Search Results - EGA European Genome-Phenome Archive

Comprehensive Genomic and Transcriptomic Analysis of Rare Cancers for Guiding of Therapy (H021)

Here we analyzed the molecular profiles and clinical outcomes of 1,310 patients (proportion of rare cancers, 75%) enrolled in a prospective observational study by the German Cancer Consortium that applies whole-genome/exome and RNA sequencing to inform the care of adults with incurable cancers. Based on 472 single and six composite biomarkers, a cross-institutional molecular tumor board provided evidence-based management recommendations, including diagnostic reevaluation, genetic counseling, and experimental treatment, in 88% of cases. Recommended therapies were administered in 362 of 1,138 patients (31.8%) and resulted in significantly improved response and disease control rates (23.9% and 55.3%, respectively) compared to previous therapies, translating into a progression-free survival ratio >1.3 in 35.7% of patients.

Study EGAS00001004813

Molecular evolution and clinical trajectories of prostate cancer identifies novel markers for risk stratification

Prostate cancer is a highly heterogeneous disease that is thought to develop over many years. Identifying the earliest somatic changes can give important insights into the tumour evolution and aid in stratifying high- from low-risk diseases. Here we pursued integrative whole-genome, transcriptome and methylome-based analysis of early-onset prostate cancer patients. Characterisation of genomic alterations across 270 PCa tumours revealed age-related genomic alterations and mutation signatures including BRCAness and APOBEC. We used methylation- and expression-data to identify four molecular subgroups, which included a highly aggressive tumour subgroup that frequently involved recurrent duplications and increased expression of ESRP1. Analysis of 12,000 tissue-microarray tumour samples demonstrated that ESRP1 is a candidate biomarker associated with faster proliferation rate and shorter time to relapse. We combine the patterns of molecular co-occurrence, risk-stratification and subgroup information to deconvolute tumor heterogeneity, which reveal complex but recurrent clinical trajectories of prostate cancer.

Study EGAS00001002923

Exome sequencing of familial high-grade serous ovarian carcinoma reveals heterogeneity for rare candidate susceptibility genes

High-grade serous ovarian carcinoma (HGSOC) has a significant hereditary component, approximately half of which cannot be explained by known genes. To discover genes, we analyse germline exome sequencing data from 516 BRCA1/2-negative women with HGSOC, focusing on genes enriched with rare, protein-coding loss-of-function (LoF) variants. Overall, there is a significant enrichment of rare protein-coding LoF variants in the cases (p < 0.0001, chi-squared test). Only thirty-four (6.6%) have a pathogenic variant in a known or proposed predisposition gene. Few genes have LoF mutations in more than four individuals and the majority are detected in one individual only. Forty-three highly-ranked genes are identified with three or more LoF variants that are enriched by three-fold or more compared to GnomAD. These genes represent diverse functional pathways with relatively few involved in DNA repair, suggesting that much of the remaining heritability is explained by previously under-explored genes and pathways.

Study EGAS00001004235

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

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

Dataset EGAD00001004088

ENCORAFENIB COMBINED WITH BINIMETINIB FOR BRAFV600E-MUTATED RELAPSED/REFRACTORY MULTIPLE MYELOMA: THE PHASE II GMMG-BIRMA TRIAL (Hipo_K08K)

Activating BRAF mutations are rare events in multiple myeloma but have been shown to be promising therapeutic targets in small case studies. This multicenter phase II trial assessed the efficacy and safety of the BRAF/MEK inhibitors, encorafenib and binimetinib, in patients with relapsed/refractory multiple myeloma (RRMM) carrying an activating BRAFV600E mutation. Twelve RRMM patients with a median of five prior lines of therapy were enrolled. The study met its primary endpoint with 10 patients achieving at least a partial response according to IMWG criteria (overall response rate 83.3%). Responses occurred rapidly within the first cycle and deepened over time. The median progression-free survival (PFS) was 5.6 months and overall survival was 55% at 24 months. Genomic profiling revealed RAS mutations and structural variants involving the BRAF locus to be drivers of resistance to BRAF/MEK inhibition in RRMM. This trial demonstrates the value of translationally driven clinical trials in selected patient populations.

Study EGAS00001005973

Repli-seq data for 'Replication timing alterations are associated with mutation acquisition during tumour evolution in breast and lung cancer'

The essential process of DNA replication timing during each cell cycle is highly regulated ensuring the correct duplication of the genome. The extent and importance of alterations in this process during malignant transformation has not been extensively explored. Here, we evaluate the impact of altered replication timing (ART) on cancer evolution by analysing replication-timing sequencing of cancer and normal cell lines and 952 whole-genome sequenced lung and breast tumours. We find 6%-18% of the cancer genome displays ART. Genomic regions with a change from early to late replication exhibit an increased mutation rate and distinct mutational signatures, while regions changing from late to early contain genes with increased expression and present a preponderance of APOBEC3-mediated mutation clusters and associated driver mutations. We demonstrate that ART is a relatively early event during cancer evolution and that ART may have a stronger correlation with mutation acquisition than alterations in chromatin structure.

Study EGAS00001007773

Sequence data for study: Mobilization of tissue-resident memory CD4+ T lymphocytes from bone marrow and their contribution to a systemic secondary immune reaction

Resident memory T lymphocytes (TRM) of epithelial tissues and the bone marrow protect their host tissue. To what extent these cells are mobilized and contribute to systemic immune reactions is less clear. Here we show that in secondary immune reactions to the measles-mumps-rubella (MMR) vaccine, CD4+ TRM are mobilized into the blood within 16 to 48 hours after immunization. This mobilization of TRM is cognate: TRM recognizing other antigens are not mobilized, unless they cross-react with the vaccine. We also demonstrate through methylome analyses that TRM are mobilized from the bone marrow. These mobilized cells make significant contribution to the systemic immune reaction, as evidenced by their T-cell receptor Vβ clonotypes represented among the newly generated circulating memory T-cells, 14 days after vaccination. Thus, TRM of the bone marrow confer not only local, but also systemic immune memory.

Study EGAS00001005475

Single-cell RNA-seq and spatial transcriptomics data for the sarcoidosis baseline project

Granulomas are lumps of immune cells that can form in various organs. Most granulomas appear unstructured, yet they have some resemblance to lymphoid organ formation. To better understand granuloma formation, we performed single-cell sequencing and spatial transcriptomics on granulomas from patients with sarcoidosis and bioinformatically reconstructed the underlying gene-regulatory networks. We discovered an immune stimulatory environment in granulomas that repurposed transcriptional programs associated with lymphoid organ development. Granuloma formation followed characteristic spatial patterns and involved genes linked to immunometabolism, cytokine and chemokine signaling, and extracellular matrix remodeling. Three cell types emerged as key players in granuloma formation: metabolically reprogrammed macrophages, cytokine-producing Th17.1 cells, and fibroblasts with inflammatory and tissue remodeling phenotypes. Pharmacological inhibition of one of the identified processes attenuated granuloma formation in a sarcoidosis mouse model. We show that human granulomas adopt characteristic aspects of normal lymphoid organ development in aberrant combinations, indicating that granulomas constitute aberrant lymphoid organs.

Study EGAS00001006970

MINCR is a MYC-induced lncRNA able to modulate MYC’s transcriptional network in Burkitt lymphoma cells

Despite the established role of the transcription factor MYC in cancer, little is known about the impact of a new class of transcriptional regulators, the long non-coding RNAs (lncRNAs), on the way MYC is able to influence cellular transcriptome. To this aim we have intersected RNA-sequencing data from two MYC-inducible cell lines and from a cohort of 91 mature B-cell lymphomas carrying, or not carrying, genetic variants resulting in MYC over-expression. By this approach, we identified 13 lncRNAs differentially expressed in IG-MYC-positive Burkitt lymphoma and regulated in the same direction by MYC in the model cell lines. Among them we focused on a lncRNA that we named MINCR, for MYC-Induced long Non-Coding RNA, showing a strong correlation with MYC expression in MYC-positive lymphomas and also in pancreatic ductal adenocarcinomas. To understand its cellular role we performed RNA interference (RNAi) experiments and found that MINCR knock-down is associated with a reduction in cellular viability, due to an impairment in cell cycle progression. Differential gene expression analysis following RNAi showed a strongly significant enrichment of cell cycle genes among the genes down-regulate following MINCR knock-down. Interestingly these genes are enriched in MYC binding sites in their promoters, suggesting that MINCR acts as a modulator of MYC transcriptional program. Accordingly, following MINCR knock-down, we observed a reduction in the binding of MYC to the promoters of selected cell cycle genes. Finally we provide evidences that down-regulation of AURKA, AURKB and CTD1 may explain the reduction in cellular proliferation observed upon MINCR knock-down. We therefore suggest that MINCR is a newly identified player in the MYC transcriptional network able to control the expression of cell cycle genes.

Dataset EGAD00001001441

Exome sequencing of blastic plasmacytoid dendritic cell neoplasms

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive haematological malignancy derived from precursors of plasmacytoid dendritic cells. Due to the rarity of BPDCNs our knowledge of their molecular pathogenesis was until recently confined to observations describing reccurent chromosomal deletions involving chromosomes 5q, 12p, 13q, 6q, 15q and 9. A recent publication went on to delineate the common deleted regions using aCGH and demonstrated that these centred around known tumour suppressor genes including CDKN2A/B (9p21.3), RB1 (12p13.2-14.3), CDKN1B (13q11-q12) and IKZF1 (7p12.2). These mutations are found recurrently in several different cancers and in most cases are thought to be involved in tumour progression rather than initiation. However, the well-defined nature and cellular ontogeny of these neoplasms suggests strongly that they share one or a few characteristic mutations as has been demonstrated for other uncommon but well-defined neoplasms such as Hairy Cell Leukemia (BRAF) and ovarian Granulosa Cell tumours (FOXL2).

Dataset EGAD00001000406

Preferential infiltration of unique Vγ9Jγ2‐Vδ2 T cells into glioblastoma multiforme

Glioblastoma multiforme (GBM) is clinically highly aggressive as a result of evolutionary dynamics induced by cross-talk between cancer cells and a heterogeneous group of immune cells in tumor microenvironment. The brain harbors limited numbers of immune cells with few lymphocytes and macrophages; thus, innate‐like lymphocytes, such as γδ T cells, have important roles in antitumor immunity. Here, we characterized GBM‐infiltrating γδ T cells, which may have roles in regulating the GBM tumor microenvironment and cancer cell gene expression. V(D)J repertoires of tumor‐infiltrating and blood‐circulating γδ T cells from four patients were analyzed by next-generation sequencing-based T-cell receptor (TCR) sequencing in addition to mutation and immune profiles in four GBM cases. In all tumor tissues, abundant innate and effector/memory lymphocytes were detected, accompanied by large numbers of tumor‐associated macrophages and closely located tumor‐infiltrating γδ T cells, which appear to have anti-tumor activity. The immune-related gene expression analysis using the TCGA database showed that the signature gene expression extent of γδ T cells were more associated with those of cytotoxic T and Th1 cells and M1 macrophages than those of Th2 cells and M2 macrophages. Although the most abundant γδ T cells were Vγ9Vδ2 T cells in both tumor tissues and blood, the repertoire of intratumoral Vγ9Vδ2 T cells was distinct from that of peripheral blood Vγ9Vδ2 T cells and was dominated by Vγ9Jγ2 sequences, not by canonical Vγ9JγP sequences that are mostly commonly found in blood γδ T cells. Collectively, unique GBM‐specific TCR clonotypes were identified by comparing TCR repertoires of peripheral blood and intra‐tumoral γδ T cells. These findings will be helpful for the elucidation of tumor-specific antigens and development of anticancer immunotherapies using tumor-infiltrating γδ T cells.

Dataset EGAD00001004862

Dataset for colorectal_cancer-RNA

Rare cancer sequencing data of 97 runs in tumor/control pairs, which were uploaded to umbrella studies. The sequencing was always paired

Dataset EGAD00001008855

Dataset for head_and_neck_cancer-RNA

Rare cancer sequencing data of 92 runs in tumor/control pairs, which were uploaded to umbrella studies. The sequencing was always paired

Dataset EGAD00001008861

MutWP5: CRUK Mutographs of Cancer: Cancer Mastectomy (Exome)(Novaseq)

Sequencing of LCM-derived microbiopsies from 40 women who underwent mastecomies due to breast cancer. LCM and sequencing will be conducted on both normal, unaffected breast, and, where possible, tumour tissue. Goal to assess the mutational burden, spectrum, and clonal dynamics within the tissue, and compare findings between the normal and associated cancer tissues. Whole-genome sequencing will be conducted on samples identified as promising from the initial targeted data. Results from this poriton of the study will be compared to women who had cosmetic breast reduction surgeries and those who are BRCA carriers. . This dataset contains all the data available for this study on 2023-03-08.

Dataset EGAD00001010117

Recurrent DNMT3B gene rearrangements are associated with unfavorable outcome in dicentric (9;20)-positive pediatric BCP-ALL

We provide clinical data sets of Array CGH, targeted RNA-seq, total RNA-seq, whole genome bisulfite (WGBS) and whole genome DNA sequencing (WGS) obtained from bone marrow (BM) or peripheral blood (PB) mononuclear cells of 57 pediatric patients with dicentric chromosome dic(9;20) positive Acute lymphocytic leukemia (ALL), from which in 6 cases DNMT3B gene rearrangement was identified. This data is complemented by total RNA-seq and WGBS of samples from 4 additional ALL patients with a t(12;21) translocation and ETV6-RUNX1 gene fusion. DNA was isolated from BM or PB B-lymphocytes using Qiagen QIAamp DNA Blood Midi Kit to perform i) Array CGH of 58 dic(9;20) positive samples by hybridizing 500ng DNA using a Agilent 400K SurePrint G3 Custom CGH Human Genome Microarray (e-Array design 84704) ii) WGBS of 6 DNMT3B rearrangement positive samples and 4 ETV6-RUNX1 positive samples using Tecan TrueMethyl oxBS-Seq module for library preparation and Illumina NovaSeq 6000 platform to run 2x151 cycles iii) WGS of DNMT3B rearrangement positive samples using Illumina Lotus DNA Library Prep Kit followed by sequencing running 2x160 cycles on an Illumina NovaSeq 6000 platform. RNA was isolated from PB B-lymphocytes using the PerkinElmer Chemagic 360 instrument, followed by i) targeted RNA-seq of 56 dic(9;20) positive samples prepared using Illumina TruSight RNA Pan-Cancer Panel and sequenced on an Illumina MiSeq platform running 2x75 cycles ii) total RNA-seq of 6 DNMT3B rearrangement positive samples and 4 ETV6-RUNX1 positive samples utilizing TruSeq Stranded Total RNA Library Prep Gold kit and running 2x100 cycles on an Illumina NovaSeq 6000 platform.

Dataset EGAD00001011122

Genetic Discovery and Application in a Clinical Setting: Continuing a Partnership (eMERGE Phase II)

The electronic Medical Records and Genomics (eMERGE) Network is a consortium of ten participating sites funded by the NHGRI to investigate the use of electronic medical record systems for genomic research. The goal of eMERGE is to conduct genome-wide association studies in approximately 19,000 individuals using EMR-derived phenotypes and DNA from linked Biorepositories. The eMERGE Network brings together researchers with a wide range of expertise in genomics, statistics, ethics, informatics, and clinical medicine from leading medical research institutions across the country. Each center participating in the consortium is uniquely situated to provide critical resources to this highly collaborative and productive network. Each site combines a biobank or study cohort with extensive genomic data and access to clinical data derived from electronic medical records. Sites are geographically dispersed and have diverse patient populations, including two sites focusing specifically on pediatrics. The eMERGE Network is comprised of 9 sites and one coordinating center. Each site maintains its own biorepository where DNA specimens are linked to phenotypic data contained within EMRs. Children's Hospital of Pennsylvania, PI: Hakon Hakonarson, MD, PhD Cincinnati Children's Medical Center with Boston Children's Hospital, PI: John Harley, MD, PhD - CCHMC and Ingrid Holm, MD, MPH - BCH Geisinger Health System, PI: David Carey, PhD and Marc Williams, MD Group Health Cooperative with University of Washington, PI: Eric Larson, MD, MPH - GHC and Gail Jarvik, MD, PhD - UW Marshfield Clinic with Essentia Institute of Rural Health, PI: Catherine McCarty, PhD, MPH - Essentia and Murray Brilliant, PhD - Marshfield Mayo Clinic, PI: Christopher Chute, MD, DrPH and Iftikhar Kullo, MD Icahn School of Medicine at Mount Sinai, PI: Erwin Bottinger, MD Northwestern University, PI: Rex Chisholm, PhD and Maureen Smith, MS Vanderbilt University, PI: Dan Roden, MD eMERGE Coordinating Center - Vanderbilt University, PI: Paul Harris, PhD Using electronic phenotyping methods, the consortium used DNA samples from all participating sites to explore the genetic determinants of red cell indices, white blood count (WBC) differential, diabetic retinopathy, height, serum lipid levels, specifically total cholesterol, HDL (high density lipoprotein), LDL (low density lipoprotein), and triglycerides, and autoimmune hypothyroidism as well as using the phenome-wide association study (PheWAS) paradigm to replicate and discover relationships between targeted genotypes with multiple phenotypes.

Study phs000948

The Atherosclerosis Risk in Communities (ARIC) Study

The Atherosclerosis Risk in Communities (ARIC) Study, sponsored by the National Heart, Lung and Blood Institute (NHLBI), is a prospective epidemiologic study conducted in four U.S. communities. The four communities are Forsyth County, NC; Jackson, MS; the northwest suburbs of Minneapolis, MN; and Washington County, MD. ARIC is designed to investigate the etiology and natural history of atherosclerosis, the etiology of clinical atherosclerotic diseases, and variation in cardiovascular risk factors, medical care and disease by race, gender, location, and date. ARIC includes two parts: the Cohort Component and the Community Surveillance Component. The Cohort Component began in 1987, and each ARIC field center randomly selected and recruited a cohort sample of approximately 4,000 individuals aged 45-64 from a defined population in their community. A total of 15,792 participants received an extensive examination, including medical, social, and demographic data. These participants were reexamined every three years with the first screen (baseline) occurring in 1987-89, the second in 1990-92, the third in 1993-95, and the fourth and last exam was in 1996-98. Follow-up occurs yearly by telephone to maintain contact with participants and to assess health status of the cohort. In the Community Surveillance Component, currently ongoing, these four communities are investigated to determine the community-wide occurrence of hospitalized myocardial infarction and coronary heart disease deaths in men and women aged 35-84 years. Hospitalized stroke is investigated in cohort participants only. Starting in 2006, the study conducts community surveillance of inpatient (ages 55 years and older) and outpatient heart failure (ages 65 years and older) for heart failure events beginning in 2005. ARIC is currently funded through January 31, 2012. This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org) funded by the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to atherosclerosis and cardiovascular disease through large-scale genome-wide association studies of well-characterized cohorts of adults in four defined populations. Genotyping was performed at the Broad Institute of MIT and Harvard, a GENEVA genotyping center. Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington.

Study phs000090

PRE-DETERMINE: Biologic Markers and MRI SCD Cohort Study

The PRE-DETERMINE Study is a prospective, multi-center study of 5,764 patients with a history of coronary artery disease (CAD) and documentation of either a prior myocardial infarction (MI) or mild to moderate left ventricular dysfunction (LVD) with left ventricular ejection fraction (LVEF) 35-50%. Patients were enrolled at 136 sites where information on baseline demographics, clinical characteristics, pertinent past medical history, lifestyle habits, cardiac test results, and medications were collected via electronic data capture. Electrocardiograms (ECG) along with a blood sample was also collected at baseline, sent to central laboratories, and stored for future analyses. Contrast-enhanced magnetic resonance imaging (CE-MRI) scans were collected on a subset of patients and analyzed. Enrollment closed in November 2013 and patients are now being followed centrally by the Clinical Coordinating Center via mail/phone to document interim non-fatal arrhythmic events and cause-specific mortality. Questionnaires that inquire about intervening implantable cardiac defibrillator (ICD) implantations, ICD therapies, cardiac arrest, and other pertinent cardiovascular endpoints are mailed to participants every six months, and follow-up telephone calls are made to non-responders. Study endpoints are being confirmed through review of medical records, interviews with next-of-kin, and autopsy reports, if available.The primary objective of PRE-DETERMINE is to determine whether biologic markers and ECGs can be utilized to advance sudden cardiac death (SCD) risk prediction in patients with coronary heart disease (CHD) and LVEF >30-35%. The overarching goal of the study is to identify a series of markers that alone or in combination specifically predict risk of arrhythmic death as compared to other causes of mortality among this at risk population of CHD patients with preserved LVEF> 30-35%. If biologic or ECG markers are identified that can specifically predict risk of ventricular arrhythmias, then these markers may serve as relatively inexpensive methods to identify those at risk. The public health impact of identifying markers could be quite substantial, leading to more efficient utilization of ICDs and advances in our understanding of mechanisms underlying SCD.Among the 95% of participants that provided a blood sample at baseline, genome wide genotyping using the Illumina Global Screening Array (GSA) has been performed. A total of 4,335 participants with European ancestry gave consent that allows genetic research and deposition of data into dbGaP.

Study phs002940

Single Cell and Spatial Transcriptomics Studies of Fibrosis in Prospective Registry in IBD Study at MGH and GI Disease and Endoscopy Registry

Stricturing disease or fibrosis is a common complication of inflammatory bowel disease (IBD), often requiring surgical intervention. This process is caused by the abnormal deposition of extracellular matrix in the context of inflammation, and thus involves crosstalk between multiple cell types including fibroblasts and immune cells. To understand the cellular interactions involved in fibrosis, we performed single cell and spatial transcriptomic analyses of biopsy or resection samples from IBD patients, diverticulitis patients or controls.For single cell analyses, intestinal samples were processed within three hours of collection by first stripping the epithelial layer with EDTA and then enzymatically digesting the underlying tissue. Cells from both the epithelial and tissue fractions were separately loaded in two channels on a 10x Chromium controller and libraries were generated with the 3'v3 Chemistry pipeline before sequencing on an Illumina sequencer. The resulting sequence data was demultiplexed and analyzed with the CellRanger pipeline to generate raw fastq files and processed gene-count matrices for each sample.For spatial transcriptomic analyses, intestinal resection samples were snap frozen in OCT (optimal cutting temperature embedding medium). Blocks were cut into 10μm sections in a cryostat and transferred to a 10x Genomics Visium slide v1. Spatially barcoded libraries were prepared according to manufacturer's instructions and sequencing on an Illumina sequencer. The resulting sequence data was processed with the SpaceRanger pipeline to generate fastq files and processed barcode-count matrices. Using the samples deposited here, we defined 68 fine-grained cell types across the ileum and colon of control and fibrotic intestinal tissues. We show that intestinal strictures were characterized by increased immune cells - including IgG+ plasma cells and CCR7hiCD4+ T cells - and inflammatory fibroblasts. We also define the transcriptional differences associated with fibrosis, with inflammatory fibroblasts in particular showing broad changes in gene expression. Spatial transcriptomics showed that key subsets colocalize within diseased tissues and identified additional populations such as interstitial cells of Cajal and enteric neurons. Further, we mapped gene expression onto intestinal biogeography, finding that known genetic risk loci are enriched within discrete spatial modules, defined by the presence of inflammatory fibroblasts and lymphoid follicles. Altogether, our datasets chart the key transcriptomic and cellular networks in stricturing CD and highlight the spatial organization of multicellular genetic risk factors.

Study phs003943

Comparison of the treated celiac disease microbiome to that of controls

Coeliac disease (CeD) is an immune-mediated disorder primarily affecting the small intestine, characterised by an inflammatory immune reaction to dietary gluten. CeD onset results from a multifaceted interplay of genetic and environmental factors. While recent data show that alterations in gut microbiome composition could play an important role, many current studies are constrained by small sample sizes and limited resolution. To address these limitations, we analysed faecal gut microbiota from two Dutch cohorts, CeDNN (128 treated CeD patients (tCeD), 106 controls) and the Lifelines Dutch Microbiome Project (24 self-reported tCeD, 654 controls), using shotgun metagenomic sequencing. Self-reported IBS (570 cases, 1710 controls) and IBD (93 cases, 465 controls) were used as comparative conditions of the gastrointestinal tract. Interindividual variation within the case and control groups was calculated at whole microbiome and strain level. Finally, species-specific gene repertoires were analysed in tCeD patients and controls. Within-individual microbiome diversity was decreased in patients with self-reported IBS and IBD but not in tCeD patients. Each condition displayed a unique microbial pattern and, in addition to confirming previously reported microbiome associations, we identify an increase in the levels of Clostridium sp. CAG:253, Roseburia hominis, and Eggerthella lenta, amongst others. We further show that the observed changes can partially be explained by gluten-free diet adherence. We also observe increased interindividual variation of gut microbiome composition among tCeD patients and a higher bacterial mutation frequency in tCeD that contributes to higher interindividual variation at strain level. In addition, the immotile European subspecies of Eubacterium rectale, which has a distinct carbohydrate metabolism potential, was nearly absent in tCeD patients. Our study sheds light on the complex interplay between the gut microbiome and CeD, revealing increased interindividual variation and strain-level variation in tCeD patients. These findings expand our understanding of the microbiome’s role in intestinal health and disease. Note that some of the data in this study belong to the Lifelines cohort. Access to this dataset can be requested via the page of the EGA data access committee EGAC00001001996. The phenotype data can be requested, for a fee, by filling the application form at https://www.lifelines.nl/researcher/how-to-apply/apply-here.

Study EGAS50000000959

RNA-seq of DF149 cells – a patient-derived xenograft model of ascites-derived, homologous recombination repair-proficient, high-grade serous ovarian carcinoma – cultured in vitro and isolated after 8 hours treatment with DMSO control (3 x biological replicates) and 2.5 µM CBL0137 (3 x biological replicates)

Background: High-grade serous ovarian carcinomas (HGSCs) are a heterogeneous subtype of epithelial ovarian cancers and include serous cancers arising in the fallopian tube and peritoneum. These cancers are now subdivided into homologous recombination repair (HR)-deficient and proficient subgroups as this classification impacts on management and prognosis. PARP inhibitors (PARPi) have shown significant clinical efficacy, particularly as maintenance therapy following response to platinum based chemotherapy in BRCA-mutant or homologous recombination (HR)-deficient HGSCs in both the 1st and 2nd line settings. However, PARPi have limited clinical benefit in HR-proficient HGSCs which make up almost 50% of HGSC and improving outcomes in these patients is now a high priority due to the poor prognosis with current standard of care. There are a number of potential lines of investigation including efforts in sensitizing HR-proficient tumors to PARPi. Herein, we aimed to develop a novel combination therapy by targeting SSRP1 using a small molecule inhibitor CBL0137 with PARPi in HR-proficient HGSOCs. Experimental design: We tested anti-cancer activity of CBL0137 monotherapy using a panel of HGSOC cell lines and patient-derived tumor cells in vitro. RNA sequencing was used to map global transcriptomic changes in CBL0137-treated patient-derived HR-proficient HGSOC cells. We tested efficacy of CBL0137 in combination with PARPi using HGSOC cell lines and patient-derived tumor cells in vitro and in vivo. Results: We show that SSRP1 inhibition using a small molecule, CBL0137, that traps SSRP1 onto chromatin, exerts a significant anti-growth activity in vitro against HGSC cell lines and patient-derived tumor cells, and also reduces tumor burden in vivo. CBL0137 induced DNA repair deficiency via inhibition of the HR repair pathway and sensitized SSRP1-high HR-proficient HGSC cell lines and patient-derived tumor cells/xenografts to the PARPi, Olaparib in vitro and in vivo. CBL0137 also enhanced the efficacy of DNA damaging platinum-based chemotherapy in HGSC patient-derived xenografts. Conclusion: Our findings strongly suggest that combination of CBL0137 and PARP inhibition represents a novel therapeutic strategy for HR-proficient HGSCs that express high levels of SSRP1 and should be investigated in the clinic.

Study EGAS00001006662

Whole Genome Study for De Novo Mutation Rates

Germline mutations are the source of evolution and contribute substantially to many health-related processes. In this study, we use whole genome deep sequencing data from parents-offspring trios to examine the de novo point mutations (DNMs) in the offspring. We studied correlation between parental ages with de novo mutation rates. This study is published in Wong WS, Solomon BD, Bodian DL, Kothiyal P, Eley G, Huddleston KC, Baker R, Thach DC, Iyer RK, Vockley JG, Niederhuber JE. New observations on maternal age effect on germline de novo mutations. Nat Commun. 2016 Jan 19;7:10486 (PMID: 26781218. Also, we studied differences in molecular signatures in paternal versus maternal origin of de novo mutations. This study is published in Jakob M. Goldmann, Wendy S.W. Wong, Michele Pinelli, Terry Farrah, Dale Bodian, Anna B. Stittrich, Gustavo Glusman, Lisenka E.L.M. Vissers, Alexander Hoischen, Jared C. Roach, Joseph G. Vockley, Joris A. Veltman, Benjamin D. Solomon, Christian Gilissen, John E. Niederhuber. Parent-of-origin specific signatures of de novo mutations. Nat Genet. 2016 Aug;48(8):935-9, PMID: 27322544.

Study phs001055

Reading about genomic analysis of pan-neuroblastoma

There are virtually no research fields that do not benefit from the large-scale genomic analysis that are so popular nowadays. For research into diseases with highly diverse clinical behavior like pediatric neuroblastoma, nevertheless, this type of approach has been a game-changer. Samuel W. Brady and colleagues, from St. Jude Children’s Research Hospital in Memphis, have gathered data from 702 neuroblastomas which were profiled by whole genome sequencing (WGS, n = 205), whole exome sequencing (WES, n = 539), and/or RNA-Seq. Less than half of the samples were generated during this study, while the others were obtained from previous work. Part of the WES data was indeed deposited in EGA in 2012 (EGA study EGAS00001000213). A scratchy summary about the huge work from Samuel W. Brady and colleagues, published in Nature Communications this October 2020 “These findings suggest that the sympathetic nervous system, the tissue from which neuroblastoma arises, is susceptible to different oncogenic insults at different times during development, which could be explored in future investigations using animal models.” Conclude the authors, highlighting the importance of their findings. Pediatric neuroblastomas are classified according to clinical and molecular features into low, intermediate, and high risk. Age plays a critical role in the classification, with younger children having an overall better prognosis. The samples included in this study belonged to all ages and risk-groups: the aim of such set up is the identification of age-associated molecular aberrations. The authors defined a mutational landscape of pediatric neuroblastoma including rare driver events, impossible to pick with a smaller data set. Interestingly, most driver mutations' frequency was found to be age-related. Those include alterations on MYCN, TERT, PTPRD, and Ras pathway, in addition to the previously reported ATRX. In addition, the large data set allowed the authors to define co-existence relations between the mutations (mutual exclusion or co-occurrence) which is a crucial puzzle piece to unravel the mechanisms driving the pathogenesis. Enjoy this really interesting article, open source on Pubmed.

Blog genomic-analysis-of-pan-neuroblastoma

Development of a fully human glioblastoma-in-brain-spheroid model for accelerated translational research

In glioblastoma (GBM) the intricate interplay between tumor cells and the surrounding microenvironment plays a crucial role in tumor progression, invasion, and therapeutic resistance. So far, studying these interactions in a controlled and representative model system has been challenging. Here, we report the development of hGliCS, a human glioma-cortical spheroid model that allows the elucidation of the biology of GBM cells and their interactions with a human-specific brain-like microenvironment and neurons. GBM cells efficiently invade the cortical spheroids, forming a well-connected network of communicating cells. The heterogeneous cellular states of the GBM cells within this model closely resembled findings previously observed in glioblastoma patients and in mouse xenografts. We observed a transition from predominantly mesenchymal-like cells to heterotopic states with a high diversity. In contrast to the substantial changes observed in the tumor cell population, the impact of the GBM cells on the neurons was minimal. We further demonstrate the suitability of hGliCS to test compounds targeting tumor-specific neurobiological features.

Study EGAS50000000757

WGS of T-cell and NK-cell lymphoma for ICGC (NKTL-SG)

Lymphomas are malignancies originating from the lymphatic system and there is a worldwide significant increase in incidences of this cancer. Lymphomas can be further classified into 2 categories namely Hodgkinâ€™s (HL), and Non-Hodgkinâ€™s lymphoma (NHL). The latter can be divided further into B, T and NK cell NHL. Peripheral T-cell lymphoma (PTCL) and Natural Killer/ T-cell lymphoma (NKTL) arise from mature T lymphocytes and NK cells. The more common subtypes include NKTL, PTCL not-otherwise-specified (PTCL-NOS), systemic anaplastic large cell lymphoma (ALCL), follicular PTCL (F-PTCL), angioimmunoblastic T-cell lymphoma (AITL) and enteropathy-associated T-cell lymphoma (EATL). Whole genome analyses on T-cell and NK-cell lymphoma samples from various countries to gain a better understanding of the pathogenesis and biology of these tumors. The comprehensive profiling and comparison among patients from various countries with different etiopathogenesis will hopefully facilitate the elucidation of key pathways and underlying molecular mechanisms driving these cancers, opening up novel therapeutic strategies in the future.

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