Molecular genetic mechanism of alpha-parficle induced human cancers : Analysis of liver carcinogenesis in Thorotrast patients.

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Thorotrast, a previously used radiological contrast medium, is known to induce liver tumors consisting of hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and angiosarcoma (AS) at nearly the same instance. Pathological specimens from Thorotrast patients are valuable for assessing the relevance of long-term exposure to low dose a-particles to radiation carcinogenesis. We analyzed mutations of the p53 and the K-ras genes, microsatellite instability (MSI), and loss of heterozygosity (LOH) in pathological specimens from Thorotrast-induced ICC. The major p53 mutations observed in Thorotrast ICC were the transition type, suggesting that reactive oxygen species are not likely involved in gene mutations of Thorotrast cancers. MSI frequency in Thorotrast ICC was significantly higher than that in non-Thorotrast ICC. MSI was partly attributed to the inactivation of the hMLH1 mismatch repair gene via methylation of its promoter region. Thorotrast ICC shared LOH pattern with non-Thorotrast HCC and ICC. Furthermore, we could assess the distribution and the quantity of deposited thorium using an imaging plate and a BAS image analyzer. Thorotrast was always phagocytosed by macrophages and the distribution of thorium deposits was not always consistent with that of apoptotic cells.We conclude that Thorotrast ICC is developed through complex carcinogenic steps including genomic instability and mutations of crucial genes occurred during remodeling of the liver architecture.