Article

New Strategies in Barrett's Esophagus: Integrating Clonal Evolutionary Theory with Clinical Management

Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave., P.O. Box 19024, Seattle, WA 98109, USA.
Clinical Cancer Research (Impact Factor: 8.19). 06/2011; 17(11):3512-9. DOI: 10.1158/1078-0432.CCR-09-2358
Source: PubMed

ABSTRACT Barrett's esophagus is a condition in which the normal stratified squamous epithelium of the distal esophagus is replaced by intestinal metaplasia. For more than three decades, the prevailing clinical paradigm has been that Barrett's esophagus is a complication of symptomatic reflux disease that predisposes to esophageal adenocarcinoma. However, no clinical strategy for cancer prevention or early detection based on this paradigm has been proven to reduce esophageal adenocarcinoma mortality in a randomized clinical trial in part because only about 5% to 10% of individuals with Barrett's esophagus develop esophageal adenocarcinoma. Recent research indicates that Barrett's metaplasia is an adaptation for mucosal defense in response to chronic reflux in most individuals. The risk of progressing to esophageal adenocarcinoma is determined by development of genomic instability and dynamic clonal evolution in the distal esophagus modulated by host and environmental risk and protective factors, including inherited genotype. The challenge for investigators of Barrett's esophagus lies in integrating knowledge about genomic instability and clonal evolution into clinical management to increase the lifespan and quality of life of individuals with this condition.

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Available from: Carlo Maley, Mar 24, 2015
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    • "When gastroesophageal reflux disease (GERD) induces inflammation in the normal esophageal (NE) squamous epithelium, the damaged squamous cells are usually replaced by regeneration of more squamous cells. In some individuals, however, the reflux-damaged NE heals through a metaplastic process in which intestinal-type columnar cells (specialized intestinal metaplasia, SIM) replaces the reflux-damaged squamous epithelium [5]. This metaplasia results in Barrett's esophagus (BE), which is the recognized precursor lesion to EA [6]–[8], and increases the risk of EA by 11 times compared to that of the general population [9]. "
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    ABSTRACT: Barrett's esophagus (BE) is a metaplastic precursor lesion of esophageal adenocarcinoma (EA), the most rapidly increasing cancer in western societies. While the prevalence of BE is increasing, the vast majority of EA occurs in patients with undiagnosed BE. Thus, we sought to identify genes that are altered in BE compared to the normal mucosa of the esophagus, and which may be potential biomarkers for the development or diagnosis of BE. We performed gene expression analysis using HG-U133A Affymetrix chips on fresh frozen tissue samples of Barrett's metaplasia and matched normal mucosa from squamous esophagus (NE) and gastric cardia (NC) in 40 BE patients. Using a cut off of 2-fold and P<1.12E-06 (0.05 with Bonferroni correction), we identified 1324 differentially-expressed genes comparing BE vs NE and 649 differentially-expressed genes comparing BE vs NC. Except for individual genes such as the SOXs and PROM1 that were dysregulated only in BE vs NE, we found a subset of genes (n = 205) whose expression was significantly altered in both BE vs NE and BE vs NC. These genes were overrepresented in different pathways, including TGF-β and Notch. Our findings provide additional data on the global transcriptome in BE tissues compared to matched NE and NC tissues which should promote further understanding of the functions and regulatory mechanisms of genes involved in BE development, as well as insight into novel genes that may be useful as potential biomarkers for the diagnosis of BE in the future.
    PLoS ONE 04/2014; 9(4):e93219. DOI:10.1371/journal.pone.0093219 · 3.23 Impact Factor
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    • "The results of this study support the use of ML assessments in conjunction with histological classification of BE to better manage patients. ML assesses the presence and extent of genomic instability, which has been associated with increased risk of progression to EAC [4, 30]. A portion of microdissected targets with non-dysplastic histological classifications shared a similar ML as those with higher risk disease (HGD) and even EAC. "
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    ABSTRACT: Progression of Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC) is associated with accumulated genomic instability. Current risk stratification of BE for EAC relies on histological classification and grade of dysplasia. However, histology alone cannot assess the risk of patients with inconsistent or non-dysplastic BE histology. We, therefore, examined the presence and extent of genomic instability in advanced and less advanced BE histology using mutational load (ML). ML summarized the presence and clonality of loss of heterozygosity (LOH) mutations and the emergence of new alleles, manifested as microsatellite instability (MSI) mutations, in ten genomic loci around tumor suppressor genes associated with EAC. The ML of 877 microdissected targets from BE biopsies was correlated to their histology. Histological targets were categorized into three levels: no ML, low ML, and high ML. Increasing ML correlated with increasingly severe histology. By contrast, proportions of targets that lacked mutations decreased with increasingly severe histology. A portion of targets with non-dysplastic and low-grade histology shared a similar ML as those with higher risk and EAC disease. The addition of MSI characterization to ML helped to differentiate the ML between advanced and less advanced histology. Given that EAC is associated with accumulated genomic instability, high ML in less severe histology may identify BE disease at greater risk of progression to EAC. ML may help to better manage BE in early histological stages and when histology alone provides insufficient information.
    Journal of Gastrointestinal Cancer 01/2014; 45(2). DOI:10.1007/s12029-013-9570-y · 0.38 Impact Factor
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    • "Evaluation of CIN in Barrett's esophagus tissue has revealed that CIN is highly correlated with TP53 LOH [81]. In agreement, patients with LOH in TP53 are 16 times more likely to progress from premalignant Barrett's esophagus to esophageal adenocarcinoma than patients without TP53 LOH, supporting the hypothesis that expansion of CIN clones drive malignancy [82] [83]. Moreover, usage of integrated DNA sequence and copy number information to reconstruct the order of abnormalities in individual cutaneous squamous cell carcinomas and serous ovarian adenocarcinomas have allowed to reveal that loss of the second TP53 allele appears to precede not only the development of CIN but also a vast expansion of simple mutations [84]. "
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