Promoter hypermethylation is a major event of hMLH1 gene inactivation in liver fluke related cholangiocarcinoma.
Cholangiocarcinoma is a crucial health problem in Northeast Thailand where liver fluke infection is endemic. However, molecular genetic and epigenetic mechanisms involved in carcinogenesis of this cancer remain unclear. We attempted to study genetic and epigenetic alterations of hMLH1 gene in 65 intrahepatic cholangiocarcinoma using polymerase chain reaction (PCR) based microsatellite marker D3S1611 and methylation-specific PCR, respectively. Of 65 cases, 29 (44.6%) showed hypermethylation of hMLH1 promoter. Loss of heterozygosity (LOH) of hMLH1 was detected in 12 of 51 informative cases (23.5%). Five out of 29 (17.2%) methylated cases demonstrated LOH. Aberrant methylation of hMLH1 promoter was significantly associated with poorly differentiated type (P=0.013). Our study suggests that both genetic and epigenetic mechanisms cause the inactivation of hMLH1 where epigenetic is a major event resulting in mismatch repair deficiency and contributing to carcinogenesis of liver fluke related cholangiocarcinoma. Since, gene silencing by methylation is an early event in carcinogenesis, promoter hypermethylation of hMLH1 may be a molecular targeted therapy and prevention of liver fluke related cholangiocarcinoma.
Limpaiboon
Temduang
T
Faculty of Associated Medical Sciences, Department of Clinical Chemistry, Khon Kaen University, Khon Kaen 40002, Thailand. temduang@kku.ac.th
Khaenam
Prasong
P
Chinnasri
Patcharee
P
Soonklang
Montisha
M
Jearanaikoon
Patcharee
P
Sripa
Banchob
B
Pairojkul
Chawalit
C
Bhudhisawasdi
Vajarabhongsa
V
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001650:Bile Duct Neoplasms / Q000235:genetics* / Q000382:microbiology; D001653:Bile Ducts, Intrahepatic / Q000382:microbiology / Q000473:pathology*; D002352:Carrier Proteins; D018281:Cholangiocarcinoma / Q000235:genetics* / Q000382:microbiology; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005211:Fascioliasis / Q000150:complications; D020868:Gene Silencing; D006801:Humans; D019656:Loss of Heterozygosity; D018895:Microsatellite Repeats; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1