10850 results for "800k fc coins Navštivte Buyfc26coins.com Speciální balíčky na prázdniny a dovolené..dQVy"

in 34.22 milliseconds.

• Tourette International Collaborative Genetics (TIC Genetics) Study - NJCTS and NIMH

  The Tourette International Collaborative Genetics (TIC Genetics) Study is an international collaboration of scientists and clinicians specialized in Tourette Disorder (TD) from more than 20 sites across the United States, Europe, and South Korea. The study was established to further our understanding of the genetic architecture of tic disorders by developing a large sample of genotypically and phenotypically well-characterized affected probands and their relatives. We employ state-of-the-art genetic technologies to identify major genetic variants contributing to TD and the most commonly comorbid disorders, such as Obsessive-Compulsive Disorder (OCD) and Attention-Deficit/Hyperactivity Disorder (ADHD). TIC Genetics is a direct result of work of the New Jersey Center for Tourette Syndrome (NJCTS) Sharing Repository (Heiman et. al., 2008; PMID: 19036136), funded by a grant from NJCTS Center of Excellence. Established in 2011 (Dietrich et. al., 2015; PMID: 24771252), the TIC Genetic study focuses on both on familial genetic variants with large effects within multiplex affected pedigrees and on de novo mutations ascertained through the analysis of apparently simplex parent-child trios with non-familial tics. In May 2017, we published a whole-exome sequencing study on apparently 311 parent-child trios (Willsey et. al., 2017; PMID: 28472652). These data, both phenotypes and sequencing data, are available through dbGaP. There were 120 subject samples included in the publication that did not have consent for sharing. These are excluded from dbGaP.In November 2021, we published a whole-exome sequencing study on 13 multiplex TD families (Cao et. al., 2021). These data, both phenotypes and sequencing data, are available through dbGaP.

  Study phs001423

• Asian Immune Diversity Atlas (AIDA) sQTL

  Current efforts within the Human Cell Atlas (HCA) are largely focused on defining reference human cell types using a relatively small number of samples of predominantly European origin. However, the next phase of the HCA is likely to address the topic of human diversity by comprehensively characterizing variation in cell states across age, sex, population groups, diseases and environments. To spur this next phase, and also expand the geographical scope of the HCA, we propose an HCA-Asia seed network to generate an Asian Immune Diversity Atlas (AIDA). AIDA will generate transcriptome variation datasets from 5 major Asian population groups (Chinese, Japanese, Korean, Indian, Malay), define an atlas of Asian cell types and states, and characterize their variation associated with ethnicity, age and sex. We will also formalize a study design based on common controls that can in principle reduce technical artifacts in a broad range of comparative single cell studies. This study design will be complemented with novel algorithms designed to normalize datasets of interest against the common controls, to increase the robustness of biological inferences. In addition to providing new tools and resources to the HCA, this seed network will serve as a template for future comparative studies in the single cell field.The AIDA dataset consists of scRNA-seq (10x 5′ v2 scRNA-seq) and genotype (Illumina Infinium Global Screening Array v.3) data. In the AIDA splicing quantitative trait loci (sQTL) project, we identified 11,577 independent cis-sQTLs, 607 trans-sQTLs, and 107 dynamic sQTLs. The post-imputation genotype for the Japanese and Korean cohort will be available through dbGaP. The Singaporean (ethnically Chinese, Indian and Malay) genotypes require a data access application to the HELIOS Data Access Committee (helios_science@ntu.edu.sg). European samples are used as control.

  Study phs003848

• Genomic and epigenomic characterization of juvenile myelomonocytic leukemia (JMML)

  Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative disorder of early childhood. While some cases show spontaneous remission, allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative treatment option for the majority of patients, however, the 5-year event-free survival reaches only about 50%. Hyperactive RAS signaling is assumed to be the main driving event in JMML. It is caused by genetic alterations in CBL, KRAS, NF1, NRAS, or PTPN11 in about 90% of patients. So far, there is no clear understanding of how RAS pathway mutations relate to the heterogeneous disease biology and variable clinical outcome seen in JMML patients. As a consequence, established clinical and genetic markers fail to fully represent the observed disease heterogeneity. We hypothesized that DNA methylation profiling, either alone or in combination with genetic alterations, might provide a molecular basis for disease classification. Genome wide DNA methylation analysis using the HumanMethylation450 Bead Chip array was performed in a discovery cohort of 20 patients (19 JMML, 1 Noonan syndrome). The clinical relevance of our findings was assessed in an unselected sample set consisting of 147 consecutive patients with JMML (n=129) or Noonan syndrome (n=18) associated myeloproliferative disorder (n=18) registered in the EWOG-MDS 1998 & 2006 trials. Data integration was performed in a subset of patients with available exome sequencing (n=50) and expression profiling (n=15) data. This integrated approach identified three JMML subgroups characterized by distinct clinical and biological features. This analysis further suggested a molecular mechanism by which additional genetic events, presumably further activating the RAS-RAF-MEK-ERK pathway, mediate DNA hypermethylation via up-regulation of DNMTs in more aggressive JMML cases.

  Study EGAS00001002511

• Circulating Tumor DNA in Checkpoint Inhibitor treated Lung Cancer

  BackgroundImmune checkpoint inhibitors (ICI) are increasingly used to treat non-small cell lung cancer (NSCLC) and there is a critical need for novel predictive/prognostic biomarkers. We evaluated whether dynamics of circulating tumor (ctDNA) can identify NSCLC patients who benefit from single agent ICI.MethodsCirculating cell-free DNA (cfDNA) from 177 patients was analyzed prior ICI and at first treatment evaluation using a Commercial 77-gene panel. We performed de novo mutation calling and corrected for variants related clonal hematopoiesis. ctDNA changes were evaluated as predictors of tumor response estimated with PET/diagnostic CT and survival.ResultsMutations were detected in 159 of 174 (91.4%) analyzable patients. Most responders presented decreasing ctDNA levels, while non-responders had mixed molecular responses. Patients with a >50% molecular ctDNA decrease or no detectable ctDNA demonstrated improved PFS (5.9 versus 1.8 months; HR 0.49, 95%CI, 0.35-0.67, P < .001), and OS (18.9 versus 9.9 months; HR 0.41, 95%CI, 0.30-0.57, P < .001) compared to patients not achieving these endpoints. Clearance of mutations (and no detected ctDNA) had a similar effect (PFS HR 0.45, 95%CI, 0.32-0.61, P < .001; OS 0.37,95%CI, 0.27-0.52, P < .001) compared to patients having stable or additional mutations. After adjusting for clinical factors both >50% ctDNA decrease (HR 0.4, 95% CI, 0.3-0.6, P < .001) and clearance of mutations (HR 0.42, 95% CI, 0.3-0.6, P < .001) remained independent predictors for PFS and OS.ConclusionsctDNA testing reveals significant prognostic albeit not predictive information in ICI treated advanced NSCLC. This relevant information can be obtained with a commercial easy-to-implement ctDNA test that will facilitate extensive testing.

  Study EGAS00001004847

• Confronting historical legacies of biological anthropology in South Africa—Restitution, redress and community-centered science: The Sutherland Nine

  We describe a process of restitution of nine unethically acquired human skeletons to their families, together with attempts at redress. Between 1925–1927 C.E., the skeletonised remains of nine San or Khoekhoe people, eight of them known-in-life, were removed from their graves on the farm Kruisrivier, near Sutherland in the Northern Cape Province of South Africa. They were donated to the Anatomy Department at the University of Cape Town. This was done without the knowledge or permission of their families. The donor was a medical student who removed the remains from the labourers’ cemetery on his family farm. Nearly 100 years later, the remains are being returned to their community, accompanied by a range of community-driven interdisciplinary historical, archaeological and analytical (osteobiographic, craniofacial, ancient DNA, stable isotope) studies to document, as far as possible, their lives and deaths. The restitution process began by contacting families living in the same area with the same surnames as the deceased. The restitution and redress process prioritises the descendant families’ memories, wishes and desire to understand the situation, and learn more about their ancestors. The descendant families have described the process as helping them to reconnect with their ancestors. A richer appreciation of their ancestors’ lives, gained in part from scientific analyses, culminating with reburial, is hoped to aid the descendant families and wider community in [re-]connecting with their heritage and culture, and contribute to restorative justice, reconciliation and healing while confronting a traumatic historical moment. While these nine individuals were exhumed as specimens, they will be reburied as people.

  Study EGAS50000000971

• 'Targeted High Throughput Sequencing in Clinical Cancer Settings: Formaldehyde fixed-paraffin embedded (FFPE) tumor tissues, input amount and tumor heterogeneity'

  "Background: Massively parallel sequencing technologies have brought an enormous increase in sequencing throughput. However, these technologies need to be further improved with regard to reproducibility and applicability to clinical samples and settings. Methods: Using identification of genetic variations in prostate cancer as an example we address three crucial challenges in the field of targeted re-sequencing: Small nucleotide variation (SNV) detection in samples of formalin-fixed paraffin embedded (FFPE) tissue material, minimal amount of input sample and sampling in view of tissue heterogeneity.Results: We show that FFPE tissue material can supplement for fresh frozen tissues for the detection of SNVs and that solution-based enrichment experiments can be accomplished with small amounts of DNA with only minimal effects on enrichment uniformity and data variance. Finally, we address the question whether the heterogeneity of a tumor is reflected by different genetic alterations, e.g. different foci of a tumor display different genomic patterns. We show that the tumor heterogeneity plays an important role for the detection of copy number variations, but is of minor importance for the detection of somatic variations.Conclusions: The application of high throughput sequencing technologies in cancer genomics opens up a new dimension for the identification of disease mechanisms. In particular the ability to use small amounts of FFPE samples available from surgical tumor resections and histopathological examinations facilitates the collection of precious tissue materials. However, care needs to be taken in regard to the locations of the biopsies taken, which can have an influence on the prediction of copy number variations. Bearing these technological challenges in mind will significantly improve many large-scale sequencing studies and will - on a long-range - result in a more reliable prediction of individual cancer therapies."

  Study EGAS00001000136

• Enhancer profiling identifies epigenetic markers of endocrine resistance and reveals therapeutic options for metastatic castration-resistant prostate cancer patients (LuCaP cell line data)

  Androgen Receptor (AR) signaling inhibitors, including enzalutamide, are treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC), but resistance inevitably develops. Using metastatic samples from a prospective phase II clinical trial, we epigenetically profiled enhancer/promoter activities with H3K27ac chromatin immunoprecipitation followed by sequencing, before and after AR-targeted therapy. We identified a distinct subset of H3K27ac-differentially marked regions that associated with treatment responsiveness. These data were successfully validated in mCRPC patient-derived xenograft models (PDX). In silico analyses revealed HDAC3 as a critical factor that can drive resistance to hormonal interventions, which we validated in vitro. Critically, we identified the pan-HDAC inhibitor, vorinostat to be effective in decreasing tumor cell proliferation both in vitro and in vivo. Moreover, we uncovered evidence for HDAC3 working together with Glucocorticoid Receptor (GR) as a potential mechanism for this therapeutic effect. These findings demonstrate rationale for new therapeutic strategies including HDAC inhibitors to improve patient outcome in advanced stages of mCRPC. Project Goal: We identified H3K27ac regions associated with resistance in patient samples. Extensive analysis of these regions suggested that HDAC3 may play a role in resistance. To test this, we analyzed ChIP-seq and RNA-seq from cell lines generated from PDX LuCaP samples (recapitulating resistant and non-resistant) to validate findings in patient samples. ChIP-seq samples were used to verify the signals identified from specific factors, such as H3K27ac, AR, FOXA1, GR and HDAC3, their association with resistance and possible mechanisms of action. RNA-seq samples were analyzed to determine the effect of AR signaling in these samples in specific genes in the H3K27ac resistance-associated regions.

  Study EGAS50000000917

• Exploiting immune cell receptor information to quantify index switching in single cell transcriptome sequencing experiment

  By offering high sequencing speed and ultra-high-throughput at a low price, Illumina next-generation sequencing platforms has been widely adopted in recent years. However, an experiment with multiplexed library could be at risk of molecular recombination, known as “index switching”, which causes certain amount of reads to be assigned to an incorrect library. It is reported that a new advance, exclusion amplification (ExAmp) in conjunction with the patterned flow cell technology introduced on HiSeq 3000/HiSeq 4000/HiSeq X sequencing systems, potentially suffers from a higher rate of index switching than conventional bridge amplification. We took advantage of the diverse but highly cell-unique expression of immune cell receptors to quantify index switching on single cell RNA-seq data that were sequenced on HiSeq 3500 and HiSeq 4000. By utilizing the unique T-cell receptor (TCR) expression, we could quantify the spread-of-signal from many different wells (n=51 from total three batches) due to index switching. We used TraCer to reconstruct full-length TCR from all samples, and then used Kallisto to quantify TCR gene expression. We found index switching in all three batches of experiments investigated. The median percentage of incorrectly detected markers was estimated to be 4.2% (interquartile range (IQR): 2.0%-8.7%). We did not detect any consistent pattern of certain indices to be more prone for switching than others, suggesting that index switching is a stochastic process. We confirm that index switching is a problem that affects all samples run in multiplexed libraries on Illumina HiSeq 3500 and HiSeq 4000 platforms.

  Study EGAS00001002911

• Bladder cancer subtyping study across 4 atezo clinical trials

  Checkpoint inhibitors targeting the PD-1/PD-L1 interaction have revolutionized cancer therapy across many indications. In urothelial carcinoma (UC), several PD-1/PD-L1 inhibitors have been approved for treatment in localized and metastatic disease. While these agents provide durable clinical benefit in a number of patients, the majority do not respond. A better understanding of the molecular mechanisms underlying response and resistance is needed to tailor existing treatments and develop new therapeutics in UC. We profiled tumors from 2803 patients from four late-stage randomized clinical trials evaluating the PD-L1 inhibitor atezolizumab in metastatic UC and muscle-invasive bladder cancer by RNA-seq, a targeted DNA panel, immunohistochemistry, and digital pathology. A machine learning algorithm identified four UC transcriptional subtypes, representing luminal desert, stromal, immune, and basal tumors. Overall survival benefit from atezolizumab over standard-of-care was observed in immune and basal tumors (45% of patients). Digital pathology showed enrichment of human interpretable features in specific molecular subtypes, and a self-supervised approach could classify molecular subtypes from H&E slides with high accuracy, suggesting that machine-based image interpretation could accelerate tumor molecular profiling. Somatic alterations showed limited capacity to identify responders. Finally, mechanisms of benefit with PD-L1 blockade appeared different in immune and basal tumors, with immune tumors benefiting from B/plasma cell enrichment, while basal tumors benefited from granulocyte enrichment. This study represents the largest integration of UC molecular and curated clinical data in randomized clinical trials to date, paving the way for prospective clinical studies tailoring treatment regimens to specific tumor molecular subtypes in UC and other indications.

  Study EGAS50000000497

• Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma

  Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases. To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway were identified in 44% of tumours (21/48). Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications. Mutations in ATRX (alpha-thalassaemia/mental retardation syndrome X-linked) and DAXX (death-domain associated protein), encoding two subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres, were identified in 31% of samples overall, and in 100% of tumours harbouring a G34R or G34V H3.3 mutation. Somatic TP53 mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n=784) showed H3F3A mutations to be specific to GBM and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. This is, to our knowledge, the first report to highlight recurrent mutations in a regulatory histone in humans, and our data suggest that defects of the chromatin architecture underlie paediatric and young adult GBM pathogenesis.

  Study EGAS00001000226

• Tumor-derived cell lines as pharmacogenomic models to predict therapeutic vulnerabilities in hepatocellular carcinoma

  Hepatocellular carcinoma (HCC) is a heterogeneous aggressive malignancy with low efficacy of current therapies at advanced stages. We integrated molecular and pharmacological profiling of a large panel of liver cancer cell lines (LCCL) to assess their clinical relevance as HCC preclinical models and identify new effective therapies and biomarkers of response. We performed multi-omic analysis including whole-exome, RNA and miRNA sequencing and quantification of 126 proteins in a series 34 LCCL coupled with a screening of 29 anti-cancer agents. Molecular profiles of LCCL and primary HCC were compared and we searched for molecular features associated with drug response. Our panel of LCCL faithfully recapitulated the most aggressive molecular "proliferation class" of HCC. Genomic alterations of the RAS-MAPK pathway correlated with trametinib sensitivity that was more potent than FGFR4 inhibitors in tumor cells depending on the FGF19/FGFR4 pathway. Moreover, we showed that FGF19 amplification was only functional in tumor cells that retained a hepatocyte differentiation program with expression of FGFR4, KLB and NR1H4 highlighting the complex interplay between the genomic and transcriptomic context in drug response. We also identified drugs/combination that could target efficiently the transcriptomic "progenitor subclass of HCC", as well as specific genetic contexts such as inactivating mutations in TSC1/TSC2 and TP53 associated with higher sensitivity to the mTOR inhibitor rapamycin and the AURKA inhibitor alisertib, respectively. LCCL represent relevant preclinical models for drug-biomarker discovery in HCC and enabled to identify molecular contexts linked with particular therapeutic vulnerabilities that may be useful to stratify patients in future clinical trials

  Study EGAS00001003536

• Matching of actionable mutations with therapies in cancer patients: comparison of three commercial decision support platforms

  Purpose: In oncology, precision medicine centers on tailoring the most appropriate therapy to a patient according to their tumor molecular profile. We addressed the question whether there is a consensus in the classification of actionability of somatic variants and their alignment to treatment recommendations. To this end, we evaluated three commercial clinical decision support tools to assess their variant classification and drug matching strategies.Methods: In this two centers study 48 patients with metastatic breast (n=12), colorectal (n=17) or non-small cell lung cancer (n=19) were recruited based on circulating tumor DNA levels in peripheral blood. In individual patients’ plasma samples, we established somatic copy number alterations and somatic mutations across a 77 cancer-associated gene panel and exposed the obtained molecular profiles to the decision support packages NAVIFY Mutation Profiler (NMP; Roche), Qiagen Clinical Insight (QCI) Interpret (Qiagen) and CureMatch Bionov (CureMatch).Results: In the plasma samples, altogether 492 somatic alterations were assessed. Each decision support platform varied in their format of data input, mode of variant classification and strategies for identifying druggable targets and clinical trials, which resulted in discrepancies in tier classification as well as designations of actionability. The frequency of concordant actionable events for tier I-A or tier I-B classifications, i.e. those with the strongest clinical evidence, was only 4.3%, 9.5% and 28.4% when comparing NMP with QCI, NMP with CureMatch, and CureMatch with QCI, respectively. As a consequence, the obtained treatment recommendations differed drastically, and alignment of treatment recommendations was limited to established predictive markers.Conclusions: The lack of standards for the extraction of treatment recommendations from comprehensive tumor molecular profiling data challenge the promising concepts of precision oncology.

  Study EGAS00001004383

• Spiradenocarcinoma

  • Spiradenocarcinoma is a rare cutaneous sweat gland adnexal cancer with potential for aggressive behaviour. They are classified histologically into low- and high-grade tumours, with morphologically low-grade tumours thought to behave more favourably. However, limited information is available, with only 18 published cases. • We have collected morphologically low-grade spiroadenocarcinomas (one with a lung metastasis) and high-grade spiroadenocarcinomas, as well as some spiradenomas (benign lesions), cylindromas (another type of malignant cutaneous sweat gland adnexal tumour) and hybrid spiradenoma-cylindromas. • H&E-stained sections were reviewed, follow-up was obtained, and immunohistochemistry for Ki-67, p53 and, MYB has been performed. The tumours were solitary, measuring 0.8-7?cm (median: 2.7?cm), with a predilection for the head and neck of elderly patients (median age: 72 years; range 53-92) without gender bias. Histologically, the tumours were multinodular and located in deep dermis and subcutis. A pre-existing spiradenoma was present in all cases. The malignant component was characterized by expansile growth with loss of the dual cell population, up to moderate cytological atypia and increased mitotic activity (median: 10/10 HPF; range 1-28). Additional findings included squamoid differentiation (n=9), necrosis (n=7), and ulceration (n=5). P53 expression was variable and no significant differences were noted in the benign compared with the malignant parts of the tumours. In contrast, in the malignant components the Ki-67 proliferative index was slightly increased, and MYB expression was lost. Follow-up (median: 67 months; range: 13-132) available for 16 patients (84%) revealed a local recurrence rate of 19% but no metastases or disease-related mortality. • Here we wish to exome sequence these cases to define the first genomic landscape for this malignancy.

  Study EGAS00001001799

• Genetic Risk for Subsequent Neoplasms among Long-term Survivors of Childhood Cancer in the St. Jude Lifetime Cohort

  While childhood cancer survivors are known to be at increased risk of subsequent neoplasms (SNs), the contribution of germline mutations in cancer predisposition genes to the risk of SN is largely unknown. Whole-genome sequencing (30X) was performed on 3,006 5+ year survivors of childhood cancer (median age, 35.8 [range: 7.1-69.8] years) from the St. Jude Lifetime Cohort. Survivors underwent a comprehensive clinical assessment. Germline mutations in 156 cancer predisposition genes (SJCPG156), including a subset of 60 (SJCPG60) autosomal dominant genes with moderate to high penetrance, were classified for their pathogenicity. Piecewise exponential regression, stratified by radiation exposure, was used to evaluate the relative rate (RR) and 95% confidence interval (95% CI) of SN occurrence by mutation status. Pathogenic or likely pathogenic mutations in SJCPG156 and SJCPG60 were identified in 11.7% and 5.8% of survivors, respectively. The most frequently mutated SJCPG60 genes included RB1 (n=43), NF1 (n=22), BRCA2 (n=14), BRCA1 (n=12) and TP53 (n=10). Mutations in SJCPG60 were associated with the rate of subsequent sarcoma (RR, 10.3; 95% CI, 4.2 to 25.6) and breast cancer (RR, 13.3; 95% CI, 5.8 to 30.5) among irradiated survivors, and the rate of developing any SN (RR, 4.8; 95% CI, 2.4 to 9.4) and breast cancer (RR, 7.8; 95% CI, 2.5 to 24.0) among non-irradiated survivors. The rate of developing ≥2 histologically distinct SNs was increased 17.8-fold (95% CI, 3.5 to 89.8) among SJCPG60 mutation carriers treated without radiotherapy. Similar but attenuated associations were observed for mutations in SJCPG156. Survivors who develop a SN without prior radiotherapy or who are diagnosed with a subsequent sarcoma or breast cancer within a site of prior radiotherapy should be referred to genetic counseling.

  Study EGAS00001002499

• Profiling the unique protective properties of intracranial arterial endothelial cells

  Cardiovascular disorders, like atherosclerosis and hypertension, are increasingly known to be associated with vascular cognitive impairment (VCI). In particular, intracranial atherosclerosis is one of the main causes of VCI, although plaque development occurs later in time and is structurally different compared to atherosclerosis in extracranial arteries. Recent data suggest that endothelial cells (ECs) that line the intracranial arteries may exert anti-atherosclerotic effects due to yet unidentified pathways. To gain insights into underlying mechanisms, we isolated post-mortem endothelial cells from both the intracranial basilar artery (BA) and the extracranial common carotid artery (CCA) from the same individual (total of 15 individuals) with laser capture microdissection. RNA sequencing revealed a distinct molecular signature of the two endothelial cell populations of which the most prominent ones were validated by means of qPCR. Our data reveal for the first time that intracranial artery ECs exert an immune quiescent phenotype. Secondly, genes known to be involved in the response of ECs to damage (inflammation, differentiation, adhesion, proliferation, permeability and oxidative stress) are differentially expressed in intracranial ECs compared to extracranial ECs. Finally, Desmoplakin (DSP) and Hop Homeobox (HOPX), two genes expressed at a higher level in intracranial ECs, and Sodium Voltage-Gated Channel Beta Subunit 3 (SCN3B), a gene expressed at a lower level in intracranial ECs compared to extracranial ECs, were shown to be responsive to shear stress and/or hypoxia. With our data we present a set of intracranial-specific endothelial genes that may contribute to its protective phenotype, thereby supporting proper perfusion and consequently may preserve cognitive function. Deciphering the molecular regulation of the vascular bed in the brain may lead to the identification of novel potential intervention strategies to halt vascular associated disorders, such as atherosclerosis and vascular cognitive dysfunction.

  Study EGAS00001004479

• Exploration of coding and non-coding variants in cancer using GenomePaint.

  GenomePaint (https://proteinpaint.stjude.org/genomepaint) is a dynamic visualization platform for whole-genome, whole-exome, transcriptome, and epigenomic data, featuring a novel design that captures the inter-relatedness between DNA variations and RNA expression. Regulatory non-coding variants can be inspected and discovered along with coding variants, and their functional impact further explored by examining 3D genome and/or ChIP-seq data generated from cancer cell lines. Further, GenomePaint correlates mutation and expression patterns with patient outcomes, and can display external data such as adult cancer datasets and user-provided custom tracks. We used GenomePaint to analyze multi-omics data from 3,652 pediatric cancers representing 16 histotypes, and demonstrate the visualization features through examples, including two that led to new insights into oncogenic mechanisms in pediatric cancer. The first is the discovery of a new class of pathogenic recurrent variants that cause aberrant splicing, disrupting the RING domain of CREBBP, a driver gene frequently mutated in relapsed pediatric leukemia. The second is the cis-activation of the MYC oncogene in a subset of B-lineage acute lymphoblastic leukemia (B-ALL) via duplication of the NOTCH1-MYC enhancer (N-ME), previously discovered only in T-lineage ALL. The regulatory impact of N-ME enhancer amplification was initially confirmed by allelic imbalance in published gene expression and ChIP-seq data and verified by additional Capture-C and fluorescence in situ hybridization data generated by follow-up experiments. These examples demonstrate the power of GenomePaint in enabling not only data visualization but also integrative genomic analysis that can lead to novel biological insight for follow-up experimental validation.

  Study EGAS00001004669

• Analysis of T-cell receptor clonotypes in tumor micro-environment identifies shared cancer type-specific signatures

  Despite the conventional view that a truly random V(D)J recombination process should generate a highly diverse immune repertoire, emerging reports suggest that there is a certain bias towards the generation of shared/public immune receptor chains. These studies were performed in viral diseases where public T-cell receptors (TCR) appear to confer better protective responses. Selective pressures generating common TCR clonotypes are currently not well understood but it is believed that they confer a growth advantage. As very little is known about public TCR clonotypes in cancer, here we set out to determine the extent of shared TCR clonotypes in the intra-tumor microenvironments of virus- and non-virus- driven head and neck cancers using TCR sequencing. We report that tumor-infiltrating T-cell clonotypes were indeed shared across individuals with the same cancer type, where the majority of shared sequences were specific to the cancer type (ie viral versus non-viral). These shared clonotypes were not particularly enriched in EBV-associated nasopharynx cancer, but in both cancers, exhibited distinct characteristics, namely shorter CDR3 lengths, restricted V- and J-gene usages and also demonstrated convergent V(D)J recombination. Many of these shared TCRs were expressed in patients with a shared HLA background. Pattern recognition of CDR3 amino acid sequences revealed strong convergence to specific motifs that were unique to each cancer type, suggesting they may be enriched for specificity to common antigens found in the tumor microenvironment. The identification of shared TCRs in infiltrating tumor T-cells not only adds to our understanding of the tumor adaptive immune recognition but could also serve as disease-specific biomarkers and guide the development of future immunotherapies.

  Study EGAS00001005480

• Genetic heritage of the Baphuthi highlights an over-ethnicised notion of 'Bushman' in the Maloti-Drakensberg, southern Africa

  Using contemporary people as proxies for ancient communities is a contentious but necessary practice in anthropology. In southern Africa, the distinction between the Cape KhoeSan and eastern KhoeSan remains unclear as ethnicity labels have been changed through time and most communities were decimated if not extirpated. The eastern KhoeSan may have had genetic distinctions from neighbouring communities who speak Bantu languages and KhoeSan further away, alternatively the identity may not have been tied to any notion of biology, instead denoting communities with a nomadic 'lifeway' distinct from African agro-pastoralism. The Baphuthi of the 1800s in the Maloti-Drakensberg, southern Africa had a substantial KhoeSan constituency and a lifeway of nomadism, cattle raiding, and horticulture. Baphuthi heritage could provide insights into the history of the eastern KhoeSan. We examine genetic affinities of 23 Baphuthi to discern whether the narrative of KhoeSan descent reflects distinct genetic ancestry. Genome-wide SNP data (Illumina GSA) were merged with 52 global populations, for 160K SNPs. Genetic analyses show no support for a unique eastern KhoeSan ancestry distinct from other KhoeSan or southern Bantu-speakers. The Baphuthi have strong affinities with early-arriving southern Bantu-speaking (Nguni) communities, as the later-arriving non-Nguni show strong evidence of recent African admixture possibly related to Late-Iron Age migrations. The references to communities as 'San',and 'Bushman' in historic literature has often been misconstrued as notions of ethnic/biological distinctions. The terms may have reflected ambiguous references to non-sedentary polities instead, as seems to be the case for the eastern ‘Bushman’ heritage of the Baphuthi.

  Study EGAS00001007080

• EGA account management

  How to manage your EGA account Welcome to the documentation page for creating an EGA user. The European Genome-Phenome Archive (EGA) is a platform for archiving, managing, and sharing human genomic and phenotypic data. To submit, access, and manage requests for the data hosted on the EGA platform, users are required to register for an account. This documentation page provides step-by-step instructions for creating an EGA user account, as well as information on the different types of EGA user accounts and their associated privileges. You can check the EGA data flow for a better understanding. Manage EGA account step-by-step guide Contact Information Public Keys Password Authenticator Federated Identity Sessions Request an EGA account step-by-step guide Fill in this form.You cannot use a generic email account (e.g., Gmail). Make sure you use your institutional email account.Your email is by default your username.The criteria for a strong password is: It should contain between 8 and 32 charactersIt should contain at least one uppercase letterIt should contain at least one numberIt should contain at least one special characterYou will need to wait for the Helpdesk team to check your identity. Please allow two business days for this step.After the Helpdesk validation step, you will receive an email with a link to validate your institutional email.Click the link to verify your email. It will redirect you to the EGA website.As soon as your account has been validated, you will be able to start adding more information to your EGA profile. For that, you first need to log in using your credentials from step 1. Manage EGA account step-by-step guide As a logged-in user, go to your profile by clicking on Welcome > My Profile. To modify it, click the Edit button.You will see the following options: Contact Information In this section, you can modify the personal information of your EGA account. Public Keys Adding a public key is necessary for downloading data via Live Outbox distribution. If you don’t know how to generate your key, you can follow the instructions available on How do I create a key? Password In the Password tab, you can change your password anytime to ensure the security of your account. However, if you receive an email notifying you that your password was modified and you did not initiate the change, it could be a sign that your account has been compromised. In this case, you should immediately contact our Helpdesk team to report the issue and receive assistance in restoring your account security. Authenticator You can set your two-factor authentication (2FA) system for your EGA account as an identity and access management security method that requires two forms of identification to access resources and data. To obtain your code, please follow the instructions below, also available in the Authenticator tab in your profile. Sessions The Sessions tab displays a list of all devices where you are currently logged in as an EGA user. This includes any open sessions you have on your computer, phone, or other devices. By reviewing the list of active sessions, you can monitor the devices that have access to your account and ensure that there are no unauthorised logins. If you notice any suspicious activity, you can close the sessions from this page to immediately terminate access to your account from the unauthorised device.

  Documentation how-to-manage-your-account

• Uncovering the Genetic Architecture of Colorectal Cancer with Focus of Rare and Less Frequent Variants

  The Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) is a collaborative effort comprised of a coordinating center and scientific researchers from well-characterized cohort and case-control studies conducted in North America and Europe. This international consortium aims to accelerate the discovery of common and rare genetic risk variants for colorectal cancer by conducting large-scale meta-analyses of existing and newly generated genome-wide association study (GWAS) data, replicating and fine-mapping of GWAS discoveries, and investigating how genetic risk variants are modified by environmental risk factors. To expand these efforts, we assembled case-control sets or nested case-control sets from 20 different North American or European studies. Summary descriptions and study participant inclusions/exclusion criteria for each of these studies are detailed below. The Black Women's Health Study (BWHS): Is the largest follow-up study of the health of African-American women (Cozier et al., 2004; Rosenberg et al., 1995) [PMID: 15018884; PMID: 7722208]. The purpose is to identify and evaluate causes and preventives of cancers and other serious illnesses in African-American women. Among the diseases being studied are breast cancer, colorectal cancer, type 2 diabetes, uterine fibroids, systemic lupus erythematosus, and cardiovascular disease. The study began in 1995, when 59,000 black women from all parts of the United States enrolled through postal questionnaires. The women provided demographic and health data on the 1995 baseline questionnaire, including information on weight, height, smoking, drinking, contraceptive use, use of other selected medications, illnesses, reproductive history, physical activity, diet, use of health care, and other factors. The participants are followed through biennial questionnaires to determine the occurrence of cancers and other illnesses and to update information on risk factors. Self-reports of cancer are confirmed through medical records and state cancer registry records. Mouthwash-swish samples, as a source of DNA, were obtained from ~26,000 BWHS participants in 2002-2007. DNA was isolated from the mouthwash-swish samples at the Boston University Molecular Core Genetics Laboratory using the QIAAMP DNA Mini Kit (Qiagen). All incident colorectal cancer cases with a DNA sample were included in the present analysis. Two controls per case, selected from among BWHS participants free of colorectal cancer at end of follow-up, were matched to cases on year of birth (+/- 2 years) and geographical region of residence (Northeast, South, Midwest, and West). A total 209 colorectal cancer cases and 423 controls were sent for genotyping. Campaign Against Cancer and Heart Disease (CLUE II): The Campaign Against Cancer and Heart Disease, is a prospective cohort designed to identify biomarkers and other factors associated with risk of cancer, heart disease, and other conditions (Kakourou et al., 2015) [PMID: 26220152]. 32,894 participants were recruited from May through October 1989 from Washington County, Maryland and surrounding communities. Colorectal cancer cases (n = 297) and matched controls (n = 296) were identified between 1989 and 2000 among participants in the CLUE II cohort of Washington County, Maryland. Colorectal Cancer Study of Austria (CORSA): In the ongoing colorectal cancer study of Austria (CORSA), more than 13,000 Caucasian participants have been recruited within the province-wide screening project "Burgenland Prevention Trial of Colorectal Disease with Immunological Testing" (B-PREDICT) since 2003 (Hofer et al., 2011) [PMID: 21422235]. All inhabitants of the Austrian province Burgenland aged between 40 and 80 years are annually invited to participate in fecal immunochemical testing and haemoccult positive screening participants are invited for colonoscopy. CORSA includes genomic DNA and plasma of colorectal cancer cases, low-risk and high-risk adenomas, and colonoscopy-negative controls. Controls received a complete colonoscopy and were free of colorectal cancer or polyps. CORSA participants have been recruited in the four KRAGES hospitals in Burgenland, Austria, and additionally, at the Medical University of Vienna (Department of Surgery), the Viennese hospitals "Rudolfstiftung" and the "Sozialmedizinisches Zentrum Sud", and at the Medical University of Graz (Department of Internal Medicine). 1403 colorectal cancer and advanced colorectal adenoma cases, and 1404 matched controls were selected for the study. Distribution of factors sex and age (5 year strata) were evenly matched between cases and controls. Cancer Prevention Study II (CPS II): The CPS II Nutrition cohort is a prospective study of cancer incidence and mortality in the United States, established in 1992 and described in detail elsewhere (Calle et al., 2002; Campbell et al., 2014) [PMID: 12015775; PMID: 25472679]. At enrollment, participants completed a mailed self-administered questionnaire including information on demographic, medical, diet, and lifestyle factors. Follow-up questionnaires to update exposure information and to ascertain newly diagnosed cancers were sent biennially starting in 1997. Reported cancers were verified through medical records, state cancer registry linkage, or death certificates. The Emory University Institutional Review Board approves all aspects of the CPS II Nutrition Cohort. A total of 360 cases and 359 controls were selected for this study. Czech Republic Colorectal Cancer Study (Czech Republic CCS): Cases with positive colonoscopy results for malignancy, confirmed by histology as colon or rectal carcinomas, were recruited between September 2003 and May 2012 in several oncological departments in the Czech Republic (Prague, Pilsen, Benesov, Brno, Liberec, Ples, Pribram, Usti and Labem, and Zlin). Two control groups, sampled at the same time of cases recruitment, were included in the study. The first group consisted of hospital-based individuals with a negative colonoscopy result for malignancy or idiopathic bowel diseases. The reasons for the colonoscopy were: i) positive fecal occult blood test, ii) hemorrhoids, iii) abdominal pain of unknown origin, and iv) macroscopic bleeding. The second control group consisted of healthy blood donor volunteers from a blood donor center in Prague. All individuals were subjected to standard examinations to verify the health status for blood donation and were cancer-free at the time of the sampling. Details of CRC cases and controls have been reported previously (Vymetalkova et al., 2014; Naccarati et al., 2016; Vymetalkova et al., 2016) [PMID: 24755277; PMID: 26735576; PMID: 27803053]. All subjects were informed and provided written consent to participate in the study. They approved the use of their biological samples for genetic analyses, according to the Declaration of Helsinki. The design of the study was approved by the Ethics Committee of the Institute of Experimental Medicine, Prague, Czech Republic. All subjects included in the study were Caucasians and comprised 1792 cases and 1764 matched controls. Controls were matched to CRC cases as 1:1 ratio. Matching was done on age and sex. Age was matched on +-5 years, whereas sex was matched exactly. For the cases without matched controls, matching was done only on sex. Early Detection Research Network (EDRN): The aim of the EDRN initiative is to develop and sustain a biorepository for support of translational research (Amin et al., 2010) [PMID: 21031013]. High-quality biospecimens were accrued and annotated with pertinent clinical, epidemiologic, molecular and genomic information. A user-friendly annotation tool and query tool was developed for this purpose. The various components of this annotation tool include: CDEs are developed from the College of American Pathologists (CAP) Cancer Checklists and North American Association of Central Cancer Registries (NAACR) standards. The CDEs provides semantic and syntactic interoperability of the data sets by describing them in the form of metadata or data descriptor. A total of 352 colorectal case samples and 399 controls were selected for this study. Controls were matched to CRC cases based on age and sex. The EPICOLON Consortium (EPICOLON): The EPICOLON Consortium comprises a prospective, multicentre and population-based epidemiology survey of the incidence and features of CRC in the Spanish population (Fernandez-Rozadilla et al., 2013) [PMID: 23350875]. Cases were selected as patients with de novo histologically confirmed diagnosis of colorectal adenocarcinoma. Patients with familial adenomatous polyposis, Lynch syndrome or inflammatory bowel disease-related CRC, and cases where patients or family refused to participate in the study were excluded. Hospital-based controls were recruited through the blood collection unit of each hospital, together with cases. All of the controls were confirmed to have no history of cancer or other neoplasm and no reported family history of CRC. Controls were randomly selected and matched with cases for hospital, sex and age (+- 5 years). A total of 370 cases and 370 controls were selected for genotyping. Hawaii Adenoma Study: For this adenoma study, two flexible-sigmoidoscopy screening clinics were first used to recruit participants on Oahu, Hawaii. Adenoma cases were identified either from the baseline examination at the Hawaii site of the Prostate Lung Colorectal and Ovarian cancer screening trial during 1996-2000 or at the Kaiser Permanente Hawaii's Gastroenterology Screening Clinic during 1995-2007. In addition, starting in 2002 and up to 2007, we also approached for recruitment all eligible patients who underwent a colonoscopy in the Kaiser Permanente Hawaii Gastroenterology Department. Cases were patients with histologically confirmed first-time adenoma(s) of the colorectum and were of Japanese, Caucasian or Hawaiian race/ethnicity. Controls were selected among patients with a normal colorectum and were individually matched to the cases on age at exam, sex, race/ethnicity, screening date (+-3 months) and clinic and type of examination (colonoscopy or flexible sigmoidoscopy). We recruited 1016 adenoma cases (67.8% of all eligible) and 1355 controls (69.2% of all eligible); 889 cases and 1169 controls agreed to give a blood and 29 cases and 34 controls, a mouthwash sample. A total of 989 cases and 1185 controls were genotyped for this study. Columbus-area HNPCC Study (HNPCC, OSUMC): Patients with colorectal adenocarcinoma diagnosed at six participating hospitals were eligible for this study, regardless of age at diagnosis or family history of cancer. Patients with a clinical diagnosis of familial adenomatous polyposis were not eligible for this study. These six hospitals perform the vast majority of all operations for CRC in the Columbus metropolitan area (population 1.7 million). The institutional review board at all participating hospitals approved the research protocol and consent form in accordance with assurances filed with and approved by the United States Department of Health and Human Services. Briefly, during the period of January 1999 through August 2004, 1,566 eligible patients with CRC were accrued to the study (Hampel et al., 2008) [PMID 18809606]. A total of 1472 colorectal cancer samples had enough blood DNA remaining to be sent for genotyping. Control samples were provided by the Ohio State University Medical Center%#39;s (OSUMC) Human Genetics Sample Bank. The Columbus Area Controls Sample Bank is a collection of control samples for use in human genetics research that includes both donors' anonymized biological specimens and linked phenotypic data. The data and samples are collected under the protocol "Collection and Storage of Controls for Genetics Research Studies", which is approved by the Biomedical Sciences Institutional Review Board at OSUMC. Recruitment takes place in OSUMC primary care and internal medicine clinics. If individuals agree to participate, they provide written informed consent, complete a questionnaire that includes demographic, medical and family history information, and donate a blood sample. 4-7 ml of blood is drawn into each of 3 ACD Solution A tubes and is used for genomic DNA extraction and the establishment of an EBV-transformed lymphoblastoid cell culture, cell pellet in Trizol, and plasma. Controls were matched to CRC cases as 1:1. Matching was done on age at reference time (age_ref), race, and sex. Age_ref was matched on +-5 years. Sex and race were matched exactly. For the cases without matched controls, matching was done only on sex and race with 1:1 ratio. Since controls are fewer than cases, one control is matched on 2 cases at most. Health Professionals Follow-up Study (HPFS): A parallel prospective study to the NHS (Nurses' Health Study). The HPFS cohort comprised 51,529 men aged 40-75 who, in 1986, responded to a mailed questionnaire (Rimm et al., 1990) [PMID: 2090285]. Participants provided information on health related exposures, including current and past smoking history, age, weight, height, diet, physical activity, aspirin use, and family history of colorectal cancer. Colorectal cancer and other outcomes were reported by participants or next-of-kin and were followed up through review of the medical and pathology record by physicians. Overall, more than 97% of self-reported colorectal cancers were confirmed by medical record review. Information was abstracted on histology and primary location. Incident cases were defined as those occurring after the subject provided the blood sample. Prevalent cases were defined as those occurring after enrollment in the study but before the subject provided the blood sample. Follow-up evaluation has been excellent, with 94% of the men responding to date. Colorectal cancer cases were ascertained through January 1, 2008. In 1993-1995, 18,825 men in the HPFS mailed blood samples by overnight courier, which were aliquoted into buffy coat and stored in liquid nitrogen. In 2001-2004, 13,956 men in the HPFS who had not provided a blood sample previously mailed in a swish-and-spit sample of buccal cells. Incident cases were defined as those occurring after the subject provided a blood or buccal sample. Prevalent cases were defined as those occurring after enrollment in the study in 1986, but before the subject provided either a blood or buccal sample. After excluding participants with histories of cancer (except nonmelanoma skin cancer), ulcerative colitis, or familial polyposis, case-control sets were previously constructed. In addition to colorectal cancer cases and controls, a set of adenoma cases and matched controls with available DNA from buffy coat were selected for genotyping. Over the follow-up period, data were collected on endoscopic screening practices and, if individuals had been diagnosed with a polyp, the polyps were confirmed to be adenomatous by medical record review. Adenoma cases were ascertained through January 1, 2008. A separate case-control set was constructed of participants diagnosed with advanced adenoma matched to control participants who underwent a lower endoscopy in the same time period and did not have an adenoma. Advanced adenoma was defined as an adenoma 1 cm or larger in diameter and/or with tubulovillous, villous, or highgrade dysplasia/carcinoma-in-situ histology. Matching criteria included year of birth (within 1 year) and month/ year of blood sampling (within 6 months), the reason for their lower endoscopy (screening, family history, or symptoms), and the time period of any prior endoscopy (within 2 years). Controls matched to cases with a distal adenoma either had a negative sigmoidoscopy or colonoscopy examination, and controls matched to cases with proximal adenoma all had a negative colonoscopy. In total, 159 advanced adenoma cases and 109 controls were selected for genotyping. Leeds Colorectal Cancer Study (LCCS): Following local ethical approval, colorectal cancer cases were recruited from 1997 until 2012 in Leeds, UK through surgical clinics. Initially, funding was provided by the UK Ministry of Agriculture, Farming and Fisheries (subsequently the Food Standards Agency) and Imperial Cancer Research Fund (subsequently Cancer Research UK). Recruitment also occurred similarly in Dundee, Perth and York between the periods of 1997 and 2001 using the same protocol and the data and samples were combined. Pathologically confirmed cases were consented at outpatient clinics, providing information on known and postulated risk factors for colorectal cancer (diet, lifestyle and family history) as well as providing a blood sample for DNA. Exclusion criteria included pre-existing diverticular disease and an inability to complete the questionnaire. The General Practitioners of cases (all UK residents have a nominated General Practitioner to whom to refer initial medical queries) and these GPs were asked to send letters to other persons on their patient list of the same gender and born within 5 years of the case. Subsequently to enhance the number of controls, we systematically invited patients from selected GP practices. Diet was assessed in cases and controls using an extensive dietary and lifestyle questionnaire modified by that produced by the European Prospective Investigation in Cancer (EPIC). The frequency that each specific food items were eaten was recorded and we also obtained average fruit and vegetable consumption as a cross-check. In total, 1591 cases and 739 controls provided a DNA sample. The North Carolina Colon Cancer Studies (NCCCS I/II): The North Carolina Colon Cancer Studies (NCCCS I- colon and NCCCS II-rectal) were population-based case-control studies conducted in 33 counties of North Carolina. Cases were identified using the rapid case ascertainment system of the North Carolina Central Cancer Registry. Patients with a first diagnosis of histologically confirmed invasive adenocarcinoma of the colon (cecum through sigmoid colon) between October 1996 and September 2000 were classified as potential cases in the NCCCS I. The NCCCS II included patients with a first diagnosis of histologically confirmed invasive adenocarcinoma of the sigmoid colon, rectosigmoid, or rectum (hereafter collectively referred to as rectal cancer) between May 2001 and September 2006. Additional eligibility requirements were: aged 40-80 years, residence in one of the 33 counties, ability to give informed consent and complete an interview, had a driver's license or identification card issued by the North Carolina Department of Motor Vehicles (if under the age of 65), and had no objections from the primary physician in regards to contacting the individual. Controls, identified and sampled during the respective study dates, were selected from two sources. Potential controls under the age of 65 were identified using the North Carolina Department of Motor Vehicles records. For those 65 years and older, records from the Center for Medicare and Medicaid Services were used. Controls were matched to cases using randomized recruitment strategies. Recruitment probabilities were done using strata of 5-year age, sex, and race groups. Dietary information was collected using a modified version of the semiquantitative food frequency questionnaire developed at the National Cancer Institute. In addition, participants were asked about vitamin and mineral supplementation, special diets, restaurant eating, sodium use, and fats used in cooking. In NCCCS I, 515 colorectal cases and 687 matched controls were sent for genotyping. In NCCCS II, 796 colorectal cases and 823 controls were sent from the NCCCS II for genotyping. Controls were matched to CRC cases as 1:1 ratio. Matching was done on age, race, and sex. Age was matched on +-5 years. Race and sex was matched exactly. For the cases without matched controls, matching was done only on sex and race. Nurses Health Study (NHS): The NHS cohort began in 1976 when 121,700 married female registered nurses age 30-55 years returned the initial questionnaire that ascertained a variety of important health-related exposures (Belanger et al., 1978) [PMID: 248266]. Since 1976, follow-up questionnaires have been mailed every 2 years. Colorectal cancer and other outcomes were reported by participants or next-of-kin and followed up through review of the medical and pathology record by physicians. Overall, more than 97% of self-reported colorectal cancers were confirmed by medical-record review. Information was abstracted on histology and primary location. The rate of follow-up evaluation has been high: as a proportion of the total possible follow-up time, follow-up evaluation has been more than 92%. Colorectal cancer cases were ascertained through June 1, 2008. In 1989 -1990, 32,826 women in NHS I mailed blood samples by overnight courier, which were aliquoted into buffy coat and stored in liquid nitrogen. In 2001-2004, 29,684 women in NHS I who did not previously provide a blood sample mailed a swish-and-spit sample of buccal cells. Incident cases were defined as those occurring after the subject provided a blood or buccal sample. Prevalent cases were defined as those occurring after enrollment in the study in 1976 but before the subject provided either a blood or buccal sample. After excluding participants with histories of cancer (except nonmelanoma skin cancer), ulcerative colitis, or familial polyposis, case-control sets were previously constructed from which DNA was isolated from either buffy coat or buccal cells for genotyping. In addition to colorectal cancer cases and controls, a set of advanced adenoma cases and matched controls with available DNA from buffy coat were selected for genotyping. Over the follow-up period, data were collected on endoscopic screening practices and, if individuals had been diagnosed with a polyp, the polyps were confirmed to be adenomatous by medical record review. Adenoma cases were ascertained through June 1, 2011. A separate case-control set was constructed of participants diagnosed with advanced adenoma matched to control participants who underwent a lower endoscopy in the same time period and did not have an adenoma. Advanced adenoma was defined as an adenoma more than 1 cm in diameter and/or with tubulovillous, villous, or high-grade dysplasia/carcinoma-in-situ histology. Matching criteria included year of birth (within 1 year) and month/year of blood sampling (within 6 months), the reason for their lower endoscopy (screening, family history, or symptoms), and the time period of any prior endoscopy (within 2 years). Controls matched to cases with a distal adenoma either had a negative sigmoidoscopy or colonoscopy examination, and controls matched to cases with proximal adenoma all had a negative colonoscopy. A total of 272 cases and 236 matched controls were sent to CIDR for the advanced adenoma case-control set. Northern Swedish Health and Disease Study (NSHDS): Comprises over 110,000 participants, including approximately one third with repeated sampling occasions, from three population-based cohorts (Dahlin et al., 2010; Myte et al., 2016) [PMID: 20197478; PMID: 27367522]. The largest is the ongoing Vasterbotten Intervention Programme, in which all residents of Vasterbotten County are invited to a health examination upon turning 30 (some years), 40, 50 and 60 years of age. Extensive measured and self-reported health and lifestyle data, as well as blood samples for central biobanking in Umea, Sweden, are collected at the health exam. Leucocyte DNA samples for 1:1-matched CRC case-control sets from the NSHDS, of which 878 samples are included in this study, have been selected for genotyping. This is in addition to 354 samples from the NSHDS previously analyzed as part of the multicenter EPIC cohort. Cancer-specific and overall survival data are available for all patients. For at least 425 patients, archival tumor tissue has been analyzed for the BRAF V600E mutation and by sequencing codon 12 and 13 for KRAS mutations, as well as for MSI screening status by immunohistochemistry and for an eight-gene CIMP panel using quantitative real-time PCR (MethyLight). Ohio Colorectal Cancer Prevention Initiative (OCCPI, OSUMC): OCCPI (ClinicalTrials.gov identifier: NCT01850654) is a population-based study of colorectal cancer patients diagnosed in one of 51 hospitals throughout the state of Ohio from January 1, 2013 through December 31, 2016. The OCCPI was created to decrease CRC incidence in Ohio by identifying patients with hereditary predisposition (statewide universal tumor screening for newly diagnosed CRC patients), increase colonoscopy compliance for first-degree relatives of CRC patients, and encourage future research through the creation of a biorepository. The 51 Ohio hospitals participating in the OCCPI were selected to represent a cross-section of clinical centers in the state based on high reported volume of CRC patients, affiliation with a high volume hospital, or interest in participation. Institutional Review Board (IRB) approval was obtained by the individual hospitals, Community Oncology Programs, or by ceding review to the OSU IRB. Written informed consent was obtained. A total of 2139 colorectal cases were genotyped. Patients were considered eligible for this study if they were age 18 or older at the time of enrollment, if they had a surgical resection (or biopsy if unresectable) in the state of Ohio demonstrating an adenocarcinoma of the colorectum from 1/1/13 - 12/31/16. Matched control samples were selected from the Ohio State University Medical Center's (OSUMC) Human Genetics Sample Bank in an identical way to the selection for the Columbus-area HNPCC Study (please refer to the description for the Columbus-area HNPCC Study). Prostate, Lung, Colorectal and Ovarian Cancer Screening Trail (PLCO): PLCO enrolled 154,934 participants (men and women, aged between 55 and 74 years) at ten centers into a large, randomized, two-arm trial to determine the effectiveness of screening to reduce cancer mortality. Sequential blood samples were collected from participants assigned to the screening arm. Participation was 93% at the baseline blood draw. In the observational (control) arm, buccal cells were collected via mail using the "swish-and-spit" protocol and participation rate was 65%. Details of this study have been previously described (Huang et al., 2016) [PMID: 27673363] and are available online (http://dcp.cancer.gov/plco). For this study 1651 advanced adenoma cases and 1392 controls were selected for genotyping. Selenium and Vitamin E Prevention Trial (SELECT): The Selenium and Vitamin E Cancer Prevention Trial (SELECT) was a double-blind, placebo controlled clinical trial which explored using selenium and vitamin E alone and in combination to prevent prostate cancer in healthy men (Lippman et al., 2009) [PMID: 19066370]. Secondary endpoints included the prevention of colorectal and lung cancers. SELECT was conducted at 427 sites and centers in the United States, Canada and Puerto Rico; 35,533 men 55 years and older (50 or older if African American) were randomized beginning August 22, 2001. Supplementation was discontinued on October 23, 2008 due to futility. 308 colorectal cancer cases and 308 matched controls were selected from the SELECT population and sent for genotyping. Screening Markers For Colorectal Disease Study and Colonoscopy and Health Study (SMS-REACH): Details on this study population were previously reported (Burnett-Hartman et al., 2014) [PMID: 24875374]. Participants were enrollees in an integrated health-care delivery system in western Washington State (Group Health Cooperative, Seattle, Washington) aged 24-79 years who underwent an index colonoscopy for any indication between 1998 and 2007 and donated a buccal-cell or blood sample for genotyping analysis. Study recruitment took place in 2 phases, with phase 1 occurring in 1998-2003 and phase 2 occurring in 2004-2007. Persons who had undergone a colonoscopy less than 1 year prior to the index colonoscopy, persons with inadequate bowel preparation for the index colonoscopy, and persons with a prior or new diagnosis of colorectal cancer, a familial colorectal cancer syndrome (such as familial adenomatous polyposis), or another colorectal disease were ineligible. Patients diagnosed with adenomas or serrated polyps and persons who were polyp-free at the index colonoscopy (controls) were systematically recruited during both phases of recruitment. Approximately 75% agreed to participate and provided written informed consent. Based on medical records, persons who agreed to participate and those who refused study participation were similar with respect to age, sex, and colorectal polyp status. Study protocols were approved by the institutional review boards of the Group Health Cooperative and the Fred Hutchinson Cancer Research Center (Seattle, Washington). A total of 575 cases and 508 matched were selected for the study. Controls were matched to CRC cases as 1:1 ratio. Matching was done on age_ref, race, and sex. Age_ref was matched on +-5 years. The Women's Health Initiative (WHI): WHI is a long-term national health study that has focused on strategies for preventing heart disease, breast and colorectal cancer, and osteoporotic fractures in postmenopausal women. The original WHI study included 161,808 postmenopausal women enrolled between 1993 and 1998. The Fred Hutchinson Cancer Research Center in Seattle, WA serves as the WHI Clinical Coordinating Center for data collection, management, and analysis of the WHI. The WHI has two major parts: a partial factorial randomized Clinical Trial (CT) and an Observational Study (OS); both were conducted at 40 Clinical Centers nationwide. The CT enrolled 68,132 postmenopausal women between the ages of 50-79 into trials testing three prevention strategies. If eligible, women could choose to enroll in one, two, or all three of the trial components. The components are: Hormone Therapy Trials (HT): This double-blind component examined the effects of combined hormones or estrogen alone on the prevention of coronary heart disease and osteoporotic fractures, and associated risk for breast cancer. Women participating in this component with an intact uterus were randomized to estrogen plus progestin (conjugated equine estrogens [CEE], 0.625 mg/d plus medroxyprogesterone acetate [MPA] 2.5 mg/d] or a matching placebo. Women with prior hysterectomy were randomized to CEE or placebo. Both trials were stopped early, in July 2002 and March 2004, respectively, based on adverse effects. All HT participants continued to be followed without intervention until close-out. Dietary Modification Trial (DM): The Dietary Modification component evaluated the effect of a low-fat and high fruit, vegetable and grain diet on the prevention of breast and colorectal cancers and coronary heart disease. Study participants were randomized to either their usual eating pattern or a low-fat dietary pattern. Calcium/Vitamin D Trial (CaD): This double-blind component began 1 to 2 years after a woman joined one or both of the other clinical trial components. It evaluated the effect of calcium and vitamin D supplementation on the prevention of osteoporotic fractures and colorectal cancer. Women in this component were randomized to calcium (1000 mg/d) and vitamin D (400 IU/d) supplements or a matching placebo. The Observational Study (OS)examines the relationship between lifestyle, environmental, medical and molecular risk factors and specific measures of health or disease outcomes. This component involves tracking the medical history and health habits of 93,676 women not participating in the CT. Recruitment for the observational study was completed in 1998 and participants were followed annually for 8 to 12 years. All centrally confirmed cases of invasive colorectal cancers, or deaths from colorectal cancer were selected as potential cases from September 30, 2015 database. Controls were participants free of colorectal cancer (invasive or in situ) as of September 30, 2015. Potential cases and controls were excluded if they (1) were non-White; (2) had history of colorectal cancers at baseline; (3) lost to follow-up after enrollment; (4) DbGAP ineligible; (5) had <1.25ug of DNA; (6) selected for WHI study M26 Phase I or II; (7) selected for WHI study AS224 and also included in the imputation project. A total of 578 cases and 104,429 controls met the eligibility criteria. Each case was matched with 1 control (1:1) that exactly met the following matching criteria: age (+-5 years), 40 randomization centers (exact), WHI date (+-3 years), CaD date (+-3 years), OS flag (exact), HRT assignments (exact), DM assignments (exact), and CaD assignments (exact). Control selection was done in a time-forward manner, selecting one control for each case from the risk set at the time of the case's event. The matching algorithm was allowed to select the closest match based on a criteria to minimize an overall distance measure (Bergstralh EJ, Kosanke JL. Computerized matching of cases to controls. Technical Report #56, Department of Health Sciences Research, Mayo Clinic, Rochester MN. April 1995). Each matching factor was given the same weight. When exact matches could not be found, the matching criteria were gradually relaxed among unmatched cases and controls until all cases had found matched controls. Using the matching criteria specified above, 559 of the 578 eligible cases found exact matches. The matching criteria was then relaxed to : Age+-5, randomization centers, WHI date +- 3 years, CaD date +- 3 years, OS flag, HRT flag, DM flag, CaD flag. 17 of the remaining 19 unmatched cases found matched controls. By matching on Age+-5, randomization centers, WHI date +- 3 years, CaD date +- 3 years, OS flag, HRT flag, the remaining 2 unmatched cases found their matches.

  Study phs001415

• HGSC lines: ATACseq and RNAseq, pre- vs post-treatment with HKMTi-1-005

  Formation of a DAC to support the deposition of RNAseq and ATACseq data, from pre- vs post-treatment high-grade serous ovarian carcinoma cell lines. The lines include PEO1, PEO4, PEA2, OVCAR5, OVCAR8, and the treatment includes use of a novel epigenetic drug called HKMTi-1-005.

  Dac EGAC50000000034

• Dac for "MediMer: A versatile do-it-yourself peptide-receptive MHC class I multimer platform for tumor neoantigen-specific T cell detection"

  Dac for the Study "MediMer: A versatile do-it-yourself peptide-receptive MHC class I multimer platform for tumor neoantigen-specific T cell detection" registered for Frank Momburg, f.momburg@dkfz-heidelberg.de Marten Meyer, marten.meyer@dkfz-heidelberg.de

  Dac EGAC50000000064

• NINDS Inherited Forms of Motor Neuron Disease Study

  Sequencing data from primary fibroblasts were obtained from individuals with a family history of an inherited form of motor neuron disease (juvenile amyotrophic lateral sclerosis- ALS4).

  Study phs001322

• Treatment of genetic screening of hypertriglyceridemia type I, III, and V - HTG Amsterdam

  This is a cohort of patients with extreme hypertriglyceridemia. Patients have been screened for loss of function mutations in LPL, GPIHBP1, APOC2, APOA5 and LMF1.

  Study phs000511

• Human PI3Kγ Deficiency with Immunodeficiency and Tissue Immunopathology

  Whole exome sequencing of a trio (parents and offspring) reveals PIK3CG mutations that result in loss of protein in the child with immunodeficiency and immunopathology.

  Study phs001848