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• Tumor-derived exosomes modulate PD-L1 expression in monocytes

  In chronic lymphocytic leukemia (CLL), monocytes and macrophages are skewed toward protumorigenic phenotypes, including the release of tumor-supportive cytokines and the expression of immunosuppressive molecules such as programmed cell death 1 ligand 1 (PD-L1). To understand the mechanism driving protumorigenic skewing in CLL, we evaluated the role of tumor cell–derived exosomes in the cross-talk with monocytes. We carried out RNA sequencing and proteome analyses of CLL-derived exosomes and identified noncoding Y RNA hY4 as a highly abundant RNA species that is enriched in exosomes from plasma of CLL patients compared with healthy donor samples. Transfer of CLL-derived exosomes or hY4 alone to monocytes resulted in key CLL-associated phenotypes, including the release of cytokines, such as C-C motif chemokine ligand 2 (CCL2), CCL4, and interleukin-6, and the expression of PD-L1. These responses were abolished in Toll-like receptor 7 (TLR7)–deficient monocytes, suggesting exosomal hY4 as a driver of TLR7 signaling. Pharmacologic inhibition of endosomal TLR signaling resulted in a substantially reduced activation of monocytes in vitro and attenuated CLL development in vivo. Our results indicate that exosome-mediated transfer of noncoding RNAs to monocytes contributes to cancer-related inflammation and concurrent immune escape via PD-L1 expression.

  Study EGAS00001002377

• Human tumor ChIP-seq.

  We profiled 15 patient brain tumor samples by ChIP-seq. Inputs are provided for 16 samples, H3K27ac is provided for 15 samples, H3K27me3 is provided for 10 samples and H3K27me3 is provided for 5 samples. The raw bam files are provided.

  Dataset EGAD00001008350

• Whole Exome Sequencing of Calcitonin Producing Pancreatic Neuroendocrine Neoplasms (CT-pNENs) Indicates a Unique Molecular Signature

  Calcitonin-producing pancreatic neuroendocrine neoplasms (CT-pNENs), which can mimic clinical and laboratory features of medullary thyroid carcinoma, are an extremely rare clinical entity with approximately 60 cases reported worldwide. The molecular profile of CT-pNENs is not yet known. Whole-exome sequencing (WES) was performed on tumor and corresponding serum samples of five patients with increased calcitonin serum levels and histologically proven calcitonin-positive CT-pNENs. cBioPortal analysis and gene enrichment analysis with DAVID were performed to validate candidate genes. Immunohistochemistry was used to detect protein expression of MUC4 and MUC16 in CT-pNEN specimens. Common somatic mutations of pNENs like MEN1, ATRX and PIK3CA were identified in cases of CT-pNENs. New somatic SNVs in ATP4A, HES4, and CAV3 have not yet been described in CT-pNENs. Pathogenic germline mutations in FGFR4 and DPYD were found in three of five cases. Mutations of CALCA (calcitonin) and the corresponding receptor CALCAR were found in all five tumor samples, but none of them resulted in clinical or protein sequelae. All five tumor cases showed single nucleotide variations (SNVs) in MUC4, and four cases showed SNVs in MUC16, both of which were membrane-bound mucins. Immunohistochemistry showed protein expression of MUC4 and MUC16 in one case each, and the liver metastasis of a third case was double positive for MUC4 and MUC16. The homologous recombination deficiency (HRD) score of all tumors was low.CT-pNENs have a unique molecular signature compared to other pNEN subtypes, specifically involving the FGFR4, DPYD, MUC4, MUC16 and the KRT family genes. However, these WES data from only five cases must be interpreted with caution because causal interpretation of the mutational landscape in CT-pNENs is difficult. Further research is needed to explain differences in pathogenesis compared with other pNENs. In particular, multi-omics data such as RNASeq, methylation, and whole genome sequencing could be informative.

  Study phs003060

• Metagenomic Analysis to Identify Novel Infectious Agents in Systemic Anaplastic Large Cell Lymphoma

  Anaplastic large cell lymphoma (ALCL) is a rare T-cell non-Hodgkin lymphoma (NHL). Risk of systemic ALCL is markedly increased among immunosuppressed people, such as those with human immunodeficiency virus (HIV) infection or solid organ transplant recipients. This increased risk in immunosuppressed populations suggests a viral etiology, given similar elevations for diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, and Hodgkin lymphoma (caused by Epstein-Barr virus [EBV]) and other virus-related cancers in immunosuppressed individuals. EBV might be a plausible candidate, but most reported ALCL tumors are EBV-negative. Therefore, we conducted a metagenomic analysis of microbial associations with ALCL to determine whether a known or novel pathogen is associated with the tumor. We obtained archived formal fixed paraffin embedded (FFPE) ALCL tumor tissue from the Iowa cancer registry and an additional case from an immunosuppressed individual infected with human immunodeficiency virus. Controls included 3 diffuse large B-cell lymphomas (DLBCLs) in transplant recipients (shown to be related to Epstein-Barr virus [EBV] by in situ hybridization) and 3 breast cancers (no known viral etiology). RNA was extracted from FFPE specimens, and total RNA libraries were prepared using the KAPA RNA HyperPrep Kit (Roche). Five samples (IA01, IA53, IA57, IA07, and IA17) were sequenced on a NextSeq 500 (Illumina) and the remainder on a NovSeq 6000 (Illumina). Using novel computational approaches, we eliminated human reads and aligned residual non-human reads to known microbial references using GATK-PathSeq or conducted de novo assembly of unassigned reads using virID pipeline. Although EBV was detected in the 3 DLBCL controls, we did not detect EBV or any novel pathogen in ALCL tumors or in the breast cancers. Our study had a modest sample size and only one case arising in HIV-infected individual. Therefore, further studies are required to characterize the metagenome of systemic ALCLs, especially cases arising in immunosuppressed people.

  Study phs002064

• Exome Sequencing to Define the Landscape of Plasma Cells in Systemic Light chain Amyloidosis

  Systemic light chain amyloidosis (AL) is characterized by the deposition of immunoglobulin light chains as amyloid fibrils in different organs, where they form toxic protein aggregates. The underlying disease is a plasma cell disorder, but limited whole exome data are available. We report the findings of an exome sequencing study in AL to define a plasma cell signature and compare this to monoclonal gammopathy of undefined significance (MGUS) and myeloma (MM). Twenty-four samples from unselected newly diagnosed untreated AL patients were analysed. CD138+ cells were isolated from bone marrow cells using MACSorting (Miltenyi Biotech, Bisley, UK). Cells were lysed in RLT+ buffer and DNA/RNA extracted using the AllPrep kit (Qiagen, Manchester, UK). Peripheral blood was isolated from patients, white blood cells purified by Ficoll-Pacque and DNA extracted using the QIAamp DNA mini kit (Qiagen). There were a median of 47 acquired nonsynonymous variants (range 4-253) per patient. Thirty percent of patients yielded a mutation in a myeloma driver gene. These mutations were either clonal or sub-clonal. There was evidence of MAPK activation with NRAS mutations, NF-κB activation and DNA repair pathway alterations. Exome data were used to determine the cytogenetic groups of AL samples and identified hyperdiploidy in 33% of cases and t(11;14) in 33% of cases. All translocations were generated via class switch recombination and breakpoints on chromosome 11 fell into the expected regions. A novel translocation, unlikely to be driving disease progression was identified involving RCC1. Finally, further analysis of the APCS gene encoding for the SAP protein did not show any biased genotype in the AL population in comparison to the general population. We conclude that exome sequencing identifies a genetic make-up of AL that is similar to other plasma cell disorders such as MM and MGUS. This not only includes copy number abnormalities and translocations but also nonsynonymous mutations.

  Study EGAS00001001418

• RNA-sequencing of human skin samples obtained from SSc patients and healthy controls.

  Patient information SSc patients were recruited at the Department of Rheumatology of the Leiden University Medical Center (Leiden, The Netherlands). All patients met the American Rheumatism Association classification criteria for SSc (Subcommittee for scleroderma criteria 1980), and were classified according to LeRoy and Medsger criteria as either limited or diffuse cutaneous disease (LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA Jr, Rowell N 1988). Institutional review board approval and written informed consent was obtained before patients entered this study. Two 4 mm skin biopsies were taken from a standardized location on the most proximal part of the lower arm, distal from the elbow. In 10 patients the skin biopsy came from a clinically affected area and in 4 patients the skin was locally unaffected. One sample was used for RNA sequencing and one sample was used for immunohistochemistry. Skin biopsies from healthy individuals were commercially sourced (Tissue Solutions, UK) and collected from donors undergoing skin resection surgery and after informed consent. To match the healthy skin with patients as much as possible, skin biopsies from healthy controls were also taken from a similar position (the under-arm (for 4 controls) and leg (for 2 controls)). Healthy skin donors were selected to match the age and sex of the SSc patient cohort. Biopsies from patients and controls were equally treated and were both stored at -80°C until RNA isolation was performed. RNA from frozen skin biopsies was isolated using RNeasy kit from fibrous tissue (Qiagen, the Netherlands). RNA quantity was determined by using SimplyNano 2000 and quality was assessed on Tapestation (Agilent, the Netherlands). All samples included in the study had a RIN score above 7.0. Transcriptome characterisation and analysis RNA sequencing was performed using polyA selection and a stranded protocol using Ion Torrent next generation sequencing technology (Service XS, The Netherlands). The Ion PI Template OT2 200 Kit v3 and Ion PI Sequencing 200 Kit v3 were used according to the manufacturer’s instructions. 20 samples were run on 11 PI chips. PI chip analyses, base calling and quality checks were performed using the Torrent Server Suite. An average of 42 million 100 bp reads was generated per sample. Following quality control, reads were aligned to the human genome (Homo sapiens GRh38.78) using Bowtie2 and STAR (Dobin et al. 2013; Langmead and Salzberg 2012). Reads were first aligned with STAR. For the unmapped reads from STAR, a second alignment step was performed using bowtie2 (local very sensitive options)

  Dataset EGAD00001003832

• Gene Expression Study of Individuals with Sex Chromosome Aneuploidies

  Males and females show dramatic differences in their vulnerability to the same diseases. For example, compared to men, lupus is six times more prevalent, thyroid cancer is three times more prevalent, and unipolar depression is twice as prevalent in women. Diseases with a strong male bias include autism (5:1), dilated cardiomyopathy (3:1), and ankylosing spondylitis (5:1). Historically, such differences have been attributed solely to extrinsic factors such as circulating sex hormones or environmental influences. We hypothesized that intrinsic factors - genetic differences between XX and XY cells - have unappreciated biological consequences throughout the body and contribute to sex differences in disease incidence and severity. This hypothesis stems from our long-term effort to sequence the sex chromosomes of diverse mammalian species, which has identified a set of homologous genes on the X and Y chromosomes that are dosage-sensitive, expressed throughout the body, and encode regulators of chromatin modification, transcription, translation, and protein stability. These X- and Y-encoded genes differ in sequence and expression pattern, which likely manifests in genome-wide differences in gene regulation between XX and XY cells and influences all aspects of human biology, including sex differences in disease susceptibility. These hard-wired molecular sex differences have been largely overlooked and understudied, representing a significant gap in our knowledge of human biology.The gene expression study of individuals with sex chromosome aneuploidies takes advantage of natural human variation in sex chromosome number, i.e. sex chromosome aneuploidy, to investigate alterations in genome-wide gene expression that correlate with changes in X- and Y-chromosome dosage. We analyzed samples from 114 individuals with a variety of sex chromosome aneuploidies, including 45,X; 47,XXY; 47,XYY; 47,XXX; 48,XXYY; and 49,XXXXY. We generated lymphoblastoid cell lines (LCLs) from blood samples and, in some cases, fibroblast cultures from skin biopsies. We supplemented our collection with previously-derived cell lines. To evaluate gene expression, we performed deep profiling of the transcriptome (RNA-seq) from these LCLs and fibroblasts. We performed parallel analyses on samples collected from 62 control 46,XX and 46,XY individuals, 6 individuals with trisomy 21, and 14 individuals with structural variations of the X and Y chromosomes. In addition, we performed CRISPRi knockdowns on 3 of the 46,XX and 3 of the 46,XY fibroblast samples for the homologous transcription factors ZFX and ZFY, encoded on the X and Y chromosomes, respectively.In the April 2024 update, we added RNA-seq datasets derived from isolated CD4+ T cells and monocytes from 76 and 72 adults, respectively, with the following sex chromosome constitutions: 45,X; 46,XX; 46,XY; 47,XXX; 47,XXY; 47,XYY. These individuals are largely a subset of the same cohort described above. In addition, we performed RNA-seq on in-vitro stimulated CD4+ T cells with the following sex chromosome constitutions: 45,X; 46,XX; 46,XY; 47,XXY.In the August 2024 update, we added RNA-seq datasets generated from the following: 1) LCLs derived from individuals with AZFa deletions of the Y chromosome, 2) DDX3X and DDX3Y knockdown (via CRISPRi) in XY fibroblasts, and 3) 5-ethyl uridine (5-EU) treatment in XY and XYYYY LCLs.

  Study phs002481

• Multi-Ethnic Study of Atherosclerosis (MESA) Cohort

  MESA The Multi-Ethnic Study of Atherosclerosis (MESA) is a study of the characteristics of subclinical cardiovascular disease (disease detected non-invasively before it has produced clinical signs and symptoms) and the risk factors that predict progression to clinically overt cardiovascular disease or progression of the subclinical disease. MESA researchers study a diverse, population-based sample of 6,814 asymptomatic men and women aged 45-84. Thirty-eight percent of the recruited participants are white, 28 percent African-American, 22 percent Hispanic, and 12 percent Asian, predominantly of Chinese descent. Participants were recruited from six field centers across the United States: Wake Forest University, Columbia University, Johns Hopkins University, University of Minnesota, Northwestern University and University of California - Los Angeles. Each participant received an extensive physical exam to determine coronary calcification, ventricular mass and function, flow-mediated endothelial vasodilation, carotid intimal-medial wall thickness and presence of echogenic lucencies in the carotid artery, lower extremity vascular insufficiency, arterial wave forms, electrocardiographic (ECG) measures, standard coronary risk factors, sociodemographic factors, lifestyle factors, and psychosocial factors. Selected repetition of subclinical disease measures and risk factors at follow-up visits allows study of the progression of disease. Blood samples have been assayed for putative biochemical risk factors and stored for case-control studies. DNA has been extracted and lymphocytes cryopreserved (for possible immortalization) for study of candidate genes and possibly, genome-wide scanning, expression, and other genetic techniques. Participants are being followed for identification and characterization of cardiovascular disease events, including acute myocardial infarction and other forms of coronary heart disease (CHD), stroke, and congestive heart failure; for cardiovascular disease interventions; and for mortality. In addition to the six Field Centers, MESA involves a Coordinating Center, a Central Laboratory, and Central Reading Centers for Computed Tomography (CT), Magnetic Resonance Imaging (MRI), Ultrasound, and Electrocardiography (ECG). Protocol development, staff training, and pilot testing were performed in the first 18 months of the study. The first examination took place over two years, from July 2000 - July 2002. It was followed by four examination periods that were 17-20 months in length. Participants have been contacted every 9 to 12 months throughout the study to assess clinical morbidity and mortality. MESA Family The general goal of the MESA Family Study, an ancillary study to MESA funded by a grant from NHLBI, is to apply modern genetic analysis and genotyping methodologies to delineate the genetic determinants of early atherosclerosis. This is being accomplished by utilizing all the current organizational structures of the Multi-Ethnic Study of Atherosclerosis (MESA) and Genetic Centers at Cedars-Sinai Medical Center and University of Virginia. In the MESA Family Study, the goal is to locate and identify genes contributing to the genetic risk for cardiovascular disease (CVD), by looking at the early changes of atherosclerosis within families (mainly siblings). 2128 individuals from 594 families, yielding 3,026 sibpairs divided between African Americans and Hispanic-Americans, were recruited by utilizing the existing framework of MESA. MESA Family studied siblings of index subjects from the MESA study and from new sibpair families (with the same demographic characteristics) and is determining the extent of genetic contribution to the variation in coronary calcium (obtained via CT Scan) and carotid artery wall thickness (B-mode ultrasound) in the two largest non-majority U.S. populations. In a small proportion of subjects, parents of MESA index subjects participating in MESA Family were studied but only to have blood drawn for genotyping. The MESA Family cohort was recruited from the six MESA Field Centers. MESA Family participants underwent the same examination as MESA participants during May 2004 - May 2007. DNA was extracted and lymphocytes immortalized for study of candidate genes, genome-wide linkage scanning, and analyzed for linkage with these subclinical cardiovascular traits. While linkage analysis is the primary approach being used, an additional aspect of the MESA Family Study takes advantage of the existing MESA study population for testing a variety of candidate genes for association with the same subclinical traits. Genotyping and data analysis will occur throughout the study. MESA Air The general goal of the Multi-Ethnic Study of Atherosclerosis and Air Pollution ('MESA Air') is to prospectively examine the relation between an individual level assessment of long-term ambient air pollution exposures (including PM2.5 and the progression of subclinical cardiovascular disease in a multi-city, multi-ethnic cohort. MESA Air will also prospectively examine the relationship between an individual level assessment of long-term ambient air pollution exposures and the incidence of cardiovascular disease, including myocardial infarction and cardiovascular death. MESA AIR is funded by a grant from the United States Environmental Protection Agency to the University of Washington and subcontracts from the UW to other participating institutions. MESA Air will assess if ambient air pollution is associated with changes over time in subclinical measures of atherosclerosis and plasma markers of inflammation, oxidative damage, and endothelial activation in a longitudinal data model, adjusting for age, race/ethnicity, socioeconomic status, and specific cardiovascular risk factors (such as diabetes, hypertension, smoking, and diet). The study will similarly assess if the incidence of cardiovascular events is associated with long-term exposure to ambient air pollution, using a proportional hazards model. The study includes refinement of statistical tools, and explores joint/independent effects of acute and long-term pollutant exposure in the occurrence of cardiovascular disease. The MESA Air study is built on the foundation of the ongoing MESA study. The parent MESA Study cohort is located in six geographic areas ('Field Centers') that capture tremendous exposure heterogeneity, comparable to or greater than the variability in locations of prior U.S. cohort studies. In addition to the six Field Centers, the study involves a Coordinating Center, a Central Laboratory, and Reading Centers for Computed Tomography (CT), ultrasound and air pollution data. The cohort for the MESA Air study currently includes 6226 subjects: 5479 enrolled in the parent MESA study; 257 recruited specifically for this study, and 490 recruited from the MESA Family study. The entire MESA Air cohort will be followed over a 10-year project period for the occurrence of cardiovascular disease events. On two occasions over the ten-year study period, 3600 subjects from the MESA Air cohort, residing in nine locales, will undergo computed tomography scanning to assess presence and extent of coronary artery calcification (CAC), and ultrasound of the carotid artery to determine intima-media thickness (IMT). We will also repeatedly assess plasma markers of inflammation, oxidative damage, and endothelial function in 720 subjects. MESA Air adds state-of-the-art air pollution exposure assessment information to the MESA cohort study, and introduces new subjects and outcome measures to achieve our aims. The study will assess long-term individual-level exposure to ambient air pollutants for each subject using community-scale monitoring, outdoor spatial variation, subject proximity to pollution sources, pollutants' infiltration efficiency, and personal time-activity information. The exposure models will be validated using detailed monitoring in a subset of subjects. The MESA Cohort is utilized in the following dbGaP substudies. To view genotypes, analysis, expression data, other molecular data, and derived variables collected in these substudies, please click on the following substudies below or in the "Substudies" box located on the right hand side of this top-level study page phs000209 MESA Cohort. phs000420 MESA SHARe phs000283 MESA CARe phs000403 MESA ESP Heart-GO

  Study phs000209

• Small molecule inhibitors of LOXL synergize with 5-AZA to restore erythropoiesis in myeloid neoplasms

  Objectives: Bone marrow (BM) stroma and microenvironmental factors in the BM milieu of myeloid neoplasms are increasingly being recognized as novel perspective therapeutic targets. Lysyl oxidases (LOX/LOXL) are crucial enzymes that cross-link collagen and contribute to the deposition of aberrant stiff extracellular matrix (ECM) in the BM of patients with myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). Here, we studied whether inhibition of LOX/LOXL enzymes produced by BM-derived MSCs favors the differentiation of MDS/MPN hematopoietic stem cell and progenitor cells (HPSCs) and enhances the effects of 5-azacytidine (5-AZA). Methods: Primary co-cultures of MSCs and HPSCs were established from n=31 MDS/MPN patients and treated with the pan-LOX/LOXL inhibitor PXS-5505, 5-AZA or the combination of both for 4 days. At the end of co-culture, HSPC differentiation was assessed by CFU assays and flow cytometry. In some of the experiments, MSCs monolayers were pre-treated or not with PXS-5505 for 6 days and decellularized using 20 mM ammonia. Subsequently, autologous HSPCs were cultured on ECM matrices in the presence of 5-AZA or PXS-5505 + 5-AZA combination with or without inhibitors of integrin signaling such as blebbistatin, Y-27632 and αvβ3-integrin blocking antibodies. Patient-derived xenografts (PDX) were established in NSG mice based on intrafemoral co-injection of HSPCs and autologous MSCs. PDX were treated with 3 cycles of 5-AZA (75 mg/m2), PXS-5505 (30 mg/kg on alternate days for the duration of 5-AZA treatment) or combination of both. Results: MSCs of MDS and MPN patients displayed significant overexpression of LOX/LOXL transcripts as compared to healthy age-matched controls. Remarkably, LOX/LOXL inhibition in MSCs/HSPCs co-cultures increased erythroid differentiation of patient HSPCs that had suboptimal or no response to 5-AZA alone. From a total of n=31 advanced stage MDS/MPN patients, n=11 (35.5%) responded to the combination treatment, which was evidenced by a significant increase of CD235a+CD45- erythroid cell production compared to 5-AZA/PXS/untreated arms (p<0.05). Of note, combination treatment with 5-AZA + PXS-5505 facilitated differentiation of CD235+ erythroid progenitors from HSPCs sub-clones with low mutational VAFs. The presence of MSCs was necessary for the effects of the combination treatment and required direct cell contacts between MSCs and HSPCs. Moreover, PXS-5505-mediated alterations of the ECM composition alone were sufficient to induce erythroid differentiation. Inhibition of integrin-mediated signaling using blebbistatin, Y-27632 and αvβ3-integrin antibodies completely abrogated the effects of PXS-5505 induced erythroid differentiation. In vivo, the combination of PXS-5505 + 5-AZA favored erythroid differentiation of HSPCs and confirmed the in-vitro results. The combination treatment of 5-AZA + PXS-5505 induced the greatest reduction of disease burden as assessed by decrease of spleen indexes, total engraftment rates, BM fibrosis and mutational VAF profiles. Conclusions: The combination of 5-AZA + LOX/LOXL inhibitor PXS-5505 in MDS and MPN synergistically restores erythropoietic differentiation of primary HSPCs. The effect is dependent of contact interaction between HSPCs and niche components, such as MSCs and MSCs-derived ECM. Our data propose a strong rationale for a BM niche targeted combination treatment with 5-AZA + PXS-5505 in transfusion dependent MDS and MPN, which will be assessed in forthcoming clinical trials.

  Study EGAS00001006174

• The Genomic Landscape of Mongolian Hepatocellular Carcinoma

  Background and Hypotheses: Mongolia has the highest reported incidence of - and mortality from - hepatocellular carcinoma (HCC) in the world, which is between three and seven times higher than that observed in other high-incidence populations, such as South Korea, Thailand, and China. Although its causative factors and underlying tumor biology remain unknown, risk factors such as chronic hepatitis B virus and/or hepatitis C virus infection are highly prevalent. Moreover, Mongolia has an extraordinarily high prevalence of hepatitis delta virus (HDV), more than ten times above the global estimate, which we hypothesize as a major driver of Mongolian hepatocarcinogenesis. By performing a comprehensive and integrative genomic characterization, we aimed to identify robust molecular subclasses and driver features informative of the etiology and progression of the disease. This study, the first one of this nature ever to be conducted on a Mongolian cohort, identifies similarities to previous studies performed on other populations (which reflect general characteristics of liver carcinogenesis) as well as unique features of Mongolian HCC. Study Design and Methods: Clinical information and paired tumor/non-tumor liver tissue samples were obtained from 76 HCC patients undergoing surgery at the National Cancer Center of Mongolia. Transcriptome sequencing and whole exome sequencing were performed on all tumor and non-tumor samples, followed by bioinformatics processing and quality control. Consensus clustering and regularized Cox regression analyses were performed on transcriptome data. Driver mutations and mutational signatures were assessed. These results were compared to those from 373 HCC patients of different races and ethnicities and diverse etiologies. Furthermore, molecular subclass gene signatures from multiple previous studies were assessed for validation. Results and Conclusions: Using a transcriptomics-based unsupervised approach, we identified four molecular subclasses among Mongolian HCC cases, which were associated with different patient survival outcomes. These molecular subclasses were mapped to signatures reported in other HCC cohorts, showing significant associations consistent with survival outcomes. A supervised analysis determined risk scores strongly associated with survival, consistent with the four molecular subclasses. Mutational signature analysis using recently published COSMIC and Environmental Agents Compendia identified signatures with distinct prevalence among HDV+ and HVD- groups. Signatures differentially associated with HDV+ include mutational patterns linked to alkylating agents (such as temozolomide), tobacco chewing and exposures to 1,8-Dinitropyrene and furan, whereas HDV- appeared differentially associated with aristolochic acid II. In addition to common driver mutations (TP53, CTNNB1) frequently found in pan-cancer analysis, Mongolian HCC exhibits several unique drivers (most notably GTF2IRD2B, PNRC2, and SPTA1), the latter of which may be linked to HDV infection. These results suggest the existence of new molecular mechanisms at play in Mongolian hepatocarcinogenesis.

  Study phs002000