Allelotypic Characteristics of Thorotrast-Induced Intrahepatic Cholangiocarcinoma: Comparison to Liver Cancers not Associated with Thorotrast

Abstract

To elucidate the genetic alterations that are specific to Thorotrast-induced liver cancers and their possible roles in tumorigenesis, we analyzed loss of heterozygosity (LOH) at 37 loci. Our previous study of liver cancers that were not associated with Thorotrast found LOH at 9 of these loci to be characteristic of intrahepatic cholangiocarcinoma (ICC), at 19 to be characteristic of hepatocellular carcinoma (HCC), and at 9 to be common to both ICC and HCC. LOH analysis was also performed in tissues of cholangiolocellular carcinoma, which is thought to originate from a common stem cell progenitor of hepatocytes and bile duct epithelial cells. We found frequent LOH at D4S1538, D16S2624 and D17S1303 to be common to all the subtypes of liver cancers, independent of the specific carcinogenic agent. In contrast, LOH at D4S1652 generally was not observed in Thorotrast-induced ICC. LOH analysis revealed that Thorotrast-induced ICC shares some LOH features with both ICC and HCC that were not induced by Thorotrast; however, it is more similar to ICC than to HCC in terms of genetic changes. This study could narrow down the crucial chromosomal loci whose deletions are relevant to hepatobiliary carcinogenesis irrespective of the carcinogenic agent. The study of LOH at loci other the those crucial ones may help us understand how the phenotype of liver cancers is determined.

Analysis of carcinogenic mechanisms of liver cancers induced by chronic exposure to alpha-particles from internally deposited Thorotrast

“…These suggest that p53 mutations happened at the late stages of carcinogenic steps induced by Thorotrast. (Liu et al, 2004) Genetic changes in Thorotrast ICC revealed LCI values in between non-Thorotrast HCC and ICC, and similar to those for Compared with non-Thorotrast ICC, Thorotrast ICC showed a significantly higher frequency of MSI. Mononucleotide repeats are useful for the identification of the MSI-H group of tumors (Boland et al, 1998).…”

“…In order to quantify the similarity of an LOH pattern to the ICC-or HCC-specific pattern, we defined a liver cancer index (LCI). In terms of genetic changes, liver cancers with positive LCI are classified into ICC and those with negative LCI into HCC, respectively (Liu et al, 2004). We defined the case as an MSI-positive (MSI+) tumor if a tumor had more than two loci with MSI out of five loci examined by PCR.…”

Mechanisms of liver carcinogenesis by chronic exposure to alpha-particles form internally deposited Thorotrast

“…LOH analysis suggested that Thorotrast ICC develops from a stem cell that can differentiate into either bile duct epithelial cells or hepatocytes. LOH pattern suggested that minimally required genetic changes for the development of hepatobiliary cancers are common among different carcinogenic causes including radiation exposure [1]. LOH frequency of Thorotrast AS was higher than that of non-Thorotrast and tended to be higher in larger chromosomes and in the long arm compared with smaller chromosomes and the short arm.…”

The Uneven Irradiation of a Target Cell and Its Dynamic Movement Can Mathematically Explain Incubation Period for the Induction of Cancer by Internally Deposited Radionuclides

“…different among species, organs, type of radiation and so on (Tanooka 2001). Th-ICC is thought to develop from stem cells that can differentiate into either bile duct epithelial cells or hepatocytes (Liu et al 2004). The long-term incubation period may partly attribute to the limited number and distribution of those stem cells (Ohtake et al 2008).…”