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• Pakistan_Damgaard2018

  Genotype data for 140 present-day individuals from five populations in Pakistan in The first horse herders and the impact of early Bronze Age steppe expansions into Asia DOI: 10.1126/science.aar7711. Sampling details are presented in supplementary section S2.1 Data generation

  Dataset EGAD00010001678

• Regulatory Elements active in Insulinomas

  Characterization of regulatory elements active insulinomas, assessed by the presence of H3K27ac. This study also includes characterization of H3K27me3 in control pancreatic beta cells.

  Study EGAS50000000319

• Genomewide association studies in ankylosing spondylitis

  The aim of this study was to identify genes associated with ankylosing spondylitis susceptibility in British and Australian individuals of European descent.

  Study EGAS00000000104

• ATAC-seq in KMS11 vs TKO cells

  ATAC-seq to determine chromatin accessibility in t(4;14) Myeloma cell line KMS11 and KMS11 cells with knock-out of the translocated NSD2 allele.

  Study EGAS50000000076

• MicroC in KMS11 and TKO cells

  MicroC to show high resolution chromatin interactions in t(4;14) Myeloma cell line KMS11 and KMS11 cells with knock-out of translocated NSD2 allele (KMS11 TKO).

  Study EGAS50000000078

• Stem-like peripheral helper T cells seed their effector counterpart in rheumatoid arthritis

  The dynamics of helper T cells in the synovium of rheumatoid arthritis was investigated using scRNA-seq, scTCR-seq, and spatial transcriptome.

  Study JGAS000774

• Homologous recombination deficiency derived from whole-genome sequencing predicts platinum response in triple-negative breast cancers

  To identify predictive biomarkers of response and resistance to platinum agents in PDX models of triple-negative breast cancer

  Study EGAS00001006393

• ExHiBITT – Exploring Host microBIome inTeractions in Twins – a colon multiomic cohort study

  The objective of the colonoscopy study is to carry out the 16s sequencing of colon biopsies and faecal samples provided in ExHiBITT study to compare potential fluctuations in the microbiota of different sites.

  Dataset EGAD00001010936

• Unmapped sequencing reads of EGAD00001007002

  Bam files of unmapped sequencing reads of samples in EGAD00001007002. When utilized in combination with corresponding aligned bam files in dataset EGAD00001007002, they contain all sequencing reads of samples.

  Dataset EGAD00001007647

• Mutation analysis of 10 genes in plasma DNA of RCC patients

  Mutation analysis of 10 frequently mutated genes in renal cell carcinoma (BAP1, KDM5C, MET, MTOR, PBRM1, PIK3CA, PTEN, SETD2, TP53, VHL) in plasma DNA of RCC patients using a custom QIASeq panel (MonRec Cohort)

  Dataset EGAD00001005806

• In Utero MPN Twin WGS Data

  The dataset contains sequencing data generated for the publication 'In utero origin of myelofibrosis presenting in adult monozygotic twins after a prolonged disease latency.

  Dataset EGAD00001008319

• scRNA-seq dataset for AD and Pso patients

  This dataset contains scRNA-seq fastq files to the paper entitled "Single-cell profiles reveal distinctive immune response in atopic dermatitis in contrast to psoriasis". The details of experiment setup was described in the paper.

  Dataset EGAD00001010106

• Exome sequencing reads of paediatric glioblastoma

  Whole exome sequencing of paediatric glioblastoma with mutations reported in the manuscript: Mutations in ACVR1, FGFR1 and TP53 associate with tumor location in histone H3 K27M pediatric midline high-grade astrocytoma

  Dataset EGAD00001000792

• Deep-Seq: Resistance to anti-EGFR therapy in colorectal cancer

  In this study we performed ultra deep sequencing of genes associated with anti-EGFR resistance, such as KRAS, BRAF, PIK3CA, and EGFR in 17 plasma-DNA samples from a total of 10 patients treated with anti-EGFR therapy.

  Dataset EGAD00001000688

• Idiopathic Pulmonary Fibrosis Network AntiCoagulant Effectiveness in Idiopathic Pulmonary Fibrosis (IPFNet-ACE-IPF-BioLINCC)

  Data Access NOTE: Please refer to the "Authorized Access" section below for information about how access to the data from this accession differs from many other dbGaP accessions. Objectives: The ACE-IPF trial tested the hypothesis that treatment with warfarin at recognized therapeutic doses would reduce rates of mortality, hospitalization, and declines in Forced Vital Capacity (FVC) in subjects with Idiopathic pulmonary fibrosis (IPF).Background: IPF is a chronic, progressive lung disease of unknown cause characterized by the histopathologic pattern of usual interstitial pneumonia. The median survival of patients with IPF after the onset of symptoms is 2 to 5 years. Prior animal and human studies in pulmonary fibrosis provide a compelling rationale to examine anticoagulation as a therapeutic approach in IPF. Large epidemiologic studies link IPF with thrombosis-related clinical events, such as an increased risk of acute coronary syndrome and deep vein thrombosis. The suspected causal relationship may extend beyond simple coagulation cascade-induced thrombus formation, as procoagulant enzymes may directly stimulate fibrosis via cell surface receptor - mediated responses.Participants: Patients aged 35 to 80 years with progressive IPF were potentially eligible. Progressive IPF was defined as a history of (1) worsening of dyspnea, or (2) physiologic deterioration defined as an absolute decline of either FVC greater than or equal to 10% or DlCO greater than or equal to 15%, a reduction in arterial oxygen saturation of greater than or equal to 5%, or progression of radiographic findings. Between December 14, 2009 and April 1, 2011, 145 subjects were enrolled: 72 in the warfarin group and 73 in the placebo group. The mean age for the population was 67 years. 27% of the subjects were women and 92% were white.Participants were excluded if they met any of the following criteria: current indication for, or treatment with, warfarin, prasugrel, or clopidogrel combined with aspirin; the presence of an increased risk of bleeding; a recent cerebral vascular accident or gastrointestinal bleeding; any current signs or symptoms of severe, progressive, or uncontrolled comorbid illness; and their presence on the active list for lung transplantation. Design: ACE-IPF was a double-blind, randomized, placebo-controlled trial of warfarin targeting an international normalized ratio (INR) of 2.0 to 3.0 in patients with IPF. Subjects were randomized in a 1:1 ratio to warfarin or matching placebo for a planned treatment period of 48 weeks. Study subjects were provided two strengths of warfarin tablets (1 mg and 2.5 mg) or matching placebos. Subjects measured their INR with encrypted meters at least weekly. Participants were seen at screening, baseline, and at 16, 32, and 48 weeks after enrollment. Home monitoring was validated by plasma INR measurement at the week 1 and 16 visits.The primary outcome was a composite endpoint based on the time to all-cause mortality; nonelective, nonbleeding hospitalization; or a decrease in the absolute FVC greater than or equal to 10% from baseline value. Secondary outcome measures included rates of mortality, hospitalization, respiratory-related hospitalization, acute exacerbation, bleeding, cardiovascular events, and changes over time in FVC, 6-minute walk test distance, DlCO, plasma fibrin D-dimer levels, and quality of life (QOL).Conclusions: The study did not show a benefit for warfarin in the treatment of patients with progressive IPF and was terminated due to excess mortality in the warfarin treatment group. Treatment with warfarin was associated with an increased risk of mortality in an IPF population who lacked other indications for anticoagulation.Reported causes of death indicated 11 of the 14 were respiratory-related in the warfarin group versus three of the three in the placebo group. There were also three cardiovascular deaths in the warfarin group versus none in the placebo group. No deaths were attributed to bleeding. The warfarin group also demonstrated an increased rate of combined all-cause hospitalization and all-cause mortality. (Am J Respir Crit Care Med. 2012 Jul 1;186(1):88-95.)

  Study phs004070

• Resuscitation Outcomes Consortium (ROC) Cardiac Epidemiologic Registry (Cardiac Epistry) Version 3 (ROC-Cardiac Epistry 3-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Available Data The ROC Cardiac Epistry version 3 include all cardiac arrest cases entered into the ROC database from April 1, 2011 to June 30, 2015. This is separate from versions 1 and 2 because of the major changes in how and which data were collected. Version 3 represents the following major changes to the structure and data collection: separate ED Arrival and Hospital Admits forms, mandatory ED and Hospital elements and a revamped CPR Process form. For ROC traumatic injury Epistry data please see: ROC-Trauma Epistry Objectives To build a prospective population-based registry of participants with out-of-hospital cardiac arrest responded to by Emergency Medical Services (EMS). Specific aims included: to establish whether the results of Resuscitation Outcomes Consortium (ROC) trials can be generalized to the larger population of participants that experience cardiac arrest; to more fully establish the burden of cardiac arrest; and to examine the relationships between variation in EMS structure and process, regional and periodic factors, and participant outcomes. Background Cardiac arrest is a common, serious, debilitating and costly public health problem. Although there has been a steady decline in morbidity and mortality from most cardiovascular diseases, high mortality rates for out-of-hospital cardiac arrests continue to pose a challenge for healthcare providers and a significant public health burden. The Resuscitation Outcomes Consortium (ROC) was established in 2004 to conduct clinical research in the areas of cardiopulmonary arrest and life-threatening traumatic injury with the overall goal of improving resuscitation outcomes. Participant and care characteristics can predict favorable outcomes in cardiac arrests, but there is still a wide variation in outcomes that is not well understood. EMS factors such as service level, number of responding providers, use of procedures or drugs in the field, training, quality assurance/feedback, and response time intervals also vary significantly by region. Variations in geographic, socioeconomic and periodic factors may also be associated with differences in outcomes. Prior to ROC Cardiac Epistry, there were no North American population-based registries for out-of-hospital cardiac arrests. Therefore there was a need for standardized data collection of out-of-hospital cardiac arrests in diverse geographic locations in order to identify the independent effects of prognostic or treatment factors accounting for variations in survival. Participants There were 120,306 participants. Design ROC Epistry collected standardized data regarding episode-specific factors, participant demographics, clinical information, pre-hospital interventions and disposition, hospital information, and participant outcome for all out-of-hospital cardiac arrests in the ROC regions. Each ROC site had to ensure capture of all eligible cases within the EMS service areas. Out-of-hospital data were extracted from existing databases whenever possible and augmented with targeted review of EMS reports. Hospital data were abstracted directly from the hospital file in most cases. Alternative methods included linkage to death registries and obituaries if the death occurred within 30 days. Sites submitted data using a web-based interface or batch uploads. Participants were not contacted directly.

  Study phs003726

• Resuscitation Outcomes Consortium (ROC) Cardiac Epidemiologic Registry (Cardiac Epistry) Versions 1 and 2 (ROC-Cardiac Epistry 1 and 2-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Available Data: The ROC Cardiac Epistry versions 1 and 2 include all cardiac arrest cases entered into the ROC database from December 1, 2005 to April 1, 2011. ROC Cardiac Epistry 3 includes cardiac arrest cases captured between 2011 and 2015, and introduced significant changes in how and which data were collected.For ROC traumatic injury Epistry data, please see: ROC-Trauma Epistry Objectives: To build a prospective population-based registry of participants with out-of-hospital cardiac arrest responded to by Emergency Medical Services (EMS). Specific aims: to establish whether the results of Resuscitation Outcomes Consortium (ROC) trials can be generalized to the larger population of participants that experience cardiac arrest;to more fully establish the burden of cardiac arrest; and to examine the relationships between variation in EMS structure and process, regional and periodic factors, and participant outcomes.Background: Cardiac arrest is a common, serious, debilitating and costly public health problem. Although there has been a steady decline in morbidity and mortality from most cardiovascular diseases, high mortality rates for out-of-hospital cardiac arrests continue to pose a challenge for healthcare providers and a significant public health burden. The Resuscitation Outcomes Consortium (ROC) was established in 2004 to conduct clinical research in the areas of cardiopulmonary arrest and life-threatening traumatic injury with the overall goal of improving resuscitation outcomes. Participant and care characteristics can predict favorable outcomes in cardiac arrests, but there is still a wide variation in outcomes that is not well understood. EMS factors such as service level, number of responding providers, use of procedures or drugs in the field, training, quality assurance/feedback, and response time intervals also vary significantly by region. Variations in geographic, socioeconomic and periodic factors may also be associated with differences in outcomes.Prior to ROC Cardiac Epistry, there were no North American population-based registries for out-of-hospital cardiac arrests. Therefore there was a need for standardized data collection of out-of-hospital cardiac arrests in diverse geographic locations in order to identify the independent effects of prognostic or treatment factors accounting for variations in survival. Participants: The registry included 109,326 cardiac arrest events from 264 EMS agencies transporting to 287 acute care hospitals from the following regional centers: Birmingham, Alabama; Dallas, Texas; Iowa City, Iowa; Milwaukee, Wisconsin; Pittsburgh, Pennsylvania; Portland, Oregon; San Diego, California; Seattle/King County, Washington; Ottawa, Ontario; Toronto, Ontario; and Vancouver, British Columbia.Design: ROC Epistry collected standardized data regarding episode-specific factors, participant demographics, clinical information, pre-hospital interventions and disposition, hospital information, and participant outcome for all out-of-hospital cardiac arrests in the ROC regions. Each ROC site had to ensure capture of all eligible cases within the EMS service areas. Out-of-hospital data were extracted from existing databases whenever possible and augmented with targeted review of EMS reports. Hospital data were abstracted directly from the hospital file in most cases. Alternative methods included linkage to death registries and obituaries if the death occurred within 30 days. Sites submitted data using a web-based interface or batch uploads. Participants were not contacted directly.

  Study phs003803

• A Genome-Wide Association Analysis in Angiotensin-Converting Enzyme (ACE) Inhibitor-Associated Angioedema and ACE Inhibitor-Exposed Controls; A Collaboration between the NIH Pharmacogenomics Research Network and the RIKEN Yokohama Center for Genomic Medicine

  The purpose of this study is to identify genetic predictors of ACE inhibitor-associated angioedema. In addition to preventing the formation of the pressor angiotensin II, ACE inhibitors prevent the carboxyl-terminal degradation of the vasoactive substances bradykinin and substance P. Angioedema is hypothesized to result from defective amino-terminal degradation of bradykinin or substance P in patients in whom ACE is inhibited. For example, activity of dipeptidyl peptidase IV (DPP-IV), the enzyme responsible for the inactivation of substance P when ACE is inhibited, is decreased in patients with angioedema. In preliminary studies, we have identified SNPs in the DPP4 gene that associate with DPP-IV activity and, in blacks, with risk of angioedema. This project will use genome-wide genotyping to compare 250 cases and 568 ACE inhibitor-exposed control subjects (131 cases and 288 controls ascertained at Vanderbilt and 70 cases and 280 controls ascertained at the Marshfield Clinic). We plan a 2-stage analysis of associations between SNPs and angioedema - first, we will study DPP4 SNPs for association with angioedema and, second, we will explore associations using the full GWAS data set. Depending on the platform, additional DPP4 SNPs will be used to fully tag common genetic variants in both African American and European American samples. Based on the HapMap data, there are 14 tagging SNPs in people of European descent and 34 in Yoruba (selection criteria MAF>0.05 and r2>0.8). Cases were defined as having ACE inhibitor-associated angioedema if they had had swelling of the lips, throat, tongue or face while taking an ACE inhibitor but had never had angioedema while not taking an ACE inhibitor. For simplicity, intestinal edema was excluded. Control subjects were treated for at least 6 months with an ACE inhibitor without angioedema. Because black Americans are known to be overrepresented among patients with ACE inhibitor-associated angioedema, control subjects were prespecified to be 50% black American, 50% white American, and 50% female. At Vanderbilt, the medical history, including the history of angioedema, was confirmed by a research nurse or physician using a detailed case report form. Characteristics of Vanderbilt cases appear in the Table. At Marshfield, medical history will be confirmed by chart review. The Marshfield cohort is 98% white American and 57% female with a mean age of 47.2 years.

  Study phs000438

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

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

  Study phs003348

• Mucociliary Clearance Consortium (MCC) Longitudinal Study of Primary Ciliary Dyskinesia: Participants 5-18 Years of Age

  The purpose of this longitudinal study protocol is to define age-related prevalence of phenotypic characteristics and the progression of key features of lung disease in participants with one of these disorders, Primary Ciliary Dyskinesia (PCD). In PCD, the abnormal structure and function of cilia results in impaired clearance of secretions and consequent obstruction and chronic recurrent infection in the airways, sinuses and middle ears. Although it seems likely that the onset of PCD airway disease occurs early in childhood, as has been reported for cystic fibrosis (CF), the clinical course of PCD lung disease is not well defined, nor, is the time course of emergence of specific microbial pathogens, or the age of onset and rate of progression of airway disease and bronchiectasis. This longitudinal study is designed to define the rate of progression of PCD lung function in participants between 5-18 years of age using spirometry which tracks well with lung impairment and prognosis in other disorders of the airways such as cystic fibrosis. This longitudinal protocol will also systematically track other specific outcomes, including pathogens infecting the airways (assessed by respiratory cultures), and age at onset and progression of airway damage and bronchiectasis (assessed by high-resolution computerized tomography, HRCT, of the chest). Blood will be collected for DNA to test for genetic mutations. The blood samples will be processed to establish a cell line (lymphocyte transformation) for a source of DNA for future genetic studies, in participants with disease. For participants unable to provide a blood sample, a buccal sample will be obtained for DNA.

  Study phs000596

• Whole Transcriptome Sequencing of Resectable Stage III/IV Melanoma Evaluated After Starting Hu14.18-IL2 Predicts Outcome

  Background: We analyzed whole transcriptome sequencing in tumors from 23 patients with stage III or IV melanoma from a pilot trial of the anti-GD2 immunocytokine, hu14.18-IL2, to identify predictive immune and/or tumor biomarkers in melanoma patients at high risk for recurrence. Methods: Patients were randomized to receive the first of 3 monthly-courses of hu14.18-IL2 immunotherapy either before (Group A) or after (Group B) complete surgical resection of all known disease. Tumors were evaluated by histology and whole transcriptome sequencing. Results: We report here that tumor infiltrating lymphocyte (TIL) levels directly associate with relapse-free survival (RFS) and overall survival (OS) in resected tumors from Group A, where early responses to the immunotherapy agent could be assessed. TIL levels directly associated with a previously reported immune signature which associated with RFS and OS, particularly in Group A tumors. In Group A tumors there were decreased cell cycling gene RNA transcripts, but increased RNA transcripts for repair and growth genes. We found that outcome (RFS and OS) was directly associated with several immune signatures and immune-related RNA transcripts and inversely associated with several tumor growth-associated transcripts, particularly in Group A tumors. Most of these associations were not seen in Group B tumors. Conclusion: We interpret these data to signify that both immunologic and tumoral cell processes, as measured by RNAseq analyses detected shortly after initiation of hu14.18-IL2 therapy are associated with long term survival and could potentially be used as prognostic biomarkers in tumor resection specimens obtained after initiating neoadjuvant immunotherapy. Note: RNA sequences and expression data can be found at NCBI GEO GSE133713

  Study phs001947

• Exome Sequencing for Diseases of the Immune System: X-linked Immunodeficiency with Magnesium Defect, EBV Infection, and Neoplasia (XMEN)

  The etiologies of primary immunodeficiencies often yield novel insights about the immune system. Although a genetic etiology has been suspected for patients with abnormally low CD4+ T cells in the absence of HIV infection or any known causes of lymphopenia, no genetic mutation has been described to date for any case of primary CD4 lymphopenia. In this study, we characterized a non-consanguineous family with two non-HIV infected boys exhibiting an inverted CD4 to CD8 T cell ratio and a history of recurrent chronic viral infections since birth. Consistent with a decreased thymic output of CD4+ T cells, the percentage of CD31+ cells in the CD4+ naive population of these patients was decreased. In addition, the activation of T cells was significantly impaired in the patient upon TCR stimulation. Given the mother's T cells show completely skewed X chromosome inactivation, we suspected that the nature of this disease is X-linked. We performed X-chromosome exon-capture targeted single-end Solexa sequencing on two brothers and the mother and found a 10 base pair deletion at an intron-exon junction of Magnesium Transporter 1 (MAGT1), a Mg2+ specific transporter. We confirmed that this deletion leads to altered splicing, frameshift, early termination of the mRNA, and deficient protein expression in the lymphocytes of the two patients. Moreover, knockdown of this transporter in T cells isolated from healthy donors can recapitulate the observed T cell activation defect while its ectopic expression in the patients' lymphocytes can restore T cell stimulation. Our discovery highlights the significance of this transporter to T cell function.

  Study phs000365

• Ghana Prostate Study

  Participants were recruited through the Ghana Prostate Study-a population-based component, and a clinical component. The population-based component was a probability sample designed using the 2000 Ghana Population and Housing Census data in an attempt to recruit approximately 1,000 men aged 50-74 years in the Greater Accra region (~3 million people), which successfully recruited 1,037 healthy men between 2004 and 2006 with a response percentage of 98.8 %. Consented individuals underwent an in-person interview, and within 7 days had a digital rectal examination (DRE) and provided an overnight fasting blood sample for prostate-specific antigen (PSA) testing, biomarker assays, and genetic analysis. Subjects who had a positive screen by PSA (>2.5 ng/ml) or DRE underwent a transrectal ultrasound-guided biopsy. A total of 73 histologically confirmed prostate cancer cases were identified through the population-based screening component of the Ghana Prostate Study and were included in the case population in the published GWAS (Cook et al., Human genetics, 2013). From the remaining 964 screen-negative individuals, 836 had at least 20 μg DNA extracted and available for analysis, and 500 of these were matched to cases for analysis by age (in 5-year categories). In the Ghana Prostate Study, we recruited 676 prostate cancer cases at Korle Bu Teaching Hospital in Accra, Ghana, between 2008 and 2012. All consented cases were interviewed and provided an overnight fasting blood sample. At the time of selection for this analysis we had recruited 582 prostate cancer cases, from which we selected 427 for analysis. Combined with the 73 cases diagnosed through the population-based component of the study, this yielded 500 available prostate cancer cases for analysis.

  Study phs000838

• Lung Cancer Genetic Study Among Asian Never Smokers

  The Lung Cancer Genetic Study Among Asian Never Smokers includes data from four population-based studies conducted among Asian women: the Shanghai Women's Health Study (SWHS), the Hwasun Cancer Epidemiology Study (HCES1 and HCES2), the Female Lung Cancer Consortium in Asia (FLCCA, including sFLCA), and the Guangzhou Lung Cancer Study (GLCS). Shanghai Women's Health Study (SWHS): The SWHS is a population-based prospective cohort study of approximately 75,000 adult women who were recruited between 1997 and 2000. The cohort has been followed by a combination of record linkage and active follow-ups. Lung cancer patients identified in the SWHS and non-cases were included in the current study.Hwasun Cancer Epidemiology Study-Lung Cancer (HCES1 and HCES2): The HCES is a hospital-based case-control study whose goal is to identify factors of the cancer development and clinical progression in a Korean population. Included in this project were 299 female lung cancer cases from HCES2, who were diagnosed between April 2004 and February 2013 at Chonnam National University Hwasun Hospital, a cancer specified hospital in Jeollanam-do province, South Korea. Controls were randomly selected from women with no previous cancer diagnosis at enrollment in the Namwon Study and the Dong-gu study, ongoing community-based cohort studies in South Korea. A total of 1,103 controls (273 from HCES1 and 830 from HCES2) were genotyped by MEGA. Guangzhou Lung Cancer Study (GLCS): The GLCS is a case-control study including never-smoking women lung cancer cases and controls from Guangzhou, China.In this study, the DNA samples of 1,195 subjects from SWHS and GLCS were genotyped using whole exome sequencing (WES), and the DNA samples of 7,174 subjects from SWHS, HCES1, HCES2, FLCCA, and sFLCA were genotyped using the Multi-Ethnic Global Array (MEGA).

  Study phs002366

• Genome and gene analysis of gastrointestinal cancer and elucidation of its clinicopathological significance

  Cancer develops through the accumulation of genetic and epigenetic aberrations. To identify sequential molecular alterations that occur during the development of hepatocellular carcinoma (HCC), we molecularly compared 52 early and 108 overt HCC samples by genome sequencing. Gene mutations in the p53/RB1 pathway, WNT pathway, MLLs, SWI/SNF complexes, and AKT/PI3K pathway were common in HCC. In the early phase of all entities, TERT was the most frequently upregulated gene owing to diverse mechanisms. Despite frequent somatic mutations in driver genes, including CTNNB1 and TP53, early HCC was a separate molecular entity from overt HCC as each had a distinct expression profile. Notably, WNT target genes were not activated in early HCC, regardless of CTNNB1 mutation status, because ?-catenin did not translocate into the nucleus due to the E-Cadherin/?-catenin complex at the membrane. Conversely, WNT targets were definitively upregulated in overt HCC with CTNNB1 mutation associated with downregulation of CDH1 and hypomethylation of CpG islands in the target genes. Similarly, cell cycle genes downstream of the p53/RB pathway were upregulated only in overt HCC with TP53 and/or RB1 gene mutations associated with chromosomal deletion of 4q and/or 16q. Differing from the expression profile, HCC was epigenetically distinguished into four subclasses: normal-like methylation, global-hypomethylation (favorable prognosis), stem-like methylation (poor prognosis), and CpG island methylation. These methylation statuses were globally maintained through HCC progression. Taken together, additional molecular events besides driver gene mutations cooperatively contribute to transcriptional activation of downstream targets as HCC progresses, according to the methylation status of the associated genes.

  Study JGAS000233