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• Utility of Capillary Blood in Gene Expression Studies

  The FAA Functional Genomics Team examined the feasibility of analyzing gene expression profiles using capillary blood collected by fingerstick, with the goal of developing practical fingerstick blood collections to expand blood collection capabilities and allow large-scale or field-based collections. We compared the RNA sequencing results obtained from two different capillary blood collection and RNA extraction methods with the results obtained from a standard venous blood collection and RNA extraction protocol. We also compared capillary blood processing methods, as well as fingerstick locations, within one capillary collection/extraction method. Within each method we sought to distinguish male from female participants to assess the capacity of each collection/extraction method for gene expression profiling. The study population included 40 participants aged 18-60 who were free from any acute illness or any illness that would preclude blood collection. We determined that capillary blood possesses large-scale significant differences from venous blood and that the two capillary methods produced similar gene expression profiles. We further determined that all methods were useful for detecting gene expression differences between assessed groups (male and female participants in this case). We conclude that capillary blood is suitable for gene expression profiling in quantities as low as 100 μL whole blood, but recommend that researchers should rely on a single blood collection method if they desire to compare results between individual studies. Raw sequencing files (.fastq) from this study are available in dbGaP.

  Study phs003496

• The Chromatin Landscape of Pathogenic Transcriptional Cell States in Rheumatoid Arthritis

  In this study, we characterized 24 rheumatoid arthritis (RA) synovial tissue chromatin classes (i.e., cell states defined by chromatin accessibility) across 5 cell types (T, B/plasma, myeloid, stromal, and endothelial). We also investigated the transcription factors that may regulate these chromatin classes, their connections to transcriptional cell states in a proposed superstate model, and their interplay with RA pathology through associations with histological parameters and risk variants.As part of the Accelerating Medicines Partnership (AMP) network, we obtained 18 synovial tissue samples from 14 RA and 4 osteoarthritis (OA) patients for this study. Samples were collected from 7 clinical sites. We performed a 10x single cell ATAC-seq experiment on each sample.We further collected synovial tissue samples from 11 RA patients and 1 OA patient from 2 clinical sites; each sample was used for a 10x single cell multimodal ATAC and Gene Expression experiment.For additional support of the proposed superstate model, we also collected peripheral blood mononuclear cells (PBMCs) from 4 RA patients, sorted for 4 populations (CD4+CD127-CD25hi Tregs, CD4+CD127-CD25int Tregs, CD4+CD25-PD1+CXCR5- TPH, CD4+CD25-PD1+CXCR5+ TFH), tagged each population with a hashing antibody, and pooled populations for one multimodal sequencing run.The FASTQ files are available for controlled access via dbGaP. Additional data can be found on Synapse.The presence of pooled subjects inflates the automatically-generated subject count; the actual consented subject count for this data is 34.

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• Comprehensive Genomic Characterization of Translocation Renal Cell Carcinoma

  Xp11 translocation renal cell carcinoma (tRCC) is a rare, female-predominant cancer driven by a fusion between the TFE3 gene on chromosome Xp11.2 and a partner gene on either chrX or an autosome. It remains unknown what types of rearrangements underlie TFE3 fusions, whether fusions can arise from both the active (chrXa) and inactive X (chrXi) chromosomes, and whether TFE3 fusions from chrXi translocations account for the female predominance of tRCC. To address these questions, we performed haplotype-specific analyses of chrX rearrangements in tRCC whole genomes. We show that TFE3 fusions universally arise as reciprocal translocations and that oncogenic TFE3 fusions can arise from chrXi:autosomal translocations. Female-specific chrXi:autosomal translocations result in a 2:1 female-to-male ratio of TFE3 fusions involving autosomal partner genes and account for the female predominance of tRCC. Our results highlight how X chromosome genetics uniquely constrains somatic chrX alterations and underlies cancer sex differences.This version of the dbGaP study provides a comprehensive set of whole genome data and tables with clinical information collected for the 16 patients (15 pateints as tRCC and 1 patient as ccRCC) in the study cohort. The data also contains 12 RNA-seq samples used in the study and analyses. We anticipate that this data will considerably advance our molecular and genetic understanding of oncogenic translocations in TFE3-tRCC involving inactive chromosome X and its role in cancer sex bias.

  Study phs003008

• METABRIC miRNA landscape

  MicroRNAs (miRNAs) are key players in cancer pathogenesis1. They display differential expression across breast cancer subtypes, and play oncogenic and tumor-suppressive roles2-6. A systematic study of the global miRNA landscape in breast cancer and the factors shaping it has not been undertaken. Here we report the results of profiling miRNA expression in 1,302 breast tumors with detailed clinical annotation and long-term follow-up, and for which matching genomic and mRNA expression data were available7. This provides a comprehensive view of the quantity, distribution and variation of the miRNA population and dissects how much genomic, transcriptional and post-transcriptional events contribute to miRNA expression architecture. The key clinical parameters and cellular pathways related to the miRNA landscape are identified, exemplified by context-dependent interaction with cell adhesion and Wnt signaling. Strikingly, in breast cancer miRNAs appear to act as modulators of mRNA-mRNA interactions rather than molecular switches. We demonstrate an important modulatory role for miRNAs in the biology of breast tumors devoid of somatic copy number aberrations, a common subtype where immune response is prominent. Remarkably, prognostic miRNA signatures derived in this subtype are consistently prognostic across several other subtypes and validate in external cohorts. These findings represent a new framework to study the biology of miRNA in human cancer.

  Study EGAS00000000122

• Risk Factors for Asymptomatic Diverticulosis

  Data for this analysis came from a prospective study of colonic diverticulosis at the University of North Carolina Hospital in Chapel Hill, North Carolina (NIH R01DK094738). This is a case-control genetic and transcriptomic study to identify the genetic and cellular determinants underlying colonic diverticulosis and the relationship with other gastrointestinal disorders. The study inclusion and exclusion are described below. DNA and RNA sequencing were performed on colonic tissue from 404 patients with (N=172) and without (N=232) diverticulosis. We assessed variation in the transcriptome associated with diverticulosis and integrated this variation with human intestine single-cell RNA-seq data. We integrated our expression quantitative trait loci with GWAS using Mendelian Randomization. A polygenic risk score analysis examined associations between severity of diverticulosis and other gastrointestinal disorders. We identified 38 genes with differential expression and 17 genes with varied transcript usage linked to diverticulosis. Our results suggest tissue remodeling as a primary mechanism for diverticula formation. The presence of diverticulosis was linked to stromal and epithelial cells in the colon including endothelial cells, myofibroblasts, fibroblasts, goblet, tuft, enterocytes, neurons, and glia. MR highlighted five genes including CCN3, CRISPLD2, ENTPD7, PHGR1, and TNFSF13. In diverticulosis cases, ENTPD7 upregulation was confirmed. A greater burden of diverticula was positively correlated with genetic predisposition to diverticulitis. The data related to the study including total RNA-Seq, SNP array and imputed genotypes will be available through dbGaP.

  Study phs003556

• The Dynamic Immune Behavior of Primary and Metastatic Ovarian Carcinoma

  Patients with high-grade serous ovarian carcinoma are usually diagnosed at an advanced stage and often develop resistance to conventional therapy. Epithelial ovarian tumors have been shown to be rich in CD8+ lymphocytes, which infiltrate both primary and omental sites. In recent years, several prominent studies have highlighted a positive association between the presence of these immune cells and a good prognosis; however, clinical trials of immune checkpoint inhibitors have so far shown unsatisfactory results in ovarian cancer. In this study, we used an innovative combination of single-cell sequencing and spatial transcriptomics to identify the molecular mechanisms that lead to immunosuppression in primary and metastatic HGSC. Primary tumors consistently showed a more active immune microenvironment than did omental tumors. In addition, while several immune cell subtypes were present in all samples, their relative abundance differed between primary and omental tumors. Finally, we found that primary tumors were mostly populated by dysfunctional CD4 and CD8 T cells in later stages of differentiation, while omental tumors were mostly populated by naïve immune cells; this, in turn, was correlated with expression changes in the interferon α and γ pathways in epithelial cells, showing that cross-communication between the epithelial and immune compartments is important for immune suppression in ovarian cancer. These findings can impact the timing and choice of immune-modulating drugs and should be considered when planning treatment for patients with high-grade serous ovarian carcinoma.

  Study EGAS50000000038

• The Genomic and Transcriptomic Landscape of a HeLa Cell Line

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

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• HuBMAP: A Spatially Resolved Molecular Atlas of Human Endothelium

  The human circulatory system plays a vital role in the proper functioning of every organ in the human body. Because vascular related diseases, such as atherosclerosis, do not occur homogeneously throughout the vascular tree, differences in the endothelium of various organs must exist. There is even evidence of heterogeneity of adjacent endothelial cells. We are studying normal endothelium throughout the body and across individuals of different ages to characterize these differences. The first step will be to procure normal tissue samples from a wide range of organs. From disaggregated samples of these tissues, we will perform single cell combinatorial indexing (sci-) to generate chromatin accessibility (sci-ATAC-seq) and transcriptome (sci-RNA-seq) data from millions of single cells across hundreds of samples.  Molecular heterogeneity might correlate with multiple facets of the anatomical distribution of endothelium, including vascular vs. lymphatic, arteries vs. veins, capillaries vs. larger vessels, differences between organs, organ zonation, cell-to-cell differences, etc. Based on heterogeneous markers defined from deep profiling of disaggregated cells, we will employ seqFISH to spatially relate the distinct endothelial subpopulations arising from the single nuclei data to histologic preparations. For example, this will allow us to identify subpopulations with particular markers as arterial, capillary, venous, or lymphatic. The end product will include multiparameter images in which the complete gene expression and chromatin accessibility profile can be interactively visualized for every cell.

  Study phs002267

• Delineating pediatric brain tumor progression using single-nuclei sequencing

  Pediatric brain cancers are the most common solid tumors in children with varying survival rates depending on molecular features of cancer cells and associated microenvironment. Several studies have used single-cell RNA sequencing to define transcriptional programs active in cancer cells and highlighted supportive roles of non-cancerous cells embedded in these tumors. Although application of single-cell RNA sequencing technology has expanded our understanding of intratumoral heterogeneity and underlying transcriptional mechanisms in brain tumors at diagnosis, mechanisms of disease remains elusive. Therefore, the purpose of this proposal is to characterize cellular and transcriptional states of malignant and non-malignant compartments at primary diagnosis and at relapse. In this study, we performed single-nuclei sequencing of 42 patient samples taken at various disease stages (initial diagnosis, progressive disease, and relapsed disease) from 20 patients with low-grade glioma or Atypical Teratoid Rhabdoid Tumor (ATRT). Bulk whole genome and RNA-seq data for these samples are available from the Children’s Brain Tumor Network and the Gabriella Miller Kids First Data Resource Center. Findings from our study will help define the mechanistic shifts of tumor and non-cancerous cells over course of disease progression. Collectively with the single-cell Pediatric Cancer Atlas funded, this project lays the foundation of an important data set focused on lethal relapsed cancers that can continue to be expanded to identify cancer-intrinsic and extrinsic microenvironmental factors supporting recurrence of pediatric brain tumors.

  Study EGAS50000001288

• Systematic Growth Factor Profiling Platform for 3D Tumor Models Reveals EstradiolResponsive Cellular Mechanisms of Immunotherapy Resistance

  Epithelial ovarian cancer (EOC) exhibits significant molecular heterogeneity, which is thought to be influenced by the tumor microenvironment (TME). However, the specific factors driving this heterogeneity remain poorly understood. In this study, we integrated growth factoromics and genomic data to identify TME factors contributing to EOC heterogeneity and immunosuppression. Our analysis revealed distinct subgroups of EOC samples with differential responsiveness to specific growth factors, particularly estradiol and R-spondin. Notably, samples with high responsiveness to estradiol and Wnt (C1 cluster) were enriched in the Mesenchymal (MES) molecular subtype, while samples with high responsiveness to R-spondin (C2 cluster) were associated with the Differentiated (DIF) and Immunoreactive (IMR) subtypes. We discovered that the G protein-coupled estrogen receptor (GPER), rather than the classical estrogen receptor alpha (ERα), was the key mediator of estrogen responsiveness and a determinant of molecular subtype classification. Single-cell sequencing analysis identified subsets of estrogen-responsive malignant cell (MAL.PDCD5) and cancer-associated fibroblast (FB.TNFSF10), which were associated with immunosuppressive patterns in the TCGA cohort. Importantly, the interaction between these cell populations significantly increased upon estrogen treatment, suggesting a potential mechanism by which estrogen signaling may contribute to the development of an immunosuppressive TME. Our findings highlight the critical role of estrogen signaling in shaping the molecular heterogeneity and immunosuppressive TME of EOC and provide novel insights into potential therapeutic targets for overcoming immunosuppression in this malignancy.

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