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.
Methylation Gallbladder Cancer Tumor-suppressor genes
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Ajiki T, Onoyama H, Yamamoto M, et al. p53 protein expression and prognosis in gallbladder carcinoma and premalignant lesions. Hepatogastroenterology 1996;43:521–6.PubMedGoogle Scholar
Hanada K, Tsuchida A, Iwao T, et al. Gene mutations of K-ras in gallbladder mucosae and gallbladder carcinoma with an anomalous junction of the pancreaticobiliary duct. Am J Gastroenterol 1999;94:1638–42.CrossRefPubMedGoogle Scholar
Itoi T, Watanabe H, Ajioka Y, et al. APC, K-ras codon 12 mutations and p53 gene expression in carcinoma and adenoma of the gall-bladder suggest two genetic pathways in gall-bladder carcinogenesis. Pathol Int 1996;46:333–40.CrossRefPubMedGoogle Scholar
Kiguchi K, Carbajal S, Chan K, et al. Constitutive expression of ErbB-2 in gallbladder epithelium results in development of adenocarcinoma. Cancer Res 2001;61:6971–6.PubMedGoogle Scholar
Kohya N, Miyazaki K, Matsukura S, et al. Deficient expression of O(6)-methylguanine-DNA methyltransferase combined with mismatch-repair proteins hMLH1 and hMSH2 is related to poor prognosis in human biliary tract carcinoma. Ann Surg Oncol 2002;9:371–9.PubMedGoogle Scholar
Quan ZW, Wu K, Wang J, et al. Association of p53, p16, and vascular endothelial growth factor protein expressions with the prognosis and metastasis of gallbladder cancer. J Am Coll Surg 2001;193:380–3.CrossRefPubMedGoogle Scholar
Roa I, Villaseca M, Araya J, et al. p53 tumour suppressor gene protein expression in early and advanced gallbladder carcinoma. Histopathology 1997;31:226–30.CrossRefPubMedGoogle Scholar
Suzuki T, Takano Y, Kakita A, Okudaira M. An immunohistochemical and molecular biological study of c-erbB-2 amplification and prognostic relevance in gallbladder cancer. Pathol Res Pract 1993;189:283–92.CrossRefPubMedGoogle Scholar
Tanno S, Obara T, Fujii T, et al. Proliferative potential and K-ras mutation in epithelial hyperplasia of the gallbladder in patients with anomalous pancreaticobiliary ductal union. Cancer 1998;83:267–75.CrossRefPubMedGoogle Scholar
Wistuba II, Albores-Saavedra J. Genetic abnormalities involved in the pathogenesis of gallbladder carcinoma. J Hepatobiliary Pancreat Surg 1999;6:237–44.CrossRefPubMedGoogle Scholar
Shi YZ, Hui AM, Li X, et al. Overexpression of retinoblastoma protein predicts decreased survival and correlates with loss of p16INK4 protein in gallbladder carcinomas. Clin Cancer Res 2000;6:4096–100.PubMedGoogle Scholar
Herman JG, Umar A, Polyak K, et al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci U S A 1998;95:6870–5.CrossRefPubMedPubMedCentralGoogle Scholar
Ahrendt SA, Eisenberger CF, Yip L, et al. Chromosome 9p21 loss and p16 inactivation in primary sclerosing cholangitis-associated cholangiocarcinoma. J Surg Res 1999;84:88–93.CrossRefPubMedGoogle Scholar
Tannapfel A, Benicke M, Katalinic A, et al. Frequency of p16(INK4A) alterations and K-ras mutations in intrahepatic cholangiocarcinoma of the liver. Gut 2000;47:721–7.CrossRefPubMedPubMedCentralGoogle Scholar
Tannapfel A, Sommerer F, Benicke M, et al. Genetic and epigenetic alterations of the INK4a-ARF pathway in cholangiocarcinoma. J Pathol 2002;197:624–31.CrossRefPubMedGoogle Scholar
Wong N, Li L, Tsang K, et al. Frequent loss of chromosome 3p and hypermethylation of RASSF1A in cholangiocarcinoma. J Hepatol 2002;37:633–9.CrossRefPubMedGoogle Scholar
Gerdes B, Ramaswamy A, Kersting M, et al. p16(INK4a) alterations in chronic pancreatitis-indicator for high-risk lesions for pancreatic cancer. Surgery 2001;129:490–7.CrossRefPubMedGoogle Scholar
Taniai M, Higuchi H, Burgart LJ, Gores GJ. p16INK4a promoter mutations are frequent in primary sclerosing cholangitis (PSC) and PSC-associated cholangiocarcinoma. Gastroenterology 2002;123:1090–8.CrossRefPubMedGoogle Scholar
Issa JP, Ahuja N, Toyota M, et al. Accelerated age-related CpG island methylation in ulcerative colitis. Cancer Res 2001;61:3573–7.PubMedGoogle Scholar
Azarschab P, Porschen R, Gregor M, et al. Epigenetic control of the E-cadherin gene (CDH1) by CpG methylation in colectomy samples of patients with ulcerative colitis. Genes Chromosomes Cancer 2002;35:121–6.CrossRefPubMedGoogle Scholar
Paimela H, Karppinen A, Hockerstedt K, et al. Poor prognosis of gallbladder cancer persists regardless of improved diagnostic methods. Incidence and results of surgery during 20 years in Helsinki. Ann Chir Gynaecol 1997;86:13–7.PubMedGoogle Scholar
Esteller M, Sanchez-Cespedes M, Rosell R, et al. Detection of aberrant promoter hypermethylation of tumor suppressor genes in serum DNA from non-small cell lung cancer patients. Cancer Res 1999;59:67–70.PubMedGoogle Scholar
Palmisano WA, Divine KK, Saccomanno G, et al. Predicting lung cancer by detecting aberrant promoter methylation in sputum. Cancer Res 2000;60:5954–8.PubMedGoogle Scholar
House MG, Guo M, Iacobuzio-Donahue C, Herman JG. Molecular progression of promoter methylation in intraductal papillary mucinous neoplasms (IPMN) of the pancreas. Carcinogenesis 2003;24:193–8.CrossRefPubMedGoogle Scholar
Wistuba II, Miquel JF, Gazdar AF, Albores-Saavedra J. Gallbladder adenomas have molecular abnormalities different from those present in gallbladder carcinomas. Hum Pathol 1999;30:21–5.CrossRefPubMedGoogle Scholar
Chang HJ, Jee CD, Kim WH. Mutation and altered expression of beta-catenin during gallbladder carcinogenesis. Am J Surg Pathol 2002;26:758–66.CrossRefPubMedGoogle Scholar
Matsubara T, Sakurai Y, Sasayama Y, et al. K-ras point mutations in cancerous and noncancerous biliary epithelium in patients with pancreaticobiliary maljunction. Cancer 1996;77(8 Suppl):1752–7.CrossRefPubMedGoogle Scholar
Kim SW, Her KH, Jang JY, et al. K-ras oncogene mutation in cancer and precancerous lesions of the gallbladder. J Surg Oncol 2000;75:246–51.CrossRefPubMedGoogle Scholar
Miquel JF, Covarrubias C, Villaroel L, et al. Genetic epidemiology of cholesterol cholelithiasis among Chilean Hispanics, Amerindians, and Maoris. Gastroenterology 1998;115:937–46.CrossRefPubMedGoogle Scholar