Distinct chromosomal abnormality pattern in primary liver cancer of non-B, non-C patients

Marchio, Agnès; Pineau, Pascal; Meddeb, Mounira; Terris, Benoı̂t; Tiollais, Pierre; Bernheim, Alain; Dejean, Anne

doi:10.1038/sj.onc.1203713

Cited by 97 publications

(55 citation statements)

References 31 publications

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“…Furthermore, in this group of chromosome stable tumors, 35% of HCC cases did not show recurrent gene mutation or chromosome LOH. Similar results were also found in other analyses using allelotyping or CGH to search for chromosome abnormalities (Marchio et al, 2000;Okabe et al, 2000;Wong et al, 2000;Collonge-Rame et al, 2001;Bluteau et al, 2002a). …”

Section: Global Study Of the Molecular Alterations In Hepatocellular supporting

confidence: 87%

Genetics of hepatocellular tumors

2006

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Numerous genetic alterations are accumulated during the process of hepatocarcinogenesis. These genetic alterations can be divided into two groups. The first set of genetic alterations is specific of hepatocellular tumor risk factors. It includes integration of hepatitis B virus (HBV) DNA, R249S TP53 (tumor protein p53) mutation in aflatoxin B1-exposed patients, KRAS mutations related to vinyl chloride exposure, hepatocyte nuclear factor 1a (HNF1a) mutations associated to hepatocellular adenomas and adenomatosis polyposis coli (APC) germline mutations predisposing to hepatoblastomas. The second set of genetic alterations are etiological nonspecific, it includes recurrent gains and losses of chromosomes, alteration of TP53 gene, activation of WNT/b-catenin pathway through CTNNB1/b-catenin and AXIN (axis inhibition protein) mutations, inactivation of retinoblastoma and IGF2R (insulin-like growth factor 2 receptor) pathways through inactivation of RB1 (retinoblastoma 1), P16 and IGF2R. Comprehensive analyses of these genetic alterations have defined two pathways of hepatocarcinogenesis according to the presence or the absence of chromosomal instability. Hepatitis B virus and poorly differentiated tumors are related to chromosome instable tumors associated with frequent TP53 mutations, whereas non-HBV and well-differentiated tumors are related to chromosomal stable samples that are frequently b-catenin activated. These classifications have clinical relevance as genetic alterations may also be related to prognosis.

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Section: Global Study Of the Molecular Alterations In Hepatocellular supporting

confidence: 87%

Genetics of hepatocellular tumors

2006

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“…Chromosomal aberrations were more frequent in HBV-related HCCs than in HCV-associated tumors (29). Another study has shown that HBV-associated HCCs had a significantly more frequent (40% on average) losses at 4q, 16q, and 17p than in nonviral HCC samples, suggesting that these abnormalities are much associated with HBV infection (30). Similarly, more prevalent loss on 17p, including the p53 region, was also seen in HBV-associated HCCs in another study (29).…”

Section: Discussionmentioning

confidence: 74%

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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“…4 In hepatocellular carcinoma, although genetic characterizations have indicated frequent chromosomal over-representations on 1q, 6p, 8q, 17q and 20q, and deletions on 1p, 4q, 8p, 13q, 16q and 17p, [5][6][7][8][9][10][11] emphasis on the molecular changes that underlie the tumor progression has been somewhat limited. This is mainly because the genomic basis of hepatocellular carcinoma is considered heterogeneous owing to its mixed background of histological precursors, namely cirrhosis and chronic hepatitis, and the different actions of causative agents such as viral hepatitis types B or C inductions.…”

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confidence: 99%

Regional over-representations on chromosomes 1q, 3q and 7q in the progression of hepatitis B virus-related hepatocellular carcinoma

Wong

Lai

et al. 2005

Modern Pathology

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Hepatocellular carcinoma is a highly malignant tumor that is prevalent in Southeast Asia and China, where hepatitis B viral infection is the main etiologic factor. Despite a high incidence of hepatocellular carcinoma developing in patients with viral hepatitis B-induced liver cirrhosis, the molecular events underlying the malignant liver progression remain largely unclear. In an effort to characterize the genetic abnormalities involved in the hepatitis B-related liver carcinogenesis, we performed genome-wide explorations by the technique of comparative genomic hybridization (CGH) on 100 hepatocellular carcinoma tumors that arose from hepatitis B-induced liver cirrhosis. According to the American Joint Committee on Cancer staging, four cases were classified as stage I, 69 as stage II, 23 as stage III and four as stage IV. CGH analysis indicated chromosomal instability in both early (stages I/II) and advanced (stages III/IV) stage tumors, with common gains on 1q, 8q and 17q23-q25, and losses on 4q22-q35, 8p21-p22, 13q14-q21, 16q and 17p identified in both groups (P40.05). Nevertheless, preferential sites of chromosomal defects in relation to hepatocellular carcinoma progression were also identified. Statistical correlations suggested a higher incidence of regional 1q21-q22, 3q22-q28, 7q21-q22 and 7q34-q36 over-representations in association with the advanced stage tumors (Po0.05). In this study, our novel identification of specific chromosomal aberrations in relation to the advanced stage tumors may represent a first step towards mapping genes linked to the progression of hepatocellular carcinoma. Modern Pathology (2005) 18, 686-692, advance online publication, 17 December 2004; doi:10.1038/modpathol.3800345 Keywords: hepatocellular carcinoma; hepatitis B virus; liver cirrhosis; progression Hepatocellular carcinoma is a primary liver malignancy that is highly malignant and rapidly fatal. The dismal clinical outcome is largely due to the majority of hepatocellular carcinoma tumors being asymptomatic during the natural course of the disease, consequently rendering most patients not being diagnosed in time for curative surgery. 1 By the time of clinical presentation, intra-and extrahepatic metastases are also common, which in turn has limited the scope of curative surgery. 2 In addition, the relatively high incidences of hepatocellular carcinoma recurrence, possibly from micrometastasis prior to surgical treatment, has further lowered the 5-year survival rate for individuals diagnosed with hepatocellular carcinoma. 3 The understanding of molecular events involved in the malignant liver progression thus would hold much value in the prognosis for patients with hepatocellular carcinoma.Studies on the molecular pathogenesis have guided the development of gene-based biomarkers in a number of human cancers including breast, colon, prostate and lung. 4 In hepatocellular carcinoma, although genetic characterizations have indicated frequent chromosomal over-representations on 1q, 6p, 8q, 17q and 20q, and deletions on 1p, 4q, ...

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Distinct chromosomal abnormality pattern in primary liver cancer of non-B, non-C patients

Cited by 97 publications

References 31 publications

Genetics of hepatocellular tumors

Genetics of hepatocellular tumors

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

Regional over-representations on chromosomes 1q, 3q and 7q in the progression of hepatitis B virus-related hepatocellular carcinoma

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