Search Results - EGA European Genome-Phenome Archive

Gene expression signatures associated with chronic endometritis revealed by RNA sequencing

Chronic endometritis (CE) is a persistent inflammatory condition of the endometrium characterized by the infiltration of plasma cells. CD138 immunohistochemistry is considered to improve the CE diagnosis rate. Using the number of CD138-positive cells equal or greater than five as a diagnostic criterion for CE, we identified 24 CE and 33 non-CE cases among women with infertility. We conducted RNA-sequencing analysis for these 57 cases in total as an attempt to elucidate the molecular pathogenesis of CE and to search for new biomarkers for CE. By comparing CE and non-CE groups, we identified 20 genes upregulated in the endometria of CE patients, including 12 immunoglobulin-related genes and eight non-immunoglobulin genes as differentially expressed genes. The eight genes were MUC5AC, LTF, CAPN9, MESP1, ACSM1, TVP23A, ALOX15, and MZB1. By analyzing samples in the proliferative and secretory phases of the menstrual cycle separately, we also identified four additional non-immunoglobulin genes upregulated in CE endometria: CCDC13 by comparing the samples in the proliferative phase, and OVGP1, MTUS2, and CLIC6 by comparing the samples in the secretory phase. Although the genes upregulated in CE may serve as novel diagnostic markers of CE, many of them were upregulated only in a limited number of CE cases showing an extremely high number of CD138-positive cells near or over one hundred. Exceptionally, TVP23A was upregulated in the majority of CE cases regardless of the number of CD138-positive cells. The upregulation of TVP23A in the endometria of CE cases may reflect the pathophysiology of a cell-type or cell-types intrinsic to the endometrium rather than the accumulation of plasma cells. Our data, consisting of clinical and transcriptomic information for CE and non-CE cases, helped us identify gene expression signatures associated with CE.

Study JGAS000621

In this study, blood-brain barrier (BBB)-forming brain endothelial-like cells were generated from apolipoprotein E gene allele E4 (APOE4, high AD risk) and allele E3 (APOE3, lower AD risk) carrying patient-derived induced pluripotent stem cells (iPSCs). Cells were subsequently exposed to focused ultrasound and microbubbles (FUS+MB) to induce BBB opening and their transcriptome analysed. RNA sequencing (RNA-seq) results demonstrated minimal changes in the gene expression following FUS+MB suggesting safety of FUS+MB application in the clinical setting.

The blood-brain barrier (BBB) is a major impediment to therapeutic intracranial drug delivery for the treatment of neurodegenerative diseases, including Alzheimer’s disease (AD). Focused ultrasound applied together with microbubbles (FUS+MB) is a novel technique to transiently open the BBB and increase drug delivery. Evidence suggests that FUS+MB is safe, however the effects of FUS+MB on human BBB cells, especially in relation to AD, remain sparsely investigated. Here we developed a human sporadic AD BBB cell platform to investigate the effects of FUS+MB on BBB cells and screen for the delivery of two potentially therapeutic AD antibodies. We generated BBB cells from apolipoprotein E gene allele E4 (APOE4, high AD risk) and allele E3 (APOE3, lower AD risk) carrying patient-derived induced pluripotent stem cells (iPSCs). We utilized this robust and reproducible platform to demonstrate increased delivery of potentially therapeutic antibodies across the BBB, including an analogue of Aducanumab (AduhelmTM) following FUS+MB treatment. Our results also demonstrate the safety of FUS+MB indicated by minimal changes in the cell transcriptome as well as little or no changes in cell viability and inflammatory responses within first 24 h post FUS+MB, with potentially important implications in a clinical setting. Finally, we report a more physiologically relevant hydrogel-based 2.5D BBB model as a key development for FUS+MB-mediated drug delivery screening, with potentially higher translational utility. Our results provide an important advancement for identifying FUS+MB-deliverable drugs and screening for cell- and patient-specific effects of FUS+MB, accelerating its use as a therapy in AD.

Study EGAS00001005944

Copy number profiling of primary samples and cell lines of retinoblastoma

While RB1 loss initiates retinoblastoma development, additional somatic copy number alterations (SCNAs) can drive tumor progression. Although SCNAs have been identified with good concordance between studies at a cytoband resolution, accurate identification of single genes for all recurrent SCNAs is still challenging. This study presents a comprehensive meta-analysis of genome-wide SCNAs integrated with gene expression profiling data, narrowing down the list of plausible retinoblastoma driver genes. We performed SCNA profiling of 45 primary retinoblastoma samples and 8 retinoblastoma cell lines by high-resolution microarrays. We combined our data with genomic, clinical and histopathological data of ten published genome-wide SCNA studies, which strongly enhanced the power of our analyses (N=310). Comprehensive recurrence analysis of SCNAs in all studies integrated with gene expression data allowed us to reduce candidate gene lists for 1q, 2p, 6p, 7q and 13q to a limited gene set. Besides the well-established driver genes RB1 (13q-loss) and MYCN (2p-gain) we identified CRB1 and NEK7 (1q-gain), SOX4 (6p-gain) and NUP205 (7q-gain) as novel retinoblastoma driver candidates. Depending on the sample subset and algorithms used, alternative candidates were identified including MIR181 (1q-gain) and DEK (6p gain). Remarkably, our study showed that copy number gains rarely exceeded change of one copy, even in pure tumor samples with 100% homozygosity at the RB1 locus (N=34), which is indicative for intra-tumor heterogeneity. In addition, profound between-tumor variability was observed that was associated with age at diagnosis and differentiation grades. Since focal alterations at commonly altered chromosome regions were rare except for 2p24.3 (MYCN), further functional validation of the oncogenic potential of the described candidate genes is now required. For further investigations, our study provides a refined and revised set of candidate retinoblastoma driver genes.

Study EGAS00001001715

Exploration of CNV’s and SNV’s in cancers with well-known genetic rearrangements: Identification of additional genetic changes in rearrangements-driven cancer

Specific cancers are well known to have specific gene rearrangements. Representative cancer is chronic myeloid leukemia (CML) which is famous for BCR/ABL gene rearrangements. By the way, also genetic rearrangements are not infrequently found in acute leukemia, and those include CBFB/MYH11 rearrangements, PML/RARA rearrangements, AML/ETO rearrangements, and BCR/ABL rearrangements. The situation is same is for lung adenocarcinoma of non-smokers and prostate cancers, and ALK and RET gene rearrangements are recently found. However, not all these rearrangements are sufficient to develop cancer, and it is suggested that some genetic aberrations are required for the development and progression of cancer in addition to these genetic rearrangements. In this study, we have a plan to explore the existence of additional genetic changes including single nucleotide variants (SNV’s) and copy number variations (CNV’s) in cancers with specific genetic rearrangements so as to define additional genetic changes that confer full oncogenic potential to cancer cells. So as to look at SNV’s and small indels, we are going to use whole exome sequencing (WES) data. And as for CNV’s, we are going to use array-CGH data. Also, to check the functionality of these genetic changes, we are going to use whole transcriptome data (WTS). In addition, in samples with whole genome sequencing (WGS ) data, we are going to explore genetic changes in intronic regions also. In fact, we sequenced 10 AML samples which are known to have specific genetic rearrangements. Analysis of these WGS, WES and WTS data are under the way. If we have a chance to access WES, array-CGH and WTS data of other cancer samples with specific genetic rearrangements, we would be able to compare additional genetic changes required for oncogenesis in cancer cells with various genetic rearrangements. We hope this result will enlighten our understanding of cancer genetics further.

Study EGAS00001000673

ctDNA quantification in Ewing sarcoma patients

Background. Treatment stratification and response assessment in pediatric sarcomas has relied on imaging studies and surgical/histopathological evidence of vital tumor cells. Such studies and evidence collection processes often involve radiation and/or general anesthesia in children. Cell-free circulating tumor DNA (ctDNA) detection in blood plasma is one available method of so-called liquid biopsies that has been shown to correlate qualitatively and quantitatively to some extent with the existence of vital tumor cells in the body. Our clinical observational study focused on the utility and feasibility of ctDNA detection in pediatric Ewing sarcoma (EWS) as a marker of minimal residual disease (MRD). Patients and Methods. We performed whole genome sequencing to identify the exact breakpoints in tumors known to carry the EWS-FLI1 fusion gene. Patient-specific fusion breakpoints were tracked in peripheral blood plasma using digital droplet PCR (ddPCR) before, during, and after therapy in six consecutive children and young adults with EWS. Presence and levels of fusion breakpoints were correlated with clinical disease courses. The genetic changes in the tumors were defined, and inter- and intra-individual changes in the tumor DNA copy loads were observed over time. Results. We show that the detection of ctDNA in the peripheral blood of EWS patients i) is feasible in the clinical routine and ii) allows for the longitudinal real-time monitoring of MRD activity in children and young adults. Although changing ctDNA levels correlated well with clinical outcome within patients, between patients, a high variability was observed (inter-individually) for the six patients described here. Conclusions. ctDNA detection by ddPCR is a highly sensitive, specific, feasible, and highly accurate method that can be applied in EWS for follow-up assessments as an additional surrogate parameter for clinical MRD monitoring and, potentially, also for treatment stratification in the near future.

Study EGAS00001006433

One-step generation of tumor models by base editor multiplexing in adult stem cell-derived organoids

Recent optimization of CRISPR/Cas9-mediated genome engineering has resulted in the development of base editors that can efficiently mediate C>T and A>G transitions. Combining these genome engineering tools with human adult stem cell (ASC)-derived organoid technology holds promise for disease modeling. Here, we demonstrate the application of base editors for the generation of complex tumor models in human ASC-derived hepatocyte, endometrial and intestinal organoids. First, using conventional and evolved Cas9-variants, we show efficacy of both cytosine and adenine base editors and use them to model four hot-spot point mutations in CTNNB1 in hepatocyte organoids. Next, we apply C>T base editors in endometrial organoids to insert nonsense mutations in PTEN and demonstrate tumorigenicity even in the heterozygous state. Furthermore, we use cytosine base editors for simultaneous oncogene activation (PIK3CA) and tumor-suppressor inactivation (APC and TP53). To increase the flexibility of base editor multiplexing, we then combine SpCas9 and SaCas9 base editors for simultaneous C>T and A>G editing at individual target sites. Finally, we show the power of base editor multiplexing by modeling colorectal tumorigenesis in a single step by simultaneously transfecting sgRNA’s targeting four cancer genes. Seven clonal organoid lines and one bulk wild-type control sample were paired-end whole-genome sequenced using the Illumina Novaseq 6000 system. We sequenced four clonal intestinal organoid lines harbouring engineered TP53 and FBXW7 mutations as well as three lines targeted for oncogenic APC/TP53/PIK3CA/SMAD4 mutations. This WGS showed, as previously reported, a genome-wide increase in C>T mutations due to C>T base editor off-target activity, which is not enriched in predicted off-target regions based on the sgRNA sequences. Furthermore, we confirmed the absence of editing-induced driver mutations and lack of off-target mutational hotspots created by the genomic engineering.

Study EGAS00001006886

Separation of chronic myeloid leukemia stem cells from normal hematopoietic stem cells at single-cell resolution

Chronic myeloid leukemia (CML) is a clonal disease, initiated and sustained by a subpopulation of CML stem cells (CML-SC) containing the BCR::ABL1 oncogene. Genetic markers that enrich for CML-SC have been identified, including CD26 being most specific. Genome sequencing analysis remain yet to be performed at single cell level in order to determine differences and heterogeneity in the genetic profile of CML-SC versus normal hematopoietic stem cells (HSC). Here we show that CD26 and CD33 separate CML-SC from normal HSC in freshly isolated bone marrow samples from newly diagnosed CML patients. DNA sequencing confirms that single CML-SC derived colonies are positive for BCR::ABL1 and harbor a recurrent set of patient-specific clonal somatic mutations across different CML-SC derived colonies. In contrast, marker-negative (CD26-CD33-) HSC from the same patients are negative for the BCR::ABL1 oncogene and do not carry recurrent, clonal mutation across different colonies. These results support the concept that CD26/CD33 expression separates genetically defined, clonal mutant CML-SC from normal HSC that carry individual sets of random mutations in CML patients. We provide whole exome DNA sequencing data for 23 clinical samples of CML-SC plus two buccal swipes derived normal samples. CML samples are comprised of 4 to 8 replicates from two patients, at diagnosis and after treatment. Single CML stem cells before treatment and single non-transformed HSC at remission were selected from bone marrow samples by FACS, according to genetic markers CD33+CD26+ at diagnosis and CD33+CD26-/CD33-CD26- at remission. WES libraries of colony forming assays derived CML-SC and HSC populations were prepared using Agilent SureSelect Human All Exon V6 kit and sequenced running 150 cycles (2x 75bp paired-end) on an Illumina NextSeq 500 platform. Following GATK best practices for somatic mutation calling, novel CML variants and random mutation events during remission phase were obtained.

Study EGAS00001006904

A Polygenic Score for Acute Vaso-Occlusive Pain in Pediatric Sickle Cell Disease

Recurrent acute pain, or vaso-occlusive pain crisis (VOP), is the most common complication of sickle cell disease and correlates strongly with increased hospital visits and early mortality (PMID: 1710777). While the genetics of VOP in sickle cell patients has been studied (PMID: 29205277, 27883292, 25102390, 30079801, 22925497, 29531649, 29620434, 19468207, 20172753, 22576309, 30031848, 24136375, 27603703, 29559808), it is not fully understood.Using whole genome sequencing, we interrogated the α-thalassemia deletion -α3.7 and 133 candidate single-nucleotide polymorphisms (SNPs) across 66 genes for associations with VOP in 327 SCCRIP participants followed longitudinally over 6 years. Twenty-one SNPs in 9 loci were associated with VOP, including 3 (BCL11A, MYB, and the β-like globin gene cluster) that regulate erythrocyte fetal hemoglobin (HbF) levels and 6 (COMT, TBC1D1, KCNJ6, FAAH, NR3C1, and IL1A) that were associated previously with various pain syndromes. An unweighted PGS integrating all 21 SNPs was associated with the VOP event rate (estimate, 0.35; standard error, 0.04; P = 5.9 × 10−14) and VOP event occurrence (estimate, 0.42; standard error, 0.06; P = 4.1 × 10−13). These associations were stronger than those of any single locus. Our findings provide insights into the genetic modulation of VOP in children with SCD. More generally, we demonstrate the utility of WGS for investigating genetic contributions to the variable expression of SCD-associated morbidities.For publications, written, and/or oral presentations resulting from use of this data, please cite the following information: "The original data description for A Polygenic Score for Acute Vaso-Occlusive Pain in Pediatric Sickle Cell Disease can be found here: (Journal Citation Blood Adv. 2021 Jul 27;5(14):2839-2851) (PMID: 34283174)."

Study phs002470

Discovery and validation of an ancillary genomic test of malignancy for primary melanocytic tumors

Background:Pathological diagnosis of melanocytic tumors can be difficult and prone to error. More accurate and reliable ancillary investigations than those currently available are required to improve diagnostic accuracy. Goals: (1) to generate a genomic model for distinguishing benign (nevi) from malignant (melanoma) melanocytic skin tumors, developed from a customized gene panel evaluated on a cohort of 250 nevi and melanomas. (2) To evaluate the performance of the genomic model in melanocytic tumors of uncertain diagnosis/behavior. Details: The cohort of 250 melanomas and naevi was split into a discovery set and a validation set. Our genomic model obtained an area under the curve of 95% in the discovery cohort and 96% for the validation cohort. Based on a Youden index threshold, the resulting classifier shows high specificity (>95% in the discovery and validation cohorts), with sensitivities >80% in the discovery and validation cohorts. Evaluation of the genomic model on a cohort of 110 melanocytic tumors identifies key driver mutations in agreement with the likely pathway of origin of the tumors. The probability of melanoma (p=0.02) from the genomic model was significantly associated with pathology-based estimates of malignancy for melanocytic tumors lacking pathway-defining genomic aberrations (conventional tumors). The genomic model identified 8/36 (22%) conventional tumors with unresolved malignancy to have a high probability of melanoma, with 7/8 of these cases showing negative/non-aberrant results with either fluorescent in-situ hybridization, PRAME and/or p16 immunostains. Furthermore, no evidence of malignant behavior based on the genomic model was seen in 4 conventional borderline tumors with more than 1 year follow-up. Conclusion: This genomic model can become a clinically useful ancillary tool that is highly specific for differentiating melanomas from nevi.

Study EGAS50000000887

DAC for Central African ancient demography processes NGS dataset

Title DAC Ancient tree-topologies and gene-flow processes among human lineages in Africa Contacts: Paul Verdu +33144057317 paul.verdu@mnhn.fr CNRS-MNHN-Université de Paris UMR7206 Eco-anthropology Short description The Data Access Committee for acess to genotype and sample information used in the article "Ancient tree-topologies and gene-flow processes among human lineages in Africa" by Gwenna Breton et al. 2025 ensures that data-access requests comply with the Informed Consent provided by donors, and with ethical and deontological guidelines with respect to privacy. DNA samples from individuals were collected with the subjects’ informed consent following the Declaration of Helsinki guidelines and approved by the following Ethics committees: Institut de Recherche pour le Développement (IRD, France); Cameroon Ministry of Scientific Research and Technology; Central African Republic Ministère de l’Enseignement Supérieur et de la Recherche Scientifique; France Ministère de l’Enseignement Supérieur, de la Recherche et de l’Innovation (Comité de Protection des Personnes DC-2016-2740); French Commission Nationale Informatique et Liberté CNIL (declaration n°1972648); Uganda National Council for Science and Technology; Institutional Review Board of the University of Chicago Biological Sciences Division and the Pritzker School of Medicine University of Chicago Hospitals (protocol number 16986A); Committee for the Protection of Human Subjects of the Trustees of Dartmouth College and the Dartmouth-Hitchcock Medical Center (protocol number 22410); Human Research Ethics Committee (Medical) at the University of the Witwatersrand, Johannesburg (Protocol Numbers: M980553, M050902, M090576, M10270, M180654); Working Group of Indigenous Minorities in Southern Africa (WIMSA); South African San Council (SASC); and the Swedish Ethical Review Authority (Dnr 2019-05174). Requests for accessing all or part of the Central African data used in the article "Ancient tree-topologies and gene-flow processes among human lineages in Africa", by Gwenna Breton et al. 2024 (doi - PENDING), should be addressed to the DAC providing: 1) Data can only be used to explore human genetic evolution, evolutionary ecology and population history 2) The research institution where data will be stored and were analyses will be conducted. 3) The detailed coordinates of the researcher responsible for data storage and analyses. 4) A description (max 20 sentences) of the scientific finality and context of the project and classes of methodological analyses that will be performed to achieve it using the requested data. 5) When applicable, mention also other previously published data sets that will be used jointly with the requested datas et For accessing any or all the Central African genetic data used in the article "Ancient tree-topologies and gene-flow processes among human lineages in Africa", by Gwenna Breton et al. 2024 (doi - PENDING), the requester hereby ensures that: 1) Individual donor privacy should be respected at all times. Data cannot be made publicly available under any circumstances. 2) Data cannot be shared nor transferred to a third party without re-applying for eGA access to the DAC. 3) No direct or indirect commercial use of the data can be made 4) No individual medical genetics or disease diagnostics can be performed with the data 5) No medical or legal forensic investigations can be conducted with the data 6) No genealogical research can be conducted with the data (e.g. no paternity nor maternity testing, no genetic identification, no search of relatives using other datasets) 7) Appropriate citation of the article and data set used for any scientific communication using the data 8) Data is destroyed after the completion of the project. Any further re-use of the data is subject to a novel application to the DAC.

Dac EGAC50000000447

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

Limited Association between HRR Gene Alterations and HRD in Molecular Tumor Board Cancer Samples: Who should be tested for HRD?

Alterations in Homologous Recombination Repair (HRR) Pathway genes have been found to be associated with HR-Deficiency (HRD), which is an approved biomarker for PARP Inhibitor (PARPi) treatment. The aim of a Molecular Tumor Board (MTB) is to identify molecular alterations in cancer patients with advanced tumors that may suggest off-label treatment options. So far, few studies have analyzed the presence of HRR gene mutations and their association with HRD outside of clinical studies. Currently, no data on HRD testing in the setting of a MTB have been published. For the present study, a cohort of 237 patients encompassing 24 different tumor entities was collected from the MTB of the Comprehensive Cancer Center Erlangen-EMN. We show that an elevated Genomic Instability Score (GIS ≥ 42) can occur in samples with and without mutations in HRR-related genes. Overall, 38.1% of cancer samples with BRCA1/2 mutations, 10.9% of tumors with alterations in HRR genes other than BRCA1/2, and 4.3% of cancer samples without HRR gene mutations harbored an elevated GIS. Notably, our data show that various inactivating BRCA1/2 mutations are not associated with an elevated GIS. Taken together, panCancer assessment of HRD in addition to BRCA1/2 and other HRR gene mutational analysis is recommended to guide decisions regarding PARPi treatment. Further studies are needed to establish thresholds for GIS in non-ovarian cancer entities. Finally, HRD can be observed in 4.3% of BRCA1/2 and other HRR gene wildtype cancer samples, and may emerge as an independent biomarker for PARPi in the future.

Study EGAS00001008063

Pharmacological and genomic profiling identifies NFκB-targeted treatment strategies for mantle cell lymphoma

Mantle cell lymphoma (MCL) is an aggressive malignancy characterized by poor prognosis, underscoring the need for novel therapeutic strategies1. In this study, we employed large-scale pharmacological profiling of 16 pathway inhibitors across more than 100 hematological cell line models to identify novel therapeutic approaches. This screen identified a subset of MCL cell lines that were highly sensitive to the B-cell receptor (BCR) signaling inhibitors ibrutinib and sotrastaurin (STN), which are currently in clinical trials2, 3. Sensitive MCL models exhibited chronic activation of the CARD11-BCL10-MALT1 (CBM) complex and dependency on downstream classical NFκB signaling. In contrast, insensitive cell lines displayed activation of the alternative NFκB pathway. Massively parallel transcriptome sequencing identified mutations in negative regulators of the alternative NFκB pathway in ibrutinib-insensitive cell lines. Notably, sequencing of 165 MCL patient samples revealed that components of the alternative NFκB pathway, particularly TRAF2 and BIRC3, are mutated in roughly 15% of MCL patients. Functional analyses of patient-derived BIRC3 mutant alleles indicated that these are loss-of-function mutants that constitutively activate alternative NFκB signaling. While being associated with insensitivity to ibrutinib, genetic lesions in the alternative pathway conferred dependence on NIK, a kinase that mediates signaling downstream of the TRAF2/3-BIRC2/3 complex. Thus, NIK represents a novel therapeutic target for MCL treatment, particularly for tumors refractory to BCR pathway inhibitors. Collectively, these findings reveal a pattern of mutually exclusive activation of the CBM-NFκB or alternative NIK-NFκB pathways in MCL and provide critical insights into patient stratification strategies for NFκB-pathway targeted agents.

Study EGAS00001000622

Biomarker Screen for Efficacy of Oncolytic Virotherapy in Patient-derived Pancreatic Cancer Cultures

Pancreatic ductal adenocarcinoma (PDAC) is a tumour entity with unmet medical need. To assess the therapeutic potential of oncolytic virotherapy (OVT) against PDAC, different oncolytic viruses (OVs) are currently investigated in clinical trials. However, systematic comparisons of these different OVs in terms of efficacy against PDAC and biomarkers predicting therapeutic response are lacking. We screened fourteen patient-derived PDAC cultures for their sensitivity to five clinically relevant OVs, namely serotype 5 adenovirus Ad5-hTERT, herpes virus T-VEC, measles vaccine strain MV-NIS, reovirus jin-3, and protoparvovirus H 1PV using live cell analysis, quantification of viral genome/gene expression, cell viability as well as cytotoxicity assays. Sensitivity was correlated with transcriptome profiles to identify potential predictive biomarkers for response to OVT. Patient-derived PDAC cultures showed individual response patterns to OV treatment. Twelve of fourteen cultures were responsive to at least one OV, with no single OV proving superior or inferior across all cultures. Known host factors for distinct viruses were retrieved as potential biomarkers. Compared to the basal-like molecular subtype, the quasi-mesenchymal subtype of PDAC was more sensitive to H-1PV, jin-3, and T-VEC. Expression of viral entry receptors did not correlate with sensitivity to OV treatment. Rather, cellular pathways controlling immunological, metabolic, and proliferative signalling appeared to determine outcome. For instance, high baseline expression of interferon-stimulated genes (ISGs) correlated with relative resistance to oncolytic measles virus, whereas cGAS expression was associated with exceptional response. Combination treatment of MV-NIS with a cGAS inhibitor improved tumour cell killing in several PDAC cultures.

Study EGAS00001007001

CTSP: Clinical Trial Sequencing Project

For the Clinical Trials Sequencing Project (CTSP), National Cancer Institute (NCI) will utilize whole genome sequencing and/or whole exome sequencing in conjunction with transcriptome sequencing to try to identify recurrent genetic alterations (mutations, deletions, amplifications, rearrangements) and/or gene expression signatures that would be important to the hypothesis(es) submitted by the investigators. The samples will be processed and submitted for genomic characterization using pipelines and procedures established within The Cancer Genome Analysis (TCGA) project. Data analysis will be performed as a collaboration between the National Clinical Trials Network (NCTN) Group and its investigators submitting the proposal. The investigators at the NCI-sponsored Genomic Data Analysis Center (GDAC) will characterize the samples. The NCTN Group will be responsible for providing the clinical data needed for the proposal to the open clinical system maintained by NCI CCG's Biospecimen Core Resource (BCR) at Nationwide Children's Hospital in Columbus, Ohio. The project team (Network Group/investigators and GDAC) will analyze the data together. Additionally, clinical and genomic data related to the analyses will also need to be registered by NCI and will be made available to qualified researchers via a controlled-access database (e.g., dbGaP) upon publication of the primary analysis described in the study proposal. A substudy description and its molecular data information are provided under its own page: phs001184 CTSP Diffuse Large B-Cell Lymphoma (DLBCL) CALGB 50303

Study phs001175

The Pioneer 100 Wellness Project (P100)

108 individuals (age 21-89+ years; 59% males, 41% females; 89% Caucasian; not recruited based on any specific phenotype) participated in an IRB-approved study from April 2014 to January 2015. Each individual had the genome sequenced in full. Blood was collected in clinics every three months. Additionally, participants completed at-home collections of saliva, stool, and first morning void urine every three months. Stool and saliva samples were shipped directly to the vendor by the participant, while urine was given back to the study coordinators for distribution to the proper sample vendor. For each successful participant in each round we carried out 218 clinical laboratory tests, measured up to 643 metabolites and 262 proteins, and measured the abundance of 4616 operational taxonomic units (OTUs) in the gut microbiome using 16S rRNA sequencing. The P100 study had four objectives: 1) Establish cost-efficient procedures for generating, storing and analyzing multiple sources of health data obtained over time from participants and analyzed in combination with genomic data; 2) Develop and deploy analytic tools for integrating these diverse datasets and deriving actionable information from their observed interrelationships; 3) Identify novel patterns within the streams of health data that indicate either wellness, or transitions between wellness and disease; 4) Learn how to best interface with and present longitudinal health information to individuals by studying the reactions and feedback from participants as they are presented actionable information.

Study phs001363

Integrated Epigenetic Maps of Human Embryonic, Extraembryonic and Adult Cells

Working cooperatively with other Mapping Centers and the Data Coordination Center (EDACC) funded by this Roadmap mechanism we have comprehensively mapped the epigenomes of select human cells with significant relevance to complex human disease. Our effort has been focused on cells relevant to human health and complex disease including cells from the blood, brain, breast, skin, male germ cells, extraembryonic tissues and trophoblast, and U.S. Government-approved lines of human embryonic stem cells. We have incorporated high quality, homogeneous cells from males and females, and two predominant racial groups, and biological replicates of each cell type. The resulting comprehensive maps include up to 6 histone modifications selected for their opposing roles in regulating active and inactive chromatin (H3K4me1, H3K4me3, H3K9me3, H3K9ac, H3K27ac, H3K27me3, H3K36me3), DNA methylation, miRNA and gene expression, and for select cases whole genome shotgun sequence. Our cell and data production pipeline incorporates verification and data validation with independent methods, and operates under a model motivated by increased data production and decrease cost. Our group in conjunction with the other REMC teams, the EDACC, ENCODE, Epigenetics of Human Health and Disease centers and the NIH Roadmap program are developing methods, tools and reference epigenome maps for the research community that will make the promise of epigenetics in understand and treating human complex disease a reality. Our reference epigenomes will enable new disciplines including human population epigenetics, comparative epigenomics, neuroepigenetics, and therapeutic epigenetics for tissue regeneration and reversal of disease.

Study phs000791

Genomic Predictors of Combat Stress Vulnerability and Resilience

The Genomic Predictors of Combat Stress Vulnerability and Resilience Study was designed to probe the likely hereditary basis for risk or resilience to develop PTSD and other trauma spectrum disorders. The overall guiding hypothesis was that genomic variation gives rise to risk/susceptibility traits that, when actuated by traumatic environmental stimuli, such as combat, give rise to PTSD and other stress-related phenotypes. Two studies designed to identify risk and resilience factors for combat-induced, stress-related symptoms are being conducted by our group: The Marine Resiliency Study (MRS) is a prospective PTSD study with longitudinal follow-up (pre- and post-exposure to combat stress) of US Marines bound for deployment to Iraq or Afghanistan. Extensive phenotyping includes 3 domains: Psychosocial, Psychophysiologic, and Biophysiologic. The biological and physiological measures collected were chosen in part due to their potential to serve as intermediate phenotypes for stress-related disorders. A second, cross-sectional study involves a cohort of combat-exposed active duty or previously deployed service members (CAVC), including PTSD cases and controls with comparable psychosocial and clinical phenotypes. Little information is available about the factors that explain why some trauma survivors develop stress disorders and some do not. It is hoped that the insights gained from this approach will improve understanding of the genetic contributors to PTSD, and potentially provide novel diagnostic tests and therapeutic approaches to this currently enigmatic and difficult-to-manage condition.

Study phs000864

Clinical Sequencing Exploratory Research (CSER): Clinical sequencing in cancer: Clinical, ethical, and technological studies

The Clinical Sequencing Exploratory Research (CSER) program supports multi-disciplinary projects that bring together clinicians, bioinformaticians, and ethicists to research the challenges of utilizing genomic sequence data in the clinic in the routine practice of medicine. The challenges are many and not disease-specific. Important aims of the research include: development of technical specifications and standards for sequencing in a clinical setting, investigation of methods to transmit genome-scale data to physicians in a fashion and timescale that fits the normal clinical workflow, exploration of regulatory requirements for applying genomic sequence data to patient care, study of physician and patient preferences regarding presentation of genomic information, and study of the ethical implications of returning unanticipated findings. More information about CSER and the investigators and institutions who comprise the CSER consortium can be found at http://www.genome.gov/27546194. The NEXT (New Exome Technology) Medicine Study utilizes a randomized controlled trial (RCT) structure to compare usual care (UC) practice in Medical Genetics Clinics with the introduction of a powerful research tool of whole exome sequencing plus UC practices for Colorectal Cancer and Polyposis (CRCP) in adults. In doing so, the study aims to explore the practical, economic, and ethical implications of identifying and returning incidental findings ("extra" whole exome genetic risk results not associated with CRCP that includes pharmacogenetic variants) to patients. The study will also attempt to identify novel causal genes for CRCP by studying relatives of selected research subjects.

Study phs000999

Center for Common Disease Genomics (CCDG) Neuropsychiatric: Homozygosity Mapping Consortium for Autism (HMCA)

In this study, we address the enormous challenges common complex diseases pose for genomic analysis and the enormous opportunities surmounting them offers for advancing healthcare. The common genetic disorders proposed for study are believed to have extreme locus heterogeneity, requiring the analysis of large numbers of samples to comprehensively identify the genomic variants underlying them. We propose that a combination of deep population studies and joint analysis of SNPs, indels, and structural variants, both in coding and noncoding regions, will provide the next level of understanding of common genetic disorders. Whole genome sequencing (WGS) will be critical to this next-generation approach to the genomics of complex disease. WGS will need to be accompanied by the technical ability to generate and handle very large data sets, a particular focus and strength of NYGC. WGS will also need to be accompanied by new statistical tools and algorithms, which will be developed by the strong core group committed to this proposal. An overarching goal of this proposal, one that capitalizes on the power of WGS, is to identify disease-associated variants at the individual nucleotide level. In many cases, pathogenic mutations fall in noncoding regions of the genome, which can only be fruitfully explored with WGS. A major effort was put into building new computational strategies to functionally annotate noncoding transcribed sequences, and to build new datasets to enable such strategies, opening new frontiers of understanding of disease-related regulatory variants.

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Indexing Genes Impacted by Copy Number Variation in Developmental Disorders

A challenge in clinical genomics is to predict whether copy number variation (CNV) affecting a gene or multiple genes will manifest as disease. Increasing recognition of gene dosage effects in neurodevelopmental disorders prompted us to develop a computational approach based on critical-exon (highly expressed in brain, highly conserved) examination for potential etiologic effects. Using a large CNV dataset, our updated analyses revealed significant (P < 1.64 x 10-15) enrichment of critical-exons within rare CNVs in cases compared to controls. Separately, we used a weighted gene co-expression network analysis (WGCNA) to construct an unbiased protein module from prenatal and adult tissues and found it significantly enriched for critical exons in prenatal (P < 1.15 x 10-50, OR = 2.11) and adult (P < 6.03 x 10-18, OR = 1.55) development. WGCNA yielded 1,206 proteins for which we prioritized the corresponding genes as likely to have a role in neurodevelopmental disorders. We compared the gene lists obtained from critical-exon and WGCNA analysis and found 438 candidate genes associated with CNVs annotated as pathogenic, or variants of uncertain significance (VOUS), from among 10,619 developmental delay cases. We identified genes containing CNVs previously considered to be VOUS, to be new candidate genes for neurodevelopmental disorders (GIT1, MVB12B and PPP1R9A) demonstrating the utility of this strategy to index the clinical effects of CNVs. Reprinted from Uddin et al, 2016, with permission from Scientific Reports.

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NIAID Centralized Sequencing Program

Investigators at the National Institute of Allergy and Infectious Diseases (NIAID) use next-generation sequencing technologies to help determine genetic contributions to immune diseases. These efforts have increased rates of molecular diagnosis for a subset of NIAID participants as well as uncovered fundamental insights into the cellular and signaling pathways in host defense and immune regulation. Despite these successes, analysis and interpretation of genomic data remain a substantial challenge. Simply, researchers do not understand the functional and clinical consequences of most human genetic variation. Making progress in this area requires a coordinated, systematic, and transparent approach to clinical genomics research. This protocol is specific to genetic testing and explicitly aims to both strengthen clinical care and enhance research. Probands provide biological specimens for genetic testing and primary clinical and research evaluations are completed via a research protocol at NIAID. This protocol serves as a vehicle for a programmatic effort that includes standardized phenotyping, test ordering through the Clinical Research Information System (CRIS) at the National Institutes of Health Clinical Center, sample collection and isolation, nucleic acid analysis, bioinformatics, clinical interpretation, reporting in CRIS, genetic counseling, and supporting effective use of genomics as a research tool throughout the institute. Overall, increased process standardization will support data integrity and efficiency while still accommodating the need for investigator flexibility. This study aims to generate and analyze evidence regarding the genetic contribution to diverse immune diseases studied by the NIAID intramural research program.

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Genomic and Phenotypic Profile of Sickle Cell Disease in Human Population in Cameroon

Sickle cell disease (SCD) is caused by a biallelic single nucleotide substitution in the beta-globin gene (HBB), resulting in an amino acid substitution, Glu7Val, formerly known as Glu6Val. An estimated 300,000 babies with SCD are born worldwide each year, with nearly 75% of these births being in sub-Saharan Africa. In Africa, at least 30-50% of children with untreated SCD die before the age of 5 years. Therefore, accelerating the path for novel therapies for SCD through genomics research on fetal hemoglobin (HbF) is critical. Variants in the currently known HbF‐modulating genes/loci, i.e., BCL11A, HBS1L-MYB, and XmnI-HBG2, explain only 10-20% of the variation of HbF levels in African individuals with SCD, compared with nearly 50% of the variation in HbF levels among Europeans. Expanding genomic research in populations of African ancestry could uncover the missing heritability of HbF-promoting loci. This study used the Human Heredity and Health (H3Africa) consortium SNP genotyping array developed from whole genome enriched for common variants in sub-Saharan Africans to investigate genomic variations associated with HbF levels in individuals with sickle cell anemia of the HbSS genotype from Cameroon. Two of the previously described loci, BCL11A and HBS1L-MYB were replicated, while a novel locus on chromosome 13 mapping to FLT1 was uncovered. The study therefore opens up a novel avenue for exploring SCD gene therapy.

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The Genomic and Transcriptomic Landscape of a HeLa Cell Line

HeLa is the most widely used model cell line for studying human cellular and molecular biology. To date, no genomic reference for this cell line has been released, and experiments have relied on the human reference genome. Effective design and interpretation of molecular genetic studies performed using HeLa cells require accurate genomic information. Here we present a detailed genomic and transcriptomic characterization of a HeLa cell line. We performed DNA and RNA sequencing of a HeLa Kyoto cell line and analyzed its mutational portfolio and gene expression profile. Segmentation of the genome according to copy number revealed a remarkably high level of aneuploidy and numerous large structural variants at unprecedented resolution. Some of the extensive genomic rearrangements are indicative of catastrophic chromosome shattering, known as chromothripsis. Our analysis of the HeLa gene expression profile revealed that several pathways, including cell cycle and DNA repair, exhibit significantly different expression patterns from those in normal human tissues. Our results provide the first detailed account of genomic variants in the HeLa genome, yielding insight into their impact on gene expression and cellular function as well as their origins. This study underscores the importance of accounting for the strikingly aberrant characteristics of HeLa cells when designing and interpreting experiments, and has implications for the use of HeLa as a model of human biology. Copyright Landry et al., "The Genomic and Transcriptomic Landscape of a HeLa Cell Line," G3: Genes | Genomes | Genetics (2013).

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Comprehensive molecular and clinicopathological profiling of lung adenocarcinoma in Japanese never or light smokers

Studies have yet to characterize the differences in molecular profiles of lung adenocarcinoma (LUAD) among divergent ethnic groups. Herein, we conducted comprehensive molecular profiling of LUAD in never or light smokers from Asia in order to discover novel targetable mutations and prognostic biomarkers of this distinct disease entity. Methods: We analyzed 996 cases of Asian LUAD, and performed whole-exome sequencing and/or RNA-seq in 125 cases of Asian LUAD negative for the driver oncogenes defined by conventional laboratory testing. We also investigated the clinical and pathological characteristics among the 996 cases. Results: Driver oncogenes were identified in 88 cases (70.4%) with specific hotspot mutations differing from those in The Cancer Genome Atlas (TCGA) study. Clustering based on mRNA expression profiles, but not genetic mutational ones, could predict patient prognosis. The risk score generated by the expression of a three-gene set was a strong prognostic marker for overall survival and progression-free survival in our cohort, and was further validated using TCGA cohort. Among the 996 cases, each driver alteration is distributed across all histological subtypes. Adenocarcinoma in situ was identified to harbor driver mutations, suggesting that these alterations are early events in the pathogenesis of LUAD. This study indicates the value of applying gene expression profiling for predicting the prognosis after a surgical operation, and that the identification of actionable mutations is important for optimizing targeted drugs in Japanese LUAD.

Study JGAS000215

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