Sanjeev Slehria, MD, Prateek Sharma, MD


Curr Opin Gastroenterol. 2003;19(4) 

In This Article


The ultimate goal in patients with Barrett esophagus would be to develop a panel of biomarkers that could identify patient subsets with low and high risk for cancer progression. This would be an extremely important approach in management of cancer risk in Barrett esophagus. Investigators from Seattle have previously shown that flow cytometric-increased 4N fractions and aneuploidy are predictors of progression to cancer in Barrett esophagus. People usually inherit two normal alleles of p53, and most Barrett esophagus has two normal p53 alleles. However, during progression to cancer in Barrett esophagus, one allele of p53 is inactivated by mutation and the second is lost by a mechanism termed loss of heterozygosity (LOH). 17p (p53) LOH is the most common genetic lesion in esophageal adenocarcinoma and is found to occur in 95% to 100% of cases when highly purified cell populations are evaluated.

In endoscopic biopsies from 325 patients with Barrett esophagus, 269 patients had 17 p (p53) LOH and were at increased risk for progression to esophageal adenocarcinoma as well as HGD, increased 4N, and aneuploidy.[21**] Of the 269 patients followed up prospectively, 256 had baseline 17p (p53) LOH data: 20 of 54 patients (37%) with 17p (p53) LOH developed cancer, compared with only six of 202 patients (3%) with two 17p alleles (relative risk = 16; 95% CI = 6.2, 39; P < 0.001). The 3-year cumulative incidence of cancer in those with 17p (p53) LOH was 38% (95% CI = 26, 54) compared with 3.3% (95% CI = 1.4, 8.0) for those with two 17p alleles. These results demonstrate that 17p (p53) LOH is a predictor of progression to esophageal adenocarcinoma.

The potential role of p16 in activation by CDKN2A/p16 promoter hypermethylation or loss of heterozygosity of the CDKN2A gene was investigated in samples obtained from microdissection of paraffin-embedded fixed tissue sections.[22] No methylation of the CDKN2A promoter was found in normal squamous cell epithelium of the esophagus, but methylation was detected in 82% of adenocarcinomas and 30% of Barrett esophagi. Thus methylation of CDKN2A promoter may be the predominant mechanism for p16 in activation and may occur in patients with Barrett esophagus.

cDNA microarrays are being increasingly used in current medical research, but they often have difficulty recognizing subtle differences among subgroups of patients. In contrast, methods such as artificial neural networks (ANNs) are able to recognize subtle differences in biologic entities. In a recent study using the principle of ANN in Barrett esophagus and esophageal adenocarcinomas, scanned cDNA microarray data were analyzed using bioinformatics software, significance analysis of microarrays, and ANNs.[23] Significant analysis of microarrays selected 160 differentially expressed genes between Barrett and cancer, whereas cluster analysis based on this reduced set still misclassified two Barrett esophagus samples as cancer. The ANN, trained on 12 samples, was tested against the remaining test samples, and using the 160 selected genes ANN correctly diagnosed all 10 samples in the test set.

Such studies will help selecting patients at high risk for cancer development and breaking the "genetic code" in Barrett esophagus.


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