European-American individuals of the GENOA cohort participating in the Genetics of Microangiopathic Brain Injury substudy, which investigates the genetic basis of alteration in brain structure detectable by magnetic resonance imaging.
No associated publication
Sex, Age, Specimen partView Samples
We used microarrays to identify the variation of basal gene expression level among 287 lymphoblastoid cell lines.
Radiation pharmacogenomics: a genome-wide association approach to identify radiation response biomarkers using human lymphoblastoid cell lines.
Specimen partView Samples
Background: Prostate cancer (PC), a complex disease, can be relatively harmless or extremely aggressive. To identify candidate genes involved in causal pathways of aggressive PC, we implemented a systems biology approach by combining differential expression analysis and co-expression network analysis to evaluate transcriptional profiles using lymphoblastoid cell lines from 62 PC patients with aggressive phenotype (Gleason grade > 8) and 63 PC patients with nonaggressive phenotype (Gleason grade < 5). From 13935 mRNA genes and 273 microRNAs tested, we identified significant differences in 1100 mRNAs and 7 microRNAs with false discovery rate < 0.01. We also identified a co-expression module demonstrating significant association with the aggressive phenotype of PC (p=3.67x10-11). The module of interest was characterized by over-representation of cell cycle-related genes (false discovery rate = 3.50x10-50). From this module, we further defined 20 hub genes that were highly connected to other genes. Interestingly, five of the 7 differentially expressed microRNAs have been implicated in cell cycle regulation and two (miR-145 and miR-331-3p) are predicted to target three of the 20 hub genes. Ectopic expression of these two microRNAs reduced expression of target hub genes and subsequently resulted in cell growth inhibition and apoptosis. These results suggest that cell cycle is likely to be a molecular pathway causing aggressive phenotype of PC. Further characterization of cell cycle-related genes (particularly, the hub genes) and miRNAs that regulate these hub genes could facilitate identification of candidate genes responsible for the aggressive phenotype and lead to a better understanding of PC etiology and progression [Cancer Res 2009;69(24):94907].
Gene networks and microRNAs implicated in aggressive prostate cancer.
Cell lineView Samples
Most human tumors have abnormal numbers of chromosomes, a condition known as aneuploidy. The mitotic checkpoint is an important mechanism that prevents aneuploidy through restraining the activity of the anaphase-promoting complex (APC). USP44 was identified as a key regulator of APC activation that maintains the association of MAD2 with the APC co-activator Cdc20. However, the physiological importance of USP44 and its impact on cancer biology are unknown. Here, we show that USP44 is required to prevent tumors in mice and is frequently down-regulated in human lung cancer. USP44 inhibits chromosome segregation errors independently of its role in the mitotic checkpoint by regulating proper centrosome separation, positioning, and mitotic spindle geometry, functions that require direct binding to the centriole protein, centrin. These data reveal a new role for the ubiquitin system in mitotic spindle regulation and underscore the importance of USP44 in the pathogenesis of human cancer.
USP44 regulates centrosome positioning to prevent aneuploidy and suppress tumorigenesis.
Sex, Disease, Disease stageView Samples
Background: Expression level of many genes shows abundant natural variation in human populations. The variations in gene expression are believed to contribute to phenotypic differences. Emerging evidence has shown that microRNAs (miRNAs) are one of the key regulators of gene expression. However, past studies have focused on the miRNA target genes and use loss- or gain-of-function approach that may not reflect natural association between miRNA and mRNAs. Methodology/Principal Findings: To examine miRNA regulatory effect on global gene expression under endogenous condition, we performed pair-wise correlation coefficient analysis on expression levels of 366 miRNAs and 14,174 messenger RNAs (mRNAs) in 90 immortalized lymphoblastoid cell lines, and observed significant correlations between the two species of RNA transcripts. We identified a total of 7,207 significantly correlated miRNA-mRNA pairs (false discovery rate q <0.01). Of those, 4,085 pairs showed positive correlations while 3,122 pairs showed negative correlations. Gene ontology analyses on the miRNA-correlated genes revealed significant enrichments in several biological pathways related to cell cycle, cell communication and signal transduction. Individually, each of three miRNAs (miR-331, -98 and -33b) demonstrated significant correlation with the genes in cell cycle-related biological processes, which is consistent with important role of miRNAs in cell cycle regulation. Surprisingly, most miRNA-correlated genes were not direct targets predicted by mRNA target prediction program, TargetScan, suggesting indirect endogenous relationship between miRNAs and their correlated mRNAs. Conclusions/Significance: This study demonstrates feasibility of using naturally expressed transcript profiles to identify endogenous correlation between miRNA and miRNA. By applying this genome-wide approach, we have identified thousands of miRNA-correlated genes and revealed potential role of miRNAs in several important cellular functions. The study results along with accompanying data sets will provide a wealth of high-throughput data to further evaluate the miRNA-regulated genes and eventually in phenotypic variations of human populations.
Genome-wide transcriptional profiling reveals microRNA-correlated genes and biological processes in human lymphoblastoid cell lines.
Cell lineView Samples
Multiple myeloma is a relatively common B-cell malignancy that is currently incurable. Certain recurrent genetic abnormalities characteristics of different genetic subtypes have been described. Hyperdiploid myeloma characterized by recurrent trisomies is the most common genetic subtypes. However little is know about it's biology. Another common genetic abnormality is chromosome 13 deletion which is also associated with inferior prognosis. This abnormality is already present at the pre-malignant MGUS stage and is clonally selected with disease progression. Although it is biologically and clinically important the molecular consequence of chromosome 13 deletion is unknown.
Molecular dissection of hyperdiploid multiple myeloma by gene expression profiling.
No sample metadata fieldsView Samples
Both cigarette smoking and obesity have been implicated in increased risk of clear cell renal cell carcinoma (ccRCC); however, there are limited data regarding the molecular mechanisms that underlie these associations. We used a multi-stage design to identify and validate specific molecular targets that are associated with smoking or obesity-related ccRCC.
ANKS1B is a smoking-related molecular alteration in clear cell renal cell carcinoma.
Specimen part, SubjectView Samples
Evaluation of differential expression between CLL patients in a chemoimmunotherapy trial with age-matched controls
LEF-1 is a prosurvival factor in chronic lymphocytic leukemia and is expressed in the preleukemic state of monoclonal B-cell lymphocytosis.
Specimen part, Disease, Disease stageView Samples
Whole-genome gene expression analysis has been successfully utilized to diagnose, prognosticate, and identify potential therapeutic targets for cardiovascular disease. However, the utility of this approach to identify outcome-related genes and dysregulated pathways following first-time myocardial infarction (AMI) remains unknown and may offer a novel strategy to detect affected expressome networks that predict long-term outcome. Whole-genome microarray and targeted cytokine expression profiling on blood samples from normal cardiac function controls and first-time AMI patients within 48-hours post-MI revealed expected differential gene expression profiles enriched for inflammation and immune-response pathways in AMI patients. To determine molecular signatures at the time of AMI that could prognosticate long-term outcomes, transcriptional profiles from sub-groups of AMI patients with (n=5) or without (n=22) any recurrent events over an 18-month follow-up were compared. This analysis identified 559 differentially expressed genes. Bioinformatic analysis of this differential gene set for associated pathways revealed 1) increasing disease severity in AMI patients is associated with a decreased expression of the developmental epithelial-to-mesenchymal transition, and 2) modulation of cholesterol transport genes that include ABCA1, CETP, APOA1, and LDLR is associated with clinical outcome. In conclusion, differentially regulated genes and modulated pathways were identified that predicted recurrent cardiovascular outcomes in first-time AMI patients. This cell-based approach for risk stratification in AMI warrants a larger study to determine the role of metabolic remodeling and regenerative processes required for optimal outcomes. A validated transcriptome assay could represent a novel, non-invasive platform to anticipate modifiable pathways and therapeutic targets to optimize long-term outcome for AMI patients.
Transcriptome from circulating cells suggests dysregulated pathways associated with long-term recurrent events following first-time myocardial infarction.
Specimen part, DiseaseView Samples