Microsatellite instability in thorotrast-induced human intrahepatic cholangiocarcinoma.
Thorotrast, a colloidal suspension of radioactive (232)ThO(2) that emits alpha particles, was used as a radiographic contrast during World War II. It is known to induce liver cancers, most frequently ICC, decades after injection. Since radiation induces genomic instability, we analyzed MSI in Thorotrast-induced ICC. The frequency of MSI(+) cases was 62.5% in Thorotrast ICC, whereas it was 22.7% in non-Thorotrast ICC. However, frameshift mutations of mononucleotide repeats were not observed in Thorotrast ICC. In addition, the MSI(+) phenotype was not associated with the quantity of Thorotrast deposited or the latency period of ICC induction. Promoter regions of both the hMLH1 and the hMSH2 MMR genes tended to be hypermethylated in the tumor part compared to the adjacent nontumor part in Thorotrast ICC. Methylation of the hMLH1 promoter was associated with the MSI(+) phenotype in Thorotrast ICC. In contrast, methylation status of these promoter regions was not related to MSI in non-Thorotrast ICC cases. These findings suggest that MSI induced by exposure to Thorotrast mainly reflects clonal expansion of cancer cells and is partly due to inactivation of hMLH1 by hypermethylation.
Liu
Duo
D
Department of Pathology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
Momoi
Hirohito
H
Li
Li
L
Ishikawa
Yuichi
Y
Fukumoto
Manabu
M
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D020137:Base Pair Mismatch; D001650:Bile Duct Neoplasms / Q000209:etiology / Q000235:genetics*; D001653:Bile Ducts, Intrahepatic; D002273:Carcinogens / Q000009:adverse effects*; D002352:Carrier Proteins; D018281:Cholangiocarcinoma / Q000209:etiology / Q000235:genetics*; D019175:DNA Methylation; D004260:DNA Repair; D004268:DNA-Binding Proteins; D020868:Gene Silencing; D006801:Humans; D019656:Loss of Heterozygosity; D018895:Microsatellite Repeats; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000235:genetics*; D009381:Neoplasms, Radiation-Induced / Q000209:etiology / Q000235:genetics*; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D013911:Thorium Dioxide / Q000009:adverse effects*
D048868:Adaptor Proteins, Signal Transducing; D002273:Carcinogens; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D013911:Thorium Dioxide; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein