Frequent loss of chromosome 3p and hypermethylation of RASSF1A in cholangiocarcinoma

Wong, Nathalie; Li, Libby; Tsang, K. S.; Lai, Paul B.S.; To, Ka–Fai; Johnson, Philip J.

doi:10.1016/s0168-8278(02)00269-6

Cited by 64 publications

(66 citation statements)

References 16 publications

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“…Loss of SMAD4/DPC4 associated with higher grade [3,30,35] Inactivation of p53 associated with increasing grade of dysplasia and invasion [30] IDH1 and IDH2 mutations cooccurring with increased TP53 expression and associated with DNA hypermethylation [62,66] Decreased membranous expression of β-catenin with increasing grade of BilIN [26] C-myc mutations in over 50% of cases [26] Chromosomal aberrations including gains at 7p and 8q and losses at 1p, 4q and 9p [68,69,[73][74][75][76] Decreased expression of E-cadherin in some cases of BilIN [26] Loss of SMAD4/DPC4 associated with higher grade [30,35] Aberrant methylation of p16INK4a/CDKN2 (47%), RASSFIA (56%) and APC (29%) [70,71,76] S100P: Increased immunohistochemical expression in BilIN-2 and BilIN-3 [27] BilIN: Biliary intraepithelial neoplasia; IPNB: Intraductal papillary neoplasm of the bile duct; VMC: Von Meyenburg complex; BDH: Bile duct hamartoma; BDA: Bile duct adenoma; ICC: Intrahepatic cholangiocarcinoma.…”

Section: Gross Appearancementioning

confidence: 99%

Clinical and biological significance of precursor lesions of intrahepatic cholangiocarcinoma

Ettel¹

2015

WJH

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Cholangiocarcinoma (CC) is primarily a malignant tumor of older adults most prevalent in Southeast Asia, where liver fluke infestation is high. However the etiology in western countries is unknown. Although the incidence of extrahepatic cholangiocarcinoma has remained constant, incidence of intrahepatic CC (ICC) which differs in morphology, pathogenesis, risk factors, treatment and prognosis is increasing. While this increase is associated with hepatitis C virus infection, chronic nonalcoholic liver disease, obesity, and smoking, the pathogenesis of ICC and molecular alterations underlying the carcinogenesis are not completely elucidated. Benign biliary lesions such as biliary intraepithelial neoplasia, intraductal papillary neoplasm of the bile duct, von Meyenburg complex or bile duct hamartoma, and bile duct adenoma have been associated with ICC. For each of these entities, evidence suggests or supports a role as premalignant lesions. This article summarized the important biological significance of the precursor lesions of ICC and the molecular mechanisms that may be involved in intrahepatic cholangiocarcinogenesis.

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Section: Gross Appearancementioning

confidence: 99%

Clinical and biological significance of precursor lesions of intrahepatic cholangiocarcinoma

Ettel¹

2015

WJH

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“…DNA methylation can result in epigenetic regulation of gene expression and is associated with altered expression of genes that may be involved in carcinogenesis or tumor growth, such as oncogenes, tumor suppressor genes, and DNA repair genes or other genes. Aberrant promoter methylation of several genes, such as p16, TIMP-3, hMLH1, RASSF1A, and others, has been reported in cholangiocarcinoma (9)(10)(11)(12)(13). Generally, methylation serves to modulate gene expression and represents a powerful mechanism that may contribute to tumor growth by altered expression of genes involved in tumor cell behavior.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-6 Contributes to Growth in Cholangiocarcinoma Cells by Aberrant Promoter Methylation and Gene Expression

et al. 2006

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The association between chronic inflammation and the development and progression of malignancy is exemplified in the biliary tract where persistent inflammation strongly predisposes to cholangiocarcinoma. The inflammatory cytokine interleukin-6 (IL-6) enhances tumor growth in cholangiocarcinoma by altered gene expression via autocrine mechanisms. IL-6 can regulate the activity of DNA methyltransferases, and moreover, aberrant DNA methylation can contribute to carcinogenesis. We therefore investigated the effect of chronic exposure to IL-6 on methylation-dependent gene expression and transformed cell growth in human cholangiocarcinoma. The relationship between autocrine IL-6 pathways, DNA methylation, and transformed cell growth was assessed using malignant cholangiocytes stably transfected to overexpress IL-6. Treatment with the DNA methylation inhibitor 5-aza-2 ¶-deoxycytidine decreased cell proliferation, growth in soft agar, and methylcytosine content of malignant cholangiocytes. However, this effect was not observed in IL-6-overexpressing cells. IL-6 overexpression resulted in the altered expression and promoter methylation of several genes, including the epidermal growth factor receptor (EGFR). EGFR promoter methylation was decreased and gene and protein expression was increased by IL-6. Thus, epigenetic regulation of gene expression by IL-6 can contribute to tumor progression by altering promoter methylation and gene expression of growth-regulatory pathways, such as those involving EGFR. Moreover, enhanced IL-6 expression may decrease the sensitivity of tumor cells to therapeutic treatments using methylation inhibitors. These observations have important implications for cancer treatment and provide a mechanism by which persistent cytokine stimulation can promote tumor growth. (Cancer Res 2006; 66(21): 10517-24)

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“…6, 7) In biliary tract carcinomas, E-cadherin, p16, and RASSF1A promoter methylation with loss of expression are frequently present, and ultimately result in characteristic biological features, [8][9][10][11][12][13][14] whereas DAP-kinase (death associated protein kinase) promoter methylation is infrequent in intrahepatic cholangiocarcinomas.…”

mentioning

confidence: 99%

“…4,5) It has become clear that aberrant DNA methylation of promoter region CpG islands may serve as an alternative mechanism to coding region mutation for the inactivation of tumor suppressor or tumor-related genes, and therefore methylation plays an important role in tumorigenesis. 6,7) In biliary tract carcinomas, E-cadherin, p16, and RASSF1A promoter methylation with loss of expression are frequently present, and ultimately result in characteristic biological features, [8][9][10][11][12][13][14] whereas DAP-kinase (death associated protein kinase) promoter methylation is infrequent in intrahepatic cholangiocarcinomas. 9) However, the roles of other genes, such as CHFR and RUNX3, which are recently identified tumor suppressor genes silenced by promoter hypermethylation, [15][16][17][18][19][20][21][22] remain to be elucidated.…”

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confidence: 99%

Promoter hypermethylation of DAP‐kinase is associated with poor survival in primary biliary tract carcinoma patients

et al. 2004

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To clarify the clinicopathological significance of promoter hypermethylation of tumor suppressor and tumor-related genes in biliary tract carcinomas, we examined the promoter methylation status of multiple genes in primary biliary tract carcinomas. These consisted of carcinomas of the bile duct, gallbladder, and duodenal ampulla. Surgical specimens were obtained from a total of 37 patients with biliary tract carcinoma. The cohort consisted of 23 patients with bile duct carcinoma, 9 patients with gallbladder carcinoma, and 5 patients with ampullary carcinoma. The methylation status of CHFR, DAP-kinase, E-cadherin, hMLH1, p16, RASSF1A, and RUNX3 was examined by methylation-specific polymerase chain reaction (MSP). The correlation between methylation status and clinicopathological characteristics was then assessed. The methylation frequencies of CHFR, DAP-kinase, E-cadherin, hMLH1, p16, RASSF1A, and RUNX3 genes were 16.2%, 21.4%, 27.0%, 8.1%, 24.3%, 27.0%, and 56.8%, respectively, in primary biliary tract carcinomas. The number of methylated genes per sample was 2.17 ± ± ± ±0.28 (average ± ± ± ±SD) in bile duct carcinomas, 1.80 ± ± ± ±0.97 in ampullary carcinomas, and 0.89 ± ± ± ±0.35 in gallbladder carcinomas, with a statistically significant difference between bile duct carcinomas and gallbladder carcinomas (P = = = =0.02). As for clinicopathological significance, patients with a methylated RUNX3 promoter were significantly older than those with unmethylated RUNX3 (P = = = =0.01), and DAP-kinase methylation was more frequent in poorly differentiated tumors than in well to moderately differentiated ones (P = = = =0.04). The overall survival rate was significantly lower in patients with methylated DAP-kinase (P = = = =0.009) or RUNX3 (P = = = =0.034) compared to those with unmethylated genes. Furthermore, DAP-kinase methylation-positive status was independently associated with poor survival in multivariate analyses (hazard ratio = = = =8.71, P = = = =0.024). A significant proportion of primary biliary tract carcinomas exhibited promoter hypermethylation of tumor suppressor and tumor-related genes, although bile duct carcinomas are more prone to being affected by promoter methylation than are gallbladder carcinomas. Hypermethylation of DAP-kinase appears to be a significant prognostic factor in primary biliary tract carcinomas. iliary tract carcinoma is a disease with a poor prognosis. The 5-year survival rate is less than 25% for intra-and extrahepatic bile duct carcinoma, and 32% to 61% for gallbladder carcinoma, even after radical resection of the tumor.1-3) There is no effective therapy for biliary tract carcinomas except surgical resection. Moreover, the molecular-biological mechanisms of the development of biliary tract carcinomas are less well understood than those of carcinomas of the colon, stomach, and liver.DNA methylation is an important epigenetic mechanism for suppressing gene activity by changing the chromatin structure. 4,5) It has become clear that aberrant DNA methylation of promoter region CpG isl...

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Frequent loss of chromosome 3p and hypermethylation of RASSF1A in cholangiocarcinoma

Cited by 64 publications

References 16 publications

Clinical and biological significance of precursor lesions of intrahepatic cholangiocarcinoma

Clinical and biological significance of precursor lesions of intrahepatic cholangiocarcinoma

Interleukin-6 Contributes to Growth in Cholangiocarcinoma Cells by Aberrant Promoter Methylation and Gene Expression

Promoter hypermethylation of DAP‐kinase is associated with poor survival in primary biliary tract carcinoma patients

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