Search Results - EGA European Genome-Phenome Archive

This study explored and validated the clinical application of targeted NGS of circulating tumor DNA in identifying tumor-specific mutations and uncovering clinical actionable targets in a variety of solid tumors in large patient cohorts.

Cancer is a disease of genetic alterations. Comprehensive genetic diagnosis is needed to match each patient to appropriate cancer therapy. However, acquisition of representative tumor samples is invasive and often infeasible. Circulating tumor DNA (ctDNA) is a promising non-invasive biomarker for cancer mutational profiling. Here we implemented targeted next generation sequencing (NGS) with a customized pan-cancer gene panel on 605 clinical ctDNA samples in multiple cancer types. Overall, tumor-specific mutations were identified in 87% of ctDNA samples, with mutation spectra highly concordant with their matched tumor tissues. 71% of patients have at least one clinical actionable mutation with 76% of which have suggested drugs approved or in clinical trials. In particular, our study reveals a unique mutation spectrum in Chinese lung cancer patients, which could be used to guide treatment decision and monitor the appearance of drug-resistant mutations. Taken together, our study demonstrated the clinical utility of target NGS-based ctDNA mutational profiling to guide cancer treatment decision.

Study EGAS00001002251

Cryptococcosis in Previously Healthy Adults

Cryptococcus is a fungus that causes infections most commonly in immunocompromised patients, such as those with AIDS and solid organ transplant recipients and is currently responsible for an estimated 15% of all AIDS-related deaths globally. However, in developed countries, approximately one-third of cases fall outside these groups such that cryptococcal meningoencephalitis (CM) has become the most common cause of non-viral meningitis in the U.S. Within the U.S., approximately 15-20% have no readily identifiable immune defect and cryptococcal infection in these hosts has a mortality rate of 30-50% despite optimal antifungal therapy. NIH Clinical Study Protocol 93-I-0106 (NCT00001352). The objectives of this protocol can be broadly categorized as: 1) Characterize the immunologic and genetic mechanisms predisposing to disease acquisition; 2) Understand the post-infectious inflammatory response and distinguish its consequences from those directly due to fungal growth; and 3) Management of post-infectious neuro-inflammatory syndromes associated with cryptococcal meningitis (CM). This protocol recruits patients who have microbiological evidence of cryptococcal neurologic or non-CNS disease (typically pulmonary or bone). Cerebrospinal fluid (CSF) and blood samples collected during clinical care are used to measure serum and CNS cellular and soluble cytokines as well as to perform in-situ immunohistochemistry. CSF and blood samples are also collected to measure transcriptional (gene expression), proteomic (protein), and lipidomic (lipids) changes that occur throughout disease and treatment. Observational data detailing audiological, ophthalmological and neurocognitive deficits in these patients is also recorded. We have recently described a post-infectious inflammatory syndrome (PIIRS) associated with cryptococcal meningoencephalitis (CM) which can be best described as a neuro-inflammatory state during which CM patients present with altered mental status (Montreal Cognitive Assessment Score As part of the protocol, we treat patients for either microbiological failure or neuroinflammatory sequelae by conventional therapies utilizing FDA-approved pharmaceuticals at FDA-approved doses. To understand and identify the predominant biological pathways responsible for PIIRS neuroinflammation, we examined patient CSF at baseline (at time of PIIRS diagnosis) and post-treatment with different FDA-approved pharmaceuticals at FDA-approved doses compared to CSF from non-PIIRS donors. Upstream pathway analysis of differentially expressed genes in the CSF of PIIRS patients revealed a prominent role for the JAK/STAT pathway in the pathogenesis of PIIRS and support the use of the JAK inhibitor, ruxolinib, as a pathway-instructed therapy to treat PIIRS patients. Data available through dbGaP: single cell RNA sequencing (scRNA-seq) data from CSF cells of a patient with PIIRS at the time of diagnosis and following treatment with steroids (1g solumedrol/day) and NanoString transcriptional data from CSF cells of patients with PIIRS at the time of diagnosis compared to CSF cells from non-PIIRS donors.

Study phs003871

sn-RNAseq profiling of the impact of a cytokine storm model in human cardiac organoids

We developed conditions to model conditions of diastolic dysfunction caused by inflammatory factors in human cardiac organoids. Our organoid model is based on conditions promoting maturation (Mills et al., PNAS, 2017 and Voges et al., In Revision) and incorporating human pluripotent stem cell derived cardiomyocytes, epicardial cells, fibroblasts, endothelial cells and pericytes. Following 15 days of differentiation (Voges et al., Development, 2017) we formed human cardiac organoids incorporating both our multicellular differentiation (Mills et al., PNAS, 2017) and additional endothelial cells (Voges et al., In Revision). After another 12 days of maturation in 5 days maturation medium and 5 days weaning medium (Voges et al., In Revision) human cardiac organoids were either treated with weaning medium or “cardiac cytokine storm” comprised of 100 ng/ml IFNg, 10 ng/ml IL-1 β and 10 µg/ml poly(I:C). After 48 hours human cardiac organoids were harvested and snap frozen in -80C before nuclei isolation and single nuclei RNA sequencing.Pooled hCO (~40) were homogenized in 4 mL lysis buffer (300 mM sucrose, 10 mM Tris-HCl (pH = 8), 5 mM CaCl2, 5 mM magnesium acetate, 2 mM EDTA, 0.5 mM EGTA, 1 mM DTT)(all Sigma-Aldrich) with 30 strokes of a dounce tissue grinder (Wheaton). Large pieces of hCO were allowed to settle and homogenate was passed through pre-wetted 40 µm cell strainers (Becton Dickinson). Remaining hCO material in the douncer was resuspended in 4 mL and the douncing and filtering steps were repeated twice. All steps of the homogenization were performed on ice. The filtered homogenate was centrifuged at 1500 x g for 5 min at 4oC. Nuclei pellets were then re-suspended in PBS. A fraction of resuspended nuclei were then stained with hoechst nuclear stain (1:500 dilution) and counted on a haemocytometer under fluorescent microscope.The nuclei were then re-centrifuged (1500 x g for 5 min at 4°C) and resuspended at a density to load ~5,000 nuclei per sample. Cell were loaded into the Chromium Controller (10X Genomics) for gel bead emulsion (GEM) formation. Library preparation was conducted according to the manufacturer’s recommended protocol using the Chromium Next GEM Single Cell 3’ GEM, Library & Gel Bead Kit v3.1. Libraries were sequenced on the NextSeq 500/550 v2 (Illumina) with 150 bp reads.In the snRNA-seq we note the lower than expected percentage of non-myocytes and the loss of endothelial cells (Mills et al., PNAS, 2017 and Voges et al., In Revision), indicating the protocol requires further optimization for hCO samples.

Study EGAS00001005174

The MD Anderson Colorectal Cancer Case Control Study

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the US. Driven by common disease common variants hypothesis, genome-wide association studies only identified a number of common susceptibility loci that explained a small portion of CRC heritability. We conducted a case-control study using whole exome sequencing to identify rare genetic variants with intermediate effect size that predispose individuals to colorectal cancer.

Study phs002691

Project for Development of Innovative Research on Cancer Therapeutics;Shuttle system between petient-derived xenograft and ex vivo culture for innovative platform of evaluating drug sensitivity.

We developed CTOS (cancer tissue-originated spheroid) panel covering diversity among patients for colorectal cancer, lung cancer and cervical small cell carcinoma. We then carried out exome sequence analysis of tumor tissues, cell lines and CTOS derived from patients to validate qualitative changes in preparation, culture, cell line, transplantation and passage of CTOS pathologically, biochemically, molecular biologically.

Study JGAS000089

Target bisulfite sequencing of endometrial cancer

This study aims to investigate epigenetic alterations in the HLA-A locus in endometrial cancer. Targeted bisulfite sequencing was performed to evaluate DNA methylation status of the HLA-A region in a cohort of endometrial cancer samples. The resulting data were used to assess the association between HLA-A methylation and tumor immune microenvironment. These findings contribute to understanding the role of epigenetic regulation of antigen presentation in endometrial cancer.

Study JGAS000897

Whole-genome sequencing identifies ADGRG6 enhancer mutations and FRS2 duplications as angiogenesis-related drivers in bladder cancer

Bladder cancer is one of the most common and highly vascularized cancers. To better understand its genomic structure and underlying etiology, we conducted whole-genome sequencing in 65 urothelial bladder carcinomas (the most common type of bladder cancer) and identified recurrent genetic alterations in a set of angiogenesis genes, facilitating the understanding of molecular mechanisms underlying pathological angiogenesis in this type of cancer.

Study EGAS00001003388

Detroit Research on Cancer Survivors (ROCS) and Disparities and Cancer Epidemiology - Colorectal Cancer (DANCE)

The goals for this study were as follows:1. Enroll a total of 5,060 African Americans newly diagnosed with cancer into the Detroit Research on Cancer Survivors (Detroit ROCS) Cohort. These population-based cases will be ascertained through the Detroit Metropolitan Detroit Cancer Surveillance System (MDCSS), a founding member of the NCI SEER Program. Participation at baseline will include a written, web-based, or telephone interview, saliva and/or blood collection, and tumor block retrieval, with detailed cancer-related information coming from the MDCSS registry and medical records.2. Enroll a subgroup of colorectal cancer patients identified through the Louisiana Tumor Registry (LTR). An additional 500 colorectal cancer patients, approximately half non-Hispanic white and half African American, will be identified through the LTR and enrolled into the ROCS protocol. The survey is the same survey administered to the ROCS cohort. The Louisiana (“DANCE-CRC”) cohort will not be followed beyond baseline, and blood will not be collected (tumor tissue, however, will be collected, deidentified, and sent for processing through Dr. Rozek's laboratory at Georgetown University).The proposed cohorts will provide for a broad research agenda evaluating cancer outcomes in African Americans across a variety of factors from individual, provider, health care system and community perspectives. These factors include tumor characteristics driving individualized treatment planning, quality of life after a diagnosis and recurrence. Utilizing the MDCSS registry, we will enroll a large population-based sample of African-American cases with lung, breast, colorectal, and prostate cancers and their caregivers resulting in a cohort that will provide substantial benefit to the cancer research community. KCI has a strong history of research in the African-American community and the faculty represents a breadth of experience that includes clinical oncology, genetic epidemiology, environmental exposures, quality of life, treatment decision making, racism/discrimination, and health behaviors. Drs. Schwartz and Beebe-Dimmer have been and will continue to be generous collaborators with other institutions to ensure that this resource will be extensively utilized. The proposed overall cohort will be the only one of its kind, to our knowledge, filling a substantial gap in our understanding of the determinants driving cancer outcomes in African Americans. In addition to registry data detailing cancer specifics, yearly surveys have collected information about individualized treatment experiences, heath histories, family histories, quality of life after a diagnosis, recurrence and caregiving. Population: Adult cancer survivors (see inclusion criteria in next section) Molecular Technologies: Genotyping: Infinium Expanded Multi-Ethnic Genotyping Array (MEGAEX) DNA Sequencing: Illumina NovaSeq X Plus using XLEAP-SBS (sequencing by synthesis) Whole genome sequencingPrincipal Findings: The preliminary data collected reinforces differences by race in factors affecting cancer outcomes. Variants in DNA damage repair genes and HOXB13 may be important cancer risk factors for Black men diagnosed with prostate cancer, and are more frequently observed in men with a family history of cancer. ROCS participants reported high rates of a family history of cancer. The high rate of eligibility for Cancer genetic counseling among ROCS participants supports the need for interventions to increase referrals and uptake of genetic counseling among African Americans 60% of ROCS participants reported participating in regular physical activity (PA), with 24% reporting ≥150 min/wk. There were no differences by sex, but prostate cancer survivors were the most likely to report participating in regular PA, whereas lung cancer survivors were the least likely. Survivors who reported participating in regular PA reported higher health-related quality of life and lower depression. More African American than White survivors reported financial hardship and limiting care. More White than African American survivors reported utilizing assets, while more African American survivors reported cancer-related debt. Data available in dbGaP: Individual phenotype data Individual genotype data Individual sequencing dataSample types: Germline DNA

Study phs003116

SNP array datas of 'Matched' cancer/PNE

SNP array data of 31 Matched cancer/PNE samples

Study EGAS00001003331

DNA Methylation Markers and Pancreatic Cancer Risk in 3 Cohort Studies (NHS, PHS, HPFS)

Pancreatic cancer is the 4th leading cause of cancer deaths in the US. Due to the lack of early symptoms, pancreatic cancer is difficult to identify at early stages and no screening is available for the general population. Identifying pancreatic cancer at earlier stages could significantly improve survival with increased opportunities for surgery. New high-dimensional arrays designed to measure DNA methylation levels at hundreds of thousands of CpG sites throughout the genome have opened opportunities to examine the role of DNA methylation in cancer risk using blood samples. Using this method, archived samples from prospective studies can be used to examine early changes in the DNA methylation levels in individuals who develop cancer months or years later, providing new opportunities to better understand biological mechanisms and, perhaps, identify biomarkers for early detection. Pancreatic cancer cases and matched controls were obtained from 3 large cohort studies, the Nurses' Health Study (NHS), the Physician's Health Study (PHS), and the Health Professionals Follow-up Study (HPFS), to measure DNA methylation in stored buffy coats using a nested case-control study design.

Study phs001917

Genetic Epidemiology of Ovarian Cancer Histotypes

Epithelial ovarian cancer is a highly fatal malignancy with known genetic etiology; however, it is estimated that a substantial portion of narrow sense heritability remains to be discovered. The goal of this research was to use genetic information from distantly related ovarian cancer cases to identify regions of the genome that may harbor rare risk variants for epithelial ovarian cancer. The study was conducted in the setting of the Utah Population Database, a statewide data resource in which extensive ancestry data are linked to Utah Cancer Registry records. Focusing on families with a statistically significant excess risk of epithelial ovarian cancer, we used the Infinium Global Screening Array v.3.0 to generate germline genotyping data for distantly related cases. We then applied Shared Genomic Segment Analysis to each set of related cases to identify genomic regions that may harbor ovarian cancer risk variants. Eleven regions were identified. Genotype data are available through dbGaP for one case from each pedigree. Genotype data from other ovarian cancer cases within the high-risk pedigrees as well as the pedigrees' corresponding structures can be requested and made available with approval from the Utah Resource for Genetic and Epidemiologic Research (RGE).

Study phs003140

noninvasive lung cancer subtyping

Accurate diagnosis of lung cancer is important for treatment decision-making. Currently, the gold standard for diagnosing histological subtypes of lung cancer relies on tumor biopsies. Recently, liquid biopsy, particularly cell-free DNA (cfDNA), has shown promising results in cancer detection and classification. In this study, we investigated the potential of cfDNA methylome for the noninvasive classification of lung cancer histological subtypes. Specifically, we focused on the two most prevalent lung cancer subtypes, lung adenocarcinoma and lung squamous cell carcinoma. Using a fragment-based marker discovery approach, we identified robust subtype-specific methylation markers from tumor samples. These markers were successfully validated in independent cohorts and associated with subtype-specific transcription activity. Leveraging these markers, we constructed a subtype classification model using cfDNA methylation profiles, achieving an AUC of 0.808 in the cross-validation and an AUC of 0.747 in the independent validation. Additionally, tumor copy number variations inferred from cfDNA methylome analysis revealed potential implications for treatment selection. In summary, our study demonstrates the potential of cfDNA methylome analysis for noninvasively lung cancer subtyping, offering insights for cancer monitoring and early detection.

Study EGAS00001007717

Intra-prostatic tumour evolution, steps in metastatic spread and histogenomic associations revealed by integration of multi-region whole genome sequencing with histopathological features

We performed whole genome sequencing on 42 prostate cancer samples from the prostate, seminal vesicles and regional lymph nodes of five treatment-naive patients with locally advanced disease who underwent radical prostatectomy. Using cancer cell fractions computed from single nucleotide variants and copy number alterations, we reconstructed the tumour phylogenies, which in turn allowed us to infer key molecular steps in the progression of prostate cancer in these individuals. We mapped the clonal composition of cancer sampled across the prostate in each individual and inferred the routes of spread of cancer cells within the prostate and to seminal vesicles and lymph nodes.

Study EGAS00001007438

Large Cancer Fingerprint Screening for Detection of Minimal Residual Disease.

We describe an approach for large cancer fingerprint screening and its application to cell-free DNA from patients with cancer. Our approach involves tracking somatic mutations identified from patients' tumor biopsies, in the cell-free DNA from a blood draw.

Study phs001977

exploration of biomarkers in colorectal cancer

Targeted therapies based on the molecular and histological features of cancer types are becoming standard practice. To understand the molecular basis of colorectal cancer, we performed CAGE (Cap Analysis of Gene Expression) to quantify promoter activities on 45 colorectal cancers.

Study JGAS000489

Whole-genome cfDNA TAPS sequencing data from 91 people with various types of cancer and from non-cancer controls

TAPS data in the form of BAM files from 214 samples: plasma (at 80x) and matched germline (at 30x) pairs from 61 cancer and 30 non-cancer subjects, fresh-frozen matched tumour biopsies (at 80x) from 16 subjects, as well as several follow-up plasma samples (at 80x) from 10 subjects with colorectal cancer.

Dataset EGAD50000000996

Genetic Epidemiology of Lung Cancer Consortium GWAS of Familial Lung Cancer

Familial lung cancer cases were collected by the Genetic Epidemiology of Lung Cancer Consortium (GELCC) recruitment sites: University of Cincinnati, Karmanos Cancer Institute at Wayne State University, Louisiana State University Health Sciences Center-New Orleans, Mayo Clinic, and Medical College of Ohio. Familial cases for this study came from three sources: 1) one case each from families (at least 3 affected lung cancer cases in the family) included in the linkage analysis; 2) one case from linkage-eligible families (at least 3 affected lung cancer cases in the family) but where there were insufficient biospecimens available to make them informative for linkage analysis; and 3) one case from families not eligible for the linkage study with a family history of at least one first or second degree relative affected with lung cancer. Unrelated controls were selected from 1) among the spouses of family members, thus matching on socio-economic status (SES) and ethnicity (typically) of the cases or 2) from case-control studies of lung cancer conducted in the same location in which the linkage families were collected and matched on age, sex, and race. All cases and controls self-reported as European American. Biospecimens used for normal DNA extraction included blood, saliva or mouthwash. Some samples underwent whole genome amplication.

Study phs000629

Discovery of Colorectal Cancer Susceptibility Genes in High-Risk Families

Colorectal cancer remains one of the most common cancers in the US with 146,970 new diagnoses and 49,920 deaths estimated for 2009. Colon cancer is also one of the most familial of cancers. Individuals with a first-degree relative with colon cancer have a 2- to 3-fold increased risk, and those with more than one first-degree relative with colon cancer, or a single first-degree relative affected at age 50 years, have a 3- to 6-fold greater risk than those with no family history. The most prominent high-risk colorectal cancer susceptibility genes, APC, MLH1, MSH2, MSH6, and PTEN, were all discovered more than a decade ago. Currently, mutation screening of these genes, plus a short list of additional genes that are responsible for a very small fraction of colorectal cancer, plays an important role in the clinical management of individuals with a strong family history of the disease or syndromic evidence for the presence of a gene mutation. At the other end of the risk spectrum, genome-wide association studies have identified a number of common alleles with very modest effects on colorectal cancer risk; their clinical utility has yet to be established. However, taken together, the known spectrum of genetic effects only explain about one quarter of the overall familial excess of colorectal cancer. It should be emphasized that, at present, the vast majority of individuals seen at familial cancer clinics are counseled on the basis of their family history alone because they do not have mutations in the known susceptibility genes. Accordingly, the long-term objective of this project is to identify the majority of genes responsible for the unexplained component of inherited colorectal cancer risk. Nextgen DNA sequencing is well suited for application to research questions in genetic susceptibility for which linkage analysis is confounded by extensive genetic heterogeneity. Taking advantage of unparalleled familial cancer genetics resources available through the Utah Population Database, candidate genes have been identified by sequencing all of the gene exons in the human genome from a series of colorectal cancer cases with a very strong family history of colorectal cancer not explained by one of the currently known high-risk susceptibility genes.

Study phs001787

15 Healthy controls, 25 conlonrectal cancer patients without liver metastasis and 24 conlonrectal cancer patients with liver metastasis (target capture)

Dataset EGAD00001009838

Chugai_colorectal_organoid_sequencing

Genomic and transcriptomic characterization of drug-resistant colon cancer stem cell lines.

Study EGAS00001000872

Automated system for scoring hematoxylin and eosin-stained ovarian cancer sections by identifying single cells uncovered that stromal cell ratio is a significant predictor for overall survival and progression-free survival.

Concerted efforts in genomic studies have revealed profound insights in prognostic ovarian cancer subtypes. On the other hand, abundant histology slides have been generated to date, yet their uses remain very limited and largely qualitative. Our goal is to develop automated histology analysis as an alternative subtyping technology for ovarian cancer that is cost-efficient and do not rely on DNA quality. We develop an automated system for scoring hematoxylin and eosin-stained (H&E) primary tumour sections of 91 late-stage ovarian cancer to identify single cells including cancer and stromal cells. We demonstrated high accuracy of our system based on expert pathologists’ scores (cancer=97.1%, stromal=89.1%) as well as compared to immunohistochemistry scoring (correlation=0.87). Quantitative stromal cell ratio is significantly associated with poor overall survival after controlling for clinical parameters including debulking status and age (multivariate analysis p=0.0021, HR=2.54, CI=1.40-4.60) and progression-free survival (multivariate analysis p=0.022, HR=1.75, CI=1.09–2.82). We demonstrate how automated image analysis enables objective quantification of microenvironmental composition of ovarian tumours. Our analysis reveals a strong effect of the tumour microenvironment on ovarian cancer progression and highlights the potential of therapeutic interventions that target the stromal compartment or cancer-stroma signalling in the stroma-high, late-stage ovarian cancer subset.

Study EGAS00001001694

RNAseq_Pulldown_

We propose to definitively characterise the somatic genetics of ER+ve, HER2-ve breast cancer through generation of comprehensive catalogues of somatic mutations in breast cancer cases by high coverage genome sequencing coupled with integrated transcriptomic and methylation analyses. In this experiment cDNA derived form Breast Cancer Cell lines was used in an Agilent whole exome pulldown experiment.

Study EGAS00001000230

12321 results for "cancer rna-seq"

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