Promoter methylation profiles of tumor suppressor genes in intrahepatic and extrahepatic cholangiocarcinoma

Yang B, House MG, Guo M, Herman JG and Clark DP. Mod Pathol 2005; 18(3): 412-20.
Background Tumor suppressor genes (TSGs) can be silenced through both genetic and epigenetic mechanisms. Methylation profiles in intrahepatic cholangiocarcinoma (ICC) have been described previously, however in extrahepatic cholangiocarcinoma (ECC) have not been reported. Therefore, this is the first report for methylation profile in both ICC and ECC.
Method Methylation status of 12 candidate TSGs (APC, E-cadherin/CDH1, MGMT, RASSF1A, GSTP, RAR-b, p14ARF, p15INK4b, p16INK4a, p73, hMLH1 and DAPK) were determined in 72 cases of cholangiocarcinoma (CCA), including equal number cases of ICC and ECC. A total of 10 cases of benign biliary epithelia were included as controls. The methylation status of TSGs was analyzed using methylation-specific PCR (MSP).
Result The study found that 85% of all CCA had methylation of at least one TSG. The frequency of TSG methylation in CCA was: RASSF1A (65%), p15INK4b (50%), p16INK4a (50%), APC (46%), E-cadherin/CDH1 (43%), p14ARF (38%), p73 (36%), MGMT (33%), hMHL1 (25%), GSTP (14%), RAR-b (14%) and DAPK (3%). Although single TSG methylation can be seen in benign biliary epithelium, methylation of multiple TSG was only seen in CCA. About 70% (50/72) of the CCA had three or more TSGs methylated and 52% (38/72) of cases had four or more TSGs methylated. Concerted methylation of multiple TSGs was closely associated with methylation of RASSF1A, p16 and/or hMHL1. Methylation of RASSF1A was more common in ECC than ICC (83 vs. 47%, P = 0.003) while GSTP was more frequently seen in ICC compared to ECC (31 vs. 6%, P = 0.012). Conclusion The study indicated that methylation of promoter CpG islands of TSGs is a common epigenetic event in CCA. Based on distinct methylation profiles, ICC and ECC are two closely related but biologically unique neoplastic processes. Taking advantage of the unique concurrent methylation profile of multiple genes in CCA may facilitate the distinction of CCA from benign biliary epithelium in clinical settings.
Presented by
Mr. Prasong Khaenam
Ph.D candidate in Biomedical Sciences
Date August 31st 2005
Time 12.00 – 12.30 pm
Venue Pisit Memorial Room, Faculty of Medicine