Barrett’s Epithelium to Esophageal Adenocarcinoma: Is There a “Point of No Return”?

Background: Esophageal adenocarcinoma (EA) arises from Barrett’s epithelium (BE), and chronic gastroesophageal reflux disease is considered the strongest risk factor for disease progression. All BE patients undergo acid suppressive therapy, surveillance, and BE removal by surgery or endoscopic ablation, yet the incidence of EAC continues to increase. Despite the known side effects and mortality, the one-size-fits-all approach is the standard clinical management as there are no reliable methods for risk stratification.Methods: Paired-end Illumina NextSeq500 RNA sequencing was performed on total RNA extracted from 20-week intervals (0, 20, 40, and 60 W) of an in vitro BE carcinogenesis (BEC) model to construct time series global gene expression patterns (GEPs). The cells from two strategic time points (20 and 40 W) based on the GEPs were grown for another 20 weeks, with and without further acid and bile salt (ABS) stimulation, and the recurrent neoplastic cell phenotypes were evaluated.Results: Hierarchical clustering of 866 genes with ≥ twofold change in transcript levels across the four time points revealed maximum variation between the BEC20W and BEC40W cells. Enrichment analysis confirmed that the genes altered ≥ twofold during this window period associated with carcinogenesis and malignancy. Intriguingly, the BEC20W cells required further ABS exposure to gain neoplastic changes, but the BEC40W cells progressed to malignant transformation after 20 weeks even in the absence of additional ABS.Discussion: The transcriptomic gene expression patterns in the BEC model demonstrate evidence of a clear threshold in the progression of BE to malignancy. Catastrophic transcriptomic changes during a window period culminate in the commitment of the BE cells to a “point of no return,” and removal of ABS is not effective in preventing their malignant transformation. Discerning this “point of no return” during BE surveillance by tracking the GEPs has the potential to evaluate risk of BE progression and enable personalized clinical management.

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Gene expression patterns in melanocytic cells: candidate markers for early stage and malignant transformation

The Journal of Pathology ◽

10.1002/path.1017 ◽

2001 ◽

Vol 196 (1) ◽

pp. 51-58 ◽

Cited By ~ 10

Author(s):

Clifton B. Meije ◽

Theodorus B. M. Hakvoort ◽

Guido W. M. Swart ◽

Wiete Westerhof ◽

Wouter H. Lamers ◽

...

Keyword(s):

Gene Expression ◽

Malignant Transformation ◽

Early Stage ◽

Expression Patterns ◽

Gene Expression Patterns

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Beyond Field Effect: Analysis of Shrunken Centroids in Normal Esophageal Epithelia Detects Concomitant Esophageal Adenocarcinoma

Bioinformatics and Biology Insights ◽

10.4137/bbi.s311 ◽

2007 ◽

Vol 1 ◽

pp. BBI.S311 ◽

Cited By ~ 4

Author(s):

Florin M. Selaru ◽

Suna Wang ◽

Jing Yin ◽

Karsten Schulmann ◽

Yan Xu ◽

...

Keyword(s):

Gene Expression ◽

Barrett’S Esophagus ◽

Esophageal Adenocarcinoma ◽

Barrett's Esophagus ◽

Expression Patterns ◽

Global Gene Expression ◽

Differentially Expressed ◽

Gene Expression Patterns ◽

Neoplastic Progression ◽

Esophageal Epithelium

Background and Aims Because of the extremely low neoplastic progression rate in Barrett's esophagus, it is difficult to diagnose patients with concomitant adenocarcinoma early in their disease course. If biomarkers existed in normal squamous esophageal epithelium to identify patients with concomitant esophageal adenocarcinoma, potential applications would be far-reaching. The aim of the current study was to identify global gene expression patterns in normal esophageal epithelium capable of revealing simultaneous esophageal adenocarcinoma, even located remotely in the esophagus. Methods Tissues comprised normal esophageal epithelia from 9 patients with esophageal adenocarcinoma, 8 patients lacking esophageal adenocarcinoma or Barrett's, and 6 patients with Barrett's esophagus alone. cDNA microarrays were performed, and pattern recognition in each of these subgroups was achieved using shrunken nearest centroid predictors. Results Our method accurately discriminated normal esophageal epithelia of 8/8 patients without esophageal adenocarcinoma or Barrett's esophagus and of 6/6 patients with Barrett's esophagus alone from normal esophageal epithelia of 9/9 patients with Barrett's esophagus and concomitant esophageal adenocarcinoma. Moreover, we identified genes differentially expressed between the above subgroups. Thus, based on their corresponding normal esophageal epithelia alone, our method accurately diagnosed patients who had concomitant esophageal adenocarcinoma. Conclusions These global gene expression patterns, along with individual genes culled from them, represent potential biomarkers for the early diagnosis of esophageal adenocarcinoma from normal esophageal epithelia. Genes discovered in normal esophagus that are differentially expressed in patients with vs. without esophageal adenocarcinoma merit further pursuit in molecular genetic, functional, and therapeutic interventional studies.

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Gene Expression Patterns as Potential Molecular Biomarkers for Malignant Transformation in Human Keratinocytes Treated with MNNG, Arsenic, or a Metal Mixture

Toxicological Sciences ◽

10.1093/toxsci/kfg124 ◽

2003 ◽

Vol 74 (1) ◽

pp. 32-42 ◽

Cited By ~ 15

Author(s):

D.-S. Bae

Keyword(s):

Gene Expression ◽

Malignant Transformation ◽

Expression Patterns ◽

Human Keratinocytes ◽

Molecular Biomarkers ◽

Gene Expression Patterns ◽

Metal Mixture

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Genomic DNA microarray comparison of gene expression patterns in Paracoccidioides brasiliensis mycelia and yeasts in vitro

Microbiology ◽

10.1099/mic.0.027441-0 ◽

2009 ◽

Vol 155 (8) ◽

pp. 2795-2808 ◽

Cited By ~ 23

Author(s):

Jomar Patrício Monteiro ◽

Karl V. Clemons ◽

Laurence F. Mirels ◽

John A. Coller ◽

Thomas D. Wu ◽

...

Keyword(s):

Gene Expression ◽

Transcription Factors ◽

Genomic Dna ◽

Paracoccidioides Brasiliensis ◽

Expression Patterns ◽

Gene Expression Patterns ◽

Protein Catabolism ◽

Time Points ◽

Over Time

Paracoccidioides brasiliensis is a thermally dimorphic fungus, and causes the most prevalent systemic mycosis in Latin America. Infection is initiated by inhalation of conidia or mycelial fragments by the host, followed by further differentiation into the yeast form. Information regarding gene expression by either form has rarely been addressed with respect to multiple time points of growth in culture. Here, we report on the construction of a genomic DNA microarray, covering approximately 25 % of the genome of the organism, and its utilization in identifying genes and gene expression patterns during growth in vitro. Cloned, amplified inserts from randomly sheared genomic DNA (gDNA) and known control genes were printed onto glass slides to generate a microarray of over 12 000 elements. To examine gene expression, mRNA was extracted and amplified from mycelial or yeast cultures grown in semi-defined medium for 5, 8 and 14 days. Principal components analysis and hierarchical clustering indicated that yeast gene expression profiles differed greatly from those of mycelia, especially at earlier time points, and that mycelial gene expression changed less than gene expression in yeasts over time. Genes upregulated in yeasts were found to encode proteins shown to be involved in methionine/cysteine metabolism, respiratory and metabolic processes (of sugars, amino acids, proteins and lipids), transporters (small peptides, sugars, ions and toxins), regulatory proteins and transcription factors. Mycelial genes involved in processes such as cell division, protein catabolism, nucleotide biosynthesis and toxin and sugar transport showed differential expression. Sequenced clones were compared with Histoplasma capsulatum and Coccidioides posadasii genome sequences to assess potentially common pathways across species, such as sulfur and lipid metabolism, amino acid transporters, transcription factors and genes possibly related to virulence. We also analysed gene expression with time in culture and found that while transposable elements and components of respiratory pathways tended to increase in expression with time, genes encoding ribosomal structural proteins and protein catabolism tended to sharply decrease in expression over time, particularly in yeast. These findings expand our knowledge of the different morphological forms of P. brasiliensis during growth in culture.

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Differential renal gene expression in prehypertensive and hypertensive spontaneously hypertensive rats

AJP Renal Physiology ◽

10.1152/ajprenal.00354.2004 ◽

2005 ◽

Vol 289 (3) ◽

pp. F552-F561 ◽

Cited By ~ 23

Author(s):

J. M. Seubert ◽

F. Xu ◽

J. P. Graves ◽

J. B. Collins ◽

S. O. Sieber ◽

...

Keyword(s):

Gene Expression ◽

Spontaneously Hypertensive Rats ◽

Expression Profiles ◽

Expression Patterns ◽

Differentially Expressed ◽

Gene Expression Patterns ◽

Hypertensive Rats ◽

Spontaneously Hypertensive ◽

Time Points ◽

Age Related

Development of hypertension stems from both environmental and genetic factors wherein the kidney plays a central role. Spontaneously hypertensive rats (SHR) and the nonhypertensive Wistar-Kyoto (WKY) controls are widely used as a model for studying hypertension. The present study examined the renal gene expression profiles between SHR and WKY at a prehypertensive stage (3 wk of age) and hypertensive stage (9 wk of age). Additionally, age-related changes in gene expression patterns were examined from 3 to 9 wk in both WKY and SHR. Five to six individual kidney samples of the same experimental group were pooled together, and quadruplicate hybridizations were performed using the National Institute of Environmental Health Sciences Rat version 2.0 Chip, which contains ∼6,700 genes. Twenty two genes were found to be differentially expressed between SHR and WKY at 3 wk of age, and 104 genes were differentially expressed at 9 wk of age. Soluble epoxide hydrolase ( Ephx2) was found to be significantly upregulated in SHR at both time points and was the predominant outlier. Conversely, elastase 1 ( Ela1) was found to be the predominant gene downregulated in SHR at both time points. Analysis of profiles at 3 vs. 9 wk of age identified 508 differentially expressed genes in WKY rats. In contrast, only 211 genes were found to be differentially expressed during this time period in SHR. The altered gene expression patterns observed in the age-related analysis suggested significant differences in the vascular extracellular matrix system between SHR and WKY kidney. Together, our data highlight the complexity of hypertension and the numerous genes involved in and affected by this condition.

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