Evaluation of Indication for Liver Transplantation in Primary Liver Cancers : Focused on Analysis of Multicentric Liver Cancers and Relapse of Prediction.

由于肝内胆管癌（ICCI）的预后较差，与肝细胞癌相比，其肝移植的优先性较低，因此我们对ICC进行了遗传分析以表征ICC。作为第二次世界大战期间用于血管造影剂的放射造影剂，Thorotrast在诱导ICC方面起着至关重要的作用。在过去的几年中，我们观察到p53突变中最常见的是A-T过渡变化，而p53突变在非thorotarst ICC中并不常见。我们进一步研究了mem-2基因扩增和蛋白过表达导致非thorotrast ICC中p53蛋白的抑制。结合p53突变，我们发现超过一半的非thorotarast ICC病例中p53失活，表明p53失活是ICC的重要一步。我们推测p53基因的过渡性变化是通过基因组不稳定性发生的。我们在70%以上的胸腔镜ICC病例中发现了微卫星不稳定性（MSI）。虽然MSI表型与MSI密切相关，但MSI倾向于在胸造影剂沉积量较低和ICC潜伏期较长的病例中观察到。在非胸腔造影的ICC病例中，MSI的发生率小于1/3，且没有p53突变。这些提示ICC的癌变包括有MSI和无MSI两个过程。

Since prognosis of intrahepatic cholangiocarcinoma (ICCI) is poorer and has lower priority of liver transplantation compared with hepatocellular carcinoma, we performed genetic analysis in ICC to characterize ICC.A radiological contrast medium used for angiography during World War II, Thorotrast plays a crucial role for induction of ICC.In previous years, we observed A-T transitional change most often among p53 mutations while p53 mutations are not frequent in non-Thorotarst ICC.We further investigated mem-2 gene amplification and protein overexpression which causes inhibition of p53 protein in non-Thorotrast ICC.In combination with p53 mutations, we found that p53 inactivation in more than a half of non-Thorotarast ICC cases, indicating that p53 inactivation is an important step toward ICC.We presumed that transitional changes of the p53 gene happen via genomic instability. We found microsatellite instability (MSI) in more than 70% of Thorotrast ICC cases. Although MSI phenotype was closely associated with MSI, MSI tended to be observed in the cases with lower amount of Thorotrast deposit and with longer incubation period for ICC.In non-Thorotrast ICC cases, the frequency of MSI is observed in less than 1/3 cases and those without p53 mutations. These suggest that carcinogenesis of ICC is composed of two processes with MSI and without MSI.