Search Results - EGA European Genome-Phenome Archive

A genotype-phenotype study of tumors from patients with inherited mutations in DNA repair genes

This study investigated the genomic landscape of tumors from patients with inherited mutations in DNA repair genes. The aim of this study was to determine the relationship between locus-specific loss of heterozygosity (LOH) and genomic signatures of homologous recombination-based DNA repair (HR) deficiency in tumors associated with pathogenic germline variants in DNA repair genes. Cohorts of pathogenic germline variant (PGV) carriers with different cancer types were identified via a cancer genetics registry and clinical practice at Penn Medicine and through our collaborator network. Tumors were analyzed with next generation sequencing (whole exome and/or targeted panel sequencing) with or without transcriptomic analyses. Sub-study #1 "Non-breast/ovarian tumors in germline BRCA1/2 carriers". This study investigated primary non-breast/ovarian tumors that arise in individuals with BRCA1/BRCA2 pathogenic germline variants (PGVs). Whole exome sequencing (WES) using Agilent All-Exon Kit v7 hybrid capture probes was performed on matched tumor and blood germline normal DNA on an Illumina HiSeq. Individual WES data from DNA samples from tumor and normal are available. Sub-study #2: "Breast tumors in germline CHEK2 carriers". This study investigated primary breast tumors that arise in individuals with CHEK2 pathogenic germline variants (PGVs). Whole exome sequencing (WES) using Agilent All-Exon Kit v7 hybrid capture probes was performed on matched tumor and blood germline normal DNA on an Illumina HiSeq. Whole transcriptome RNAseq was performed on tumors. Individual WES data from DNA samples from tumor and normal and RNAseq data from tumor are available. Sub-study #3: "Breast tumors in germline TP53 carriers". This study investigated primary breast tumors that arise in individuals with TP53 pathogenic germline variants (PGVs). Whole genome sequencing (WGS) and/or custom panel targeted sequencing was performed on matched tumor and blood germline normal DNA on an Illumina HiSeq. Whole transcriptome RNAseq was performed on tumors and normal breast tissue. Individual WGS or targeted data from DNA samples from tumor and normal and RNASeq data from tumor and normal are available. Sub-study #4: "Prostate tumors in germline DNA repair carriers". This study investigated prostate tumors that arise in individuals with a variety of pathogenic germline variants (PGVs). Whole genome sequencing (WGS) and/or custom panel targeted sequencing was performed on matched tumor and blood germline normal DNA on an Illumina HiSeq. Whole transcriptome RNAseq was performed on tumors and normal prostate tissue. Individual WGS or targeted data from DNA samples from tumor and normal and RNASeq data from tumor and normal are available.

Study phs003348

Ipilimumab and Decitabine in Treating Patients With Relapsed or Refractory Myelodysplastic Syndrome or Acute Myeloid Leukemia

The NCI Experimental Therapeutics Clinical Trials Network (ETCTN)/Cancer Therapy Evaluation Program (CTEP) 10026 study (NCT02890329) tested combined ipilimumab and decitabine treatment in two cohorts: Arm A consisted of patients with relapsed acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation. Arm B consisted of patients with advanced myelodysplastic syndrome (MDS) or AML that did not previously undergo stem cell transplantation. During the study, peripheral blood and bone marrow samples were obtained from study participants at study entry (screening), following the first lead-in cycle of decitabine monotherapy, during combined treatment with decitabine and ipilimumab, and at the end of treatment.This study tested the combination of the CTLA-4 blocking antibody ipilimumab and the DNA methyltransferase inhibitor decitabine in advanced myeloid disease in the transplant-naive and post-transplant context. The samples were used for bulk and single cell RNA sequencing (scRNA-seq) as well as whole exome sequencing (WES).

Study phs003015

Single Cell RNA-Seq Reveals Malignant and Stromal Programs Associated with Metastasis in Head and Neck Cancer

This study of head and neck cancer aimed to profile individual malignant, stromal, and immune cells in treatment-naive oral cavity squamous cell carcinoma, with or without matched metastatic cervical lymph nodes. Clinical and pathologic information was collected on all patients, in addition to a fresh biopsy sample from the primary tumor and/or metastatic lymph node at the time of initial surgery. Biopsy specimens were processed for single cell RNA-seq (scRNA-seq) and/or whole exome sequencing (WES). A total of ~6,000 single cells from 18 participants were included in the final dataset. Stromal and immune cells had consistent expression programs across patients. Conversely, malignant cells varied within and between tumors in their expression of signatures related to cell cycle, stress, hypoxia, epithelial differentiation, and partial epithelial-to-mesenchymal transition (p-EMT). One of the top scoring genes in this program was TGFβ-induced (TGFBI), implicating the classic EMT regulator TGFβ. Cells expressing the p-EMT program spatially localized to the leading edge of primary tumors. By integrating single-cell transcriptomes with bulk expression profiles for hundreds of tumors, we refined Head and Neck Squamous Cell Carcinoma (HNSCC) subtypes by their malignant and stromal composition, and established p-EMT as an independent predictor of nodal metastasis, grade, and adverse pathologic features. Our results provide insight into the HNSCC ecosystem and define stromal interactions and a p-EMT program associated with metastasis.

Study phs001474

Comprehensive Genomic Data Deposition for Pancreatic Cancer Precision Medicine Studies: Clinical Trials NCT02451982 and NCT02648282

This submission includes specimens from 89 pancreatic cancer patients at Johns Hopkins Hospital, comprising 41 surgically resectable and 48 locally advanced pancreatic cancer (LAPC) cases. These samples originate from two clinical studies, NCT02451982 and NCT02648282, following the Johns Hopkins Medical Institution Institutional Review Board-approved registry protocol at the Pancreatic Cancer Precision Medicine Center of Excellence Program. Written consent for specimen use, obtained from participants in the original studies, covers additional research, including this one. Biopsy specimens collected through endoscopic ultrasound-guided fine needle core biopsies or surgically resected tumors are included. NCT02451982 is a platform trial evaluating immunotherapy combinations for surgically resectable pancreatic ductal adenocarcinoma in the neo-adjuvant and adjuvant settings. It investigates the GVAX pancreatic cancer vaccine with immune-boosting cyclophosphamide, exploring immune cell trafficking and the impact of PD-1 blocking. NCT02648282 focuses on the efficacy and safety of combining cyclophosphamide, pembrolizumab, GVAX, and stereotactic body radiotherapy (SBRT) in locally advanced pancreatic cancer, with an emphasis on anti-tumor activity. Both studies provide valuable insights into innovative pancreatic cancer treatment approaches.

Study phs003600

Analyzing Somatic Mutagenesis in Systemic Sclerosis

The study was undertaken with the aim of estimating differences in the mutational burden in lung tissues from healthy vs systemic sclerosis (SSc) patients. SSc is an auto-immune disease, with patients often developing cancer. However, the etiology of this phenomenon is poorly understood. As such we sought to uncover potential molecular mechanisms prevalent within SSc tissues that might be potentiating cancer. Samples were randomly collected from individuals from two broad ethnic groups, European (EA) and African American (AA). In total, samples were obtained from 7 individuals belonging to the EA group and 4 individuals from the AA group. For this study, ethnicity was not included as a confounding variable, given that the data set has roughly comparable number of individuals from both ethnicities for the healthy and SSc cohorts. Study participants ranged in age from 37-63 years old. Median age (52 years old) of healthy individuals was comparable to the SSc cohort (~48 years old). Participants were self-described as current/former smokers or non-smokers. Lung tissues were obtained under a protocol approved by the University of Pittsburgh Institutional Review Board. Written informed consent statements were provided to the University of Pittsburgh IRB by the study participants/patients. Sample sizes were determined by the ability of bulk lung fibroblast tissues to stably propagate in culture until single cell clones could be obtained. Samples for which sufficient cell density could not be achieved for downstream high-depth sequencing analysis were excluded from the study and are not reported. Five or greater than 5 samples are collected from each cohort including healthy and SSc patients. Subjects were allocated to two basic cohorts based on diagnosis at the time of explant. Participants with no reported lung anomalies were allocated to the "healthy" cohort, whereas individuals with reported lung abnormalities, primarily SSc with pulmonary fibrosis and/or hypertension were allocated to the "SSc" cohort. All tissue samples were cultured, propagated and processed in identical fashion without requiring individual-specific protocols. Additionally, equivalent amounts of DNA were used for preparing sequencing libraries from both cohorts, and all samples were sequenced using Illumina whole genome sequencing (WGS) and analyzed using identical computational pipelines. Our study primarily discovered that there is a significantly higher burden of somatic mutations in SSc samples, compared to healthy samples. We observed an overall increase in a range of mutations in genomes of SSc patients, including single base substitutions, indels, structural variants and copy number alterations. Additionally, we uncovered a novel mutation signature associated with SSc samples, hinting at the activity of POLH in these samples, and highlighting the potential nexus between inflammation, DNA damage, and cancer.

Study phs003700

Pre-Existing Skin-Resident CD8 and γδ T Cell Circuits Mediate Immune Response in Merkel Cell Carcinoma and Predict Immunotherapy Efficacy

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with a ~50% response rate to immunotherapy. Here, we attempted to identify novel predictive biomarkers of response through extensive and deep multi-omics interrogation of 186 samples from 116 patients. We collectively integrated bulk RNAseq, single-cell RNAseq, multiplex immunofluorescence, and spatial transcriptomics. Importantly, we were also able to study 14 matched pairs of tissue samples from pre- and post-immunotherapy. In non-responders, tumors show evidence of increased tumor cell cycling, expression of neuronal stem cell markers, and IL-1α/β. Responders have evidence of increased type I/II interferon signatures and evidence of pre-existing tissue resident (Trm) CD8 or Vδ1 γδ T cells that functionally converge with overlapping antigen-specific transcriptional programs and clonal expansion of multiple T cell receptors. Spatial transcriptomics demonstrated higher co-localization of T cells with B and dendritic cells in responders, with evidence of expression of chemokines important for co-stimulation. Finally, immunotherapy increased clonal expansion or recruitment of Trm and Vδ1 cells in tumors in responders, further underscoring their therapeutic importance. These data identify potential novel actionable biomarkers and therapeutic targets for MCC.

Study phs003629

Radiation-Related Genomic Profile of Papillary Thyroid Cancer after the Chernobyl Accident

The April 26, 1986 accident at the Chernobyl nuclear power plant in northern Ukraine resulted in the release of radioactive contaminants, which were deposited in the surrounding areas in Ukraine, Belarus, and Russia. The main radiation-related health effect resulting from these exposures is the increased occurrence of thyroid cancer among individuals who were children at the time of the accident or born shortly thereafter. The purpose of this study was to conduct a comprehensive genomic landscape analysis of papillary thyroid tumors arising in individuals who were exposed as children to radioactive iodine (I-131) from the Chernobyl nuclear power plant accident.

Study phs001134

Genomic Profiling of Pediatric B-cell Acute Lymphoblastic Leukemia

Pediatric leukemia is the most common type of childhood cancer and, despite tremendous progress in treatment, remains the second leading cause of cancer deaths in children. B-cell acute lymphoblastic leukemia (B-ALL) is the most common type of pediatric leukemia. Recent studies using transcriptional profiling of large cohorts of pediatric B-ALL have shown that patients can be grouped into transcriptional subtypes that are often defined by specific driver mutations. Interestingly, many of these mutational subtypes are defined by gene fusions or rearrangements that drive altered expression of transcription factors (ETV6-RUNX1, PAX5, DUX4, TCF3-PBX1, ZNF384) or in chromatin regulatory machinery (KMT2A), suggesting that transcriptional dysregulation is a major driver of B-ALL. While the transcriptional distinctions are clear, the relationship between patients in terms of their chromatin regulatory landscape remains unclear. To address this, we profiled gene expression, open chromatin, and 3D genome folding in patient derived B-ALL samples. We identified that at the level of 3D genome organization, many chromatin interactions and looping events are shared across mutational subtypes, suggesting that shared transcriptional programs, in addition to group specific driver mutations, possibly regulate the chromatin landscape in B-ALL. Using RNA-seq and ATAC-seq data, we were able to identify "latent" signatures of expression related to non-mutant transcription factors (TFs) that also contribute to expression heterogeneity across TF subtypes. These are related to patient specific patterns of 3D genome folding, and in some cases, are predictive of disease outcomes. This study helps shed light on the chromatin landscape in B-ALL and furthers our understanding of the interactions between diverse mutant TFs that drive B-ALL and non-mutant TFs that help shape the B-ALL chromatin landscape.

Study phs003226

Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET)

STARNET is a genetics of RNA expression study of multiple disease-relevant tissues obtained from living patients with cardiovascular disease. Tissue samples are obtained from blood, atherosclerotic-lesion-free internal mammary artery (MAM) and atherosclerotic aortic root (AOR), subcutaneous fat (SF), visceral abdominal fat (VAF), skeletal muscle (SKLM), and liver (LIV) during open thorax surgery of 600 coronary artery disease (CAD) patients. All patients gave written informed consent. The inclusion criterion was eligibility for coronary artery by-pass graft (CABG) surgery. Patients with other severe systemic diseases, such as active systemic inflammatory disease or cancer, were excluded. The primary clinical end points were the SYNTAX score based on the extent of coronary atherosclerosis assessed from preoperative angiograms. The STARNET patients are Caucasians (31% females); 32% had diabetes, 75% had hypertension, and 67% had hyperlipidemia; and 33% had an MI before age 60. By New York Heart Association criteria, 45% were class I, 42% class II, 9% class III, and 1% class IV. TYPES AND RNA SEQUENCING: 566 DNA genotype and 3577 RNA-seq profiles from seven tissues from 600 STARNET CABG patients passed quality control (on average 511 RNA-seq profiles/tissue). DNA was genotyped with the OmniExpress Exome array (Illumina, ~900k SNPs) and imputed to a total of 14,098,063 DNA variant calls (6,245,505 with minor allele frequency >5%). The STARNET subjects mainly overlap with Caucasian of Northern European (Finnish) descent. RNA sequencing was performed using the HighSeq2000 platform, poly-A (LIV, SKLM, VAF, SF and blood) and ribo-zero (AOR, MAM) protocols with 50-100 bp read lengths, single end to 15-30 million read depth.

Study phs001203

DAC for study: "Combination pembrolizumab and radiotherapy induces systemic anti-tumor immune responses in immunologically-cold non-small cell lung cancer."

This is Data Access Committee will oversee data sharing for sequence data in the EGA study: "Combination pembrolizumab and radiotherapy induces systemic anti-tumor immune responses in immunologically-cold non-small cell lung cancer." This dataset includes 116 bam files from whole exome sequencing on the Illumina HiSeq2500, 102 fastq files from RNA sequencing on the Illumina NovaSeq 6000. The samples analyzed include tumor/normal DNA samples and tumor RNA samples from 72 individuals with non-small cell lung cancer treated with pembrolizumab and SBRT or pembrolizumab alone on the NCT02492568 trial.

Dac EGAC50000000202

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