DNA promoter hypermethylation of p16 and APC predicts neoplastic progression in Barrett's esophagus - PubMed (original) (raw)

DNA promoter hypermethylation of p16 and APC predicts neoplastic progression in Barrett's esophagus

Jean S Wang et al. Am J Gastroenterol. 2009 Sep.

Abstract

Objectives: Prediction of progression to cancer in patients with Barrett's esophagus (BE) is difficult using current techniques. We determined whether DNA promoter hypermethylation of genes frequently methylated in esophageal adenocarcinoma (p16 and APC) could be used as predictors of progression in BE.

Methods: We first performed a cross-sectional study to evaluate the prevalence of gene hypermethylation in biopsies from patients with normal esophagus (n=17), BE (n=102), and adenocarcinoma (n=42). We then performed a nested case-control study comparing gene hypermethylation in BE patients who progressed from baseline pathology to high-grade dysplasia or cancer (n=7) vs. patients who did not progress (n=50).

Results: None of the patients with normal esophagus had p16 or APC hypermethylation. Hypermethylation was prevalent in BE without dysplasia or low-grade dysplasia (p16=31% and APC=50%; P<0.01) and high-grade dysplasia or adenocarcinoma (p16=54% and APC=68%; P<0.001) compared with normal esophagus (not detected). Patients who progressed from baseline pathology to high-grade dysplasia or cancer had higher prevalence of hypermethylation in their initial esophagus biopsies compared with those who did not progress for both p16 (100 vs. 33%; P=0.008) and APC (86 vs. 40%; P=0.02). Hypermethylation of both p16 and APC was a strong predictor of subsequent progression to high-grade dysplasia or cancer during a mean follow-up time of 4.1 years (odds ratio (95% confidence interval)=14.97 (1.73,inf), P=0.01). Among patients who were negative for both p16 and APC hypermethylation, none progressed from baseline pathology to high-grade dysplasia or cancer.

Conclusions: Hypermethylation of both p16 and APC strongly predicts progression to high-grade dysplasia or cancer in patients with BE. Absence of p16 and APC hypermethylation is associated with a benign course.

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Conflict of interest statement

Potential competing interests: JGH isa consultant for OncoMethylome Sciences

Figures

Figure 1

Representative results from the methylation-specific PCR assay can be seen for the p16 gene. Visualization of a band in the U lane indicates the presence of unmethylated DNA in the p16 promoter, whereas a band in the M lane indicates the presence of methylated DNA in the p16 promoter. We confirmed the presence of methylated DNA by sequencing the promoter region amplified by the PCR primers. The representative gel below shows that one BE patient who initially presented with low-grade dysplasia and progressed pathologically to cancer had hypermethylated promoter DNA in the p16 gene in an esophagus biopsy taken at initial presentation. Meanwhile, another BE patient who also initially presented with low-grade dysplasia but did not progress pathologically did not have any promoter hypermethylation detected in the p16 gene on initial esophagus biopsy.

Figure 2

Probability of progression-free survival in patients with BE in relation to their gene promoter hypermethylation status in initial esophagus biopsies. There were statistically significant differences for p16 (Panel A, p=0.009), APC (Panel B, p=0.03), and both genes (p16 and APC) hypermethylated (Panel C, p=0.001) by the log-rank test.

Figure 2

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DNA promoter hypermethylation of p16 and APC predicts neoplastic progression in Barrett's esophagus - PubMed (original) (raw)