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

由于与肝细胞癌相比，肝内胆管细胞癌(ICCI)的预后较差，而且肝移植的优先级较低，因此我们在ICC中进行了基因分析，以确定ICC的特征。作为二战期间用于血管造影的放射造影剂，Thorotrast在ICC的诱导中起着关键作用。在前些年，我们观察到A-T过渡性改变在P53突变中最常见，而P53突变在非胸穿ICC中并不常见。我们进一步研究了mem-2基因扩增和蛋白过度表达导致非胸穿ICC中P53蛋白抑制的原因。结合P53突变，我们发现超过一半的非TICC病例中P53失活。提示P53失活是走向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。我们发现70%以上的胸腔积液ICC病例存在微卫星不稳定性(MSI)。虽然MSI表型与MSI密切相关，但MSI多见于Thorotrast沉积量较少和ICC潜伏期较长的病例，而在非Thorotrast ICC病例中，MSI的发生率低于1/3，且无P53突变。提示肝细胞癌的发生由两个过程组成，即有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.