Progression of gene hypermethylation in gallstone disease leading to gallbladder cancer

Michael G. House, Ignacio I. Wistuba, Pedram Argani, Ming Zhou Guo, Richard D. Schulick, Ralph H. Hruban, James G. Herman, Anirban Maitra

Research output: Contribution to journalArticlepeer-review

40 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)882-889
Number of pages8
JournalAnnals of surgical oncology
Issue number8
StatePublished - 2003


  • Cancer
  • Gallbladder
  • Methylation
  • Tumor-suppressor genes

ASJC Scopus subject areas

  • Surgery
  • Oncology


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