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- 2024-11-27 - 5 Formulär, 1 Item-grupp, 1 Dataelement, 1 Språk
Item-grupp: IG.elig
Principal Investigator: Theodora S. Ross, MD, PhD, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA, and Department of Cancer Genetics, UT Southwestern Medical Center, Dallas, TX, USA MeSH: Neoplasms,Breast Neoplasms,Ovarian Neoplasms,Peritoneal Neoplasms,Skin Neoplasms,Esophageal Neoplasms,Thyroid Neoplasms,Urinary Bladder Neoplasms,Endometrial Neoplasms,Fallopian Tube Neoplasms,Melanoma,Testicular Neoplasms,Bile Duct Neoplasms,Lung Neoplasms,Colonic Neoplasms,Adrenocortical Carcinoma,Carcinoma, Renal Cell,Colonic Polyps,Adenomatous Polyposis Coli,Lymphoma, Large B-Cell, Diffuse,Pheochromocytoma,Paraganglioma,Leiomyoma,Hemangioblastoma,Hyperparathyroidism,Pancreatic Neoplasms,Vulvar Neoplasms,Brain Neoplasms,Liver Neoplasms,Kidney Neoplasms,Prostatic Neoplasms,Glioblastoma,Oncocytoma, renal https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000942 Despite the potential of whole-genome sequencing (WGS) to improve patient diagnosis and care, the empirical value of WGS in the cancer genetics clinic is unknown. We performed WGS on members of two cohorts of cancer genetics patients: those with BRCA1/2 mutations (n = 176) and those without (n = 82). Initial analysis of potentially pathogenic variants (PPVs, defined as nonsynonymous variants with allele frequency 1% in ESP6500) in 163 clinically-relevant genes suggested that WGS will provide useful clinical results. This is despite the fact that a majority of PPVs were novel missense variants likely to be classified as variants of unknown significance (VUS). Furthermore, previously reported pathogenic missense variants did not always associate with their predicted diseases in our patients. This suggests that the clinical use of WGS will require large-scale efforts to consolidate WGS and patient data to improve accuracy of interpretation of rare variants. While loss-of-function (LoF) variants represented only a small fraction of PPVs, WGS identified additional cancer risk LoF PPVs in patients with known BRCA1/2 mutations and led to cancer risk diagnoses in 21% of non-BRCA cancer genetics patients after expanding our analysis to 3209 ClinVar genes. These data illustrate how WGS can be used to improve our ability to discover patients' cancer genetic risks. "Reprinted from doi:10.1016/j.ebiom.2014.12.003, with permission from EBioMedicine."

pht004834.v1.p1

1 Item-grupp 5 Dataelement

pht004835.v1.p1

1 Item-grupp 5 Dataelement

pht004836.v1.p1

1 Item-grupp 16 Dataelement

pht004837.v1.p1

1 Item-grupp 5 Dataelement
- 2024-03-16 - 5 Formulär, 1 Item-grupp, 11 Dataelement, 1 Språk
Item-grupp: pht004610

pht004611.v1.p1

1 Item-grupp 8 Dataelement

pht004607.v1.p1

1 Item-grupp 5 Dataelement

pht004608.v1.p1

1 Item-grupp 5 Dataelement

pht004609.v1.p1

1 Item-grupp 5 Dataelement
- 2023-11-06 - 6 Formulär, 1 Item-grupp, 2 Dataelement, 1 Språk
Item-grupp: pht010322

pht010323.v2.p1

1 Item-grupp 2 Dataelement

pht010324.v2.p1

1 Item-grupp 4 Dataelement

pht010325.v1.p1

1 Item-grupp 2 Dataelement

pht010326.v2.p1

1 Item-grupp 5 Dataelement

Eligibility

1 Item-grupp 9 Dataelement
- 2023-01-09 - 4 Formulär, 1 Item-grupp, 2 Dataelement, 1 Språk
Item-grupp: pht003322
Principal Investigator: Adam Bass, Dana-Farber Cancer Institute, Boston, MA; Broad Institute, Cambridge MA; Brigham and Women's Hospital, Boston, MA, USA MeSH: Esophageal Neoplasms https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000598 The incidence of esophageal adenocarcinoma (EAC) has risen 600% over the last 30 years. When coupled to the five-year survival rate of only 15% for this disease, identification of new therapeutic targets for EAC is of great importance. Here, we analyze the mutational spectra identified from the whole genome sequencing of 16 EACs and complete exome sequencing of 149 EAC tumors and matched germline samples. We identify a novel mutation signature marked by high prevalence of A to C transversions at AA*(N) trinucleotides. Notably, the development of EAC is preceded by pathologic intestinal metaplasia of the lower esophagus, Barrett's esophagus, itself a response to injury from gastric-esophageal reflux disease (GERD). Thus, we hypothesize to represent these AA*(N) mutations to a novel signature of GERD-induced mutagenesis. Analysis of the exome data identified 26 genes subject to statistically significant recurrent mutation. Of these 26 genes, only TP53, CDKN2A, SMAD4, and PIK3CA had been previously implicated in EAC. Novel mutations include those targeting chromatin modifying factors and novel candidate contributors to EAC: SPG20, TLR4, ELMO1 and DOCK2. Of these, ELMO1 and DOCK2 are notably direct dimerization partners that act to activate Rac1 to enhance cellular invasiveness, thus generating new hypotheses about the potential for the Rac1 pathway to be a novel target for therapy of EAC. "Reprinted from 'Unraveling the mutational complexity of esophageal adenocarcinoma', with permission from Nature Genetics."

pht003323.v2.p2

1 Item-grupp 3 Dataelement

pht003324.v2.p2

1 Item-grupp 3 Dataelement

pht003325.v2.p2

1 Item-grupp 5 Dataelement
- 2022-10-12 - 5 Formulär, 1 Item-grupp, 2 Dataelement, 1 Språk
Item-grupp: pht001256
Principal Investigator: Zhiheng Pei, MD, PhD, NYU Langone Medical Center, New York, NY, USA MeSH: Esophageal Adenocarcinoma,Barrett's Esophagus,GERD https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000260 The distal esophagus is an important anatomical area where gastric acid reflux can cause reflux esophagitis (RE), Barrett's esophagus (BE) (intestinal metaplasia), and esophageal adenocarcinoma (EA). The incidence of EA has increased 6-fold in the U.S. since the 1970s, parallel to a significant increase in the prevalence of gastroesophageal reflux diseases (GERD). Although specific host factors might predispose one to disease risk, such a rapid increase in incidence must be predominantly environmental. The cause remains unknown. Our hypothesis is that changes in the foregut microbiome are associated with EA and its precursors, RE and BE in the GERD sequence. We will conduct a case control study to characterize the microbiome in every stage of the GERD sequence as well as analyze the trend in changes in the microbiome along disease progression toward EA. Specific Aim 1. To conduct a comprehensive population survey of the foregut microbiome and demonstrate its association with GERD sequence, by a 16S rRNA gene survey. We will analyze samples of the foregut microbiome at three anatomic loci: mouth, distal esophagus, and gastric corpus. Changes of the microbiota in the distal esophagus will be correlated with the phenotypes. Spatial relationship between the esophageal microbiota and upstream (mouth) and downstream (stomach) foregut microbiotas as well as temporal stability of the microbiome-disease association will also be examined. Specific Aim 2. To define distal esophageal metagenome and demonstrate its association with GERD sequence, by shotgun metagenomic analysis. We will first classify samples of the metagenome into metagenotypes by between-sample k-mer distance and correlate the metagenotypes with the four phenotypes. Subsequent detailed analyses will include pathway-disease and gene-disease associations. DNA viruses and fungi, if identified, also will be correlated with the phenotypes. A significant association between the foregut microbiome composition and GERD sequence, if demonstrated, will be the first step for eventually testing the causal hypothesis that an abnormal microbiome is required for the development of the sequence of phenotypic changes toward EA. If EA and its precursors represent a microbial ecological disease, treating the cause of GERD might become possible, for example, by normalizing the microbiome through use of antibiotics, probiotics, or prebiotics. Causative therapy for GERD could prevent its progression and reverse the current trend of increasing incidence of EA.

Eligibility

1 Item-grupp 18 Dataelement

pht001257.v4.p2

1 Item-grupp 3 Dataelement

pht001258.v4.p2

1 Item-grupp 8 Dataelement

pht001259.v4.p2

1 Item-grupp 7 Dataelement
- 2022-10-12 - 4 Formulär, 1 Item-grupp, 3 Dataelement, 1 Språk
Item-grupp: pht002221

pht002222.v1.p1

1 Item-grupp 2 Dataelement

pht002223.v1.p1

1 Item-grupp 5 Dataelement

Eligibility

1 Item-grupp 3 Dataelement

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