4058 results for "*oma"

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• UW TAN Study of Metastatic Urothelial Carcinoma

  Patients with metastatic urothelial carcinoma treated at our institution, who elected to undergo rapid autopsy at the time of death, are included in this study. These patients agreed to submit their tissue (normal samples for germline analysis [kidney or liver] as well as primary and metastatic tumor sites [urothelial carcinoma]) and the time of autopsy. Each patient signed consent to allow study of these tissues including histologic, sequencing (DNA/RNA), and implantation in to animals as able for future study.

  Study phs001797

• Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C)

  Reprinted from http://www.haltctrial.org/ Purpose The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial is a randomized controlled trial designed to evaluate the safety and efficacy of long-term use of pegylated interferon for the treatment of chronic hepatitis C in patients who failed to respond to previous interferon therapy. The HALT-C Trial was developed to determine whether prolonged interferon therapy altered histological and clinical outcomes in a group of patients who had failed to eradicate hepatitis C virus with previous interferon treatment. Study Hypotheses In patients with chronic hepatitis C and bridging fibrosis who failed to eradicate the virus with previous interferon therapy, long-term treatment with interferon is safe and can prevent progression to cirrhosis. In patients with cirrhosis secondary to chronic hepatitis C who failed to eradicate the virus with previous interferon therapy, long-term treatment with interferon is safe and can reduce the risks of hepatic decompensation or of hepatocellular carcinoma. Study Design 1145 patients with chronic HCV and advanced hepatic fibrosis (Ishak stage 3-6) who failed to respond to previous treatment with interferon were enrolled at 10 clinical centers and entered into a Lead-in phase. They were treated with a combination of pegylated interferon (Pegasys®, Hoffmann-La Roche) 180 µg/week and ribavirin (1000-1200 mg/day) for 24 weeks. Patients who had no detectable HCV-RNA at week 20 continued on combination therapy until week 48. 662 patients who did not clear virus were randomly assigned at week 24 to either continue treatment with pegylated interferon alone (90 µg/week) for an additional 42 months, or to have treatment discontinued. All patients were followed at 3-month intervals following randomization. Liver biopsy was performed at baseline and after 1.5 and 3.5 years of treatment. Because of slower than expected enrollment and the approval by the FDA of peginterferon alfa-2b after the start of the trial, we modified the study protocol in three ways. First, criteria for admission to the trial were liberalized to allow patients to enter the trial with lower platelet and white blood cell counts than had been initially considered safe or tolerable. Second, 151 Lead-in patients and those continuing on therapy after 24 weeks who demonstrated return of viremia during or after their 48-week treatment period (called "Breakthrough" or "Relapse" patients, respectively) were allowed to return to enter the randomized trial. Third, 237 patients treated with peginterferon alfa-2b (or with peginterferon alfa-2a in licensing trials) outside the HALT-C Trial who in other respects met all study criteria, having received the equivalent of Trial Lead-in period therapy, were allowed to enter the long-term trial as "Express" patients. A total 1050 patients were randomized. Those patients who completed Month 48 were offered an "extended follow-up (observation only)" until October 2009. These visits will primarily be to identify outcome events, and to provide information to patients concerning the current status of the trial. Some questionnaires, blood tests, and an ultrasonogram will be performed. Quarterly (every 3 months) Interval history of complications, adverse events Current medications Brief physical examination Laboratory tests: liver panel, CBC, INR, AFP Child-Pugh Score Stored serum Annual Complete physical examination Ultrasound of liver 1.5 years (M24 visit, middle of study) Liver biopsy: formalin fixed histology, frozen liver tissue (subset of patients) 3.5 years (M48, end of study) Liver biopsy: formalin fixed histology, frozen liver tissue (subset of patients) Endoscopy: evaluate esophageal varices and portal hypertension After Month 48 Observation only (no treatment) to determine clinical outcomes Clinic visit every 6 months with current medications, brief PE, liver panel, CBC, AFP, stored Serum Ultrasound of liver every 6 months Outcome Variables Primary outcome variables to be assessed in the two groups of patients include: Development of cirrhosis on liver biopsy (progression of Ishak fibrosis score by 2 points or more) Development of hepatic decompensation, as shown by: Sustained increase in the Child-Turcotte-Pugh score to 7 points or higher Variceal hemorrhage Ascites Spontaneous bacterial peritonitis Hepatic encephalopathy Development of hepatocellular carcinoma Death Secondary outcomes include quality of life, serious adverse events, events requiring dose reductions, and development of presumed hepatocellular carcinoma.

  Study phs000430

• 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

• Genomic Sequencing of Ewing Sarcoma

  Pediatric Ewing sarcoma is a pediatric cancer that primarily arises from the bone. It is characterized by chimeric fusions of the EWS gene and an ETS family transcription factor. In this study, we performed massively parallel sequencing of a larger collection of Ewing sarcoma tumors to define the genomic landscape of this disease. We found that these tumors are among of the most genetically normal cancers currently characterized. There was also a marked absence of recurrent mutations in immediately targetable signaling transduction pathway genes. In this study we answer outstanding questions about ETS transcription factor expression, effects of treatment on mutational burden in Ewing sarcoma tumors, and describe patterns of tumor evolution. We also found that loss-of-function mutations in STAG2 were present in approximately 15% of Ewing sarcoma tumors and loss of STAG2 expression was associated with disease metastasis in this patient cohort.

  Study phs000804

• Transformation of Dysplasia in Barrett's Esophagus

  Complex chromosomal alterations are a hallmark of advanced cancers but rarely seen in normal tissue. The progression of precancerous lesions to malignancy is often accompanied by increasing complexity of chromosomal alterations that can drive their transformation through focal oncogenic amplifications. However, the etiology and evolution dynamics of these alterations are poorly understood. Here we study chromosomal copy-number evolution in the progression of Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC) by multi-regional whole-genome sequencing analysis of BE samples with dysplasia and microscopic EAC foci. Through haplotype-specific copy-number analysis of BE genome evolution, we identified distinct patterns of episodic copy-number evolution consistent with the outcomes of abnormal mitosis and dicentric chromosome breakage. While abnormal mitosis, including whole-genome duplication, accounts for most chromosome or arm-level copy-number changes, segmental copy-number alterations display signatures of multi-generational evolution of unstable dicentric chromosomes. Continuous evolution of dicentric chromosomes through breakage-fusion-bridge cycles and chromothripsis rapidly increases genomic complexity and diversity among BE cells, culminating in the generation of distinct focal amplifications. These mutational processes enable multiple subclones within small dysplastic areas to undergo parallel transformation to cancer following acquisition of distinct oncogenic amplifications. Our results demonstrate how chromosomal instability drives clonal diversification in precancer evolution and promotes tumorigenesis in primary human samples.

  Study phs002706

• Cutaneous Melanoma GWAS Combining Multiple Populations and Risk Phenotypes

  Most genetic susceptibility to cutaneous melanoma (CM) remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 melanoma cases (67% newly-genotyped) and 375,188 controls identified 54 significant loci with 68 independent SNPs. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with nevus count and hair colour GWAS, and transcriptome association approaches, uncovered 31 potential secondary loci, for a total of 85 CM susceptibility loci. These findings provide substantial insights into CM genetic architecture, reinforcing the importance of nevogenesis, pigmentation, and telomere maintenance together with identifying potential new pathways for CM pathogenesis.

  Study phs001868

• Molecular Features of Hepatocellular Carcinoma Associated with 18F-Fluorocholine PET/CT Imaging Phenotype

  Molecular imaging with 18F-fluorocholine PET/CT reveals two distinct imaging phenotypes for hepatocellular carcinoma (HCC) as a potential source of non-invasive insight into its molecular heterogeneity. Using gene set enrichment analyses, we found 18F-fluorocholine-avid tumors to be significantly enriched by genes comprising a subset of previously published HCC-related gene signatures. Significant gene sets included those from existing molecular classification systems for HCC as well as gene signatures predictive of clinical outcomes after tumor resection. PET/CT imaging using 18F-fluorocholine might therefore provide surrogate information about tumor molecular characteristics and prognosis in HCC.

  Study phs001784

• Structurally Complex Osteosarcoma Genomes Exhibit Limited Heterogeneity within Individual Tumors and across Evolutionary Time

  A key characteristic of osteosarcoma is extensive and complex genomic rearrangements. However, published models explaining how these genomic rearrangements occur disagree about if these rearrangements occur early in tumor progression and then are stable afterwards, or if there is ongoing genomic instability. Previous studies have employed bulk sequencing technologies to characterize genomic alterations. A limitation of this approach is that it averages all changes within the bulk sample, essentially masking intra-sample heterogeneity and making evaluation of ongoing genomic instability difficult. To overcome this limitation and compliment previous work, we utilized single-cell whole genome sequencing to quantify somatic copy number alterations (SCNA). By interrogating individual cells within a sample, we were able to examine intra-sample heterogeneity. We found that the SCNA patterns between cells within a single sample were remarkably consistent, which supports the concept that the genomes of osteosarcoma tumors are relatively stable after early genome fragmentation events.

  Study phs003209

• Detection of Colorectal Cancer Susceptibility Loci Using Genome-Wide Sequencing

  The Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) is a collaborative effort comprised of a coordinating center and scientific researchers from well-characterized cohort and case-control studies. This international consortium aims to accelerate the discovery of common and rare genetic risk variants for colorectal cancer by conducting large-scale meta-analyses of existing and newly generated genome-wide association study (GWAS) data, whole genome sequencing, replicating and fine-mapping of genetic discoveries, and investigating how genetic risk variants are modified by environmental risk factors. To expand these efforts, we assembled case-control sets or nested case-control sets from 6 different North American or European studies. Summary descriptions and study participant inclusions/exclusion criteria for each of these studies are detailed below. Cancer Prevention Study II (CPS II): The CPS II Nutrition cohort is a prospective study of cancer incidence and mortality in the United States, established in 1992 and described in detail elsewhere (Calle et al., 2002 PMID:12015775; Campbell et al., 2014 PMID:25472679). At enrollment, participants completed a mailed self-administered questionnaire including information on demographic, medical, diet, and lifestyle factors. Follow-up questionnaires to update exposure information and to ascertain newly diagnosed cancers were sent biennially starting in 1997. Reported cancers were verified through medical records, state cancer registry linkage, or death certificates. The Emory University Institutional Review Board approves all aspects of the CPS II Nutrition Cohort. We restricted to samples that had blood DNA source. Controls were matched to cases in a case/control ratio of 2:1 on reference year and sex. Darmkrebs: Chancen der Verhütung durch Screening (DACHS): This German study was initiated as a large population-based case-control study in 2003 in the Rhine-Neckar-Odenwald region (southwest region of Germany) to assess the potential of endoscopic screening for reduction of colorectal cancer risk and to investigate etiologic determinants of disease, particularly lifestyle/environmental factors and genetic factors. Cases with a first diagnosis of invasive colorectal cancer (International Classification of Diseases 10 codes C18-C20) who were at least 30 years of age (no upper age limit), German speaking, a resident in the study region, and mentally and physically able to participate in a one-hour interview, were recruited by their treating physicians either in the hospital a few days after surgery, or by mail after discharge from the hospital. Cases were confirmed based on histologic reports and hospital discharge letters following diagnosis of colorectal cancer. All hospitals treating colorectal cancer patients in the study region participated. Based on estimates from population-based cancer registries, more than 50% of all potentially eligible patients with incident colorectal cancer in the study region were included. Community-based controls were randomly selected from population registries, employing frequency matching with respect to age (5-year groups), sex, and county of residence. Controls with a history of colorectal cancer were excluded. Controls were contacted by mail and follow-up calls. The participation rate was 51%. During an in-person interview, data were collected on demographics, medical history, family history of CRC, and various life-style factors, as were blood and mouthwash samples. Routine formalin-fixed, paraffin-embedded (FFPE) tumor samples from the patients enrolled were requested from the pathology institutes and used for tumor tissue analyses. This analysis includes participants with blood source DNA that were recruited up to 2010 in this ongoing study. Controls were matched to cases on reference age and sex in a case/control ratio of 2:1. Health Professionals Follow-up Study (HPFS): A parallel prospective study to the NHS (Nurses' Health Study). The HPFS cohort comprised 51,529 men aged 40-75 who, in 1986, responded to a mailed questionnaire (Rimm et al., 1990 PMID:2090285). Participants provided information on health related exposures, including current and past smoking history, age, weight, height, diet, physical activity, aspirin use, and family history of colorectal cancer. Colorectal cancer and other outcomes were reported by participants or next-of-kin and were followed up through review of the medical and pathology record by physicians. Overall, more than 97% of self-reported colorectal cancers were confirmed by medical record review. Information was abstracted on histology and primary location. Incident cases were defined as those occurring after the subject provided the blood sample. Prevalent cases were defined as those occurring after enrollment in the study but before the subject provided the blood sample. Follow-up evaluation has been excellent, with 94% of the men responding to date. Colorectal cancer cases were ascertained through January 1, 2008. In 1993-1995, 18,825 men in the HPFS mailed blood samples by overnight courier, which were aliquoted into buffy coat and stored in liquid nitrogen. In 2001-2004, 13,956 men in the HPFS who had not provided a blood sample previously mailed in a swish-and-spit sample of buccal cells. Incident cases were defined as those occurring after the subject provided a blood or buccal sample. Prevalent cases were defined as those occurring after enrollment in the study in 1986, but before the subject provided either a blood or buccal sample. Participants with histories of cancer (except nonmelanoma skin cancer), ulcerative colitis, or familial polyposis, case-control sets were excluded. Control participants were required to be free of invasive colorectal cancer and non-invasive (stage 0 in situ) colorectal cancer. For this study, only European ancestry participants with blood source DNA and incident colorectal cancer cases were eligible for selection. Since enrollment year and sex matched exactly, controls were randomly selected in a case/control ratio of 2:1. Nurses Health Study (NHS): The NHS cohort began in 1976 when 121,700 married female registered nurses age 30-55 years returned the initial questionnaire that ascertained a variety of important health-related exposures (Belanger et al., 1978 PMID:248266). Since 1976, follow-up questionnaires have been mailed every 2 years. Colorectal cancer and other outcomes were reported by participants or next-of-kin and followed up through review of the medical and pathology record by physicians. Overall, more than 97% of self-reported colorectal cancers were confirmed by medical-record review. Information was abstracted on histology and primary location. The rate of follow-up evaluation has been high: as a proportion of the total possible follow-up time, follow-up evaluation has been more than 92%. Colorectal cancer cases were ascertained through June 1, 2008. In 1989-1990, 32,826 women in NHS I mailed blood samples by overnight courier, which were aliquoted into buffy coat and stored in liquid nitrogen. In 2001-2004, 29,684 women in NHS I who did not previously provide a blood sample mailed a swish-and-spit sample of buccal cells. Incident cases were defined as those occurring after the subject provided a blood or buccal sample. Prevalent cases were defined as those occurring after enrollment in the study in 1976 but before the subject provided either a blood or buccal sample. Participants with histories of cancer (except nonmelanoma skin cancer), ulcerative colitis, or familial polyposis, case-control sets were excluded. For this study, only European ancestry participants with blood source DNA and incident colorectal cancer cases were eligible for selection. Since enrollment year and sex matched exactly, controls were randomly selected in a case/control ratio of 2:1. Prostate, Lung, Colorectal and Ovarian Cancer Screening Trail (PLCO): PLCO enrolled 154,934 participants (men and women, aged between 55 and 74 years) at ten centers into a large, randomized, two-arm trial to determine the effectiveness of screening to reduce cancer mortality. Sequential blood samples were collected from participants assigned to the screening arm. Participation was 93% at the baseline blood draw. White colorectal cancer cases with a family history of colorectal cancer (no history of ulcerative colitis, Crohn's Disease, diverticulitis, Gardner's syndrome, Familial Polyposis) and successful genotyping from previous Peters GWAS were selected for this project. Controls were matched to cases on reference age and sex in a case/control ratio of 2:1. Women's Health Initiative (WHI): WHI is a long-term national health study that has focused on strategies for preventing heart disease, breast and colorectal cancer, and osteoporotic fractures in postmenopausal women. The original WHI study included 161,808 postmenopausal women enrolled between 1993 and 1998. The Fred Hutchinson Cancer Research Center in Seattle, WA serves as the WHI Clinical Coordinating Center for data collection, management, and analysis of the WHI. The WHI has two major parts: a partial factorial randomized Clinical Trial (CT) and an Observational Study (OS); both were conducted at 40 Clinical Centers nationwide. The CT enrolled 68,132 postmenopausal women between the ages of 50-79 into trials testing three prevention strategies. If eligible, women could choose to enroll in one, two, or all three of the trial components. The components are: Hormone Therapy Trials (HT): This double-blind component examined the effects of combined hormones or estrogen alone on the prevention of coronary heart disease and osteoporotic fractures, and associated risk for breast cancer. Women participating in this component with an intact uterus were randomized to estrogen plus progestin (conjugated equine estrogens [CEE], 0.625 mg/d plus medroxyprogesterone acetate [MPA] 2.5 mg/d) or a matching placebo. Women with prior hysterectomy were randomized to CEE or placebo. Both trials were stopped early, in July 2002 and March 2004, respectively, based on adverse effects. All HT participants continued to be followed without intervention until close-out. Dietary Modification Trial (DM): The Dietary Modification component evaluated the effect of a low-fat and high fruit, vegetable and grain diet on the prevention of breast and colorectal cancers and coronary heart disease. Study participants were randomized to either their usual eating pattern or a low-fat dietary pattern. Calcium/Vitamin D Trial (CaD): This double-blind component began 1 to 2 years after a woman joined one or both of the other clinical trial components. It evaluated the effect of calcium and vitamin D supplementation on the prevention of osteoporotic fractures and colorectal cancer. Women in this component were randomized to calcium (1000 mg/d) and vitamin D (400 IU/d) supplements or a matching placebo. The Observational Study (OS) examines the relationship between lifestyle, environmental, medical and molecular risk factors and specific measures of health or disease outcomes. This component involves tracking the medical history and health habits of 93,676 women not participating in the CT. Recruitment for the observational study was completed in 1998 and participants were followed annually for 8 to 12 years. All centrally confirmed White cases of invasive colorectal cancer, or death from colorectal cancer were selected as potential cases from the March, 2011 database. Case priory lists are: 1) have positive family history of colorectal cancer; 2) randomly select cases until we get a total of n=800 cases. Control participants were required to be White, free of invasive colorectal cancer and non-invasive (stage 0 in situ) colorectal cancer. Centrally denied cases of colorectal cancer were not allowed into the control pool. Case and control participants were subject to the following exclusion criteria: (1) had prior history of colorectal cancer at baseline; (2) had no available DNA (DNA searching as Nov 15, 2012); (3) cannot be deposited to dbGaP; (4) lost to follow-up after enrollment; (5) selected for WHI study M26 Phase II. Controls were matched to cases in a case/control ratio of 2:1. In order to get 2 cases with 1 control, cases were grouped by enrollment year (a total of 5 groups). For each year group, around 50% cases were selected to match controls. In total, 401 cases were selected to match controls. Matching was done on enrollment year, which was matched exactly. For additional information, see dbGaP: phs000200 and ClinicalTrials: NCT00000611.

  Study phs001554

• An Advanced Molecular Medicine Case Report of a Rare Human Tumor Using Genomics, Pathomics, and Radiomics

  The associated data of this study is derived from a single female patient with pulmonary sclerosing pneumocytoma (PSP). The aim of this study is to provide the most comprehensive, multi-modality sequencing study of a single case of PSP to-date. To this end, the following sequencing experiments were performed: i) RNA-Seq of the primary tumor and adjacent normal tissues (6 replicates for each tissue type), which was intended to analyze RNA-Seq fusions, gene expression, expression mutations, ii) low-pass DNA whole genome sequencing (WGS) from primary tumor tissue and germline, which was intended to analyze copy number aberrations, and iii) DNA targeted panel sequencing of lung cancer associated genes, using primary tumor tissue and germline from white blood cells, which was intended to analyze somatic mutations. Principal findings: i) the PSP hallmark mutation AKT1 (p.E17K) was detected within both the DNA and RNA, and ii) the TP53 signaling pathway was found to be statistically significant by three different pathway analysis tools of analyzing gene expression and pathway ramifications. Among proteins within the TP53 signaling pathway, the p53 inhibitor encoded by MDM2 was found to be overexpressed (by differential gene expression analysis). The original sequencing data (i.e., FastQ files) from each of the aforementioned samples will be accessible through dbGaP.

  Study phs003154

• UCSF Adult Glioma Study

  The UCSF Adult Glioma Study is a case-control study conducted at the University of California, San Francisco. The goals of the study were to discover inherited (genetic), developmental, immunologic and other risk factors for glioma and to determine molecular level tumor markers that would be helpful in classifying glioma into more homogeneous groups.

  Study phs001497

• Sézary Syndrome Originates from Heavily Mutated Hematopoietic Progenitors

  The pathogenesis of cutaneous T cell lymphoma (CTCL) remains unclear. To study the malignant transformation of CTCL, we collected matched hematopoietic stem cell (HSC) extracts from bone marrow, CD4+CD26- malignant T cells, CD4+CD26+ normal T cells, and CD34+ HSCs from apheresis performed on 4 patients. To establish the baseline for calling true mutations without using hematopoietic cells, we also cultured bone marrow fibroblasts from each patient to use as normal controls. Whole exome sequencing (WES) was performed on all samples for somatic mutation calling. We identified >200 mutations in CD34+ HSCs derived from either bone marrow or apheresis. Previously reported key oncodrivers in Sezary Syndrome were identified in autologous HSCs and malignant peripheral cells, but not in progenitor (bone marrow HSCs) cells. Also, we identified specific mutations shared by autologous HSCs and malignant peripheral cells in every patient. WES data of bone marrow HSCs, apheresis HSCs, CD4+CD26- T cells, CD4+CD26+ T cells, and fibroblasts will be available through dbGaP.

  Study phs003158

• Metastatic Colorectal Adenocarcinoma Tumor Purity Assessment from Whole Exome Sequencing Data

  As molecular medicine wields greater and greater influence on cancer patient care, including therapeutic selection, it becomes increasingly important to understand the power and deficiencies of computational tools used in decision making processes. Here we use a set of unselected metastatic colorectal tumor samples in a head-to-head comparison between the calculation of stromal content by a board certified pathologist, versus that derived from whole exome sequencing and purity assessment by a variety of common computational methods. We find that in about 1/2 of the samples the computational methods each do a poor job of assessing the percent stromal contamination, and as a result, tumor variant allele frequencies (VAFs) are low or undetected, whereas analysis of organoids derived from the same tumors yielded much higher VAFs in keeping with their lower stromal content. The whole exome sequence of our samples is available via dbGaP, accession phs003059.v1.p1.

  Study phs003059

• National Eye Institute (NEI) Ocular Hypertension Treatment Study (OHTS)

  The Ocular Hypertension Treatment Study (OHTS) is an National Eye Institute-sponsored multi-center, randomized, prospective treatment trial designed to determine whether lowering intraocular pressure (IOP) in individuals with ocular hypertension delays or prevents the development of primary open angle glaucoma (POAG). A total of 1,636 individuals with ocular hypertension between 40 and 80 years old were enrolled in the study. In addition to ocular hypertension, subjects in the OHTS were required to have normal optic nerve appearance as determined by the OHTS Optic Disc Reading Center and normal and reliable visual field tests at the time of enrollment by the OHTS Visual Field Reading Center. OHTS subjects were randomly assigned to either an observational group which received close observation or a topical medication group which received medication as needed to achieve a 20% reduction in IOP from their baseline levels. Subjects then were examined at regular intervals for optic disc cupping or visual field defects. Other clinical measures were also obtained from OHTS subjects including central corneal thickness (CCT) and intraocular pressure. The primary outcome monitored for the OHTS was the development of glaucoma in one or both eyes as defined by reproducible visual field abnormality or reproducible optic disc deterioration attributed to POAG by the masked OHTS Endpoint Committee. The OHTS study design has been reported in detail (Gordon, 1999; PMID: 10326953). The OHTS confirmed that ocular hypertension is a risk factor for developing POAG and showed that lowering IOP reduced the risk for developing POAG (Kass, 2002; PMID: 12049574). The OHTS also demonstrated that thin CCT is a significant risk factor for the development of POAG (Gordon, 2002; PMID: 12049575). Blood samples were also collected from 1,077 OHTS participants for an ancillary genetics study. DNA was prepared from these samples and used in a genome-wide association scan (GWAS) designed to identify genetic factors that control the magnitude of quantitative features of glaucoma (baseline IOP, baseline cup-to-disc ratio, and CCT). Genotypes from the GWAS and these clinical data (IOP, cup-to-disc ratio, and CCT) have been provided to dbGaP.

  Study phs000240

• Genome-Wide Characterization of Pancreatic Adenocarcinoma Patients Using Next Generation Sequencing

  In this study, we whole genome sequenced tumor/normal pairs from three pancreatic adenocarcinoma patients to separately characterize each patient with respect to somatic alterations. For 2 patients for whom tumor RNA was available, we also performed RNA sequencing to evaluate gene expression changes. While additional sequencing is needed to improve our understanding of the disease, the information acquired from this study contributes to our knowledge base on pancreatic cancer and helps to establish a foundation for identifying and developing more efficacious treatments for patients.

  Study phs000550

• Genomic Analysis of Nucleic Acid Sequences from Pancreatic Cancer

  Our study aims to perform multi-omics analysis of pancreatic ductal adenocarcinoma. We performed dual single-cell RNA sequencing and whole genome sequencing on fresh tumor specimens and dual bulk RNA-sequencing and 16S amplicon sequencing on frozen tumor specimens to identify human and non-human nucleic acid sequences. Additionally, we identified microbial sequences and found that bacterial taxonomic profiles from the same sample strongly correlated across technologies.

  Study phs003035

• Cross-site Concordance Evaluation of Tumor DNA and RNA Sequencing Platforms of CIMAC-CIDC Network

  The Cancer Immune Monitoring and Analysis Centers (CIMACs) and the Cancer Immunologic Data Commons (CIDC)  has engaged in efforts to harmonize Whole-exome (WES) and RNA-sequencing (RNA-seq) data from three different experimental platforms (MD Anderson, NCI MoCha lab, and Broad Institute) and are using a series of developed pipelines to process the early trial samples. To evaluate the consistency of tumor WES and RNA-seq profiling platforms across different centers, the CIMACs-CIDC conducted a systematic harmonization study. DNA and RNA were centrally extracted from fresh frozen (FF) and formalin-fixed paraffin-embedded (FFPE) non-small cell lung carcinoma (NSCLC) tumors and distributed to three centers for WES and RNA-seq profiling

  Study phs002295

• Multi-Omic Investigation of Beckwith-Wiedemann Syndrome Wilms Tumor

  Wilms’ Tumor (WT), also known as nephroblastoma, is one of the most common malignant kidney tumors diagnosed in children. One of the most common WT predisposition syndromes is Beckwith-Wiedemann Syndrome (BWS, OMIM: 130650), which affects approximately 1/10,000 live births. In this study, we perform Whole Exome Sequencing (WES), DNA methylation array, and messenger RNA-Sequencing (mRNA-Seq), to examine the genomic, methylomic, and transcriptomic signature of BWS WT. We analyzed six tumor-normal paired samples, three BWS tumor only samples, and four non-BWS control samples to identify BWS WT drivers.

  Study phs002769

• Gut Microbiome and Types of Colorectal Polyps

  Colorectal cancer is a heterogeneous disease arising from at least two precursors-the conventional adenoma and the serrated polyp. This dataset was used to test the relationship of the gut microbiota to specific colorectal polyp types. We included samples from two independent study populations based at colonoscopy clinics: the Centers for Disease Control and Prevention (CDC) Study of In-home Tests for Colorectal Cancer (SIT), and the New York University (NYU) Human Microbiome and Colorectal Tumor study. Gut microbiota were assessed in 667 colonoscopy-screened adults by 16S rRNA gene sequencing of stool samples, of which 540 were included in our analysis. Participants were categorized as conventional adenoma cases, serrated polyp cases, or polyp-free controls. CA cases were further classified as proximal or distal and as non-advanced or advanced. Serrated polyp cases were further classified as hyperplastic polyp or sessile serrated adenoma. Our results show associations between gut microbiome composition and presence of conventional adenomas, including reduced diversity and alterations in taxon abundance.

  Study phs001381

• The Mutational Landscape of CTCL and Sezary Syndrome

  Sezary syndrome is a leukemic and aggressive form of cutaneous T-cell lymphoma (CTCL) resulting from the malignant transformation of skin-homing central memory CD4+ T cells. To identify new genetic alterations involved in Sezary syndrome and CTCL transformation we performed whole-exome sequencing of tumor-normal sample pairs from 26 Sezary syndrome and 16 CTCL patients. These analyses revealed a distinctive pattern of somatic copy number alterations in Sezary syndrome including highly prevalent recurrent chromosomal deletions involving the TP53, RB1, PTEN, DNMT3A, and CDKN1B tumor suppressor genes. Mutation analysis identified a broad spectrum of somatic mutations involving key genes involved in epigenetic regulation (TET2, CREBBP, MLL3, BRD9, SMARCA4 and CHD3) and signaling, including mutations in MAPK1, BRAF, CARD11 and PRKG1 driving increased MAPK, NFKB and NFAT activity upon T-cell receptor stimulation. Collectively, our findings provide new insights into the genetics of Sezary syndrome and CTCL and support the development of personalized therapies targeting key oncogenically activated signaling pathways for the treatment of these diseases.

  Study phs000994

• Medulloblastoma exome sequence analysis

  Medulloblastomas are the most common malignant brain tumors in children. Identifying and understanding the genetic events that drive these tumors is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma based on transcriptional and copy number profiles. Here, we utilized whole exome hybrid capture and Illumina sequencing to identify somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs. Overall, medulloblastomas exhibit low mutation rates consistent with other pediatric tumors, with a median of 0.35 non-silent mutations per megabase. We identified twelve genes mutated at statistically significant frequencies, including previously known mutated genes in medulloblastoma such as CTNNB1, PTCH1, MLL2, SMARCA4 and TP53. Recurrent somatic mutations were identified in an RNA helicase gene, DDX3X, often concurrent with CTNNB1 mutations, and in the nuclear co-repressor (N-CoR) complex genes GPS2, BCOR, and LDB1, to our knowledge novel findings in medulloblastoma and all cancer. We show that mutant DDX3X potentiates transactivation of a TCF promoter and enhances cell viability in combination with mutant but not wild type beta-catenin. Together, our study reveals the alteration of Wnt, Hedgehog, histone methyltransferase and now N-CoR pathways across medulloblastomas and nominates the RNA helicase DDX3X as a component of pathogenic beta-catenin signaling in medulloblastoma. "Reprinted from 'MEDULLOBLASTOMA EXOME SEQUENCING UNCOVERS SUBTYPE-SPECIFIC SOMATIC MUTATION', with permission from Nature"

  Study phs000504

• Whole Exome Sequencing Analysis of Carfilzomib-Related Cardiotoxicity in Multiple Myeloma Patients

  This study investigated the contribution of germline genetic variants in protein-coding genes in carfilzomib-related cardiovascular adverse events among patients with multiple myeloma using whole-exome sequencing (WES) analysis. We analyzed 247 patients with multiple myeloma who had been treated with carfilzomib at the Moffitt Cancer Center. We identified a missense mutation in the TMSB10/TRABD2A locus that appeared to be associated with a higher risk for cardiovascular adverse events in these patients. In this submission, we will provide all the genotype data along with the phenotype data of whether or not a patient developed cardiovascular adverse events after carfilzomib treatment and all the covariates used in this analysis.

  Study phs003308

• Phylogenetic Analyses of Melanoma Reveal Complex Patterns of Metastatic Dissemination

  Subpopulations of cells in a primary melanoma can disseminate and establish metastases. Still, the precise ancestral relationship between primary tumors and their metastases is not well understood. Using whole-exome sequencing (for discovery) and targeted sequencing (for validation), we analyzed mutation patterns of primary melanomas and two or more metastases in each of 8 patients to determine their phylogenetic relationships, profiling a total of 31 total tumors. The resulting data show that in 6 of 8 cases, genetically unique cell populations in the primary metastasized in parallel to distinct anatomic sites, rather than sequentially. These data also indicate that individual metastases were sometimes founded by multiple cell populations of the primary that were genetically distinct.

  Study phs000941

• Characterization of Immune Evasion in Merkel Cell Carcinoma

  Merkel cell carcinoma (MCC) is a rare, neuroendocrine skin carcinoma that is caused by the Merkel cell polyomavirus (MCPyV) in 80% of cases and by ultraviolet (UV) damage in 20% of cases. MCC should theoretically elicit a strong cytotoxic T cell response due to the high neoantigen and viral antigen burden in MCPyV- and MCPyV+ MCC, respectively. However, MCC often escapes immune recognition and is associated with very poor prognosis at advanced stages. To systemically identify mechanisms of immune evasion in MCC, we established 11 robust MCC lines from either primary tumors or patient-derived xenografts (7 MCPyV+ and 4 MCPyV-). We then characterized these tumors and cell lines by whole exome sequencing (WES), RNA-sequencing, scRNA-sequencing, ATAC-seq, and whole genome bisulfite sequencing (WGBS). We also studied MCC transcriptional subtypes, utilizing bulk and scRNA-sequencing datasets of patient-derived tumors and cell lines to investigate profiles of neuroendocrine gene expression. The genes linked below define either a neuroendocrine or a non-neuroendocrine phenotype presence within MCC tumors.

  Study phs002260

• The genomic complexity of sporadic and inherited retinoblastoma with a matched orthotopic xenograft

  Retinoblastoma is a pediatric cancer of the developing retina. All retinoblastomas are believed to initiate with biallelic inactivation of the RB1 gene. To identify subsequent genetic lesions in retinoblastoma, we performed whole genome sequencing of tumor and normal DNA of 4 children with retinoblastoma and one matched orthotopic xenograft. Both alleles of RB1 were inactivated in the tumor samples. 3 of the patients had sporadic retinoblastoma and one patient had inherited retinoblastoma. Overall, there were few single nucleotide changes in coding regions of the genome and some of the tumors had few chromosomal lesions. There were very few new genetic lesions in the xenograft compared to the primary tumor. These data suggest that the genome in retinoblastoma is more stable than previously believed and there are relatively few recurrent genetic lesions in known cancer pathways other than the RB1 pathway.

  Study phs000352