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• ICGC Oesophageal adenocarcinoma - pilot samples

  The oesophageal project will focus on adenocarcinoma which is increasing in incidence in the UK and other developed countries and has a very poor outcome. The primary aims of this project are to deeply sequence tumour and normal genomic DNA (including the precursor condition Barrett's oesophagus when material is available) to provide a comprehensive catalogue of somatic mutations. This will be achieved through a UK-wide network of hospitals involved in a research collaboration called the OCCAMS consortium. The goal of this project is to use high quality clinical material with accurately annotated clinic-pathological, treatment and outcome data.

  Study EGAS00001000559

• ICGC Oesophageal adenocarcinoma - Barrett's samples

  The oesophageal project will focus on adenocarcinoma which is increasing in incidence in the UK and other developed countries and has a very poor outcome. The primary aims of this project are to deeply sequence tumour and normal genomic DNA (including the precursor condition Barrett’s oesophagus when material is available) to provide a comprehensive catalogue of somatic mutations. This will be achieved through a UK-wide network of hospitals involved in a research collaboration called the OCCAMS consortium. The goal of this project is to use high quality clinical material with accurately annotated clinic-pathological, treatment and outcome data.

  Study EGAS00001000726

• Whole genome sequencing, single-cell RNA sequencing, and ATAC sequencing of mesothelioma (patient, patient-derived xenograft and cell line)

  Malignant pleural mesothelioma is an aggressive pleural tumor with a poor prognosis, and elucidating its molecular mechanisms is essential for improving diagnosis and treatment. This study investigates key genes and pathways involved in tumor progression, with particular attention to the involvement of neutrophils in the tumor ecosystem of mesothelioma. We performed whole-genome sequencing and single-cell RNA sequencing (scRNA-seq) of one pleural mesothelioma tumor specimen, scRNA-seq of matched patient-derived xenograft tumors, scRNA-seq of mesothelioma-free pleural tissues from three patients, and assay for transposase-accessible chromatin using sequencing (ATAC-seq) of a patient-derived cell line.

  Study JGAS000859

• Single-cell transcriptomics identifies pathogenic T-helper 17.1 cells and pro-inflammatory monocytes in ICI-related pneumonitis

  ICI-pneumonitis is a frequent serious adverse event of cancer immunotherapy hinging on a cell-mediated immune response, though the exact pathophysiology is currently unknown. Using single-cell transcriptomics, an enrichment of pathogenic (TBX21, RORC, IFNG, IL17A, CSF2 expressing) T-helper 17.1 cells and pro-inflammatory (TNF, IL1B, IL6, IL23A expressing) monocytes was identified in ICI-pneumonitis bronchoalveolar lavage fluid, putatively engaging in a feedforward inflammatory loop. This finding yields several novel therapeutic targets for the treatment of ICI-pneumonitis. Most notably repurposing anti-IL-23 merits further research as a potential efficacious and safe treatment for ICI-pneumonitis.

  Study EGAS00001006762

• Whole-Genome Sequencing of a Healthy Aging Cohort.

  Studies of long-lived individuals have revealed few genetic mechanisms for protection against age-associated disease. Therefore, we pursued genome sequencing of a related phenotype-healthy aging-to understand the genetics of disease-free aging without medical intervention. In contrast with studies of exceptional longevity, usually focused on centenarians, healthy aging is not associated with known longevity variants, but is associated with reduced genetic susceptibility to Alzheimer and coronary artery disease. Additionally, healthy aging is not associated with a decreased rate of rare pathogenic variants, potentially indicating the presence of disease-resistance factors. In keeping with this possibility, we identify suggestive common and rare variant genetic associations implying that protection against cognitive decline is a genetic component of healthy aging. These findings, based on a relatively small cohort, require independent replication. Overall, our results suggest healthy aging is an overlapping but distinct phenotype from exceptional longevity that may be enriched with disease-protective genetic factors.

  Study EGAS00001002306

• Transdisciplinary Studies of Genetic Variation in Colorectal Cancer(CORECT): Meta-analysis

  This study is part 2 of 2 for Schumacher et al, Nat Communication. 2015 Jul 7;6:7138. Part 2 is the pooled meta-analysis of 29 different studies of 37,955 European (18,299 Cases/19,656 Controls) participants using eight different genotyping platforms/variations. table, th, td { border: 1px solid black; border-collapse: collapse; } Study Name Participants Platform CFR-1 2976 Illumina 1M, 1M Duo, Omni1 CFR-2 3053 Affymetrix Axiom MECC 1 982 Illumina Omni 2.5 MECC2 1940 Affymetrix Axiom Kentucky 2172 Affymetrix Axiom ACS/CAPII 1086 Affymetrix Axiom Melbourne 1008 Affymetrix Axiom Newfoundland 672 Affymetrix Axiom ASTERKSI 1895 Illumina 300K COLO23 212 Illumina 300K DACHS1 3417 Illumina 300K DACHS2 1173 Illumina OmniExpress DALS1 1416 Illumina 550k/610K DALS2 874 Illumina 300K HPFS1 457 Illumina OmniExpress HPFS2 348 Illumina OmniExpress HPFS AA 658 Illumina OmniExpress MEC 674 Illumina 300K NHS1 1168 Illumina OmniExpress NHS2 340 Illumina OmniExpress NHSAA 1091 Illumina OmniExpress OFCCR 1172 Affymetrix 100k/500K PHS 771 Illumina OmniExpress PMH 402 Illumina 300K PLCO1 2509 Illumina 550k/610K PLCO2 901 Illumina 300K VITAL 573 Illumina 300K WHI1 1999 Illumina 550k/610K WHI2 573 Illumina 300K Since this study is a meta-analysis no corresponding phenotype, pedigree, sample, subjects, or primary molecular data are available. Each contributing study/platform will have fulfilled its own DBGAP submission commitment. This DBGAP entry is for European participants in the the pooled meta-analysis exclusively.

  Study phs001499

• Targeted Linked-Read DNA-seq Analysis of Castration-Resistant Prostate Cancers

  Androgen receptor (AR) inhibition is standard of care for advanced prostate cancer (PC). However, its efficacy is limited by progression to castration-resistant PC (CRPC), usually due to AR re-activation via mechanisms that include AR amplification and structural rearrangement. These two classes of AR alterations often co-occur in CRPC tumors, but it is unclear whether this reflects intercellular or intracellular heterogeneity of AR. It is important to resolve the mechanisms of AR genomic rearrangements to develop new therapies and predictive biomarkers for PC. We developed a targeted linked-read DNA sequencing assay to interrogate alterations in AR and a panel of genes known to be amplified or mutated in CRPC. Linked-read DNA-sequencing libraries were generated using the 10X Genomics Chromium platform and subjected to hybridization enrichment using a custom-designed Agilent SureSelect bait panel. Post-capture DNA-seq libraries were pooled and sequenced on an Illumina HiSeq 2500 using 2x150 bp settings. This targeted linked-read DNA-seq assay was used to interrogate a set of 6 benchmarking samples harboring known AR gene rearrangements and other alterations in AR, as well a panel of 6 patient-derived xenograft CRPC tumors and 23 clinical CRPC tumors. In this cohort, we identified a subset of samples that developed complex, multiply-rearranged AR gene structures in conjunction with very high AR copy number. The data that will be made available through dbGaP are raw FASTQ files.

  Study phs003343

• Whole exome sequencing to discover genetic variation associated with aortopathy in Turner Syndrome

  Turner syndrome is a disorder affecting only girls and women, which is caused by a complete or partial loss of the second sex chromosome. Girls and women with Turner syndrome have a variety of phenotypes. Of interest to this study is aortopathy, including bicuspid aortic valve (BAV) and thoracic aortic dilation (TAD) in which we know that 25 - 50% of girls with Turner syndrome are born with. The aorta is the main artery that conducts the blood out of the heart. The aortic valve guards the entrance to the aorta. When the aortic valve has two leaflets instead of the usual three it is called a BAV. BAV is more common than all other congenital heart defects combined. BAV commonly causes obstructions to blood flow out of the heart or become leaky over time. BAV often occurs in combination with TAD. In Turner syndrome, TADs are increased 50-100 fold compared to the general population. Currently, there are no effective approaches or pre-surgical treatments for aortic disease. Therefore, progression of aortic disease in individuals with BAV/TAD can result in catastrophic aortic dissection, rupture, and death. Our goal is to leverage DNA sequencing and carefully curated patient samples to gain a better understanding of the molecular mechanisms that cause these inter-related aortic diseases.

  Study phs001531

• The European Bank for Induced Pluripotent stem cells (EBiSC) is designed to address the increasing demand by iPSC researchers for quality-controlled, disease-relevant research grade iPSC lines, data and cell services.In this study Whole Genome Sequencing was performed on a selection of lines from the project.

  Induced pluripotent stem (iPS) cells have the potential to significantly advance drug development and health research, yet collections of stem cells are scattered across the world, their quality cannot always be guaranteed, and accessing them is often difficult. The goal of EBiSC is to establish a European iPS cell bank that will be the ‘go-to’ resource for the characterisation, storage and distribution of high quality iPS cells. Ultimately, EBiSC will become an independent organisation, distributing high quality iPS cells on a not-for-profit basis to scientists worldwide.

  Study EGAS00001002755

• Molecular Profiling of Gallbladder Cancer (MPOG)

  The purpose of this study is to investigate the underlying genetic factors involved in gallbladder cancer.

  Study phs001404

• Identification of ALS Associated Genes Using Whole Genome Sequencing

  The overall aim of this study is to discover of novel genetic elements associated with amyotrophic lateral sclerosis (ALS). Towards this goal, we have performed exome and whole genome sequencing for over 2000 samples. This data will be process and harmonized to yield high quality variant calling. These variants will be combined with control cohorts to identify novel genetic elements associated with ALS through case: control analyses.

  Study phs001585

• The prevalence and clinical characteristics of TECTA-associated autosomal dominant hearing loss.

  TECTA is well known as the causative gene for autosomal dominant mid-frequency hearing loss observed in various populations. In this study, we performed next-generation sequencing analysis of a large Japanese hearing loss cohort from unrelated autosomal dominant hearing loss families, to estimate the prevalence and phenotype-genotype correlations in patients with TECTA mutations.

  Study JGAS000201

• ICU transcriptomics: Assessing the role of the host immune response in patients with ventilator-associated pneumonia

  This is a study of 100 patients with the aim to provide transcriptomic sequencing data analysis of cells isolated from bronchioalveolar lavage and blood samples from critically ill patients with pneumonia on an intensive care unit in order to investigate the host contribution to disease. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Dataset EGAD00001015407

• Microbiome-Host Interactions in Oral Squamous Cell Carcinoma: a Metatranscriptomic Exploratory Study

  Oral cancer (predominantly squamous cell carcinoma; OSCC) is the 14th most prevalent malignancy worldwide, accounting for more than 300,000 new cases and 145,000 deaths annually. Despite advances in cancer treatment modalities, OSCC continues to have poor prognosis with 5-year survival rates less than 50%. Although use of tobacco and alcohol consumption constitute the major risk factors, there is emerging evidence for the role of the microbiome in OSCC. However, studies on the association between the microbiome and OSCC has so far focused on compositional analysis and has been largely limited to the bacterial component of the microbiome. The aim of this study is to characterize the transcriptional activity (function) as well as composition of the multi-kingdom microbiome associated with OSCC and correlate it with the gene expression of the host using ultra-deep metatranscriptome sequencing, which will provide new insight into the role of the microbiome in OSCC and the possible mechanisms by which the tumor’s microbial community may influence on its behavior. This project comprises RNA-Seq data from twenty OSCC tumor/normal tissue pairs and twenty tongue scraping samples from healthy controls. However, due to consent constraints, the human sequences from the control data are filtered out.

  Study phs002678

• Sequencing and analysis of a South Asian-Indian personal genome

  India with over 1.3 billion people is estimated to carry three times more genetic diversity compared to Europe. Next-generation sequencing technologies have facilitated the understanding of diversity by enabling whole genome sequencing at greater speed and lower cost. While multiple genomes from people of European and a few of Asian descent have been sequenced, only recently a single male genome from the Indian subcontinent at sufficient depth and coverage was published. We have in this study sequenced and analyzed the genome of a South Asian Indian female (SAIF) from the Indian state of Kerala. We identified over 3.4 million SNPs in this genome including over 89,873 private variations. Comparison of the SAIF genome with several published personal genomes revealed that this individual shared ~50% of the SNPs with each of these genomes. Analysis of the SAIF mitochondrial genome showed that it is closely related to the U1a3 haplogroup which has been previously observed in Kerala. We assessed the SAIF genome for SNPs with health and disease consequences and found that the individual was at a higher risk for multiple sclerosis and a few other diseases. In assessing SNPs that modulate drug response we found a variation that predicts a favorable response to metformin used for treating diabetes. SNPs predictive of adverse reaction to warfarin indicated that the SAIF individual is not at risk for bleeding if treated with typical doses of warfarin. In addition to these, we report the presence of several other SNPs of medical relevance.

  Study EGAS00001000328

• Functional Analysis of Genetic Variants in African Americans with Breast Cancer

  The goal of this study is to identify and characterize novel genetic variants associated with a predisposition to breast cancer (BCa) in African Americans (AAs) using a family case-family control study design. Variants of unknown clinical significance (VUS) were characterized using bioinformatics tools. Future studies will further characterize select VUSs using in vitro genomic editing methods and functional assays to determine the functional consequences. The targeted sequencing data is made available for 85 actionable cancer genes. These genes have been previously classified with deleterious mutation(s) and whose phenotype results in a specific, defined medical recommendation(s).

  Study phs002977

• mRNA-seq of paired Follicular Lymphoma (FL) patient samples before and after high-grade transformation to DLBCL (FL vs. tFL) from FFPE tissues

  The aim of this study was to analyze transcriptional changes in paired samples of follicular lymphoma (FL) and its histological transformation (tFL). Transformation of FL is an adverse event in the course of the disease and is associated with poor outcome. Several genetic aberrations have been linked to tFL pathogenesis, but gene expression changes and microenvironmental interactions have not been well characterized. We performed RNA profiling of FL and paired tFL samples transformed to DLBCL (n=11 pairs). For RNA profiling, we utilized libraries prepared using RNA isolated from archival FFPE tissues.

  Study EGAS50000000941

• miRNA-seq of paired Follicular Lymphoma (FL) patient samples before and after high-grade transformation to DLBCL (FL vs. tFL) from FFPE tissues

  The aim of this study was to analyze transcriptional changes in paired samples of follicular lymphoma (FL) and its histological transformation (tFL). Transformation of FL is an adverse event in the course of the disease and is associated with poor outcome. Several genetic aberrations have been linked to tFL pathogenesis, but gene expression changes and microenvironmental interactions have not been well characterized. We performed miRNA profiling of FL and paired tFL samples transformed to DLBCL (n=10 pairs). For miRNA profiling, we utilized libraries prepared using RNA isolated from archival FFPE tissues.

  Study EGAS50000000942

• Divergent WNT Signaling and Drug Sensitivity Profiles within Hepatoblastoma Tumors and Organoids

  Hepatoblastoma, the most prevalent pediatric liver cancer, almost always carries a WNT-activating CTNNB1 mutation, yet exhibits notable molecular heterogeneity. To characterize this heterogeneity and identify novel targeted therapies, we perform comprehensive analysis of hepatoblastomas and tumor-derived organoids using single-cell RNA-seq/ATAC-seq, spatial transcriptomics, and high-throughput drug profiling. We identify two distinct tumor epithelial signatures: hepatic ‘fetal’ and WNT-high ‘embryonal’, displaying divergent WNT signaling patterns. The fetal group is enriched for liver-specific WNT targets, while the embryonal group is enriched in canonical WNT target genes.

  Study EGAS50000000561

• Alternative lengthening of telomeres in childhood neuroblastoma from genome to proteome

  Telomere maintenance by telomerase activation or alternative lengthening of telomeres (ALT) is a major determinant of poor outcome in neuroblastoma. Here, we screen for ALT in primary and relapsed neuroblastomas and characterize its features using multi-omics profiling. We aim to deepen the knowledge about the biology and clinical features of ALT-positive neuroblastomas by enriching ALT tumors in the study cohort independent of ATRX mutation status. Using a combination of genomic, transcriptomic and proteomic profiling, we provide evidence that this subgroup is clinically and molecularly distinct.

  Study EGAS00001004349

• Long-Term Outcome in Offspring and Mothers of Dexamethasone-Treated Pregnancies at Risk for Classical Congenital Adrenal Hyperplasia Owing to 21-Hydroxylase Deficiency

  Summary The purpose of this study is to perform the first long-term follow up study both of adolescents and young adults with a history of prenatal treatment with dexamethasone and of their mothers and to test for adverse medical or behavioral side effects. The emphasis will be on the outcome of this prenatal treatment in those fetuses who are not affected with steroid 21-hydroxylase deficiency (21OHD) form of congenital adrenal hyperplasia (CAH) and are either heterozygotes or homozygote-unaffected. Prenatal treatment of 46,XX fetuses with 21OHD (via administration of dexamethasone to the pregnant mother) has been shown to reduce the masculinization of the genitalia and, thereby, the later need for 'corrective' feminizing genital surgery and potential impairment of sexual functioning. Along with the suppression of excess prenatal androgen production and reduction of prenatal masculinization of the genitalia in 46,XX fetuses with 21OHD, prenatal dexamethasone treatment may reduce the behavioral masculinization that is well documented in untreated 46, XX patients with 21OHD. Those fetuses who are partially treated until diagnosis of an unaffected status (heterozygous or homozygous-unaffected) will be studied as well. This latter group is of importance because these fetuses are being unnecessarily treated, but we have no way of diagnosing the unaffected status before the 8th week of gestation when treatment must begin for the female fetus who is affected. As treatment is necessary only until term in the female fetus affected with classical CAH, male fetuses and unaffected or heterozygous female fetuses do not require treatment. Thus, only one out of eight fetuses will require prenatal treatment until term. Findings of adverse effects of glucocorticoid treatment in non-human mammals [1, 2] have raised concerns among other clinicians and investigators about potential adverse side effects of such treatment on the developing human. Thus, this study will address this concern and investigate the potential adverse side effects of prenatal treatment. Detailed Description Females with classical CAH owing to 21-hydroxylase deficiency are born with ambiguous genitalia due to the production of excess androgens in utero. Prenatal treatment with dexamethasone was inaugurated in 1978 by Maguelone Forest and has been the standard of practice in the United States since 1986. Dexamethasone, which crosses the placental barrier, suppresses the fetal adrenal gland production of androgens, thus preventing ambiguous genitalia in the affected female. Children of both sexes are prenatally treated as soon as pregnancies at risk are confirmed. Treatment in females with 21OHD continues to term, but is discontinued in males and unaffected females. To date, 685 pregnancies have been diagnosed, of which 366 fetuses were treated. These investigators will study prenatally treated adolescents and adults 12 years and older with respect to medical and behavioral outcomes (see Table 5). In addition, mothers of children prenatally treated for varying periods of time for suspected 21OHD will be studied for long-term side effects of dexamethasone treatment administered during pregnancy. The long-term outcome in these children and their mothers has never before been studied.

  Study phs001317

• Separation of chronic myeloid leukemia stem cells from normal hematopoietic stem cells at single-cell resolution

  Chronic myeloid leukemia (CML) is a clonal disease, initiated and sustained by a subpopulation of CML stem cells (CML-SC) containing the BCR::ABL1 oncogene. Genetic markers that enrich for CML-SC have been identified, including CD26 being most specific. Genome sequencing analysis remain yet to be performed at single cell level in order to determine differences and heterogeneity in the genetic profile of CML-SC versus normal hematopoietic stem cells (HSC). Here we show that CD26 and CD33 separate CML-SC from normal HSC in freshly isolated bone marrow samples from newly diagnosed CML patients. DNA sequencing confirms that single CML-SC derived colonies are positive for BCR::ABL1 and harbor a recurrent set of patient-specific clonal somatic mutations across different CML-SC derived colonies. In contrast, marker-negative (CD26-CD33-) HSC from the same patients are negative for the BCR::ABL1 oncogene and do not carry recurrent, clonal mutation across different colonies. These results support the concept that CD26/CD33 expression separates genetically defined, clonal mutant CML-SC from normal HSC that carry individual sets of random mutations in CML patients. We provide whole exome DNA sequencing data for 23 clinical samples of CML-SC plus two buccal swipes derived normal samples. CML samples are comprised of 4 to 8 replicates from two patients, at diagnosis and after treatment. Single CML stem cells before treatment and single non-transformed HSC at remission were selected from bone marrow samples by FACS, according to genetic markers CD33+CD26+ at diagnosis and CD33+CD26-/CD33-CD26- at remission. WES libraries of colony forming assays derived CML-SC and HSC populations were prepared using Agilent SureSelect Human All Exon V6 kit and sequenced running 150 cycles (2x 75bp paired-end) on an Illumina NextSeq 500 platform. Following GATK best practices for somatic mutation calling, novel CML variants and random mutation events during remission phase were obtained.

  Study EGAS00001006904

• Acquisition_of_additional_mutations_drives_accelerated_progression_of_NPM1_positive_CMML_to_AML_

  This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/We performed exome sequencing on serial samples from a patient with CMML who progressed to AML. The exome sequencing suggests that NPM1, TET2 and DNMT3a mutations were present in the dominant clone in the CMML sample and that NRAS is a new subclonal mutation in the AML sample. Diagnostic data shows the presence of a FLT3-ITD mutation in the AML sample, which is likely to have driven progression. Here we are performing re-sequencing of the putative driver and some passenger mutations which appear to be in the same clone to validate these mutations and to verify the relative quantification of these abnormalities .

  Study EGAS00001000619

• The Innate Immune Response as a Therapeutic Target for Cutaneous Leishmaniasis

  The overall goal of the proposed project is to identify innate host functions that contribute to cure or failure during antileishmanial drug therapy, and their related biomarkers. Results from this project enabled the identification of host-specific predictive and prognostic signatures of therapeutic responsiveness, and the bases for rational selection of host-targeted therapeutics that redirect inflammation and revert pathogenicity. Through sequential transcriptomic profiling of blood monocytes (Mo), neutrophils (Nφ), and eosinophils (Eφ) over the course of systemic treatment with meglumine antimoniate, we discovered that a heightened and sustained Type I interferon (IFN) response signature is a hallmark of treatment failure (TF) in Cutaneous Leishmaniasis (CL) patients. The transcriptomes of pre-treatment, mid-treatment and end-of-treatment samples were interrogated to identify predictive and prognostic biomarkers of TF. Results from this study instigate the evaluation of Type-I IFN responses as new immunological targets for host-directed therapies for treatment of CL, and highlight the feasibility of using transcriptional signatures as predictive biomarkers of outcome for therapeutic decision making.

  Study phs003545

• 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