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• A Population Genomics Study Using a Disease-Targeted Cell model: Integration of

  The common genetic variants associated with complex traits typically lie in non-coding DNA and may alter gene regulation in a cell type-specific manner. Consequently, the choice of tissue or cell model in the dissection of disease associations is important. We carried out an expression quantitative trait loci (eQTL) study of primary human osteoblasts (HOb) derived from 95 unrelated donors of Swedish origin, each represented by two independently derived primary lines to provide biological replication. We combined our data with publicly available information from a genome-wide association study (GWAS) of bone mineral density (BMD). The top 2000 BMD-associated SNPs were tested for cis-association of gene expression in HObs and in lymphoblastoid cell lines (LCLs) using publicly available data and showed that HObs have a significantly greater enrichment (threefold) of converging cis-eQTLs as compared to LCLs. The top 10 BMD loci with SNPs showing strong cis-effects on gene expression in HObs were selected for further validation using a staged design in two cohorts of Caucasian male subjects. All 10 variants were tested in the Swedish MrOS Cohort (n = 3014), providing evidence for two novel BMD loci (SRR and MSH3). These variants were then tested in the Rotterdam Study (n = 2090), yielding converging evidence for BMD association at the 17p13.3 SRR locus. The cis-regulatory effect was further fine-mapped to the proximal promoter of the SRR gene (rs3744270). Our results suggest that primary cells relevant to disease phenotypes complement traditional approaches for prioritization and validation of GWAS hits for follow-up studies. Reprinted from Grundberg E, Kwan T, Ge B et al., Genome Res Nov 2009, with permission from Genome Research, Cold Spring Harbor Press, PMID:19654370.

  Study phs000225

• The ClinSeq Project: Piloting Large-Scale Genome Sequencing for Research in Genomic Medicine

  ClinSeq is a pilot project to investigate the use of whole-genome sequencing as a tool for clinical research. By piloting the acquisition of large amounts of DNA sequence data from individual human subjects, we are fostering the development of hypothesis-generating approaches for performing research in genomic medicine, including the exploration of issues related to the genetic architecture of disease, implementation of genomic technology, informed consent, disclosure of genetic information, and archiving, analyzing, and displaying sequence data. In the initial phase of ClinSeq, we are enrolling roughly 1000 participants; the evaluation of each includes obtaining a detailed family and medical history, as well as a clinical evaluation. The participants are being consented broadly for research on many traits and for whole-genome sequencing. Initially, Sanger-based sequencing of 300-400 genes thought to be relevant to atherosclerosis is being performed, with the resulting data analyzed for rare, high-penetrance variants associated with specific clinical traits. The participants are also being consented to allow the contact of family members for additional studies of sequence variants to explore their potential association with specific phenotypes. Here, we present the general considerations in designing ClinSeq, preliminary results based on the generation of an initial 826 Mb of sequence data, the findings for several genes that serve as positive controls for the project, and our views about the potential implications of ClinSeq. The early experiences with ClinSeq illustrate how large-scale medical sequencing can be a practical, productive, and critical component of research in genomic medicine. Reprinted from Genome Res. 2009 Sep; 19(9): 1665-1674, with permission from Genome Research, PMID: 19602640.

  Study phs000971

• 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

• 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

• 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.

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• 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.

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• 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

• 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.

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• 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.

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• '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

• 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

• 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

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• 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.

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• 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.

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• 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.

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• 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.

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• 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

• Evaluation of size selection on cancer specific sequencing libraries

  A couple of previously characterized and sequenced libraries will be repeated using a couple of differing size selection criteria and skim sequenced using an Illumina HiSeq. The resulting sequence will be analyzed to determine the optimal DNA library size for our specific downstream analysis.

  Dataset EGAD00001000301

• Trynka_sceQTL_genotypes

  Blood samples were obtained from 119 healthy individuals of British ancestry. Genomic DNA was isolated from a suspension of PBMCs from each individual using a DNA isolation kit (Qiagen). Genotyping was then performed using the Infinium CoreExome-24 (v1.3) chip (Illumina).

  Dataset EGAD00010002291

• Converging and evolving immuno-genomic routes towards immune escape in breast cancer

  This study explores the evolution of tumor and blood immune microenvironment and related mechanisms that shape breast cancer progression, culminating in a heterogeneous lethal cancer.

  Study EGAS00001004956

• Exome Chip Study of NIMH Controls

  Here, we report exome chip genotyping results of 1052 samples from the NIMH control set, a collection of healthy controls for general research use. The samples are all unrelated.

  Study phs000630

• Tumor heterogeneity and acquired drug resistance in FGFR2 fusion-positive cholangiocarcinoma through rapid research autopsy

  Whole exome sequencing was performed on blood and tumor specimens (collected from biopsy or rapid research autopsy) from a patient with FGFR2 fusion positive cholangiocarcinoma.

  Study phs001830

• Clinical and molecular features of early onset pancreatic cancer

  A retrospective cohort study on the clinical and molecular features of early onset pancreatic cancers (i. e. diagnosed at <50 years old) in comparison with later onset tumors.

  Study EGAS50000000362

• Autosomal dominant macular dystrophy associated with THRB: identification of new families and variants 

  This study aims to refine the ophthalmologic phenotype, report a novel THRB variant, and investigate the impact of these splicing variants at the protein level.

  Study EGAS50000000861

• ACUITI

  This study assessed the feasibility and performance of a tumor-informed circulating tumor DNA (ctDNA) assay in patients with metastatic HR+/HER2- breast cancer receiving endocrine therapy and CDK4/6 inhibitors.

  Study EGAS50000000962

• DAC for EGA study: Multi-omic analyses from a randomized phase II study of epigenetic priming followed by nivolumab in previously treated metastatic non-small cell lung cancer

  This is the Data Access Committee for the EGA study: Multi-omic analyses from a randomized phase II study of epigenetic priming followed by nivolumab in previously treated metastatic non-small cell lung cancer (temp ID 800).

  Dac EGAC50000000563

• Colon adenomas and adenocarcinomas and matched mucosae

  Whole exome sequencing in sporadic colorectal cancers (CRC) and advanced adenomas (Ad-As), and their paired healthy mucosa, for a deeper understanding of the biology of this cancer.

  Study EGAS00001007255

• Whole exome sequencing (bam files) of 55 samples of myxofibrosarcoma and 44 matched pairs

  Myxofibrosarcoma (MFS) is a rare subtype of sarcomas in the elderly, whose genetic basis is poorly understood. To elucidate it, the whole exome sequence was performed.

  Study EGAS00001005442

• S_CORT_Stratification_in_COloRecTal_cancer_

  Colorectal cancer samples will be submitted for Illumina sequencing using a custom capture of 116 genes implicated in colorectal tumourigenesis. Driver mutations will be detected and ultimately correlated with phenotypic data.

  Study EGAS00001001521

• Genomic landscape of Chordoid Glioma

  Chordoid glioma (ChG) is a characteristic, slow growing and well-circumscribed diencephalic tumor, whose mutational landscape is unknown. We analyzed primary chordoid glioma samples by whole exome sequencing, RNAseq

  Study EGAS00001002433

• ChIP_sequencing_in_Cancer_Cell_Lines

  The project is to evaluate the genomic binding sites of the histone demethylase JARID1C. This gene was recently identified in CGP as a novel recessive cancer gene in human renal cell carcinoma.

  Study EGAS00001000203

• Combined genetic and transcriptome analysis of patients with Systemic Lupus Erythematosus (SLE)

  A comprehensive profiling of the genomic architecture of Systemic Lupus Erythematosus (SLE) by combining genetic and transscriptomic analysis by RNA-seq.

  Study EGAS00001003662

• Whole_exome_sequencing_of_additional_thyroid_disease_cases

  Whole-exome sequencing of a cohort of families (probands and affected/unaffected relatives) suffering from one of two rare thyroid disorders: congenital hypothyroidism (CH) and resistance to thyroid hormone (RTH).

  Study EGAS00001001114

• CLL_targeted_exome_sequencing

  Aim to characterise cancer gene landscape in CLL, particularly in cases with mutated POT1 gene. Treatment-naïve CLL cases will be interrogated by targeted exome sequencing using a cancer gene panel.

  Study EGAS00001001963

• Whole Exome Sequencing of Localized Prostate Cancer Patients

  We performed whole-exome sequencing on localized prostate cancer patients to validate tumor content as part of a single-cell RNA sequencing study of localized prostate cancer patients.

  Study EGAS00001005685

• Methylation of Ewing sarcoma tumors (ICGC)

  Ewing sarcoma (ES) is a primary bone tumor initiated by an EWSR1-ETS gene fusion. To characterize the methylation of Ewing sarcoma, reduced representation bisulfite sequencing was performed.

  Study EGAS00001002161

• Targeted_gene_fusion_sequencing__Fus_seq__in_mesothelioma

  This is a small pilot data set to test the feasibility of cDNA exomes across 1200 cancer cell line panel. cDNA exomes or Fus-seq is further explained in this studies Abstract.

  Study EGAS00001000390

• Whole genome sequencing (bam files) of 5 samples of myxofibrosarcoma and 5 matched pairs

  Myxofibrosarcoma (MFS) is a rare subtype of sarcomas in the elderly, whose genetic basis is poorly understood. To elucidate it, the whole genome sequence was performed.

  Study EGAS00001005444

• Targeted-capture sequencing (bam files) of 81 samples of myxofibrosarcoma and 44 matched pairs

  Myxofibrosarcoma (MFS) is a rare subtype of sarcomas in the elderly, whose genetic basis is poorly understood. To elucidate it, the Targeted-capture sequencing was performed.

  Study EGAS00001005443

• TB-DAR Whole Genome Sequencing Study

  116 Whole Genome Sequencing (WGS) samples from the TB-DAR study, which consists of a cohort of adult pulmonary tuberculosis patients recruited in Dar es Salaam, Tanzania.

  Study EGAS00001005850

• Targeted_NanoSeq_Sperm

  Targeted NanoSeq in sperm samples provided by healthy patients. A custom-designed panel of ~200 genes will be used to achieve high depth coverage (aiming for ~1000X at panel sites).

  Study EGAS00001005920

• Dataset with genome-wide array data from Algerian Amazigh (Chaoui and Mozabite) and non-Amazigh individuals

  In this study we perform a genetic characterization of different Amazigh populations in Algeria and assess the impact of recent demography on their genomes.

  Study EGAS00001007235

• WGS of human colorectal cancer organoid exposed to genotoxic pks+ E. coli

  Organoid cultures were exposed to two different E.Coli strains and a dye control with three biological duplicates. Their original culture was harvested as a control. In total 10 organoid cultures were whole-genome sequenced using the Novaseq6000 platforms. The data is deposited as .bam format.

  Dataset EGAD00001005416

• RNAseq data from NEN patient derived tumor organoids (PDTOs) and matched parental tumors - SA

  The dataset includes fastq files from 2 LCNEC tumors and matched PDTOs. The sequencing was done with either a Nextseq 2000 or a NovaSeq 6000 instrument.

  Dataset EGAD00001009993

• Hi-C sequencing from a variety of pediatric brain tumors

  Hi-C (n=72) data from a variety of pediatric brain tumors including ependymoma (PFA, PFB, Ste, spinal), medulloblastoma (G3, G4, SHH), high grade glioma (H3K27 and H3-WT), pilocytic astrocytoma, and more. Raw data provided as FASTQ. Data generated on Illumina HiSeq2500.

  Dataset EGAD00001007914

• WES data of primary tumors and metastasis corresponding to three patients

  Fastq files of WES data. Primary tumor and/or metastasic samples of three chRCC patients. DNA libraries were produced using the SureSelect XT HumanAllExon V5 kit (Agilent Technologies), and sequencing was performed in a HiSeq instrument (Illumina) using a 100-bp paired-end mode.

  Dataset EGAD00001010173