Hypermethylated APC DNA in plasma and prognosis of patients with esophageal adenocarcinoma

Background: The adenomatous polyposis coli (APC) locus on chromosome 5q21-2 2 shows frequent loss of heterozygosity (LOH) in esophageal carcinomas. How ever, the prevalence of truncating mutations in the APC gene in esophageal carcinomas is low. Because hypermethylation of promoter regions is known to affect several other tumor suppressor genes, we investigated whether the A PC promoter region is hypermethylated in esophageal cancer patients and whe ther this abnormality could serve as a prognostic plasma biomarker, Methods : We assayed DNA from tumor tissue and matched plasma from esophageal cance r patients for hypermethylation of the promoter region of the APC gene. We used the maximal chi-square statistic to identify a discriminatory cutoff v alue for hypermethylated APC DNA levels in plasma and used bootstrap-like s imulations to determine the P value to test for the strength of this associ ation. This cutoff value was used to generate Kaplan-Meier survival curves. All P values were based on two-sided tests. Results: Hypermethylation of t he promoter region of the APC gene occurred in abnormal esophageal tissue i n 48 (92%) of 52 patients with esophageal adenocarcinoma, in 16 (50%) of 32 patients with esophageal squamous cell carcinoma, and in 17 (39.5%) of 43 patients with Barrett's metaplasia but not in matching normal esophageal ti ssues. Hypermethylated APC DNA was observed in the plasma of 13 (25%) of 52 adenocarcinoma patients and in two (6.3%) of 32 squamous carcinoma patient s. High plasma levels of methylated APC DNA were statistically significantl y associated with reduced patient survival (P = .016), Conclusion: The APC promoter region was hypermethylated in tumors of the majority of patients w ith primary esophageal adenocarcinomas. Levels of hypermethylated APC gene DNA in the plasma may be a useful biomarker of biologically aggressive dise ase in esophageal adenocarcinoma patients and should be evaluated as a pote ntial biomarker in additional tumor types.