV genetic architecture of the increased risk of congenital heart defects in Down syndrome

  Here we aimed to contribute to the description of the genetic architecture of Congenital heart defect (CHD) in Down syndrome (DS), and report the results of a genome-wide association study using samples from DS individuals with and without CHD. CHD is a common developmental defect of DS occurring in 40% of cases. This case-control GWAS includes 187 DS with CHD as cases, and 151 DS without CHD as controls.

  Study EGAS00000000129

• Genome-wide association study in multiple human prion diseases suggests genetic risk factors additional to PRNP

  We conducted GWAS of sporadic CJD, variant CJD, iatrogenic CJD, inherited prion disease, kuru and resistance to kuru despite attendance at mortuary feasts. After quality control we analysed 2000 samples and 6015 control individuals (provided by the Wellcome Trust Case Control Consortium and KORA-gen), for 491032-511862 SNPs in the European study. Association studies were done in each geographical and aetiological group followed by several combined analyses.

  Study EGAS00000000097

• Differential gene expression in the colon mucosa of irritable bowel syndrome patients with diarrhea-predominant symptoms

  The aim of this study is to characterize the pathophysiology of the irritable bowel syndrome (IBS) on the functional level and in parallel on the gene expression level. For this purpose RNAseq of mucosal biopsies was performed. The data from the differential expression analysis will be further processed by Ingenuity Pathway Analysis (IPA) software to gather Information on activated or inhibited signaling pathways in the disease.

  Study EGAS50000000046

• Multi-omic characterisation of PBMCs in IBD

  We generated 10X, droplet-based Multiome (paired RNA+ATAC) data of PBMCs in 38 IBD patients. Patients are either UC or CD patients. To test the responsiveness of the cells to bacterial stimuli, we stimulated samples with either RPMI, LPS or S. Salmonella (total: 80 samples). Single-nuclei libraries are multiplexed across donors. Genotypes are provided in this dataset to perform genetic demultiplexing, phenotypes providing mapping information to retrace donors / pools / stimulations.

  Study EGAS50000000140

• Correlative Genomic Analysis of Durvalumab plus Pazopanib Combination in Patients with Advanced Soft Tissue Sarcomas

  We conducted an open-label, phase 2 study to determine the activity of the anti-VEGF receptor tyrosine-kinase inhibitor, pazopanib, combined with the anti-PD-L1 immune checkpoint inhibitor, durvalumab, in unselected advanced sarcomas. In addition, we conducted whole exome and transcriptomic sequencing with pre-treatment tissue biopsy to correlate clinical outcomes with molecular and genomic biomarkers to identify patients who would most likely benefit from the combination treatment.

  Study EGAS50000000082

• Tamoxifen Response at Single Cell Resolution in Estrogen Receptor Positive Primary Human Breast Tumors

  Primary breast tissue, normal and cancerous, was collected immediately after resection. The tissue was dissociated and treated with 10uM tamoxifen or control media for 12 hours in suspension. Single cell libraries were then created using a 10x Genomics gel bead droplet-based kit and sequenced via Illumina sequencing platforms. Differences in cell response to tamoxifen was observed between cell types and distinct responsive and unresponsive cell populations were determined.

  Study phs003186

• Myocardial Infarction Genetics Exome Sequencing Consortium: German Heart Center in Munich

  The Munich-MI study is a case-control cohort study recruited at the German Heart Center in Munich, Germany. It is focused on understanding the genetic contributors to early myocardial-infarction (MI) in the German population. All exome sequencing was performed at the Broad Institute of Harvard and MIT; samples sequence capture was performed using Illumina's ICE Capture reagent and sequencing was performed on an Illumina HiSeq 2000 or 2500.

  Study phs000916

• Genomic profiles associated with response to immunotherapy in adolescent and young adult patients with melanoma

  The patterns of immune infiltration and treatment responses are unclear due to genomic and clinicopathological differences in AYA patients compared to those of older patients, and these patterns and differences may contribute to the lack of response to immunotherapy. This study fills the research gaps in understanding the molecular profiles of AYA melanoma and the key immunosuppressive signalling pathways contributing to tumour growth and resistance to immunotherapy

  Study EGAS50000000238

• Prognostic whole-genome and transcriptome signatures in colorectal cancers

  Colorectal cancer (CRC) is caused by a sequence of somatic genomic alterations affecting driver genes in core cancer pathways1. To understand the functional and prognostic impact of cancer-causing somatic mutations, we analysed the whole genomes and transcriptomes of 1,063 primary CRCs in a population-based cohort with long-term follow-up. This study constitutes the largest integrated genome and transcriptome analysis of CRC to date, and links mutations, gene expressions and patient outcomes.

  Study EGAS50000000124

• Reconstitution of Human Brain Cell Diversity in Organoids via Four Protocols [scRNAseq]

  Single-cell RNA-sequencing of brain organoids at day 120 grown in four distinct growth protocols designed to generate dorsal (D) and ventral (V) forebrain, midbrain (M) and striatum (S) tissue using eight different pluripotent stem cell lines. Per per cell line-protocol combination two organoids (biological replicates) were grown. For cell line 176 the experiment was conducted in two independent biological replicates (repititions E1 and E2).

  Study EGAS50000000662

• MOSAIC - Multi-Omics Spatial Atlas In Cancer

  MOSAIC is a collaborative initiative founded by Owkin, Lausanne University Hospital (CHUV), Charité Universitätsmedizin Berlin, University Hospital Erlangen (UKER), Gustave Roussy Institute in Paris, and University of Pittsburgh. The goal of MOSAIC is to build the largest collection of spatial omics data in cancer. By integrating comprehensive high quality clinical annotations with advanced deep profiling techniques, MOSAIC aims to uncover novel cancer subtypes and identify key drug targets and biomarkers within them.

  Study EGAS50000000689

• Integrated targeted deep sequencing reveals unique tissue-of-origin and donor cell-free DNA signatures in transplant recipients

  We have developed a targeted deep methylation sequencing assay that integrates cell-free DNA (cfDNA) tissue-of-origin analysis with donor-derived cfDNA quantification to non-invasively monitor transplant health. In this study, liver and kidney transplant recipients were assessed in conjunction with healthy controls to characterize the dynamic patterns of cfDNA release and clearance, and to identify distinct tissue injury signatures throughout the transplant journey.

  Study EGAS50000000987

• Genetic analyses in patients with T or NK cells-associated disorders

  We conduct somatic gene mutation analysis in various diseases involving T cells or NK cells and clarify the gene mutation profile. By comparing clinical information and the results of mutation analysis, we will identify gene groups that influence the onset and refractoriness of the disease. As the analysis continues, the results of mutation analysis may become part of diagnostic criteria in the future, or provide basic data for the development of new therapeutic agents.

  Study JGAS000658

• Genetic analyses in patients with T or NK cells-associated disorders

  We conduct somatic gene mutation analysis in various diseases involving T cells or NK cells and clarify the gene mutation profile. By comparing clinical information and the results of mutation analysis, we will identify gene groups that influence the onset and refractoriness of the disease. As the analysis continues, the results of mutation analysis may become part of diagnostic criteria in the future, or provide basic data for the development of new therapeutic agents.

  Study JGAS000709

• Single cell long read whole genome sequencing reveals somatic transposon activity in human brain

  The advent of single cell DNA sequencing revealed astonishing dynamics of genomic variability, but failed at characterizing smaller to mid size variants that on the germline level have a profound impact. In this work we discover novel dynamics in three brains utilizing single cell long-read sequencing. This provides key insights into the dynamic of the genomes of individual cells and further highlights brain specific activity of transposable elements.

  Study EGAS50000001156

• OTOF mutation analysis with massively parallel DNA sequencing in 2,265 Japanese sensorineural hearing loss patients.

  The OTOF gene, encoding otoferlin, is reported to be one of the major causes of non-syndromic recessive sensorineural hearing loss, and is also reported to be the most common cause of non-syndromic recessive auditory neuropathy spectrum disorder (ANSD). In the present study, we performed OTOF mutation analysis using massively parallel DNA sequencing (MPS) to reveal the frequency and clinical characteristics of OTOF-related hearing loss in a large hearing loss population.

  Study JGAS000166

• Development of blood-based biomarkers for precision medicine in castration-resistant prostate cancer

  Cell-free DNA (cfDNA) testing is emerging as a tool for cancer precision medicine. However, little is known about the clinical significance of low-frequency variants detected in circulating cell-free tumor DNA (ctDNA) from castration-resistant prostate cancer (CRPC) patients. We conducted targeted sequencing of cfDNA and paired leukocyte DNA from CRPC patients using molecular barcodes, and ctDNA variants with a variant allele frequency ??? 0.1% were detected using an in-house pipeline.

  Study JGAS000330

• Transcriptome analysis of a novel human iPSC-derived 3D cortical tissue model - WT, APP KI, Abeta-treated, Abeta/Aducanumab-treated

  Single-cell RNA-seq analysis of human iPSC-derived microglia/astrocytes/neurons in a novel, human in vitro 3D cortical tissue model. Samples include distinct conditions (each as biological duplicates): - wild-type cells from cultures after 1 month (WT_1mo, cell lines: A18, KOLF) and 3 months (WT_3mo, cell lines: SA2, KOLF, A18) of culturing - knock-in cells from cultures carrying three familial AD mutations in the APP gene (Swedish, Iberian, Arctic; introduced by CRISPR/Cas9-mediated knock-in) after 3 months of culturing (KI_3mo, cell lines: SA2, A18) - subset of WT 1 month-old samples were exposed to 500nM synthetic Abeta42 for 2 consecutive feeds, and a subset of these subsequently treated with 1µg/ml Aducanumab antibody for 14 days

  Dataset EGAD50000002031

• Identification of mutations and structural rearrangements in plasma DNA form metastatic prostate cancer patients

  In this study we analysed patients with metastatic prostate cancer to scan their tumor genomes noninvasively in plasma DNA. We enriched 1.3 Mbp of seven plasma DNAs (4 CRPC cases: CRPC1-3 and CRPC5; 3 CSPC cases: CSPC1-2 and CSPC4) including exonic sequences of 55 cancer genes and 38 introns of 18 genes, where fusion breakpoints have been described using Sure Select Custom DNA Kit.

  Study EGAS00001000453

• Whole genome and RNA sequencing of paediatric glioblastoma in the ICGC PedBrain project

  Paediatric glioblastoma (pedGBM) is characterised by substantial intertumoural heterogeneity. In order to identify the genetic lesions underlying tumourigenesis, we analysed whole genomes and transcriptomes of pedGBMs and in vitro model systems by next generation sequencing. Novel fusions of the receptor tyrosine kinase MET lead us to investigate targeted therapy using MET inhibitors. This study is part of the International Cancer Genome Consortium PedBrain Tumor Project (ICGC PedBrain, http://www.pedbraintumor.org/).

  Study EGAS00001001139

• Prime editing for functional repair in patient-derived disease models

  Prime editing is a novel genome editing technology using fusion proteins of Cas9-nickase and reverse transcriptase, that holds promise to correct a wide variety of genetic defects. We succeeded in efficient prime editing and functional recovery of disease-causing mutations in patient-derived liver and intestinal stem cell organoids. Whole genome sequencing of did not detect off-target mutations or a mutational signature induced by prime editing.

  Study EGAS00001004611

• Identification of recurrent mutations in Cushing’s disease

  The overall goal of the Identification of recurrent mutations in Cushing’s disease project is to study the impact of whole-exome sequencing (WES) on the clinical care of cancer patients and oncology provider practices. The aims of Project are to implement and establish the feasibility of WES in patients with USP8 wild-type corticotroph adenomas; to develop a framework for understanding of the molecular mechanism of the pathogenesis of corticotroph adenoma.

  Study EGAS00001003029

• Molecular characterization of endothelial cells under conditions associated with hematopoietic niche formation in humans

  Using a combinatory approach of cell purification and transcriptomics, we identify a subset of endoglin-expressing endothelial cells enriched in human bone marrow during fetal ontogeny and regeneration after chemotherapeutic injury. Comprehensive transcriptional characterization by massive parallel RNA sequencing of these cells revealed a remarkable phenotypic and molecular similarity to murine H endothelium as well as activation of pathways and angiocrine factors implicated in hematopoiesis, osteogenesis and angiogenesis.

  Study EGAS00001002736

• Deep intronic homozygous variation in PSMC3 causes a syndromic neurosensory disorder combining deafness and cataract

  The association of congenital deafness and early-onset cataracts inherited as a recessive trait is a rare combination described in only a few syndromes with very few genes identified to date. We propose that the PSMC3 proteasome subunit dysfunction leads to a novel human syndrome that includes early-onset cataracts and deafness and suggest that Rpt5 plays a major role in inner ear and lens development.

  Study EGAS00001003942

• Whole-exome sequencing of ovarian clear cell carcinoma in clinical outliers

  Whole-exome sequencing dataset for the Australian Ovarian Cancer Study (AOCS) and The Jikei University School of Medicine (JIKEI) ovarian clear cell carcinoma (OCCC) clinical outliers project, representing 10 donors. Although OCCC are commonly resistant to platinum based chemotherapy, good clinical outcomes are observed in a subset of patients. Exome sequencing was performed in 10 patients who had either unusually long survival (N=5) or had a very short time to progression (N=5).

  Study EGAS00001004248

• Differential gene expression in the colon mucosa of irritable bowel syndrome patients with mixed type symptoms

  The aim of this study is to characterize the pathophysiology of the irritable bowel syndrome (IBS) on the functional level and in parallel on the gene expression level. For this purpose RNAseq of mucosal biopsies was performed. The data from the differential expression analysis will be further processed by Ingenuity Pathway Analysis (IPA) software to gather Information on activated or inhibited signaling pathways in the disease.

  Study EGAS00001004835

• Clinical impact of immune checkpoint inhibitor (ICI) response, DNA damage repair (DDR) gene mutations and immune-cell infiltration in subtypes of metastatic melanoma

  Our study identified that immune cell infiltration and DNA damage repair (DDR) gene mutations may have an impact in response to immune checkpoint inhibitors (ICI) treatment in metastatic melanoma but differs among melanoma subtypes. Therefore, a comprehensive understanding of the role of immune infiltration cells, DDR gene mutations and copy number alterations could act as prognostic biomarkers for the ICI treatment among metastatic melanoma subtype patients.

  Study EGAS00001005781

• RNA sequencing data of in vitro differentiated megakaryocyte cells transduced with E527K and WT SRC

  For RNA sequencing (RNAseq), CD34+ hematopoietic stem cells (HSC) were isolated from healthy controls before transduction with WT-SRC and E527K-SRC lentiviral vectors in triplicate and differentiation to MK. RNA was extracted from the complete cell population as the aim was to detect differences in genes regulating MK maturation and differentiation. A total of six WT-SRC and six E527K-SRC RNA samples were used for RNAseq to identify differentially expressed genes.

  Study EGAS00001005808

• RNA-sequencing of mechanical stress induced osteoarthritis-like damage in aged human cartilage explants treated with the anti-deiodinase iopanoic acid

  The current study aimed to confirm chondroprotective effects of the D2 inhibitor iopanoic acid (IOP) in an ex vivo aged human osteochondral explant model in which injurious mechanical stress is applied to inflict OA-like damage. This dataset contains RNA-seq (Illumina HiSeq X ten) of osteochondral explant cartilage from aged human patients that underwent a joint replacement surgery due to OA (N=10 donors; n=21 explants).

  Study EGAS00001006242

• Profiling of 27 type 2 diabetes GWAS loci using next-generation (NG) capture C in a human beta-cell model

  Most type 2 diabetes association signals are due to variants that impact gene regulation but identifying the genes they impact is challenging. We generated interaction profiles at 27 T2D GWAS loci using next-generation (NG) capture C in a human beta-cell model ( EndoC-betaH1) and contrasted our maps with public Hi-C/promoter capture Hi-C maps in EndoC-betaH1 cells or human islets.

  Study EGAS00001006105

• RNA sequencing of NK cells in human lung

  Human lung tissue-resident NK cells (trNK cells) are likely to play important roles in viral infections, inflammation and cancer. However, knowledge about lung trNK cells is lacking but is fundamental for exploiting these cells in therapeutic approaches. Here we analysed the transcriptome of CD69+CD49a+CD103+CD16-CD56bright, CD69+CD49a+CD103-CD16-CD56bright, CD69+CD49a-CD103-CD16-CD56bright, CD69-CD49a-CD103-CD16-CD56bright, and CD56dimCD16+NKG2A+CD57- NK cells isolated from human lung.

  Study EGAS00001003544

• Follicular lymphoma at diagnosis, treated in first line with immunochemotherapy

  We performed targeted NGS in Follicular lymphoma samples at diagnosis. Explored clinico-genetic correlations and assessed four clinical or clinicogenetic risk models (FLIPI, FLIPI-2, PRIMA-IP or m7-FLIPI-molecular score) in patients with symptomatic FL who received frontline immunochemotherapy. Out of 191 patients with FL grade 1-3a, 109 were successfully genotyped. Treatment consisted on rituximab (R) plus CVP/CHOP (72.5%) or R-bendamustine (R-B) (27.5%).

  Study EGAS00001006674

• RNA-seq of cultured human hematopoietic stem and progenitor cells from umblical cord blood in cytokine-rich ex vivo culture conditions following sphingolipid modulation

  In order to elucidate the biological pathways altered by sphingolipid modulation with N-(4-hydroxyphenyl) retinamide (4HPR) treatment in human HSPC that may contribute to the restraint in proliferation while promoting persistence of HSC self-renewal, as well as determine the mechanism of synergy in enhancement of HSC self-renewal with CB CD34+ agonists UM171 and StemRegenin 1 (SR1), we performed RNA-sequencing (RNA-Seq) of 3 pools of lin-CB cells following 2 or 4 days with DMSO, 4HPR, UM171+SR1 or 3-Factor (4HPR+UM171+SR1). We identified modulation of sphingolipid metabolism regulates self-renewal through activating coordinated stress pathways that coalesce on endoplasmic reticulum stress and autophagy programs.

  Dataset EGAD00001005140

• Deep targeted DNA sequencing dataset for the study "Molecular characteristics in Burkitt lymphoma over age groups"

  We performed deep targeted DNA sequencing with a panel of 134 selected cancer-related genes previously identified to be recurrently mutated in BL/B-AL. A Nextera rapid capture custom kit was designed using the Illumina DesignStudio. For every gene, all regions in which previous mutations had been described were covered. For 40 of these genes, the entire coding sequence was covered. Targeted deep sequencing was performed on a MiSeq-Sequencer using MiSeq Reagent Kit v2 (300 cycle) with 24 samples per run. There are 396 samples in this targetedDNAseq-dataset with 298 tumors (288 patients and 10 cell lines) and 98 normals. There are 132 female, 262 male, and 2 unknown gender samples in this dataset.

  Dataset EGAD00001007708

• Targetable NOTCH1 rearrangements in reninoma - RNA

  Reninomas are exceedingly rare renin-secreting kidney tumours that derive from juxtaglomerular cells, specialised smooth muscle cells that reside at the vascular inlet of glomeruli. They are the central component of the juxtaglomerular apparatus which controls systemic blood pressure through the secretion of renin. We assessed somatic changes in reninoma and found structural variants that generate canonical activating rearrangements of NOTCH1, whilst removing its negative regulator, NRARP. Accordingly, in single reninoma nuclei we observed excessive renin and NOTCH1 signalling mRNAs, with a concomitant non-excess of NRARP expression. Re-analysis of previously published reninoma bulk transcriptomes further corroborates our observation of dysregulated Notch pathway signalling in reninoma. Our findings reveal NOTCH1 rearrangements in reninoma, therapeutically targetable through existing NOTCH1 inhibitors, and indicate that unscheduled Notch signalling may be a disease-defining feature of reninoma.

  Dataset EGAD00001010889

• Acquisition of additional mutations drives accelerated progression of NPM1 positive CMML to AML

  This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/ We performed exome sequencing on serial samples from a patient with CMML who progressed to AML. The exome sequencing suggests that NPM1, TET2 and DNMT3a mutations were present in the dominant clone in the CMML sample and that NRAS is a new subclonal mutation in the AML sample. Diagnostic data shows the presence of a FLT3-ITD mutation in the AML sample, which is likely to have driven progression. Here we are performing re-sequencing of the putative driver and some passenger mutations which appear to be in the same clone to validate these mutations and to verify the relative quantification of these abnormalities .

  Dataset EGAD00001002194

• Targetable NOTCH1 rearrangements in reninoma

  Reninomas are exceedingly rare renin-secreting kidney tumours that derive from juxtaglomerular cells, specialised smooth muscle cells that reside at the vascular inlet of glomeruli. They are the central component of the juxtaglomerular apparatus which controls systemic blood pressure through the secretion of renin. We assessed somatic changes in reninoma and found structural variants that generate canonical activating rearrangements of NOTCH1, whilst removing its negative regulator, NRARP. Accordingly, in single reninoma nuclei we observed excessive renin and NOTCH1 signalling mRNAs, with a concomitant non-excess of NRARP expression. Re-analysis of previously published reninoma bulk transcriptomes further corroborates our observation of dysregulated Notch pathway signalling in reninoma. Our findings reveal NOTCH1 rearrangements in reninoma, therapeutically targetable through existing NOTCH1 inhibitors, and indicate that unscheduled Notch signalling may be a disease-defining feature of reninoma.

  Dataset EGAD00001010887

• Relevance of TMPRSS2, CD163/CD206 and CD33 in clinical severity stratification of COVID-19

  Our main objective is to incorporate new markers to classify COVID-19 patients based on mild or severe disease progression. To achieve this, we characterize SNP genotypes in critical genes involved in SARS-CoV infection (ACE2 (rs2285666), MX1 (rs469390), and TMPRSS2 (rs2070788) variants) and study the monocyte population by mass cytometry (CyTOF). Finally, the results obtained will be integrated to search for the best set of predictors of disease aggressiveness.

  Study EGAS00001007003

• Genetic scoring guide for personalized risk assessment in pediatric B-cell precursor Acute Lymphoblastic Leukemia

  In this study a next-generation sequencing based method was applied to comprehensively screen for recurrent, disease-relevant copy number aberrations in a cohort of Hungarian patients. Diagnostic bone marrow samples from 260 children with B-cell acute lymphoblastic leukemia and were investigated by digital multiplex ligation-dependent probe amplification using the disease-specific D007 probemix. Whole chromosome gains and losses, as well as subchromosomal copy number aberrations were simultaneously profiled.

  Study EGAS00001007239

• Whole Exome Sequencing of Congenital Diaphragmatic Hernia Patients and Trios

  Congenital diaphragmatic hernia (CDH) is a common and severe birth defect characterized by structural defects of the diaphragm and by pulmonary hypoplasia. Congenital diaphragmatic hernia patient may present either as an isolated phenotype or together with other congenital anomalies in a complex phenotype. Despite the clinical significance of CDH, the underlying genetic and developmental pathways are incompletely understood. In order to establish a catalog of human genetic variation for this condition, we performed whole exome sequencing (WES) on 275 carefully phenotyped individuals with CDH in the Pediatric Surgical Research Laboratories at the Massachusetts General Hospital (Boston, MA, USA) and Boston Children's Hospital (Boston, MA, USA). The exome data generated are valuable for comparison of candidate genes derived from WES of other CDH cohorts or affected kindreds, and to provide ideal candidates for further functional studies with the ultimate goal of enhancing our understanding of the heterogeneous and, possibly, oligogenic molecular etiology of CDH. While familial clustering has been reported in rare kindreds, the majority of probands with CDH have no family history of CDH leading to the hypothesis that de novo variants are an important and relatively frequent etiological mechanism. In the second version of the study, we performed WES analysis on 87 trios, to assess the contribution of de novo mutations in the etiology of diaphragmatic and pulmonary defects and to identify previously unknown candidate genes. This dbGaP submission includes WES data on: (a) 20 new probands, (b) 9 probands also reported in the previous version (dbGaP accession no. phs000783.v1.p1), (c) 174 unaffected parents, including the parents of 67 previously reported probands. Combined analysis with other available cohorts of congenital diaphragmatic hernia revealed a genome-wide enrichment of likely gene-disrupting de novo variants (i.e., nonsense, frameshift or splice site), and missense de novo variants predicted in silico to be damaging.

  Study phs000783

• Genetic Studies of Chronic Kidney Disease (CKD)

  The Genetic Studies of Chronic Kidney Disease (CKD) is an ongoing genetic research and biobanking protocol which aims to elucidate the genetic basis CKD. The study recruits patients seen at the Columbia University Medical Center (CUMC) Nephrology Division for the evaluation and care of CKD. All patients clinically diagnosed with CKD are eligible to participate; there are no inclusion or exclusion criteria related to age, sex/gender, and/or race/ethnicity. In addition to office visits, patients are recruited in contexts including perinatal care and nonprofit events for patients with various forms of CKD; recruitment tools include bilingual informational brochures, flyers, and consent forms. All individuals provide informed consent; for minors, signature of the parent/guardian is required. Consent includes: use of biosamples given for genetic studies, and the request to be re-contacted if medically actionable genetic findings are identified. In the case of the latter, such research-level findings are first validated in a clinically certified (CLIA) laboratory environment, using a second sample given by the individual at the time of re-contact; following CLIA validation, the individual is once again re-contacted, and, assuming he or she still desires return of these results, they can then be returned. Following the above consent process to participate in the study, individuals provide a single biosample (generally, a venous blood sample), from which DNA is extracted using standard protocols and used for genetic studies, such as exome sequencing. Basic clinical and demographic data, including sex/gender, age, and race/ethnicity are also collected. All data collected is stored in a secure computerized database, with patient samples anonymized using numerical identifiers; the relation of this identifier to patients' names is kept in a locked computer file in a centralized database. Electronic data complies with all HIPAA and other privacy and security regulations, and resides on a firewall server maintained by the CUMC IT department.

  Study phs001828

• Transcriptomic Analysis of HIV-Infected Cells

  Defining the attributes of rare CD4 T cells that harbor latent HIV under therapy with anti-retroviral agents has been challenging due to difficulties in identifying and isolating these cells. These cells represent an important barrier to cure, and characterizing them would aid the design and development of novel HIV cure strategies. In this study, we addressed this challenge using a custom microfluidic technology named Focused Interrogation of cells by Nucleic acid Detection and Sequencing (FIND-seq) that isolates HIV-infected cell transcriptomes, based on HIV DNA detection. We applied this method to HIV DNA+ memory CD4 T cells isolated from blood from five persons with HIV who were receiving anti-retroviral agents. After curating samples based on data quality, we proceeded with bioinformatics analysis from three persons. This analysis identified six transcriptomic pathways that were inhibited in HIV DNA+ cells compared to HIV DNA- cells. These included death receptor signaling, necroptosis signaling, and anti-proliferative G-alpha12/13 signaling. Furthermore, we identified two gene clusters, including 60 and 85 genes, that were significantly associated with HIV DNA+ cells identified by co-expression network analysis. These genes included negative regulators of HIV transcription that were higher in HIV DNA+ cells, positive regulators of HIV transcription that were lower in HIV DNA+ cells, and other genes involved in the negative regulation of mRNA translation, additional RNA processing functions, and the regulation of cellular state and fate. We further examined these signatures in transcriptomic data from CD4 T cell subsets sorted by flow cytometry from nine persons with HIV. We found a partial similarity between the smaller cluster of genes and the signature of CCR6- peripheral TFH cells. Raw sequencing data from all eleven human participant samples included in the study are available. These include samples from two participants who were studied only by FIND-seq, three participants who were studied by both FIND-seq and flow cytometry and six participants who were studied only by flow cytometry.

  Study phs003095

• GATA2 Deficiency and the MonoMAC Syndrome

  The aim of this study was to identify the germline mutation(s) in an extended family with individuals having MonoMAC Syndrome/GATA2 deficiency but lacking a canonical GATA2 mutation. GATA2 deficiency patients develop bone marrow failure, severe immunodeficiency and may progress to myeloid malignancies, including myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and chronic myelomonocytic leukemia (CMML). The definitive treatment for GATA2 deficiency is a bone marrow transplant. Approximately 90% of GATA2 deficiency patients have a known de novo or inherited germline mutation in the GATA2 gene, but ~10% have no identified mutation. The study was initiated with the first patient and her second cousin, both of whom were treated for MonoMAC Syndrome and received bone marrow transplants at the NIH. Pedigree analysis and clinical evaluation identified the individuals in several generations of these patients' near and distant relatives who are/were presenting or carrying the disease manifestations of GATA2 deficiency. Whole Genome Sequencing (WGS) was employed on these patients' two related nuclear families to identify variants that segregated with the disease trait and carrier status of their families. Genotyping was confirmed with direct DNA sequencing of these and other family members within the extended family across generations. A single base adenine-to-thymidine change was identified in a highly conserved enhancer element ~117,000 bp upstream of the GATA2 gene. It creates a new Composite Element, a DNA motif known to be critical in the regulation of hematopoiesis. This variant is unique to this family and is not present in dbSNP or other variant databases. It segregates with the disease trait and obligate carriers throughout a large pedigree. In vitro studies show that this variant drives allele-specific overexpression of the GATA2 gene in cultured cells and luciferase assays. The WGS sequence from the nuclear families will be shared on dbGaP.

  Study phs003269

• Genomic and Immune Profiling of Breast Cancer Brain Metastases

  Previous work has shown that breast cancer brain metastases (BCBrM) can have unique molecular profiles compared to extracranial tumors (ECTs), resulting in some patients demonstrating subtype switching between primary/extracranial tumors and brain metastases. Description of the biology of BCBrM and associations between biological features and clinical outcomes, particularly between molecular intrinsic subtypes, will facilitate the design of rational therapies for patients with BCBrM. To better characterize the molecular profiles of BCBrM, we conducted whole exome sequencing (WES) and total RNA sequencing (RNA-Seq) on BCBrM tissues, regardless of clinical or molecular subtype, obtained from a cohort of 42 patients from Duke University Medical Center. This cohort adds valuable patient samples to the field and enables strengthened investigation of somatic mutations, copy number alterations, gene expression profiles, and immune populations within and between BCBrM patients and other similar cohorts. The Duke BCBrM cohort includes clinical and molecular annotation of the 42 patient specimens and their associated WES and RNA-Seq data. Clinical and molecular (PAM50) intrinsic subtypes in ECTs and brain metastases were largely concordant within patients. There were observed differences in intrinsic subtype calls between frozen and FFPE specimens of the same tissue, with discordance mostly observed with LumB calls. Copy number alterations in chromosomal regions included clinically relevant genes, and somatic alterations were largely conserved within patients across matched samples, with few genes, including TP53, being recurrently altered in the majority of patient specimens. In matched FFPE brain metastasis and ECT samples, we observed differentially expressed genes and pathways that had increased or decreased expression in brain metastasis, including in oxidative phosphorylation and DNA repair. Survival outcomes for patients differed by intrinsic molecular subtypes, with some association between expression of select gene pathways and survival. Data available through dbGaP will be the sequencing data and sample attributes from BCBrM tissues obtained from 42 patients from Duke University Medical Center.

  Study phs003673

• Emirati Genome Project subset of 43,608 WGS samples for population-scale variant discovery and allele frequency mapping.

  Here, we present a comprehensive genomic characterization of a cohort of 43,608 Emirati genomes sequenced as part of the Emirati Genome Program (EGP). This study identified more than 421 million single nucleotide variants and indels and more than 600 million copy number- and structural variants. Small variants had 756 million molecular effects annotated. Of the identified variants, 69.04% were observed with more than one allele. Of 7.7 million polymorphic variants having an allele frequency (AF) of more than 5% in EGP, 1,348 have a predicted deleterious effect on a protein. Characterization of global variation reveals that EGP represents a genetic continuum encompassing the range of African, Asian, and European populations. It is best described by two Arabian, an Eurasian, and an African component, with the predominant Arabian component linked to mitochondrial haplogroups J and T, which are commonly attributed to the Middle East. Various aneuploidies of sex chromosomes were detected in 93 individuals overall and of chromosome 21 in 41 individuals. The median inbreeding coefficient and cumulative runs of homozygosity (ROHs) lengths were increased due to extensive consanguinity, being largest in the groups with Arabian main ancestry components and higher than reported for Qatar. Families were identified based on genetic relatedness and classified into 264 families with unrelated parents and 247 families with third- and fourth-degree consanguineous parents. Representative consanguineous pedigrees of families in EGP were outlined. Cumulative ROHs were affected by the main ancestry component and significantly increased in offspring of consanguineous parents, with a pronounced difference between 3rd and 4th-degree relatedness. Investigation of cumulative AFs of variants causing Mendelian diseases highlighted genes related to alpha- and beta-thalassemia (HBB, HBA2). It showed a high burden of variants causing severe recessive diseases, metabolic and retinal disorders, and hearing loss. In summary, EGP represents a landmark effort in characterizing the genetic diversity of the Emirati population, leveraging the largest Middle Eastern cohort reported to date.

  Study EGAS50000001071

• Human Dorsal Root Ganglion RNA Landscape Profiling for Neuropathic and Chronic Pain

  Bulk and spatial RNA sequencing were performed on human Dorsal Root Ganglia (DRGs), peripheral sensory nerves and nodose ganglia and relative gene abundances were calculated. Various analyses were performed: Human DRG gene expression profiles were contrasted with a panel of gene expression profiles of relevant tissues in human and mouse (integrating, among other sources, datasets from ENCODE and GTex) in order to identify. DRG-enriched gene expression, co-expression modules of DRG-expressed genes, and key transcriptional regulators in humans. Contrasting the human and mouse DRG transcriptomes to identify DRG-enriched gene expression patterns that were conserved between human and mouse, identifying putative cell types of expression of these genes, and potential known drugs that might target the corresponding gene products. Characterization of non-coding RNA profile of human and mouse DRGs. Characterization of DRG-enriched alternative splicing and alternative transcription start site usage based transcript variants in humans and mouse, and the overlap between these two species. Contrasting of human DRG and GTex human tibial nerve samples to identify putative axonally transported mRNAs in sensory neurons. Human DRG and peripheral nerves transcriptomes from donors suffering from neuropathic and/or chronic pain were contrasted with controls to identify. Differentially expressed genes, pathways and regulators path play a potential role in neuronal plasticity, electrophysiological activity, immune signaling and response. Predictive models (Random Forests) were built to jointly predict the sex and pain state of samples based on information contained solely in autosomal gene expression profile. Gene co-expression modules were identified and gene set enrichment analysis performed.to identify sample - pathway associations, and to broadly characterize plasticity in human DRG cell types. Spatial transcriptomics was performed on human DRGs and nodose ganglia to obtain near single-neuron resolution. We identified distinct clusters of human DRG sensory neurons. We characterized the expression of different gene families (e.g., GPCRs, sodium channels, potassium channels, etc.). We investigated differences between male and female neurons.

  Study phs001158

• Molecular analysis of diffuse cerebellar gliomas

  Among diffuse gliomas, oligodendrogliomas show relatively better prognosis, respond well to radiotherapy and chemotherapy, and seldom progress to very aggressive tumors. To elucidate the genetic and epigenetic background for such behavior and tumor evolution during tumor relapse, we comparatively analyzed 12 pairs of primary and recurrent oligodendrogliomas with 1p/19q-codeletion. Initial treatment for these patients was mostly chemotherapy alone. Temozolomide was used for 3, and procarbazine, nimustine and vincristine (PAV chemotherapy) were used for 7 patients. World Health Organization histological grade at recurrence was mostly stable; it was increased in 2, the same in 9, and decreased in 1 cases. Whole-exome sequencing demonstrated that the rate of shared mutation between the primary and recurrent tumors was relatively low, ranging from 3.2-57.9% (average, 33.3%), indicating a branched evolutionary pattern. The trunk alterations that existed throughout the course were restricted to IDH1 mutation, 1p/19q-codeletion, and TERT promoter mutation, and mutation of the known candidate tumor suppressor genes CIC and FUBP1 were not consistently observed between primary and recurrent tumors. Multiple sampling from different regions within a tumor showed marked intratumoral heterogeneity. Notably, in general, the number of mutations was not significantly different after recurrence, remaining under 100, and no hypermutator phenotype was observed. FUBP1 mutation, loss of chr. 9p21, and TCF12 mutation were among a few recurrent de novo alterations that were found at recurrence, indicating that these events were clonally selected at recurrence but were not enough to enhance malignancy. Genome-wide methylation status, measured by Illumina 450 K arrays, was stable between recurrence and the primary tumor. In summary, although oligodendroglioma displays marked mutational heterogeneity, histological malignant transformation accompanying events such as considerable increase in mutation number and epigenetic profile change were not observed at recurrence, indicating that noticeable temporal and spatial genetic heterogeneity in oligodendrogliomas does not result in rapid tumor progression.

  Study JGAS000106

• Genetic_Heterogeneity_of_the_familial_gastric_neuroendocrine_tumors

  Gastric neuroendocrine tumors (gNETs) occur with an estimated frequency of 2 per 100,000 in the general population. Type I gastric neuroendocrine tumors (NETs) represent the 75% of gNTEs and arise from gastric enterochromaffin-like (ECL) cells. They have late age of onset and usually benigh course. Classically, hypergastrinemia in patients who have autoimmune atrophic gastritis, causes hyperplasia of gastric ECL cells that progresses into type I gastric NETs and parietal cell (PC) destruction. The genetic bases in families with this disease are unknown. We performed an exome sequencing study of an atypical aggressive familial gNETs case (with early age onset, nodal infiltrations and gastric adenocarcinomas) that followed a recessive model. We identified a deleterious mutation in homozygosis in the ATP4A gene, which encodes the proton pump responsible for acid secretion by gastric parietal cells. This mutation lead to achlorhydria first, and hypergastrinemia and gNET developing as consequence (Calvete et al. 2014). Recently, two more families with gNETs, classical clinical traits and recessive model have been studies by WES but we didn't find any mutation in the ATP4a gene. However, putative mutations affecting genes that contribute to the development and the integrity of PC have been found suggesting that genetic alterations associated to this disorder target to a unique cell type (parietal cells). In order to cinfirm this hypothesis, it is necessary the search for new genes implicated in the gNETs, more familial cases are needed to be studied. We have identified four more new familial gNETs cases. Here, we propose their study by WES. The first family is formed by thress siblings with gNETs. The other families include two siblings with gNETs. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001002273

• Next-Generation Sequencing of RNA and DNA Isolated from Paired Fresh-Frozen and Formalin-Fixed Paraffin-Embedded Samples of Human Cancer and Normal Tissue

  Formalin-fixed, paraffin-embedded (FFPE) tissues are an invaluable resource for clinical research. However, nucleic acids extracted from FFPE tissues are fragmented and chemically modified making them challenging to use in molecular studies. We analysed 23 fresh-frozen (FF), 35 FFPE and 38 paired FF/FFPE specimens, representing six different human tissue types (bladder, prostate and colon carcinoma; liver and colon normal tissue; reactive tonsil) in order to examine the potential use of FFPE samples in next-generation sequencing (NGS) based retrospective and prospective clinical studies. Two methods for DNA and three methods for RNA extraction from FFPE tissues were compared and were found to affect nucleic acid quantity and quality. DNA and RNA from selected FFPE and paired FF/FFPE specimens were used for exome and transcriptome analysis. Preparations of DNA Exome-Seq libraries was more challenging (29.5 % success) than that of RNA-Seq libraries, presumably because of modifications to FFPE tissue-derived DNA. Libraries could still be prepared from RNA isolated from two-decade old FFPE tissues. Data were analysed using the CLC Bio Genomics Workbench and revealed systematic differences between FF and FFPE tissue-derived nucleic acid libraries. In spite of this, pairwise analysis of DNA Exome-Seq data showed concordance for 70-80 % of variants in FF and FFPE samples stored for fewer than three years. RNA-Seq data showed high correlation of expression profiles in FF/FFPE pairs (Pearson Correlations of 0.90 +/- 0.05), irrespective of storage time (up to 244 months) and tissue type. A common set of 1,494 genes was identified with expression profiles that were significantly different between paired FF and FFPE samples irrespective of tissue type. Our results are promising and suggest that NGS can be used to study FFPE specimens in both prospective and retrospective archive-based studies in which FF specimens are not available.

  Study EGAS00001000737

• Deep single-cell RNA sequencing data for 11138 T cells from tumour, adjacent normal tissue and peripheral blood of treatment-naive CRC patients. The DATA ACCESS AGREEMENT is provided at https://github.com/zhangyybio/single-T-cell-data-access. Applicants can request access to the data by directly downloading it or by sending an email to cancerpku@pku.edu.cn. The process that is used to approve an application includes verifying the institution, participants and research purposes of the application. In general this process will take about two weeks. In principal, any scientific research program complying with the laws and bioethic regulation policies of China will be approved.

  T cells are central players in cancer immunotherapy1, yet some of their fundamental properties such as development and migration within tumours remain elusive. The enormous T cell receptor (TCR) repertoire, required for recognising foreign and self-antigens2,3, could serve as lineage tags to track these T cells in tumours4. Here, we obtained transcriptomes of 11,138 single T cells from 12 colorectal cancer (CRC) patients and developed STARTRAC (Single T-cell Analysis by Rna-seq and Tcr TRACking) indices to quantitatively analyse dynamic relationships among 20 identified T cell subsets with distinct functions and clonalities. While both CD8+ effector and “exhausted” T cells exhibited high clonal expansion, they were independently connected with tumour-resident CD8+ effector memory cells, implicating a TCR-based fate decision. Of the CD4+ T cells, the majority of tumour-infiltrating Tregs showed clonal exclusivity, whereas certain Treg clones were developmentally linked to multiple TH clones. Notably, we identified two IFNG+ TH1-like clusters in tumours, the GZMK+ TEM and CXCL13+ TH1-like clusters, which were associated with distinct IFN-γ-regulating transcription factors, EOMES/RUNX3 and BHLHE40, respectively. Only CXCL13+BHLHE40+ TH1-like cells were preferentially enriched in tumours of microsatellite-instable (MSI) patients, which might explain their favourable response rates to immune-checkpoint blockade. Furthermore, we found IGFLR1 to be highly expressed in both CXCL13+BHLHE40+ TH1-like and CD8+ exhausted T cells and possessed co-stimulatory functions. Our integrated STARTRAC analyses provides a powerful avenue to comprehensively dissect the T cell properties in CRC, which could shed new insights into the dynamic relationships of T cells in other cancers

  Study EGAS00001002791

• A common single nucleotide variant in T is strongly associated with chordoma

  Chordoma is a rare malignant bone tumor that expresses the transcription factor T. We conducted an association study of 40 patients with chordoma and 358 ancestry-matched, unaffected individuals with replication in an independent cohort. Whole-exome and Sanger sequencing of T exons reveals a strong risk association ( allelic odds ratio (OR) = 4.9, P = 3.3x10-11, CI= 2.9-8.1) with the common (minor allelic frequency >5%) non-synonymous SNP rs2305089 in chordoma, which is exceptional in cancer genetics.

  Dataset EGAD00001000226

• Targeted sequencing (paired) of HR genes in primary and metastatic patient-derived xenografts (PDXs) of colorectal cancer (CRC)

  The dataset includes DNA targeted paired-wise (2 FASTQ per sample) sequencing of a manually curated panel of 44 genes with a documented role in homologous recombination (HR), a pathway of DNA damage response. Sequencing was conducted in 69 tumors from patients with metastatic colorectal cancer after serial passaging in mice (patient-derived xenografts, PDXs). For each PDX model profiled for HR gene mutations, therapeutic annotation of response to FOLFIRI (a chemotherapeutic regimen consisting of the combination of 5-fluorouracil and irinotecan) is available.

  Dataset EGAD50000000107

• Proteogenomic Landscape of Squamous Cell Lung Cancer

  To provide a detailed analysis on how genomic and transcriptomic alterations related to proteome level changes in squamous cell lung cancer (SCC), we performed an integrated analysis incorporating DNA copy number, somatic mutations, expression RNA-sequencing, and expression proteomics in 108 SCC nested within clinical outcome, tumor pathology, and other clinically relevant data.

  Study phs001781

• Contribution of Genetic Polymorphisms to the Abuse Liability of Oxycodone

  The proposed study examined the prevalence of various genetic polymorphisms thought to be involved in opioid abuse among current heroin users. In addition to providing blood samples for genetics analysis, participants completed a number of questionnaires that allowed us to learn detailed information about their current and history of opioid drug use.

  Study phs001559

• Cancer Risk Estimates Related to Susceptibility Genes (CARRIERS)

  The CARRIERS study utilized custom amplicon-based variant screening of known cancer predisposition genes in germline DNA from breast cancer cases and age matched unaffected controls taken from predominantly cohort-based breast cancer case-control studies to establish the risks of breast cancer associated with pathogenic variants in these genes.

  Study phs002820

• Metabolism and Genetics of Hypobetalipoproteinemia

  Hypobetalipoproteinemia is characterized by extremely low levels of low-density lipoprotein cholesterol. Familial hypobetalipoproteinemia (FHBL) is a monogenic form of hypobetalipoproteinemia caused by mutations in the APOB gene. There are cases of hypobetalipoproteinemia not caused by mutations in APOB, however. The purpose of this study is to identify novel genetic causes of hypobetalipoproteinemia.

  Study phs000561

• B Cell Receptor Study From Early Breast Cancer Tumour Samples

  B and T cells are key components of the adaptive immune system and play an important role in anti-cancer immunity. In this study, we performed an integrative analysis of the B cell and T cell repertoires across 25 serial breast tumour biopsies from 10 patients during neoadjuvant therapy.

  Study EGAS50000000241

• CHEK2 molecular manuscript

  This study investigated the molecular landscape of 17 tumors from 9 individuals with biallelic germline pathogenic variants in CHEK2. Tumors included breast and non-breast cancers, and WES and sWGS bam files from the tumors are included in this submission. WES data was aligned to GRCh37 and sWGS data to GRCh38.

  Study EGAS50000000080

• Breakfast trial transcriptomic profiles

  The dataset consists in fastq files generated with RNA sequencing of 55 samples from 29 patients with stage I-III TNBC treated with anthracycline-taxane chemotherapy plus fasting-mimicking diet plus/minus metformin in the context of the BREAKFAST trial (NCT04248998). Samples are fresh-frozen tumor samples at baseline and 14-21 days after the first treament cycle sequenced to identify early predictors of treatment activity. Each sample is sequenced in multiple lanes (four or eight lanes each) and in paired ends mode (R1 and R2 fastq files). Samples were sequenced by an Illumina Nextseq500 platform.

  Dataset EGAD50000000968

• Patient-Derived Follicular Lymphoma Spheroids recapitulate lymph node signaling and immune profile, uncovering galectin-9 as a novel immunotherapeutic target

  RNA-seq data from CD20+ sorted cells obtained from peripheral blood and lymph node Follicular Lymphoma patients. These samples were unstimulated after thawing and additionally, peripheral blood samples were stimulated during 7 days in culture as described in Dobaño-López C et. al.)

  Study EGAS50000000233

• RNASeq from PC12 cell lines (derived from PPGL) cultivated under 21% (normoxia) and 1% (hypoxia) oxygen conditions.

  RNASeq fastq files from PC12 cells (derived from rat PPGL) were cultivated in normoxia conditions (37˚C, 5% CO2 and 21% O2 balanced with N2) or in hypoxia conditions in a hypoxic incubator (37˚C, 5% CO2 and 1% O2 balanced with N2), for short time (12h, 24h, and 48h) or prolonged time (36 days). Samples at each timepoint were cultured in triplicate (total 24 paired end fastq files). Sequencing was performed with the Illumina NovaSeq6000.

  Dataset EGAD50000001200

• RNA-seq of granulosa cells from 8 IVF patients in two age groups

  This dataset contains raw sequencing data of mRNA from granulosa cell samples from 8 human patients undergoing in vitro fertilization. All patients were normal responders referred for male infertility and were grouped into two age groups (younger than 31 or older than 38 years old). Each sample contains all granulosa cells collected from one patient on one collection date. Raw sequencing fastq files are available in this dataset, count tables are available in ArrayExpress (E-MTAB-13496).

  Dataset EGAD50000001210

• Admixture histories of São Tomé e Príncipe.

  In this study, we aim to reconstruct the complex genetic admixture histories of the population of São Tomé e Príncipe, an archipelago in the Gulf of Guinea that experienced successive waves of forced and deliberate migration from Africa since the 15th century, during and after the Trans-Atlantic Slave Trade.

  Study EGAS50000000920

• Dataset of DNA methylation profiles of 189 pediatric central nervous system, soft tissue, and bone tumors

  The research of CNS tumors brought knowledge about the role of epigenetics in these tumors. Certain subgroups of tumors are defined solely by their epigenetic profiles. In this study we carried on epigenetic profiling using targeted methylation sequencing of aproximately 180 pediatric CNS and Sarcoma tumor samples.

  Study EGAS50000000051

• WGS of Five Pancreatic Cancer Patients-Tumor and Normal

  We performed whole genome sequence on tumor-derived and normal cell lines from patients who had terminal pancreatic cancer and consented for rapid autopsy upon their death. The 5 samples are from Dr. Christine Iacobuzio-Donahue's rapid autopsy program as reported in Boland et al. (PLOSOne, 2024, In Press, PMID 38352348).

  Study phs003775

• SF3B1 splicing signature

  We describe individuals with de novo pathogenic variants in SF3B1. SF3B1 is a core component of the U2 snRNP complex that ensures accurate branchpoint and 3′ splice-site recognition, and its mutations induce aberrant splicing that contributes to tumorigenesis, notably in myelodysplastic syndromes. We aim to study splicing defects associated with constitutional pathogenic variants.

  Study EGAS50000001473