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From the Departments of Surgery (MGH, RDS) and Pathology (PA, RHH, AM), The Johns Hopkins Medical Institutions, Baltimore, Maryland; Department of Oncology (MG, RHH, JGH), The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland; and Department of Pathology (IIW), Pontificia Universidad Catolica de Chile, Santiago, Chile.
Correspondence: Address correspondence and reprint requests to: Michael G. House, MD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Tumor Biology, 1650 Orleans Street, Room 543, Baltimore, MD 21231-1000; Fax: 410-614-9884; E-mail: mgh{at}jhu.edu
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.
Key Words: Methylation • Gallbladder • Cancer • Tumor-suppressor genes
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