Search Results - EGA European Genome-Phenome Archive

A Genomic Atlas of Systemic Interindividual Epigenetic Variation in Humans (GTEx)

Methylation of cytosines in CpG dinucleotides is an epigenetic mechanism with essential roles in mammalian development. To explore its functions in cellular differentiation, unbiased analysis of CpG methylation by whole genome bisulfite sequencing (WGBS) has been used to characterize epigenetic differences among different human tissues and cell types. Meanwhile, human interindividual variation in DNA methylation that is not cell-type specific has attracted relatively little attention. Systemic interindividual epigenetic variation is important, however, because like genetic variation it is a potential determinant of phenotypic variation and can be assessed in any easily obtainable DNA sample. Since systemic epigenetic variants originate in the preimplantation embryo, their establishment can be influenced by periconceptional environment, and potentially provide information about lifetime risks relevant to global health, obesity, and cancer.We elucidated systemic interindividual variation in CpG methylation in the human genome. We studied brain, heart, and thyroid tissues (representing all three germ layer lineages) from each of 10 donors in the NIH Gene-Tissue Expression (GTEx) project. We performed deep whole genome bisulfite sequencing for these 30 samples, achieving a sequencing depth of over 50x coverage per sample. We identified 9,926 correlated regions of systemic interindividual variation (CoRSIVs). These regions, comprising just 0.1% of the human genome, often correlate with one another over long genomic distances, are associated with transposable elements and subtelomeric regions, conserved across various human ethnic groups, and particularly sensitive to periconceptional environment. While genetic variation appears to influence methylation at most CoRSIVs, many show no evidence of genetic influence, suggestive of 'pure' epigenetic variation. At CoRSIVs, interindividual variation in DNA methylation in an easily biopsied tissue predicts expression in other tissues, and genes associated with these loci are implicated in a range of human disorders. In addition to charting a previously unrecognized molecular level of human individuality, this atlas of human CoRSIVs provides a resource for future population-based investigations into how interindividual epigenetic variation modulates risk of disease.Version 2 now also includes Target Capture Sequencing of CoRSIVs in 808 tissues (188 GTEx Donors). Focusing on the CoRSIVs identified by analyzing WGBS data, a target-capture bisulfite sequencing assay was developed. Using the genotype data of 188 GTEx donors, we assessed mQTL by capturing each CoRSIV (including 1 kb flanking regions) and quantifying methylation by bisulfite-seq. The target-capture bisulfite sequencing data are available to download via the AnVIL project.Version 3 now included WGBS data from three tissues (heart, brain, thyroid) data from 10 African American individuals from GTEx cohort. At exceptional human genomic regions, DNA methylation states are established stochastically in the early embryo and maintained during cellular differentiation, yielding systemic (i.e. not tissue-specific) interindividual epigenetic variation. Previous screens for such correlated regions of systemic interindividual variation (CoRSIVs) were limited to White Americans. Here, we describe the first multi-racial human CoRSIV screen. We integrate deep whole-genome bisulfite sequencing data for three tissues from each of ten Black and ten White donors in the NIH Genotype-Tissue Expression program. This approach identifies twice as many CoRSIVs among Black than White Americans. Establishment of CoRSIV methylation is sensitive to periconceptional environmental exposures including assisted reproduction, seasonal variation, and famine. CoRSIV-associated genes are enriched for GWAS variants linked to cancer and neurodevelopment. Although only 15% of Black CoRSIVs overlap with those among White individuals, both sets are associated with the same specific families of transposable elements. Moreover, within multiple cell lines, ranked enrichments of transcription factor binding to Black and White CoRSIVs are exquisitely coordinated, indicating that CoRSIV methylation states established in the early embryo play a crucial role in guiding subsequent cellular differentiation.

Study phs001746

Whole Exome Sequencing of Chronic Lymphocytic Leukemia

The somatic genetic basis of chronic lymphocytic leukemia (CLL), a common and clinically heterogenous adult leukemia, remains poorly understood. Massively parallel sequencing technology now provides a method for systematic discovery of genetic alterations that underlie disease, and for uncovering new therapeutic targets and biomarkers. In study version 2, we presented a dataset consisting of DNA sequencing from 169 CLL samples (with matched germline controls). Samples were collected from patients displaying a wide range of characteristics representing the broad clinical spectrum of CLL. Understanding the mutational landscape of CLL provides a starting point for systematic analyses to address fundamental questions in CLL, including how mutated genes alter cellular networks and phenotypes, and thereby contribute to disease heterogeneity. Intratumoral heterogeneity plays a critical role in tumor evolution. To define the contribution of DNA methylation to heterogeneity within tumors, we performed genome-scale bisulfite sequencing of >100 primary chronic lymphocytic leukemias (CLLs; data presented in study version 3). Compared with 26 normal B cell samples, CLLs consistently displayed higher intrasample variability of DNA methylation patterns across the genome, which appears to arise from stochastically disordered methylation in malignant cells. Transcriptome analysis of bulk and single CLL cells revealed that methylation disorder was linked to low-level expression. Disordered methylation was further associated with adverse clinical outcome. We therefore propose that disordered methylation plays a similar role to that of genetic instability, enhancing the ability of cancer cells to search for superior evolutionary trajectories.Samples from this study were included in the CLL-map project, which integrated genomic, transcriptomic and epigenomic data from 1,148 patients to portray the landscape of genetic mutations and molecular phenotypes in CLL, and assess their association with patient outcome.We conducted high-throughput dynamic BH3 profiling, a functional assay that measures the initiation of apoptotic signaling after ex vivo exposure to drugs, for interrogation of >60 CLL samples with exome, transcriptome and methylome sequencing. FDA-approved 42 drugs were used in this screen, which revealed associations between ex vivo drug response with molecular features. After augmenting study version 4 with additional RNA and methylome data, the entire dataset now includes RNA sequencing of primary CLLs from 82 subjects and of B-cells from 6 healthy donors, and methylome sequencing of primary CLLs from 121 subjects and of samples from 11 healthy donors.

Study phs000435

Metatranscriptomic Sequencing of Biological Samples in Immunocompromised Children

Respiratory disease in immunocompromised children can include a broad array of microbiome perturbations and infections as well as inflammation and injury to the tissue. Here we describe RNA-based next generation sequencing (mNGS) of lower respiratory samples from immunocompromised children, including those with cancer, immunodeficiencies, and a history of solid organ or stem cell transplant. We identified a rich cross-domain pulmonary microbiome containing bacteria, fungi, RNA viruses, and DNA viruses in each patient. Lower respiratory samples largely include bronchoalveolar lavage samples with some other sample types as well. A subset of patients have paired blood and/or nasal samples also sequenced for comparative analysis.

Study phs001684

Kids First and INCLUDE: Down Syndrome, Heart Defects, and Acute Lymphoblastic Leukemia

This project is a collaboration with the trans-NIH INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE (INCLUDE) Project, which seeks to improve health and quality-of-life for individuals with Down syndrome, and NHLBI's TransOmics for Precision Medicine (TOPMed) program, which seeks to apply omics technologies to improve scientific understanding of the fundamental biological processes that underlie heart, lung, blood, and sleep (HLBS) disorders. The data is also available at the INCLUDE Data Hub.Down syndrome (DS), which occurs due to trisomy 21, is one of the strongest risk factors for both congenital heart disease (CHD) and acute leukemia. For instance, children with DS have a 2000-fold increased risk of atrioventricular septal defects (AVSD) and a 20-fold increased risk of acute lymphoblastic leukemia (ALL). An important and innovative aspect of the Kids First program is understanding the overlap between structural birth defects and childhood cancer. Notably, the background of DS predisposes children to both of these phenotypes, however, the genomic architecture of risk remains largely undiscovered. In this joint Kids First/TOPMed/INCLUDE project, we are currently including >2,000 samples for whole-genome sequencing, including: 1) paired germline-tumor samples from children with DS-ALL; and 2) samples from families with DS-CHD. This work will advance our understanding of the developmental pathways that may lead to both structural birth defects and childhood cancer.The objectives of this study are to determine the genetic variants underlying AVSD and ALL risk in children with DS. Therefore, the aims of our study are: 1) compare whole-genome sequencing (WGS) data between children with documented DS-AVSD and children with DS who have structurally normal hearts to identify genetic variants that perturb heart development; and 2) compare WGS data between children with documented DS-ALL and children (from Aim 1) with DS who do not have a known history of ALL. We will also examine associations between germline mutations and somatic genomic features. This study will address the fundamental question of why children with DS have an elevated risk of AVSD and ALL. Insights into the genes that drive DS-AVSD and DS-ALL may have implications for improved genetic counseling, surveillance, clinical management, and treatment strategies for these children. Additionally, our findings may inform targeted therapies or interventions for children without DS who are at risk for structural birth defects and cancer.Additional Pediatric Cardiac Genetics Consortium (PCGC) data from children affected with Down syndrome and congenital heart disease are accessible through two separate dbGaP studies: phs001138 (Kids First) and phs001194 (TOPMed).

Study phs002330

Integrative Somatic and Germline Computational Biology to Redefine Clinical Actionability in Solid Tumors

Version 1: Neuroendocrine tumors (NETs) are rare cancers that arise in the gastrointestinal tract and pancreas. The fundamental mechanisms driving gastroenteropancreatic NETs (GEP-NETs) growth remain incompletely elucidated; however, the heterogeneous clinical behavior of GEP-NETs suggests that both cellular lineage dynamics and tumor microenvironment influence tumor pathophysiology. Here, we performed single-cell RNA-sequencing (scRNA-seq) of fresh resections of GEP-NETs, including four pancreatic NETs, three small intestinal NETs, and one perigastric NET. We used single-cell sequencing to investigate the tumor and immune cellular landscapes of GEP-NET patients. Malignant GEP-NET gene and regulon expression was compared with normal, gastrointestinal endocrine cell differentiation and fate determination stages. We further characterized immune-immune and immune-tumor interaction networks within GEP-NETs, identifying novel therapeutic opportunities in the myeloid compartment of the microenvironment. Our findings highlight the transcriptomic heterogeneity that distinguishes the cellular landscapes of GEP-NET anatomic subtypes and reveal potential avenues for future precision medicine therapeutics.Version 2: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare malignancies with variable clinical behavior. To better understand the cellular and molecular programs underlying GEP-NET pathophysiology, we performed single-cell RNA-sequencing (scRNA-seq) and ATAC-sequencing (scATAC-seq) of 38 tumors, including 21 pancreatic and 17 small intestinal NETs, across both primary and metastatic sites. We used these approaches to comprehensively profile the tumor and immune microenvironments at single-cell resolution, revealing lineage-specific transcriptional states, distinct chromatin accessibility patterns, and diverse immune interactions. This work provides a foundational resource for understanding GEP-NET heterogeneity and for identifying new avenues for therapeutic intervention.

Study phs003141

Single-Cell RNA-Sequencing of Human Prostatectomy Tissue

The tissue microenvironment in prostate cancer is profoundly altered. How prostate cancer cells and their precursors mediate those changes is unclear, in part due to the inability to longitudinally study the disease evolution in human tissues. To overcome this limitation, we performed extensive single-cell RNA-sequencing (scRNA-seq) to assess the transcriptional profiles of the tissue microenvironment in prostate tissues from prostatectomies from men diagnosed with prostate cancer. For each subject, benign-enriched and tumor-enriched tissues were collected from the peripheral zone of the prostate. Additionally, to understand zone-specific differences of the prostate, benign tissues were also collected from the transition and central zones.

Study phs003480

Pooled Mutant KRAS-Targeted Long Peptide Vaccine Combined with Nivolumab and Ipilimumab for Patients with Resected MMR-p Colorectal and Pancreatic Cancer

Phase 1 study for patients with resected PDAC after neoadjuvant and/ or adjuvant chemotherapy and/or radiation, as well as patients with metastatic colorectal cancer who have exposure to 2 or more lines of chemotherapy, to evaluate safety and the immune response to pooled mutant-KRAS peptide vaccine (KRAS peptide vaccine) with poly-ICLC adjuvant in combination with nivolumab and ipilimumab.

Study phs003425

Gabriella Miller Kids First (GMKF) Pediatric Research Program in Susceptibility to Ewing Sarcoma Based on Germline Risk and Familial History of Cancer

Ewing sarcoma (EWS) is a deadly bone cancer that occurs in children and adolescents. Mounting evidence suggests that a genetic predisposition exists for this pediatric cancer, although the specific genetic contribution has yet to be identified. EWS has never been linked to a specific cancer predisposition syndrome, although several case reports have been published that describe siblings and cousins with EWS. Furthermore, neuroectodermal tumors appear to occur more commonly in families with EWS. The two consistent epidemiology findings in EWS include a very strong Caucasian predilection and increased rates of hernia in EWS patients and their family members. Finally, the role of genetic microsatellite repeats in EWS tumorigenesis has been recently described, and these GGAA microsatellites are polymorphic in repeat size and location across the genome. The study goals of this Kids First project include (1) To identify cancer predisposition genes in EWS trios increasing disease risk, (2) To identify genome-wide GGAA microsatellite repeats in EWS trios increasing disease risk, and (3) To identity de novo mutation and structural variant rates in EWS trios reflecting underlying DNA repair defects that increase disease risk. As part of the Kids First Common Fund initiative, this study proposal will further elucidate the genetic contribution to pediatric cancer development. Around 375 of these trios were selected for whole genome sequencing as part of the Gabriella Miller Kids First fund. The EWS trios have been collected as part of the Children's Oncology Group's AEPI10N5 Study ("Genetic Epidemiology of Ewing Sarcoma"), and each trio has associated phenotypic data including a detailed family history. We will interrogate the sequence data using our genomic analysis pipeline at the University of Utah and the Utah Science Technology and Research initiative's (USTAR) Center for Genetic Discovery. We will look for the genetic contribution to EWS and the sequence data with be shared in a repository designated by the Kids First Common Fund. The WGS of these ~375 EWS trios will help us to understand the genetic origins of a deadly childhood cancer and may lead to novel strategies for prevention and treatment.

Study phs001228

Ghana Breast Health Study

The Ghana Breast Health Study (GBHS) was a multi-disciplinary, population-based case-control study conducted in Accra and Kumasi, Ghana that was designed to investigate breast cancer etiology especially for more aggressive breast cancers which are more prevalent in African ancestry women. The study enrolled 2,202 women with lesions suspicious for breast cancer of which 1071 were pathologically confirmed invasive breast cancer cases and 2,106 frequency matched population-based controls enumeration of households using 110 census-defined geographic areas within Ghana's Ashanti, Central, Eastern, and Greater Accra Regions. GHBS participants were between the ages of 18 to 74 years of age. Breast cancer cases were recruited at the time they presented with lesions suspicious of breast cancer at three hospitals: Korle Bu Teaching Hospital (Accra), Komfo Anoyke Teaching Hospital (Kumasi) and Peace and Love Hospital (Kumasi). These hospitals are the primary providers of treatment for breast cancer in Ghana, allowing for cases in our study to represent most breast cancers diagnosed in these areas during the study period. The following publications describe the GBHS in detail: Brinton LA et al. Design considerations for identifying breast cancer risk factors in a population-based study in Africa. Int J Cancer 2017;140:2667-2677 (PMID:28295287). Ahuno ST, et al. Circulating tumor DNA is readily detectable among Ghanaian breast cancer patients supporting non-invasive cancer genomic studies in Africa. NPJ Precis Oncol. 2021 Sep 17;5(1):83 (PMID: 34535742).

Study phs002387

The Prostate, Lung, Colon, Ovary Screening Trial (PLCO)

The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial is a large population-based randomized trial designed and sponsored by the National Cancer Institute (NCI) to determine the effects of cancer screening on cancer-related mortality and secondary endpoints in over 150,000 men and women aged 55 to 74. The screening component of the trial was completed in 2006. However, participants have been under follow-up for cancer incidence and mortality since that time. In addition, PLCO included a large biological sample biorepository which has served as a unique resource for cancer research, particularly for etiologic and early-marker studies. As part of these efforts, PLCO has been used for a number of genome-wide association, exome sequencing and methylome studies for different types of cancer and precancerous conditions.

Study phs001286

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