Search Results - EGA European Genome-Phenome Archive

Single Cell Genome Sequence for DLP+ library A96173A

Single Cell Genome Sequence for triple negative breast cancer patient-derived xenograft SA501 passage 15 on DLP+ library A96173A

Dataset EGAD00001009459

WGS data of colorectal cancer patients

36 samples from individuals with colorectal tumors, whole genome sequencing

Dataset EGAD00001007746

Single Cell Genome Sequence for DLP+ library A96174A

Single Cell Genome Sequence for triple negative breast cancer patient-derived xenograft SA501 passage 11 on DLP+ library A96174A

Dataset EGAD00001009460

Single Cell Genome Sequence for DLP+ library A96213A

Single Cell Genome Sequence for triple negative breast cancer patient-derived xenograft SA501 passage 6, cell line SA1090 on DLP+ library A96213A

Dataset EGAD00001009477

Synchronous Colorectal Cancer genome sequencing

Here, we performed a characterisation of 12 tumours and matched normal samples from 3 syCRC patients by whole genome sequencing: Patient A (tumours A1 and A2), Patient B (tumours B1-B5), and Patient C (tumours C1-C5). Somatic SNVs, indels and stuructural variants were called.

Dataset EGAD00001006131

CancerSEEK ctDNA FASTQ files

Sequencing data from 1,005 cancer patients and 812 healthy controls. All samples prepared using Safe-SeqS technology and sequenced on an Illumina MiSeq and/or HiSeq instrument. Paired FASTQ files for correspond to read 1 and the index read present (R and I respectively).

Dataset EGAD00001003931

PELICAN45 RNAseq Dataset

RNAseq in cryostat-microdissected metastatic and primary prostate cancer tissues and matched noncancerous tissues from the same study subjects.

Dataset EGAD00001009997

Dataset for NSCLC-EXON

Rare cancer sequencing data of 42 runs in tumor/control pairs, which were uploaded to umbrella studies. The sequencing was always paired

Dataset EGAD00001008892

Whole Genome Sequencing for Korean Diffuse Gastric Cancer

Fastq files for the whole genome sequencing data (Illumina HiSeq 2500; 32.6-fold) for two diffuse gastric cancers revealing the fusion breakpoints. 2102T: CTNND1-ARHGAP26 gene fusion (g.chr11:57,578,103-g.chr5:142,358,707) 354T: ANXA2-MYO9A gene fusion (g.chr15:60,656,550-g.chr15:72,157,966)

Dataset EGAD00001003953

Single Cell Genome Sequence for DLP+ library A96177C

Single Cell Genome Sequence for triple negative breast cancer patient-derived xenograft SA604 passage 6 on DLP+ library A96177C

Dataset EGAD00001009462

Whole genome sequencing of RIKEN liver cancers

RIKEN collection of WGS reads of 530 liver cancer and matched blood samples from 260 donors.

Dataset EGAD00001001642

multi-region sequencing of tumor samples from PDAC patients

This study includes 542 of multi-region sampled whole exome sequencing data from 83 pancreatic cancer patients in 6 individual experiments : Kras wildtype, local recurrence, treatment-naive (MetomeV2), radiotherapy plus chemotherapy (Radome), chemotherapy-only group (Treatome) and Proj_B-100-478.

Dataset EGAD00001011109

Bone marrow single cell genomics from blood cancer samples

Four different types of transcriptomic single-cell sequencing of blood from childhood B acute lymphoblastic leukemia.

Dataset EGAD00001011055

Ovarian cancer/normal cell lines

We performed whole genome sequencing of nine OC patient-derived cell lines and one normal cell line (HOSEpiC) to analyze if the cell lines harbor OC-typical genomic aberrations absent in normal cells and to relate genomic features to drug sensitivities.

Dataset EGAD00001003146

Genomic alteration in Korean Young Age Diffuse Gastric Cancers

To identify recurrent somatic alterations in this unique subset of gastric cancers, whole exome and SNP6 analyses were performed using frozen cancer tissue. The somatic mutation analyses were also performed using blood of the same patients.

Dataset EGAD00001001984

Genomic Analyses of Germline and Somatic Variation in High-Grade Serous Ovarian Cancer

The goal of this study was to identify and characterize germline and somatic genetic variation in women with high grade serous ovarian cancers treated at a single cancer center and their associations with relapse-free and overall survival. We conducted paired tumor/normal targeted next-generation sequencing of 577 genes in pathways of DNA repair, response to DNA damage, cell-cycle regulation, programmed cell death, MAPK, and P13K/AKT/MTOR signaling in 114 tumors from 71 women. In addition, we investigated single copy number alterations (SCNAs) and loss of heterozygosity in a subset of 61 tumors. We validated our results with data from ovarian tumors in TCGA. Our results were similar to other studies of high-grade serous carcinomas. As an example, we found that approximately one third of the tumors harbored loss of function variants in homologous recombination genes and that >90% had TP53 somatic mutations. Through GISTIC analysis of the OncoScan data on tumor DNA from 61 cases, we identified several regions of high copy number alterations including including NOTCH3 and PIK3R2 that were significantly associated with an increase in cancer recurrence and a reduction in overall survival. We identified few changes in mutation profiles where we had multiple tissues, either from multiple surgeries or from the primary site to metastatic sites within the same surgery. However, we did not investigate copy number alterations in multiple tissues from the same individuals, and so it may be that copy number alterations are more important. Data available through dbGAP will be the BAM files and the phenotypic data on the tumor samples, the age, race, ethnicity of the participants and their outcomes, and the Oncoscan OSCHP files.

Study phs003198

Investigating the Role of Neddylation in the Repair of Topoisomerase I-Mediated DNA Damage in Colorectal Cancer

Colorectal cancer is one of the most lethal cancers worldwide. First-line chemotherapy for metastatic CRC (mCRC) entails a combination of irinotecan with 5-fluorouracil and leucovorin (FOLFIRI). Irinotecan is a prodrug that is converted within the cell to its active metabolite SN38, a potent TOP1 inhibitor. TOP1 relieves DNA torsional strain arising from DNA metabolism by cleaving one strand of the DNA duplex and forming an enzyme-DNA covalent intermediate that can be trapped by inhibitors. The resulting TOP1 DNA-protein crosslinks (TOP1-DPCs) interfere with replication and transcription and induce cell death if left unrepaired. I have established the role of the ubiquitin-proteasome pathway in TOP1-DPC repair, but it remains unknown how ubiquitylation is activated. One possibility is that collision between advancing replication forks and the DPCs triggers a specific ubiquitin ligase to target DPCs for degradation. The DDB1-CUL4 (Cullin 4)-RBX1 (CRL4) ubiquitin ligase complex performs a salient role in both replication and DNA repair upon its activation by auto-NEDD8 modification (neddylation), but it is unknown whether it plays a role for TOP1-DPC repair. We plan to define the role of neddylation for TOP1-DPC repair during replication and examine irinotecan plus pevonedistat (PEV), a NEDD8-activating enzyme inhibitor in multiple clinical trials, in CRC patient-derived preclinical models including 3D organoids. The three in-house organoids, from which samples have been submitted to dbGaP, were sequenced as a means of verifying their identity as colon cancer organoids, to allow us to investigate the combination of TOP1 inhibitors and PEV and the molecular mechanisms underlying this drug combination in these organoids.

Study phs003257

Clinical and Molecular Features of Acquired Resistance to Immunotherapy in Non-Small Cell Lung Cancer

PD-(L)1 blockade has been shown to promote durable responses in non-small cell lung cancer (NSCLC) patients and has been rapidly incorporated into the treatment regimens for many with advanced disease. Despite this, mechanisms of acquired resistance (AR) to PD-(L)1 have not been well understood. To address the clinical and molecular landscape of AR to PD-(L)1 blockade in NSCLC patients, a large clinical cohort of AR to PD-(L)1 blockade in lung cancer was examined. In conjunction, a systematic genomic and transcriptomic analysis in a subset of patients (n = 29) with available tissue samples was conducted. To investigate the molecular mechanisms of AR to PD-1 blockade from pre- and/or post-treatment tumors, microarray-based whole transcriptome expression data for 29 tumor samples, and whole exome sequencing (WES) data from 34 tumor samples was generated from this subset. Microarray data was uploaded to the Gene Expression Omnibus (GEO) database. Most AR tumors showed retained or increased inflammatory characteristics with significant upregulation of IFNγ which was suggestive of persistent albeit insufficient anti-tumor immune response. This finding expounds upon the prior pre-clinical and translational data supporting the intricate role of IFNγ in sensitivity and resistance to immunotherapy. Whereas initial IFNγ exposure may be fundamental to T cell activation (a hallmark of immune response), persistent IFNγ related effects and upregulation may potentially signal immune dysfunction and IFNγ insensitivity in contrast. The inflammatory phenotypes identified have implications for future rational development of new immunotherapy strategies for patients with AR.

Study phs002834

Sequencing of 3D Organoids Derived From Colorectal Cancer Patients

This study focuses on the whole-exome sequencing (WES) of patient-derived organoids (PDOs) established from colorectal cancer (CRC) tumors collected at Columbia University. CRC remains a major cause of cancer-related mortality due to its metastatic progression and resistance to therapy. To model CRC at the patient level, we generated 3D organoid cultures from primary and metastatic tumors, preserving their genetic and phenotypic characteristics. The study cohort consists of 9 CRC patients with microsatellite-stable adenocarcinomas from the ascending, transverse, and descending colon, as well as the rectum, with differentiation statuses ranging from well to moderate and moderate-poor. Notably, for one patient, we generated organoids from both the primary tumor and matched liver metastases, allowing for a comparative analysis of tumor evolution. PDOs were derived from these tumors and subjected to WES at early passage to profile somatic mutations, copy number variations, and other genomic alterations to identify mutational signatures. Mutations identified in the PDOs were cross-referenced and confirmed with mutational data from the Columbia Solid Tumor Panel, which was conducted on all tumor tissues prior to organoid establishment. Molecular technologies employed include next-generation sequencing (NGS) for WES, enabling high-resolution characterization of the genomic landscape of CRC PDOs. WES of PDOs allowed us to classify tumor samples based on oncogenic mutations and mutation types, with a specific focus on PIK3CA. Notably, the efficacy of PI3Kα-specific pharmacologic inhibitors in suppressing organoid growth was dependent on the mutational status of KRAS and PIK3CA, underscoring the importance of genomic context in therapeutic response. The dataset available through dbGaP includes raw WES data from CRC PDOs.

Study phs003965

The phase II Neo-Pembro trial: neoadjuvant pembrolizumab in stage IV high-grade serous ovarian cancer

While immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, their efficacy in high-grade serous ovarian cancer (HGSOC) remains limited. Nevertheless, some patients achieve lasting responses, emphasizing the need to understand how the tumor microenvironment and molecular characteristics influence ICI response. We hypothesized higher efficacy of ICI when used in the neoadjuvant setting and preceded by induction chemotherapy. The phase 2 Neo-Pembro study (NCT03126812) included 33 untreated patients with stage IV HGSOC who were planned for 6 cycles of carboplatin-paclitaxel and interval cytoreductive surgery. Pembrolizumab (pembro) was added from cycle two and continued for one year. The primary objective was to assess intratumoral immune activation, through multiplexed immunofluorescence and immune-related gene expression. Our data provide evidence of immune activation, characterized by an increase in CD3+, CD8+, CD8+/FOXP3+ ratio, and TNF-α and interferon-γ signaling, and was most evident in major pathologic responders, which were 9/33 patients (27%, 95%CI 14-46) at time of surgery. Pathologic response was strongly associated with overall survival. At a median follow-up of 52.8 months, 8/9 major responders were alive, including 6 patients without recurrence, and 4 of 24 minor responders were alive, including one patient without recurrence. PD-L1 expression and homologous recombination deficiency were predictive of major response and may serve as potential biomarkers, warranting further exploration. In a post-hoc comparison, major responders treated with pembro had significantly better overall survival than major responders in a historic cohort treated without pembro. Our data indicate that immune activation was stronger in the subset of major pathologic responders and these patients may derive long-term survival benefits from the addition of neoadjuvant pembro.

Study EGAS50000000781

Persistence of circulating tumor DNA in breast cancer patients during neoadjuvant treatment is a significant predictor of poor tumor response

Purpose:Accurate assessment of response during neoadjuvant systemic treatment (NST) poses a major clinical challenge. Therefore, a minimally-invasive assessment of tumor response based on cell-free circulating tumor DNA (ctDNA) may be beneficial to guide treatment decisions.Experimental Design: We profiled 93 genes in tissue from 193 early breast cancer patients. Patient-specific assays were designed to track ctDNA during NST from 145 patients with available plasma. ctDNA presence and levels were correlated with complete pathological response (pCR) and residual cancer burden (RCB) as well as with clinicopathologic characteristics of the tumor to identify potential proxies for ctDNA release. Moreover, we tested the predictive value of driver events identified in the tumor.Results:At baseline, ctDNA could be detected in 63/145 (43.4%) patients and persisted in 25/63 (39.7%) patients at mid-therapy (MT) and 15/63 (23.8%) patients at the end of treatment. ctDNA detection at MT was significantly associated with higher RCB (OR 0.062, 95% CI 0.01-0.48, P=0.0077). Out of 31 patients with detectable ctDNA at MT, 30 patients (96.8%) were non-responders (RCB II, n=8; RCB III, n=22) and only one patient responded to the treatment (RCB I). Considering all 145 patients with baseline (BL) plasma, none of the patients with RCB 0 and only 6.7% of patients with RCB I had ctDNA detectable at MT, while 30.6% and 29.6% of patients with RCB II/III, respectively, had a positive ctDNA result. Conclusion:Overall, our results demonstrate that the detection and persistence of ctDNA at mid-therapy may have the potential to negatively predict response to neoadjuvant treatment and identify patients who will not achieve pCR or be classified with RCB II/III.

Study EGAS00001005798

Dynamics of genomic clones in breast cancer patient xenografts at single cell resolution

Human cancers, including breast cancers, are comprised of clones differing in mutation content that evolve dynamically in space and time following principles of Darwinian evolution, underpinning important emergent features such as drug resistance and metastasis. Human breast cancer xenoengraftment is used as a means of capturing and studying tumour biology, and breast tumour xenografts are generally assumed to be reasonable models of the originating tumours. However the consequences and reproducibility of engraftment and propagation on the genomic clonal architecture of tumours has not been systematically examined at single cell resolution. Here we show by both deep genome and single cell sequencing methods, the clonal dynamics of initial engraftment and subsequent serial propagation of primary and metastatic human breast cancers in immunodeficient mice. In all cases examined, clonal selection on engraftment was observed in both primary and metastatic breast tumours, varying in degree from extreme selective engraftment of minor (<5% of starting population) clones to moderate, polyclonal engraftment. Furthermore, ongoing clonal dynamics during serial passaging is a feature of tumours experiencing modest initial selection. Through single cell sequencing, we show that major mutation clusters estimated from tumour population sequencing relate predictably to the most abundant clonal genotypes, even in clonally complex and rapidly evolving cases. Finally, we show that similar clonal expansion patterns can emerge in independent grafts of the same starting tumour population, indicating that genomic aberrations can be reproducible determinants of evolutionary trajectories. Our results show that measurement of genomically defined clonal population dynamics will be highly informative for functional studies utilizing patient-derived breast cancer xenoengraftment.

Study EGAS00001000952

Whole exome sequencing of small cell neuroendocrine cancer of the cervix

In order to improve treatment selection for high grade neuroendocrine carcinomas of the cervix (NECC), we performed a comparative genomic analysis between this rare tumor type and other cervical cancer types, as well as extra-cervical neuroendocrine small cell carcinomas of the lung and bladder. We performed whole exome sequencing on fresh-frozen tissue from 15 NECCs and matched normal tissue. We then identified mutations and copy number variants using standard analysis pipelines. Published mutation tables from cervical cancers and extra-cervical small cell carcinomas were used for comparative analysis. Descriptive statistical methods were used and a two-sided threshold of P < .05 was used for significance. In the NECC cohort, we detected a median of 1.7 somatic mutations per megabase (range 1.0-20.9). PIK3CA p.E545K mutations were the most frequency observed oncogenic mutation (4/15 tumors, 27%). Activating MAPK pathway mutations in KRAS (p.G12D) and GNAS (p.R201C) co-occurred in two tumors (13%). In total we identified PI3-kinase or MAPK pathway activating mutations in 67% of NECC. When compared to NECC, lung and bladder small cell carcinomas exhibited a statistically significant higher rate of coding mutations (P < .001 for lung; P = .001 for bladder). Mutation of TP53 was uncommon in NECC (13%) and was more frequent in both lung (103 of 110 tumors [94%], P < .001) and bladder (18 of 19 tumors [95%], P < .001) small cell carcinoma. These comparative genomics data suggest that NECC may be genetically more similar to common cervical cancer subtypes than to extra-cervical small cell neuroendocrine carcinomas of the lung and bladder. These results may have implications for the selection of cytotoxic and targeted therapy regimens for this rare disease.

Study EGAS00001003142

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

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

Study EGAS00001004383

Studies in the Natural History and Pathogenesis of Childhood-Onset and Adult-Onset Idiopathic Inflammatory Myopathies

The present study compares transcript and protein regulation in peripheral blood of adult and juvenile dermatomyositis (DM) patients vs. healthy control subjects to identify novel pathways in active patients under treatment. Whole blood data is submitted representing transcript and protein expression, including 14 adult DM and 11 juvenile DM (JDM) patients, and 11 healthy pediatric controls. Whole blood RNA was examined using Affymetrix Human U133 Plus 2.0, and whole blood protein measurements were obtained using SOMAscan Assay v3.2 aptamer-based DNA probes.Expression of 1,124 gene loci were significantly altered at the transcript or protein levels across DM or JDM, with 70 genes shared. A subset of interferon-stimulated genes was elevated. Innate immune markers specific to neutrophil granules and neutrophil extracellular traps were up-regulated in both DM and JDM. Pathway analysis revealed up-regulation of PI3K/AKT, ERK, and p38 MAPK signaling. Up-regulated components shared by DM and JDM included: cytokine:receptor pairs LGALS9:HAVCR2, LTF/NAMPT/S100A8/HSPA1A:TLR4, CSF2:CSF2RA, EPO:EPOR, FGF2/FGF8:FGFR; several Bcl-2 components; and numerous glycolytic enzymes. Pathways unique to DM included sirtuin signaling, aryl hydrocarbon receptor signaling, protein ubiquitination, and granzyme B signaling.

Study phs003270

Whole Exome and Transcriptome Sequencing in Sporadic ALS

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a fatal and devastating neurodegenerative disorder that causes the progressive death of upper and lower motor neurons. Although many efforts have been done to elucidate molecular factors involved in the onset and progression of the disorder, the causes of ALS are yet unknown and undefined. Transcriptome studies, based mostly on microarrays, have revealed multiple perturbations of the motor neuron function, supporting the current idea that several cellular events contribute to the pathobiology of the disease, including mitochondrial dysfunction, enhanced apoptosis, glutamate-mediated excitotoxicity, free radical injury, protein misfolding, abnormal calcium metabolism and altered axonal transport. In the present study, we have deeply sequenced the whole transcriptome of ventral horns of the human lumbar spinal cord from matched control and ALS post-mortem donors. Whole exome sequencing from the same donors has also been performed to exclude known genetic variants associated to the familiar form of ALS. In addition, to characterize the ALS transcriptome we have sequenced the RNA fraction at low molecular weight in the same tissues and individuals. Genomic and transcriptomic reads have been generated using the Illumina HiSeq2000 sequencer.

Study phs000747

Ischemia Reperfusion Responses in Human Lung Transplants at the Single Cell Resolution

Ischemia reperfusion is an unavoidable step of organ transplantation. Development of therapeutics for lung injury during transplantation has proved challenging; understanding lung injury from human data at the single cell resolution is required to accelerate the development of therapeutics. Donor lung biopsies from six human lung transplant cases were collected at the end of cold preservation and 2-hour reperfusion and underwent single cell RNA sequencing. Donor and recipient origin of cells from the reperfusion timepoint were deconvolved. Gene expression profiles were (1) compared between each donor cell type between timepoints and (2) compared between donor and recipient cells. Inflammatory responses from donor lung macrophages were found after reperfusion with upregulation of multiple cytokines and chemokines, especially IL-1 and IL-1. Significant inflammatory responses were found in alveolar epithelial cells (featured by CXCL8) and lung endothelial cells (featured by IL-6 upregulation). Different inflammatory responses were noted between donor and recipient monocytes and CD8+ T cells. The inflammatory signals and differences between donor and recipient cells observed provide insight into the cellular and molecular mechanisms of ischemia reperfusion induced lung injury. Further investigations may lead to the development of novel targeted therapeutics.

Study EGAS50000000490

Harnessing Epigenetic Regulators to improve HSC-based lentiviral gene therapy

Curative benefits of autologous and allogeneic transplantation of hematopoietic stem cells (HSCs) have been proven for various diseases. However, the low number of true HSCs that can be collected from patients and subsequently in vitro maintenance and expansion of true HSCs for genetic correction remain challenging. Addressing this issue, we here focused on optimizing culture conditions to improve the ex vivo expansion of true HSCs for gene therapy purposes. In particular, we explore the use of epigenetic regulators to enhance the effectiveness of HSC-based lentiviral (LV) gene therapy. The HDAC inhibitor Quisinostat and the bromodomain inhibitor CPI203 each promote ex vivo expansion of functional HSCs, as validated by xenotransplantation assays and single cell RNA-sequencing analysis. We confirmed the stealth effect of LV transduction on the loss of HSC numbers in commonly used culture protocols, while addition of Quisinostat or CPI203 improved expansion of HSCs in transduction protocols. Of note, we demonstrated that addition of Quisinostat improved LV transduction efficiency of HSCs and early progenitors. Our suggested culture conditions highlight the potential therapeutic effect of epigenetic regulators in hematopoietic stem cell biology and their clinical applications to advance HSC-based gene correction.

Study EGAS50000000175

Somatic Mutations in Individual Skin Cells

Ultraviolet (UV) radiation is the primary cause of melanoma through the acquisition of driver mutations in melanocytes. It also plays a significant role in oncogenesis in other skin cells, such as keratinocytes. However, the mutational profiles vary widely among different skin cancers, and the early mutational processes in different cell types from the same skin, is not well understood. Additionally, our preliminary studies also suggest that the mutation burden in different skin cells vary significantly based on risk factors such as the anatomical site and the use of tanning beds. To explore this, we employed innovative Next Generation Sequencing (NGS) tools to perform a site-matched comparison of the genomic landscapes of melanocytes, keratinocytes, and fibroblasts. From 20 biopsies of physiologically normal skin, collected from various anatomical sites across 16 donors, we have performed DNA-sequencing on 106 melanocytes, 78 keratinocytes and 13 fibroblasts. Of these samples, we have also simultaneously performed RNA-sequencing on 78 melanocytes, 46 keratinocytes and 9 fibroblasts. For normal bulk DNA, we also performed targeted (UCSF500; n=9) or exome sequencing (n=8) of skin or saliva samples from the donors.

Study phs003683

Defining Cutaneous Gene Expression Signatures in Juvenile Dermatomyositis

Skin inflammation in juvenile dermatomyositis (JDM) can signal disease onset or flare up and prevent complete disease remission. Our objective was to evaluate JDM cutaneous expression signatures through tape stripping in both lesional and non-lesional skin and as compared to paired blood. A total of 28 JDM and 20 control (CTL) patients participated in the study. All patients had tape strip sampling of non-lesional (NL) skin at enrollment visit. Within our JDM cohort, paired lesional (L) skin was additionally sampled if rash was present. 16/28 of JDM patients had at least one additional skin sample associated with a follow-up (FU) visit (total number of follow-up samples included = 26 NL and 4 L). We identified a common innate immune signature in both lesional and non-lesional JDM skin. Using unsupervised hierarchical clustering of skin expression data, we distinguished a JDM molecular subgroup characterized by a mitochondrial dysfunction signature. In comparison to blood expression data, we determined that skin may more effectively highlight the JDM subgroup characterized by a mitochondrial dysfunction expression signature. Data available include bulk RNA-sequencing data from tape strips and blood of the JDM and control patients from this study.

Study phs003884

Omic Studies in Children's Respiratory and Environmental Workgroup (CREW) Cohorts

Children's Respiratory Research Workgroup (CREW) is an NIH-funded project consisting of multiple individual U.S. cohorts and three scientific centers working together to identify phenotypes and causes of childhood asthma. CREW will include data from a large number of children and their families, with broad diversity in terms of ethnicity, family characteristics, neighborhoods and geographic locations. One of the primary goals of CREW is to put together sets of data and samples of participating cohorts to identify phenotypes of childhood asthma (i.e. specific subtypes of asthma that can be distinguished by clinical features such as natural history, triggers, exacerbation frequency, concurrent allergies, lung function, sex, etc). Omics studies will include genotyping, methylation, and RNA sequencing. By integrating the DNA genotyping with the expression, immunologic and clinical data, we will identify eQTL, inflammation QTL, and lung function QTL, as well as QTL associated with other biomarkers. Analyses will identify genetic, epigenetic, transcriptional and protein/metabolite profiles that are associated with specific exposures or phenotypes. As we obtain mechanistic insights about personal and early life risk factors, we will connect asthma phenotypes with underlying causes and pathogenic mechanisms to define endotypes of childhood asthma.

Study phs004036

Biallelic loss of function PAX4 variants are a Novel Cause of Transient Neonatal Diabetes

The identification of genes in which loss of function (LoF) variants cause neonatal diabetes mellitus (NDM) can provide unique insights into the development and function of human pancreatic beta cells. We describe the identification of biallelic PAX4 LoF variants in 2 unrelated individuals with transient NDM: one due to a homozygous p.(Arg126*) PAX4 stop gain variant and a second due to a homozygous c.-352_104del 2.65kb deletion affecting the first 4 exons and promoter of the PAX4 Matched Annotation from NCBI and EMBL-EBI select transcript. We confirmed reduced transcript expression due to nonsense mediated decay for the e p.(Arg126*) variant in CRISPR-edited iPSC-derived pancreatic endoderm cells. Analysis of PAX4 binding through integration of CUT&RUN and RNA-sequencing in PAX4 depleted endocrine cells identified genes directly regulated by PAX4 involved in both pancreatic islet development and glucose-sensitive insulin secretion. The remitting and relapsing diabetes in both probands demonstrates that in contrast to mice PAX4 is not essential for the development of pancreatic beta-cells and supports differences in the requirements of functional beta-cell mass across the life-course.

Study EGAS50000000857

Response to tumor-infiltrating lymphocyte adoptive therapy is associated with preexisting CD8+ T-myeloid cell networks in melanoma

Adoptive cell therapy (ACT) using ex vivo–expanded tumor-infiltrating lymphocytes (TILs) can eliminate or shrink metastatic melanoma, but its long-term efficacy remains limited to a fraction of patients. Using longitudinal samples from 13 patients with metastatic melanoma treated with TIL-ACT in a phase 1 clinical study, we interrogated cellular states within the tumor microenvironment (TME) and their interactions. We performed bulk and single-cell RNA sequencing, whole-exome sequencing, and spatial proteomic analyses in pre- and post-ACT tumor tissues, finding that ACT responders exhibited higher basal tumor cell–intrinsic immunogenicity and mutational burden. Compared with nonresponders, CD8+ TILs exhibited increased cytotoxicity, exhaustion, and costimulation, whereas myeloid cells had increased type I interferon signaling in responders. Cell-cell interaction prediction analyses corroborated by spatial neighborhood analyses revealed that responders had rich baseline intratumoral and stromal tumor–reactive T cell networks with activated myeloid populations. Successful TIL-ACT therapy further reprogrammed the myeloid compartment and increased TIL-myeloid networks. Our systematic target discovery study identifies potential T-myeloid cell network–based biomarkers that could improve patient selection and guide the design of ACT clinical trials.

Study EGAS50000001217

Non-neuronal TGF-β–mediated extracellular matrix remodeling drives neurodegeneration in a PSP-Richardson syndrome model

Progressive supranuclear palsy-Richardson syndrome (PSP-RS) is a devastating neurodegenerative disorder marked by rapid motor decline, cognitive impairment, and widespread accumulation of pathological tau. Yet, the molecular triggers of sporadic PSP-RS remain elusive. In this study, we combined patient-derived midbrain organoids with integrative multi-omics to uncover a previously unrecognized pathological cascade. At the core lies an early and aberrant activation of TGF-β signaling, which initiates profound extracellular matrix (ECM) remodeling and aberrant integrin-mediated focal adhesion. This cascade leads to persistent hyperactivation of PI3K/AKT and MAPK/ERK pathways, disrupting cytoskeletal integrity, impairing autophagy, promoting pathological tau phosphorylation and mislocalization, and ultimately driving synaptic degeneration. Single-cell RNA sequencing revealed an ectopic expansion of vascular leptomeningeal-like cells (VLMCs), a collagen-producing population, accompanied by a broad ECM gene dysregulation unique to PSP-RS. Remarkably, pharmacological blockade of TGF-β, AKT, ERK, or mTOR signaling reversed tau pathology and restored synaptic integrity. These findings position TGF-β-driven ECM remodeling as a master regulator of neurodegeneration in sporadic PSP-RS and unveil multiple actionable therapeutic targets for this currently untreatable disease.

Study EGAS50000001236

Oncoprint GSCCs

Glioblastoma (GBM) remains the most malignant primary brain tumor, with a median survival rarely exceeding 2 years. Tumor heterogeneity and an immunosuppressive microenvironment are key factors contributing to the poor response rates of current therapeutic approaches. GBM-associated macrophages (GAMs) often exhibit immunosuppressive features that promote tumor progression. However, their dynamic interactions with GBM tumor cells remain poorly understood. Here, we used patient-derived GBM stem cell cultures and combined single-cell RNA sequencing of GAM-GBM co-cultures and real-time in vivo monitoring of GAM-GBM interactions in orthotopic zebrafish xenograft models to provide insight into the cellular, molecular, and spatial heterogeneity. Our analyses revealed substantial heterogeneity across GBM patients in GBM-induced GAM polarization and the ability to attract and activate GAMs – features that correlated with patient survival. Differential gene expression analysis, immunohistochemistry on original tumor samples, and knock-out experiments in zebrafish subsequently identified LGALS1 as a primary regulator of immunosuppression. Overall, our work highlights that GAM-GBM interactions can be studied in a clinically relevant way using co-cultures and avatar models, while offering new opportunities to identify promising immune-modulating targets.

Study EGAS00001007481

HCA_Thymus_Disease

Single cell RNA sequencing on thymic cells from children with syndromic diseases such as Trisomy 21 and inflammatory/autoimmune diseases such as myasthenia gravis. Our group has previously performed atlasing of the healthy human thymus using single cell transcriptomics and obtained an unprecedented understanding of human thymus throughout development. In this study, we intend to survey diseased human thymus and compare this to healthy to obtain a better understanding of thymic dysfunction in human diseases. The diseases we will survey include congenital conditions such as Down's syndrome, CHARGE syndrome, DiGeorge syndrome as well as acquired diseases such as myasthenia gravis and thymic hyperplasia. We intend to perform genetic and genomic study on the samples, including expression analysis. This will not only help us to understand the cells and molecular pathways affected in dysfunctional thymus; but may also lead to generalisable understandings in human genetic diseases and inflammatory/autoimmune diseases. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

Study EGAS00001004310

The mission of the BIOS Consortium is to create a large-scale data infrastructure and to bring together BBMRI researchers focusing on integrative omics studies in Dutch Biobanks.

The advent of the genome-wide association study (GWAS) led to the successful identification of thousands of variants that are robustly associated with complex disease phenotypes. Dutch biobanks played a substantial role in these discoveries. For most of these variants, however, the mechanisms through which they contribute to these phenotypes remain unknown. The BIOS Consortium applies a functional genomics approach that integrates genome-wide genetic data with data on the epigenome and transcriptome to elucidate these mechanisms. Over 4000 samples from BBMRI-NL biobanks with in-depth information on disease phenotypes and GWAS data are being enriched with RNA-sequencing and genome-wide DNA methylation data. The same is true for samples with whole-genome sequencing data from GoNL. This unique data infrastructure provides a powerful platform to evaluate key questions in integrative omics from establishing comprehensive eQTL and meQTL catalogues to linking molecular pathways across omics levels to phenotypic outcomes.

Study EGAS00001001077

Biased allelic expression in human primary fibroblast single cells.

The study of gene expression in mammalian single cells using genomic technologies now provides the possibility to investigate the patterns of allelic gene expression. We have used single-cell RNA sequencing to detect the allele-specific mRNA level in 203 single human primary fibroblast cells over 133,633 unique heterozygous single nucleotide variants (hetSNVs). We have observed that at the snapshot of analyses each cell contains mostly transcripts from one allele from the majority of genes; indeed 76.4% of the hetSNVs display stochastic monoallelic expression in single cells. Remarkably, adjacent hetSNVs exhibit haplotype consistent allelic ratio; in contrast distant sites located in two different genes are independent of the haplotype structure. Moreover, the allele-specific expression in single cells correlated with the abundance of the cellular transcript. We observed that genes expressing both alleles in majority of the single cells at a given time point are rare and enriched in highly expressed genes. The relative abundance of each allele in a cell is controlled by some regulatory mechanisms since we observed related single-cell allelic profiles according to genes. Overall, these results have direct implications in cellular phenotypic variability.

Study EGAS00001001009

BARIA baseline first 100 individuals transcriptomes

Prevalence of obesity and associated diseases, including type 2 diabetes mellitus, dyslipidaemia and non-alcoholic fatty liver disease (NAFLD), are increasing. Underlying mechanisms, especially in humans, are unclear. Bariatric surgery provides the unique opportunity to obtain biopsies and portal vein blood-samples. Methods The BARIA Study aims to assess how microbiota and their metabolites affect transcription in key tissues and clinical outcome in obese subjects and how baseline anthropometric and metabolic characteristics determine weight loss and glucose homeostasis after bariatric surgery. We phenotype patients undergoing bariatric surgery (predominantly laparoscopic Roux-en-Y gastric bypass), before weight loss, with biometrics, dietary and psychological questionnaires, mixed meal test (MMT) and collect fecal-samples and intra-operative biopsies from liver, adipose tissues and jejunum. We aim to include 1500 patients. A subset (approximately 25%) will undergo intra-operative portal vein blood-sampling. Fecal-samples are analyzed with shotgun metagenomics and targeted metabolomics, fasted and postprandial plasma-samples are subjected to metabolomics, and RNA is extracted from the tissues for RNAseq-analyses. Data will be integrated using state-of-the-art neuronal networks and metabolic modeling. Patient follow-up will be ten years.

Study EGAS00001005704

Kidney_transplant_nephrectomy_scRNAseq

Single cell transcriptomics study of tissue from human kidney transplant nephrectomies Tissue is acquired from kidney transplant nephrectomies, homogenised and disaggregated to a single cell suspension prior to droplet encapsulation single cell RNAseq (10X protocol) or plate based single cell RNAseq (SS2 protocol). Human tissues, including the kidney are seeded with a tissue resident immune cell network throughout life. These cells may self renew in situ or be replaced by circulating precursors which enter the tissue in response to tissue specific niche and inflammatory signals. We are using single cell RNA sequencing of kidney transplant nephrectomy tissue to 1) understand the immune cell populations which are resident within the human kidney 2) identify which of these populations is donor or recipient derived. 3) Uncover the temporal dynamics of donor/recipient chimerism in the the human kidney following transplantation. 4) Understand transcriptional differences between organs removed for a variety of reasons (infection, chronic rejection, vascular emergencies) This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

Study EGAS00001003935

Germline biallelic mutation affecting the transcription factor Helios causes pleiotropic defects of immunity

We studied a patient with recurrent respiratory infections and hypogammaglobulinemia and identified a germline homozygous missense mutation in IKZF2 encoding Helios (p.Ile325Val). We show that HeliosI325V retains DNA-binding and dimerization properties, but loses interaction with several partners, including epigenetic remodelers HDAC1, HDAC3 and the ATAC complex. Single-cell RNA-sequencing of peripheral blood mononuclear cells revealed gene expression signatures indicative of a shift towards pro-inflammatory, effector-like status in the patient’s T cells. We observed an upregulation of the anti-inflammatory gene, TSC22D3, encoding the glucocorticoid-induced leucine zipper (GILZ), whose expression was reported to increase upon IL-2 deprivation. We validated this finding in primary T cells, where we observed a pronounced reduction in IL-2 production upon their stimulation, together with a defect in their ability to proliferate, rendering them more anergic. Collectively, we identify a novel germline-encoded inborn error of immunity and define a role for Helios in conventional T cells, whereby interactions with specific binding partners is necessary to mediate the transcriptional programs that enable T-cell homeostasis in health and disease.

Study EGAS00001005675

Identification of Germline Monoallelic Mutations in IKZF2 in Patients with Immune Dysregulation.

Helios, encoded by IKZF2, is a member of the Ikaros family of transcription factors with pivotal roles in T-follicular helper, NK- and T-regulatory cell physiology. Somatic IKZF2 mutations are frequently found in lymphoid malignancies. Although germline mutations in IKZF1 and IKZF3, encoding Ikaros and Aiolos, have recently been identified in patients with phenotypically similar immunodeficiency syndromes, the effect of germline mutations in IKZF2 on human hematopoiesis and immunity remains enigmatic. We identified germline IKZF2 mutations (one nonsense (p.R291X)- and 4 distinct missense variants) in six patients with systemic lupus erythematosus, immune thrombocytopenia or EBV-associated hemophagocytic lymphohistiocytosis. Patients exhibited hypogammaglobulinemia, decreased number of T-follicular helper and NKcells. Single-cell RNA sequencing of PBMCs from the patient carrying the R291X variant revealed upregulation of pro-inflammatory genes associated with T-cell receptor activation and T-cell exhaustion. Functional assays revealed the inability of HeliosR291X to homodimerize and bind target DNA as dimers. Moreover, proteomic analysis by proximity-dependent Biotin Identification revealed aberrant interaction of 3/5 Helios mutants with core components of the NuRD complex conveying HELIOS mediated epigenetic and transcriptional dysregulation.

Study EGAS00001005874

Targeted therapy of advanced parathyroid carcinoma guided by genomic and transcriptomic profiling (hipo_021)

Parathyroid carcinoma (PC) is an orphan malignancy with a high risk of recurrence after surgery. Tumor-directed systemic treatments for PC are not established. We used whole-genome and RNA sequencing in four patients with advanced PC to identify molecular alterations that could guide clinical management. In two cases, the genomic and transcriptomic profiles provided targets for experimental therapies that resulted in biochemical response and prolonged disease stabilization: (i) immune checkpoint inhibition with pembrolizumab based on high tumor mutational burden and a single-base substitution signature associated with APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) overactivation; (ii) multi-receptor tyrosine kinase inhibition with lenvatinib due to overexpression of FGFR1 and RET and, later in the course of disease, PARP inhibition with olaparib prompted by signs of defective homologous recombination DNA repair. In addition, our data provided new insights into the molecular landscape of PC with respect to the genome-wide footprints of specific mutational processes and pathogenic germline alterations. These data underscore the potential of comprehensive molecular analyses to improve care for patients with ultra-rare cancers based on insight into disease biology.

Study EGAS00001006747

The impact of BNT162b2 mRNA vaccine against SARS-CoV-2 on adaptive and innate immune responses

The mRNA-based BNT162b2 protects against severe disease and mortality caused by SARS-CoV-2 through induction of specific antibody and T-cell responses. Much less is known about its broad effects on immune responses against other pathogens. In the present study, we investigated the specific adaptive immune responses induced by BNT162b2 vaccination against various SARS-CoV-2 variants, as well as its effects on the responsiveness of human immune cells upon stimulation with heterologous viral, bacterial, and fungal pathogens. BNT162b2 vaccination induced effective humoral and cellular immunity against SARS-CoV-2 that started to wane after six months. We also observed long-term transcriptional changes in immune cells after vaccination, as assessed by RNA sequencing. Additionally, vaccination with BNT162b2 modulated innate immune responses as measured by the production of inflammatory cytokines when stimulated with various microbial stimuli other than SARS-CoV-2, including higher IL-1/IL-6 release and decreased production of IFN-α. Altogether, these data expand our knowledge regarding the overall immunological effects of this new class of vaccines and underline the need of additional studies to elucidate their effects on both innate and adaptive immune responses.

Study EGAS00001006818

Single-cell profiling of co-cultures of GSCCs and macrophages

Glioblastoma (GBM) remains the most malignant primary brain tumor, with a median survival rarely exceeding 2 years. Tumor heterogeneity and an immunosuppressive microenvironment are key factors contributing to the poor response rates of current therapeutic approaches. GBM-associated macrophages (GAMs) often exhibit immunosuppressive features that promote tumor progression. However, their dynamic interactions with GBM tumor cells remain poorly understood. Here, we used patient-derived GBM stem cell cultures and combined single-cell RNA sequencing of GAM-GBM co-cultures and real-time in vivo monitoring of GAM-GBM interactions in orthotopic zebrafish xenograft models to provide insight into the cellular, molecular, and spatial heterogeneity. Our analyses revealed substantial heterogeneity across GBM patients in GBM-induced GAM polarization and the ability to attract and activate GAMs – features that correlated with patient survival. Differential gene expression analysis, immunohistochemistry on original tumor samples, and knock-out experiments in zebrafish subsequently identified LGALS1 as a primary regulator of immunosuppression. Overall, our work highlights that GAM-GBM interactions can be studied in a clinically relevant way using co-cultures and avatar models, while offering new opportunities to identify promising immune-modulating targets.

Study EGAS00001007482

Genome‐wide postnatal changes in immunity following fetal inflammatory response

The fetal inflammatory response (FIR) increases the risk of perinatal brain injury, particularly in extremely low gestational age newborns (ELGANs, < 28 weeks of gestation). One of the mechanisms contributing to such a risk is a postnatal intermittent or sustained systemic inflammation (ISSI) following FIR. The link between prenatal and postnatal systemic inflammation is supported by the presence of well‐established inflammatory biomarkers in the umbilical cord and peripheral blood. However, the extent of molecular changes contributing to this association is unknown. Using RNA sequencing and mass spectrometry proteomics, we profiled the transcriptome and proteome of archived neonatal dried blood spot (DBS) specimens from 21 ELGANs. Comparing FIR‐affected and unaffected ELGANs, we identified 782 gene and 27 protein expression changes of 50% magnitude or more, and an experiment‐wide significance level below 5% false discovery rate. These expression changes confirm the robust postnatal activation of the innate immune system in FIR‐affected ELGANs and reveal for the first time an impairment of their adaptive immunity. In turn, the altered pathways provide clues about the molecular mechanisms triggering ISSI after FIR, and the onset of perinatal brain injury.

Study EGAS00001003635

SINGLE-CELL RNA SEQUENCING Single-cell RNA sequencing was performed on 13 ‘mild-moderate’ and 10 ‘critical’ COVID19 PBMC samples

Summary Epidemiological and clinical reports have indicated that SARS-CoV-2 virulence hinges upon the triggering of an aberrant host immune response, more so than on direct virus-induced cellular damage. To elucidate the immunopathology underlying COVID-19 severity, we performed cytokine and multiplex immune profiling in mild-moderate and critically ill COVID-19 patients. Hypercytokinemia in COVID-19 differed from the IFN-γ-driven cytokine storm in macrophage activation syndrome, and was more pronounced in critical versus mild-moderate COVID-19. Systems modelling of cytokine levels paired with deep-immune profiling showed that classical monocytes drive this hyper-inflammatory phenotype and that a reduction in T-lymphocytes correlates with disease severity, with CD8+ cells being disproportionately affected. Expression of antigen presenting machinery was also reduced in critical disease. Furthermore, we found that neutrophils contributed to disease severity and local tissue damage by amplification of hypercytokinemia and the formation of neutrophil extracellular traps. Together these findings suggest a myeloid-driven immunopathology, in which hyperactivated neutrophils and an ineffective adaptive immune system act as mediators of COVID-19 disease severity.

Study EGAS00001005039

An alternative splicing modulator decreases mutant HTT and improves the molecular fingerprint in Huntington’s disease patient neurons

Huntington's disease (HD) is a neurodegenerative disorder caused by poly-Q expansion in the Huntingtin (HTT) protein. Here, we delineate elevated mutant HTT (mHTT) levels in patient-derived cells including fibroblasts and iPSC derived cortical neurons using a GLP approved HTT assay. HD patients’ fibroblasts and cortical neurons recapitulate aberrant alternative splicing as a molecular fingerprint of HD. Branaplam is a splicing modulator currently tested in a phase II study in HD (NCT05111249). The drug lowers total HTT (tHTT) and mHTT levels in fibroblasts, iPSC, cortical progenitors, and neurons in a dose dependent manner at an IC50 consistently below 10nm without inducing cellular toxicity. Branaplam promotes inclusion of non-annotated novel exons. Amongst, a 115bp frameshift-inducing exon in the HTT transcript in Branaplam treated cells from Ctrl and HD patients leading to a profound reduction of HTT RNA and protein levels. Importantly, Branaplam ameliorates aberrant alternative splicing in HD patients’ fibroblasts and cortical neurons. These findings highlight the applicability of splicing modulators in the treatment of CAG repeat disorders and decipher their molecular effects associated with the pharmacokinetic and -dynamic properties in patient-derived cellular models.

Study EGAS00001006289

Genome-Wide Association Study of HCC in Non-Asian USA Population

This GWAS of HCC relied on existing biological and data resources from 7 USA sites and one Canadian site which allows for the integration of genetic and environmental data. Total of 2199 case patients and 1103 non cancer controls were genotyped. Case patients are defined as patients with pathological or radiological diagnosis of HCC with and without chronic hepatitis C virus infection. Study was restricted to Caucasian population without prior infection with chronic HBV infection. All DNA samples were extracted from peripheral blood. Study population of the participated sites are: Site-1: University of Texas MD Anderson Cancer Center A hospital based-case-control study was initiated at UT MD Anderson Cancer Center in 2000 and approved by the Institutional Review Board of The University of Texas M. D. Anderson Cancer Center. Study design was previously described in detailed (1-3). Written informed consent for an interview and for a biological sample was obtained from each participant. At time of diagnosis prior to treatment exposure. Case patients were recruited from the population of patients with newly diagnosed HCC who were evaluated and treated at the institution's gastrointestinal medical and surgical oncology outpatient clinics. Inclusion criteria were as follows: a pathologically confirmed diagnosis of HCC, U.S. residency, and the ability to communicate in English. Patients with concurrent or past history of other types of cancers were excluded. Control subjects were healthy spouses of patients with cancers other than liver, gastrointestinal, lung, or head and neck (smoking-related cancers) undergoing treatment at our institution. Eligibility criteria for control subjects were the same as those for patients, except that control subjects could not have ever had cancer. A short, structured questionnaire was used to screen potential control subjects on the basis of eligibility criteria. Control subjects and patients were recruited simultaneously. Case patients and control subjects were interviewed by well-trained interviewers who followed a written protocol to guide ascertainment and reduce surveillance, interviewer, and recall bias. No proxy interviews were conducted. The interviewers used a structured and validated questionnaire to collect information about demographic characteristics and potential risk factors for HCC such as personal smoking history, alcohol use, medical history, occupational history, and family history of cancer. Blood samples from cases and controls were tested for HBV and HCV. HCV antibodies, hepatitis B surface antigen, and antibodies to hepatitis B core antigen were detected by use of a third-generation enzyme-linked immunosorbent assay (ELISA) (Abbott Laboratories, North Chicago, IL). Important clinical information were retrieved from patients' medical records. Total of 1188 case patients and 278 controls from MD Anderson study were genotyped. Site-2: Mayo Clinic Case patients and controls included in the study from Mayo clinic were recruited as part of Mayo International Hepatobiliary Neoplasia Register and Biorepository. Only USA patients and controls were participated. All cases and controls signed informed consent indicating their willingness to participate in genetic studies. Epidemiological and clinical data were collected from participants and retrieved from medical records. Total of 522 HCC case patients and 182 controls were genotyped in this study. Site-3: Toronto University Molecular Epidemiology of Hepatobiliary Tumors (HBT study, CAPCR 09-0289) is a hospital-based study that includes 1710 patients diagnosed with liver, bile duct or gallbladder adenocarcinoma (Hepatocellular carcinoma - HCC; cholangiocarcinoma - CCA; and gall bladder adenocarcinoma -GBCa) recruited at University Health Network (UHN) between 2009 and 2018. HBT study is a prospective study of cancer patients that collects self-reported demographic and epidemiological data, medical records/clinical information and blood samples for research purposes. Eligible patients recruited between 2009 and March 15 2016 were selected to participate in the Genome-Wide Association Study in Patients with Hepatocellular Carcinoma (GWAS in HCC, CAPCR 15-9943-CE), a sub-study of the HBT study. Eligible prospective patients recruited after March 15 2016 signed the Addendum to the HBT consent form and became eligible to participate in the GWAS in HCC study. Total of 271 cases and 21 controls were genotyped from Toronto University Site-4: University of Pittsburgh The design of the study has been described previously (4-6). Briefly, this population-based study enrolled 120 HCC patients and 230 matched controls from black, Hispanic, and non-Hispanic white residents of Los Angeles County who were between 18 and 74 years of age at diagnosis from January 1995 through December 2001. HCC Cases were identified through the Los Angeles County Cancer Surveillance Program. We sought to recruit up to two control subjects per case from the neighborhoods where HCC patients resided at the time of diagnosis, who were matched to the index case by sex, age (within 5 years), and race (Hispanic white, non-Hispanic white, black). Blood samples (plasma and buffy coat), medical and lifestyle factors were collected from all consenting participants. Total of 65 cases and 60 controls were genotyped in this study Site-5: South Western Dallas Under IRB approval, HCC Cases and controls were prospectively collected since 2015 from the outpatient Liver clinics from Parkland Health and Hospital System and UT Southwestern Medical Center, two large health systems in Dallas TX. A Total of 31 cases and 29 controls were genotyped from site 5. Site-6: Columbia University HCC patients from Columbia are those recruited as part of the Herbert Irving Comprehensive Cancer Center Database Shared Resource which seeks to recruit all cancer patients for potential future studies. The PI is Dr. Katherine Crew AAAL5871. This resource collects sociodemographic, lifestyle and clinical data on patients as well as a blood sample. Those who indicated on their consent form that they would participate in genetic studies were included. Total of 79 case patients with HCC were genotyped from Columbia University. Site-7: University of Michigan The study population included from University of Michigan were included from a prospective study of with chronic HCV infection recruited in Ann Arbor Patients who had under- gone liver transplantation, known coinfection with HIV, life expectancy <12 months due to extra-hepatic illnesses, or were receiving HCV treatment at enrolment, were excluded. Protocol, surveys, and data forms were developed where each enrolled patient completed the same questionnaire All patients provided written informed consent before enrolment in the study. The study was approved by the institutional review board or ethics committee at the University of Michigan. Detailed study description was previously published (7). Total of 44 cases and 347 controls were genotyped Site-8: Veteran Administration Medical Center in Houston This research including written informed consent form was jointly approved by Institutional Review Boards for the Baylor College of Medicine and the Michael E. DeBakey VA Medical Center in Houston, Texas. Study details have been previously published (8). Briefly, we prospectively recruited consecutive HCV-infected veterans prior to their previously scheduled HCV clinic visit at a large tertiary care VA medical center between May 1, 2009 and December 31, 2012. Patients completed a research assistant (RA) administered survey interrogating medical and risk factor history including lifetime alcohol use, had anthropometric measurements taken, and completed a fasting venipuncture for performance of the FibroSure-ActiTest as a measure of hepatic pathology. We restricted our current analysis to individuals who were: (1) White male veterans between 18 and 70 years; (2) had no history of HCC, liver transplant, decompensated liver disease including ascites, dementia, or psychosis; (3) were serologically-confirmed to have chronic HCV and to be negative for both HIV and active HBV infection; (4) were not currently receiving anti-HCV pharmacotherapy; and (5) had FibroSURE testing shown F3/F4 fibrosis consistent with cirrhosis.

Study phs001744

ChIP-seq of GOF p53 mutants

Gain-of-function TP53 mutations were detected in 41.3% of cases, in which co-occurring del(17p) underscored a dominant effect in >25%. Missense mutations of TP53 clustered within the core DNA-binding domain, where R249S was most common. To explore the transcriptional effect of mutant p53(R249S), we performed chromatin immunoprecipitation-sequencing in the HCC cell line HKCI-11, which has a p53(R249S) mutation, and the human hepatocyte line MIHA, which is p53(WT). The results revealed distinct binding profiles between wildtype p53 and p53 mutant.

Study EGAS00001002463

11750 results for "cancer rna-seq"

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