title: Hypermethylated APC DNA in plasma and prognosis of patients with esophageal adenocarcinoma.
abstract: BACKGROUND
  The adenomatous polyposis coli (APC) locus on chromosome 5q21-22 shows frequent loss of heterozygosity (LOH) in esophageal carcinomas. However, 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 APC promoter region is hypermethylated in esophageal cancer patients and whether this abnormality could serve as a prognostic plasma biomarker.
  
  
  METHODS
  We assayed DNA from tumor tissue and matched plasma from esophageal cancer patients for hypermethylation of the promoter region of the APC gene. We used the maximal chi-square statistic to identify a discriminatory cutoff value for hypermethylated APC DNA levels in plasma and used bootstrap-like simulations to determine the P: value to test for the strength of this association. This cutoff value was used to generate Kaplan-Meier survival curves. All P values were based on two-sided tests.
  
  
  RESULTS
  Hypermethylation of the promoter region of the APC gene occurred in abnormal esophageal tissue in 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 tissues. Hypermethylated APC DNA was observed in the plasma of 13 (25%) of 52 adenocarcinoma patients and in two (6.3%) of 32 squamous carcinoma patients. High plasma levels of methylated APC DNA were statistically significantly associated with reduced patient survival (P =.016).
  
  
  CONCLUSIONS
  The APC promoter region was hypermethylated in tumors of the majority of patients with primary esophageal adenocarcinomas. Levels of hypermethylated APC gene DNA in the plasma may be a useful biomarker of biologically aggressive disease in esophageal adenocarcinoma patients and should be evaluated as a potential biomarker in additional tumor types.
authors.affiliation: Department of Biochemistry and Molecular Biology and Norris Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA.
authors.forename: K
authors.initials: K
authors.lastname: Kawakami
authors.forename: J
authors.initials: J
authors.lastname: Brabender
authors.forename: R V
authors.initials: RV
authors.lastname: Lord
authors.forename: S
authors.initials: S
authors.lastname: Groshen
authors.forename: B D
authors.initials: BD
authors.lastname: Greenwald
authors.forename: M J
authors.initials: MJ
authors.lastname: Krasna
authors.forename: J
authors.initials: J
authors.lastname: Yin
authors.forename: A S
authors.initials: AS
authors.lastname: Fleisher
authors.forename: J M
authors.initials: JM
authors.lastname: Abraham
authors.forename: D G
authors.initials: DG
authors.lastname: Beer
authors.forename: D
authors.initials: D
authors.lastname: Sidransky
authors.forename: H T
authors.initials: HT
authors.lastname: Huss
authors.forename: T R
authors.initials: TR
authors.lastname: Demeester
authors.forename: C
authors.initials: C
authors.lastname: Eads
authors.forename: P W
authors.initials: PW
authors.lastname: Laird
authors.forename: D H
authors.initials: DH
authors.lastname: Ilson
authors.forename: D P
authors.initials: DP
authors.lastname: Kelsen
authors.forename: D
authors.initials: D
authors.lastname: Harpole
authors.forename: M B
authors.initials: MB
authors.lastname: Moore
authors.forename: K D
authors.initials: KD
authors.lastname: Danenberg
authors.forename: P V
authors.initials: PV
authors.lastname: Danenberg
authors.forename: S J
authors.initials: SJ
authors.lastname: Meltzer
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism*; D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D001471:Barrett Esophagus / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000097:blood* / Q000302:isolation & purification; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D016009:Chi-Square Distribution; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics*; D004273:DNA, Neoplasm / Q000097:blood* / Q000302:isolation & purification; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism*; D005753:Gastric Mucosa / Q000378:metabolism; D006801:Humans; D019656:Loss of Heterozygosity; D008745:Methylation; D016133:Polymerase Chain Reaction / Q000379:methods; D011230:Precancerous Conditions / Q000378:metabolism; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm