Multicentric Independent Development of Hepatocellular Carcinoma Revealed by Analysis of Hepatitis B Virus Integration Pattern

Sakamoto, Michiie; Hirohashi, Setsuo; Tsuda, Hitoshi; Shimosato, Yukío; Makuuchi, Masatoshi; Hosoda, Yasuhiro

doi:10.1097/00000478-198912000-00009

Cited by 103 publications

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“…Sakamoto et al similarly found that, by analyzing the mode of HBV integration, recurrence of very well-differentiated HCCs was a reflection of MO. 8 On the other hand, Kondo et al reported that very well-differentiated HCCs, as determined by histopathological examination, may also metastasize. 26 Our case 4 was a well-differentiated example that was proven to be the consequence of IM by PCR of HBV-flanking human genome junctions.…”

Section: Discussionmentioning

confidence: 99%

“…The diagnosis of IM or MO is mainly based on pathological findings as reported by the Liver Cancer Study Group of Japan 7 with modifications, 6,[8][9][10][11] or on the analysis of HBV-DNA integration by Southern blotting in cases of HBV-associated HCC. 8,[12][13][14][15][16][17][18] The pathological criteria for MO reflect the multistep nature of HCC development. Metastasis does not appear to occur from atypical adenomatous hyperplasia or very well-differentiated HCCs (Edmondson' s grade I) with maintenance of a relatively normal trabeculae structure, so that these cases can be considered to be primary de novo cancers.…”

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confidence: 99%

“…2,6 Aggressive therapy may not be warranted in cases with widespread metastatic dissemination, but in cases with MO, intervention should be taken within the limits of liver functional reserve. The diagnosis of IM or MO is mainly based on pathological findings as reported by the Liver Cancer Study Group of Japan 7 with modifications, 6,[8][9][10][11] or on the analysis of HBV-DNA integration by Southern blotting in cases of HBV-associated HCC. 8,[12][13][14][15][16][17][18] The pathological criteria for MO reflect the multistep nature of HCC development.…”

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Determination of the Clonal Origin of Multiple Human Hepatocellular Carcinomas by Cloning and Polymerase Chain Reaction of the Integrated Hepatitis B Virus Dna

et al. 1999

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The poor prognosis of hepatocellular carcinoma (HCC) is partly the result of the high rate of recurrence that is caused either by intrahepatic metastasis (IM) or independent multicentric occurrence (MO). For convenience, discrimination of IM and MO is based on pathological findings, but reliable parameters are not sufficiently established. In the case of hepatitis B virus (HBV)-associated HCC, molecular discrimination of IM from MO can be achieved by comparison of integrated HBV DNAs. However, Southern blotting cannot be used for this purpose when one tumor is saved in frozen form and the other is in paraffin-embedded form. To solve this problem, we employed polymerase chain reaction (PCR) assays to confirm the clonality of primary and recurrent tumors. From the frozen tissue, we determined the junction between the integrated HBV and flanking genomic DNA by molecular cloning, and checked the existence of an identical junction in the DNA of paraffinembedded tissue by PCR. Using this method, as well as Southern blotting, we proved in 6 of 8 patients that two nodular HCC lesions resected metachronously or simultaneously were caused by MO, while the remaining 2 cases were caused by IM. In 1 IM case, band patterns between two HCCs detected by Southern blotting were not identical. (HEPATOLOGY 1999;29:1446-1452.) Hepatocellular carcinoma (HCC), one of the most common cancers in many parts of the world, is the third-leading cause of death from malignancy in Japan. In 1995, HCC was responsible for about 30,000 deaths, and the number of deaths continues to increase in Japan. 1 Improvement in imaging modalities and strict follow-up of patients with hepatitis B virus (HBV) or hepatitis C virus, including measurement of serum tumor markers, allows early detection of HCCs. In spite of technical advances in the treatment of HCC, such as surgical resection, percutaneous ethanol injection therapy, and microwave coagulation therapy, the longterm survival rate is still low. One of the major reasons for this poor prognosis is the high rate of recurrence, which is 20% to 40% within 1 year, and about 80% in 5 years after curative operation in Japan. 2-5 HCC recurrence may be the result of intrahepatic metastasis (IM) or independent multicentric occurrence (MO). Discrimination between the two is important not only for the study of hepatocarcinogenesis, but also for determination of therapeutic strategies. Some groups have reported that HCC with IM recurs earlier and has a poorer prognosis than its MO counterpart. 2,6 Aggressive therapy may not be warranted in cases with widespread metastatic dissemination, but in cases with MO, intervention should be taken within the limits of liver functional reserve. The diagnosis of IM or MO is mainly based on pathological findings as reported by the Liver Cancer Study Group of Japan 7 with modifications, 6,[8][9][10][11] or on the analysis of HBV-DNA integration by Southern blotting in cases of HBV-associated HCC. 8,[12][13][14][15][16][17][18] The pathological criteria for MO reflect the multiste...

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Section: Discussionmentioning

confidence: 99%

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Determination of the Clonal Origin of Multiple Human Hepatocellular Carcinomas by Cloning and Polymerase Chain Reaction of the Integrated Hepatitis B Virus Dna

et al. 1999

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“…The Pearson correlation coefficients were interpreted using the scale provided by Salkin, where an R between 0.8 and 1.0 is defined as very strong, between 0.6 and 0.8 as strong, between 0.4 and 0.6 as moderate, between 0.2 and 0.4 as weak and between 0.0 and 0.2 as very weak or no relationship [56]. In this study, the criteria employed to define the intrahepatic metastasis was as follows: (1) Whether they represent portal-vein tumor thrombi or grew contiguously with vascular thrombi, (2) whether they are small compared to the tumor that they surround, (3) whether a single tumor is present near the main tumor but is much smaller in size and exhibits the same histology [57]. In addition, we mainly employed the Edmondson and Steiner grading system (EGS) to determine the histopathological grade of HCC, and two categories were considered (low grade, EGS I-II; high grade, III-IV) [58].…”

Section: Lentiviral Vector Construction Package and Infectionmentioning

confidence: 99%

Amplification of MPZL1/PZR promotes tumor cell migration through Src-mediated phosphorylation of cortactin in hepatocellular carcinoma

et al. 2013

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We have previously identified 1 241 regions of somatic copy number alterations (CNAs) in hepatocellular carcinoma (HCC). In the present study, we found that a novel recurrent focal amplicon, 1q24.1-24.2, targets the MPZL1 gene in HCC. Notably, there is a positive correlation between the expression levels of MPZL1 and intrahepatic metastasis of the HCC specimens. MPZL1 can significantly enhance the migratory and metastatic potential of the HCC cells. Moreover, we found that one of the mechanisms by which MPZL1 promotes HCC cell migration is by inducing the phosphorylation and activation of the pro-metastatic protein, cortactin. Additionally, we found that Src kinase mediates the phosphorylation and activation of cortactin induced by MPZL1 overexpression. Taken together, these findings suggest that MPZL1 is a novel pro-metastatic gene targeted by a recurrent region of copy number amplification at 1q24.1-24.2 in HCC.

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“…1 The high incidence of recurrence is the most crucial prognostic factor for patients with HCC. 2 Through a combination of pathologic and genetic approaches, recurrence of HCC has been divided into 2 types: multicentric occurrence of new tumors [3][4][5] and intrahepatic metastasis of the original HCC. Several clinicopathologic studies have shown that the incidence of intrahepatic metastasis is higher in HCC with an infiltrative growth pattern than in HCC with an expansive growth pattern.…”

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Inhibition of intrahepatic metastasis of human hepatocellular carcinoma by Rho-associated protein kinase inhibitor Y-27632

Sakamoto²,

et al. 2001

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Hepatocellular carcinoma (HCC) is one of the most common tumors worldwide, and is currently the third-leading cause of cancer death among males in Japan. 1 The high incidence of recurrence is the most crucial prognostic factor for patients with HCC. 2 Through a combination of pathologic and genetic approaches, recurrence of HCC has been divided into 2 types: multicentric occurrence of new tumors 3-5 and intrahepatic metastasis of the original HCC. Several clinicopathologic studies have shown that the incidence of intrahepatic metastasis is higher in HCC with an infiltrative growth pattern than in HCC with an expansive growth pattern. 6 In a previous study, a high incidence of loss of heterozygosity of chromosome 16 was reported in HCC with intrahepatic metastasis. 7

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Multicentric Independent Development of Hepatocellular Carcinoma Revealed by Analysis of Hepatitis B Virus Integration Pattern

Cited by 103 publications

References 0 publications

Determination of the Clonal Origin of Multiple Human Hepatocellular Carcinomas by Cloning and Polymerase Chain Reaction of the Integrated Hepatitis B Virus Dna

Determination of the Clonal Origin of Multiple Human Hepatocellular Carcinomas by Cloning and Polymerase Chain Reaction of the Integrated Hepatitis B Virus Dna

Amplification of MPZL1/PZR promotes tumor cell migration through Src-mediated phosphorylation of cortactin in hepatocellular carcinoma

Inhibition of intrahepatic metastasis of human hepatocellular carcinoma by Rho-associated protein kinase inhibitor Y-27632

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