Molecular Changes in Hepatocellular Dysplastic Nodules on Microdissected Liver Biopsies

Maggioni, Marco; Coggi, Guido; Cassani, Barbara; Bianchi, Paolo; Romagnoli, Solange; Mandelli, Alessandra; Borzio, Mauro; Colombo, Piergiuseppe; Roncalli, Massimo

doi:10.1053/jhep.2000.18425

Cited by 75 publications

(47 citation statements)

References 29 publications

(39 reference statements)

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“…This low incidence of allelic losses was consistent with those in previous reports (11,13,18) and also our previous report on mostly HBVassociated cirrhotic livers but with concomitant HCC (17). From the previous reported series, the FAL indices in cirrhosis vary from 0.05 to 0.15 (11,13,18). The etiologies in the previous studies consisted of a mixture of both chronic HBV and HCV infection, with HBV-associated cirrhosis ranging from 21% to 44% of their cases and HCV-associated cirrhosis ranging from 33% to 55%.…”

Section: Discussionsupporting

confidence: 93%

“…Although LOH was observed at z1 of the 19 loci in 70.8% of the cirrhotic livers, the mean FAL index was low, at 0.09. This low incidence of allelic losses was consistent with those in previous reports (11,13,18) and also our previous report on mostly HBVassociated cirrhotic livers but with concomitant HCC (17). From the previous reported series, the FAL indices in cirrhosis vary from 0.05 to 0.15 (11,13,18).…”

Section: Discussionsupporting

confidence: 92%

“…In general, the genetic profile of liver DNs is poorly understood. There are only a few reports on the allelic or chromosomal changes of DNs in the literature (10)(11)(12)(13). However, in most of these reports, only a small number of chromosomes were examined.…”

Section: Introductionmentioning

confidence: 99%

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Hepatitis B Virus–Associated Multistep Hepatocarcinogenesis: A Stepwise Increase in Allelic Alterations

Lee

Wong

2008

Cancer Research

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Hepatocarcinogenesis is a multistep process, but systematic analysis using a genetic or molecular approach to accurately delineate the different stages of hepatocellular carcinoma (HCC) development is scarce. In this study, we used genomewide allelotyping to systematically evaluate the allelic alterations in the multisteps of hepatitis B virus-associated hepatocarcinogenesis. The overall fractional allelic loss (FAL) indices of cirrhosis, dysplastic nodules (DN), and HCC were significantly different, with a clear stepwise increase (P < 0.001). Loss of heterozygosity (LOH) was uncommon in cirrhotic livers (n = 24; mean FAL index F SD, 0.09 F 0.09; median, 0.07). In contrast, LOH was common in our 74 HCC nodules, which were predominantly hepatitis B virus-associated (mean FAL index F SD, 0.40 F 0.23; median, 0.38). The 18 DNs had FAL index (mean F SD, 0.27 F 0.19; median, 0.20) in between that of cirrhosis and HCC. Importantly, high-grade DNs had FAL index significantly higher than that of low-grade DNs (P = 0.031) and close to that of HCC, indicating that high-grade DNs were genetically closer to HCC. However, there was no significant difference in FAL indices between primary HCCs and their corresponding intrahepatic metastases, but this absence of major allelic losses in this transformation to a metastatic phenotype does not exclude small-scale chromosomal losses or gene deletions. To conclude, hepatitis B virus-associated hepatocarcinogenesis is a multistep process accompanied by stepwise increase in allelic losses from cirrhosis and low-and high-grade DN to HCC. Such allelic losses contribute to promote tumor development and progression. [Cancer Res 2008;68(14):5988-96]

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 92%

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Hepatitis B Virus–Associated Multistep Hepatocarcinogenesis: A Stepwise Increase in Allelic Alterations

Lee

Wong

2008

Cancer Research

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“…Indeed we found that most cirrhoses and the vast majority of malignant tumors had promoter methylation affecting at least a single gene. Thus, in addition to well-recognized molecular abnormalities such as loss of heterozygosity, deletion, and point mutation, [16][17][18][19][20] inactivation of cell cycle inhibitors by epigenetic mechanisms seems to play an important role in human hepatocarcinogenesis. We have also found that methylated cirrhosis usually associates to methylated HCC, suggesting a common mechanism of gene inactivation from cirrhosis to HCC.…”

Section: Discussionmentioning

confidence: 99%

Methylation framework of cell cycle gene inhibitors in cirrhosis and associated hepatocellular carcinoma

et al. 2002

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One of the main regulatory pathways reported to be altered in hepatocellular carcinoma (HCC) is that of cell cycle control involving RB1 gene-related cell inhibitors. We investigated p14 ARF , p15 INK4B M ethylation of normally unmethylated CpG islands is an alternative mechanism for loss of function of tumor suppressor genes in human cancer. p16 INK4A is one of the most important tumor suppressor genes belonging to the family of cell cycle inhibitors, encoding a protein that binds competitively to cyclin-dependent-kinase-4 proteins. In hepatocellular carcinoma (HCC), methylation of p16 INK4A promoter has already been documented with variable frequency. [1][2][3][4] Wong et al. 5 recently reported p16 INK4A promoter methylation in 81% of sera samples of patients with methylated HCC. This result is particularly interesting for early diagnosis and possible therapeutic implications because promoter methylation is potentially reversible. It is known that cirrhosis is a favorable background for HCC development so that, not unexpectedly, p16 INK4A methylation was also recently reported by Kaneto et al. 6 in 30% of cirrhoses, suggesting its potential clinical use for selecting patients at high risk for HCC.The functional significance of promoter methylation was also established in a number of studies showing that this epigenetic abnormality usually corresponds the abrogation of messenger RNA (mRNA) synthesis and protein expression in both tumoral and nontumoral liver tissue. 3,4,6 Interestingly, concurrent inactivation of tumor suppressor genes of RB1 gene-related pathways such as p16 INK4A , p14 ARF , and p15 INK4B by promoter methylation has been shown not only in many types of human tumors, such as meningiomas, central nervous system lymphomas, and glial tumors, 7-9 but also in early preneoplastic Abbreviations: HCC, hepatocellular carcinoma; PCR, polymerase chain reaction. From the

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“…28 In the current investigation, the 1p36-p34 region was explored in more detail to identify new early deletions in human hepatocarcinogenesis. D1S2843 (1p36.12) and D1S513 (1p34.3) were found to be more frequently deleted than the other loci in HCCs, DNs, and CNs adjacent to them.…”

Section: Discussionmentioning

confidence: 99%

An early lesion in hepatic carcinogenesis: Loss of heterozygosity in human cirrhotic livers and dysplastic nodules at the 1p36-p34 region

et al. 2001

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Loss of heterozygosity (LOH) of chromosome 1 has been suggested, by karyotyping, to be an initial episode in human hepatocarcinogenesis. However, this alteration has not yet been investigated in cirrhotic nodules (CNs) or dysplastic nodules (DNs). In an initial study from explanted or resected cirrhotic livers, LOH in 1p36-p32 was examined in 31 hepatocellular carcinomas (HCCs), 25 low-grade dysplastic nodules (LGDNs), and 24 high-grade dysplastic nodules (HGDNs). In HCCs, LOH was detected most frequently at loci D1S2843 (1p36.1) (28.6%), D1S513 (1p34.3) (29.2%), and MYCL1 (1p34.1) (28.6%). In HGDN and LGDN, LOH incidences at D1S513 were 11.1% and 13.6%, respectively. To further refine those results and to determine sequential relationships among CN, DN, and HCC, LOH was next studied in an additional 53 HCCs, 56 HGDNs, 30 LGDNs, and 215 CNs from 11 explanted human cirrhotic livers, including 30 "nodule-in-nodule" lesions. Seven markers between D1S2843 (1p36.12) and MYCL1 (1p34.1), and 1 each at D1S484 (1q24.1), IGF2R-3 (6q26), and TP53 (17p13.1) were used. LOH at D1S2843 and D1S513 was detected in HCCs (20.4% and 23.5%, respectively), HGDNs (7.7% and 18.5%), LGDNs (13.6% and 6.9%), and CNs surrounding either HCCs or DNs (7.4% and 8.3%). These results demonstrate that LOH at D1S2843 and D1S513 are early events in human liver carcinogenesis. Because 85% or more of hepatocellular carcinoma (HCC) occur in cirrhotic livers in Western patients, 1 it is possible that certain cirrhotic nodules (CNs) could become preneoplastic. This could be followed, putatively, by the appearance of dysplastic nodules (DNs) and HCCs. A body of evidence resulting from histology 2 and imaging modalities 3 has, over the past decade, documented the relationship between the dysplastic nodular lesions seen mostly in cirrhotic livers and HCC. [2][3][4] DNs have been classified as low-grade (LGDN) and highgrade (HGDN) according to the criteria proposed by the International Working Party. 5 LGDNs have mild atypia, while HGDNs have one or more of the following: high nuclearcytoplasmic ratio, nuclear hyperchromasia, irregular nuclear contour, plates more than 2 cells wide, pseudoglandular formation, cytoplasmic basophilia, and resistance to iron accumulation. 5 However, the molecular mechanisms implicated in this progression remain unknown. Because of the lack of markers for early genetic changes, the only direct evidence at the molecular level for a DN3 HCC sequence has come from the integrated pattern of hepatitis B virus (HBV) DNA of a HCC located within an HGDN (a so-called "nodule-in-nodule" lesion) in a cirrhotic liver. 6 In this study, the HGDN and HCC were from an identical clone. Examination of the mechanisms of transformation of DN would be more feasible if other early molecular markers were to be found.

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Molecular Changes in Hepatocellular Dysplastic Nodules on Microdissected Liver Biopsies

Cited by 75 publications

References 29 publications

Hepatitis B Virus–Associated Multistep Hepatocarcinogenesis: A Stepwise Increase in Allelic Alterations

Hepatitis B Virus–Associated Multistep Hepatocarcinogenesis: A Stepwise Increase in Allelic Alterations

Methylation framework of cell cycle gene inhibitors in cirrhosis and associated hepatocellular carcinoma

An early lesion in hepatic carcinogenesis: Loss of heterozygosity in human cirrhotic livers and dysplastic nodules at the 1p36-p34 region

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