title: Progression of gene hypermethylation in gallstone disease leading to gallbladder cancer.
abstract: BACKGROUND
  Aberrant methylation of tumor-suppressor genes is associated with a loss of gene function that can afford selective growth advantages to sporadic neoplastic cells arising during gallbladder inflammation.
  
  
  METHODS
  Fifty-four gallbladder neoplasms were selected from tumor banks in the United States and Chile. Each of the neoplasms was subjected to methylation-specific polymerase chain reaction to detect promoter methylation associated with six candidate tumor-suppressor genes (p16, APC, methylguanine methyltransferase, hMLH1, retinoic acid receptor beta-2, and p73) implicated in multiple human cancer types.
  
  
  RESULTS
  Aberrant methylation of any of the six candidate tumor-suppressor genes was detected in 72% of the gallbladder neoplasms, 28% of the cases of chronic cholecystitis, and in only 1 of the 15 normal gallbladder controls. The four most commonly methylated genes in the gallbladder cancers were p16 (56%), p73 (28%), APC (27%), and hMLH1 (14%). Significant differences in gene methylation were discovered between US gallbladder cancers and those from Chile, where gallbladder cancer is one of the leading causes of cancer-related deaths. APC methylation was present in 42% of the US cases but in only 14% of the Chilean tumors (P =.028). p73 methylation was common among the Chilean cancers (40%) compared with those from the United States (13%; P =.034).
  
  
  CONCLUSIONS
  The acquisition of hypermethylation at multiple tumor-suppressor gene-promoter sites may contribute to tumor formation and progression within the chronically inflamed gallbladder. The apparent differences in methylation patterns among the Chilean and US gallbladder cases may indicate a unique biology associated with this cancer in different parts of the world.
authors.affiliation: Department of Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21231-1000, USA. mgh@jhu.edu
authors.forename: Michael G
authors.initials: MG
authors.lastname: House
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
authors.forename: Pedram
authors.initials: P
authors.lastname: Argani
authors.forename: MingZhou
authors.initials: M
authors.lastname: Guo
authors.forename: Richard D
authors.initials: RD
authors.lastname: Schulick
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
authors.forename: James G
authors.initials: JG
authors.lastname: Herman
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D002677:Chile; D002764:Cholecystitis / Q000235:genetics* / Q000473:pathology*; D002908:Chronic Disease; D019175:DNA Methylation; D005260:Female; D005706:Gallbladder Neoplasms / Q000235:genetics* / Q000473:pathology; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D014481:United States