Quantitative evaluation of genomic instability as a possible predictor for development of hepatocellular carcinoma: Comparison of loss of heterozygosity and replication error

Kawai, Hirokazu; Suda, Takafumi; Aoyagi, Yoshinobu; Isokawa, Osamu; Mita, Yusaku; Waguri, Nobuo; Kuroiwa, Takashi; Igarashi, Masato; Tsukada, Kazuhiro; Mori, Shigeki; Shimizu, Takahiro; Suzuki, Yuzuru; Abe, Yoichi; Takahashi, Toru; Nomoto, Minoru; Asakura, Hitoshi

doi:10.1053/jhep.2000.7298

Cited by 64 publications

(24 citation statements)

References 15 publications

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“…LOH is indicative of allelic imbalance and can be used to assess overall genomic integrity. 42 Unstable genomes harbor a greater extent of LOH compared with those that are genetically stable. The presence of allelic imbalance (LOH) did not correlate with EBV infection status in the PEL cell lines.…”

Section: Cnv Not Loh Distinguishes Ebv-positive From Ebv-negative Pelmentioning

confidence: 99%

Tumor suppressor genes FHIT and WWOX are deleted in primary effusion lymphoma (PEL) cell lines

Roy

Sin

Damania

et al. 2011

Blood

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Section: Cnv Not Loh Distinguishes Ebv-positive From Ebv-negative Pelmentioning

confidence: 99%

Tumor suppressor genes FHIT and WWOX are deleted in primary effusion lymphoma (PEL) cell lines

Roy

Sin

Damania

et al. 2011

Blood

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“…In HBV-mediated HCC the rate of chromosomal aberrations is significantly increased in comparison to HCC associated with other risk factors (2)(3)(4). However, the mechanism by which genomic changes initiate HCC development is not yet understood (5)(6)(7). Herein, employing the HBV X protein (pX) as the oncogenic signal, we investigate whether pX expression induces chromosomal abnormalities, resulting in HCC pathogenesis.…”

mentioning

confidence: 99%

Hepatitis B Virus X Protein Increases the Cdt1-to-Geminin Ratio Inducing DNA Re-replication and Polyploidy

Rakotomalala¹,

Studach²,

Wang

et al. 2008

Journal of Biological Chemistry

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Hepatitis B virus X protein (pX) is implicated in hepatocellular carcinoma pathogenesis by an unknown mechanism. Employing the tetracycline-regulated pX-expressing 4pX-1 cell line, derived from the murine AML12 hepatocyte cell line, we demonstrate that pX induces partial polyploidy (>4N DNA). Depletion of p53 in 4pX-1 cells increases by 5-fold the polyploid cells in response to pX expression, indicating that p53 antagonizes pX-induced polyploidy. Dual-parameter flow cytometric analyses show pX-dependent bromodeoxyuridine (BrdUrd) incorporation in 4pX-1 cells containing 4N and >4N DNA, suggesting pX induces DNA re-replication. Interestingly, pX increases expression of endogenous replication initiation factors Cdc6 and Cdtl while suppressing geminin expression, a negative regulator of rereplication. In comparison to a geminin knockdown 4pX-1 cell line used as DNA re-replication control, the Cdt1/geminin ratio is greater in 4pX-1 cells expressing pX, indicating that pX promotes DNA re-replication. In support of this conclusion, pX-expressing 4pX-1 cells, similar to the geminin knockdown 4pX-1 cells, continue to incorporate BrdUrd in the G 2 phase and exhibit nuclear Cdc6 and MCM5 co-localization and the absence of geminin. In addition, pX expression activates the ATR kinase, the sensor of DNA re-replication, which in turn phosphorylates RAD17 and H2AX. Interestingly, phospho-H2AX-positive and BrdUrd -positive cells progress through mitosis, demonstrating a link between pX-induced DNA re-replication and polyploidy. Our studies highlight a novel function of pX that likely contributes to hepatocellular carcinoma pathogenesis. Chronic hepatitis B virus (HBV)4 infection results in the development of hepatocellular carcinoma (HCC) by the fourth or fifth decade (1) by an unknown mechanism. In HBV-mediated HCC the rate of chromosomal aberrations is significantly increased in comparison to HCC associated with other risk factors (2-4). However, the mechanism by which genomic changes initiate HCC development is not yet understood (5-7). Herein, employing the HBV X protein (pX) as the oncogenic signal, we investigate whether pX expression induces chromosomal abnormalities, resulting in HCC pathogenesis.The link between HBV-mediated HCC and pX is derived both from clinical evidence (8) as well as animal and cell culture transformation studies (9). Specifically, integration of HBV DNA into the host genome occurs at early steps of clonal tumor expansion, with most tumors displaying sustained expression of pX (8). Importantly, pX, which is essential for the viral life cycle (10), is a multifunctional protein inducing activation of the cellular mitogenic ras-raf-MAPK, c-Jun NH 2 -terminal kinase, and p38MAPK pathways (11) and transcription of select viral and cellular genes (9). These pX activities deregulate cellular gene expression, resulting either in unscheduled cell cycle progression (12) or apoptosis (13), depending on the growth conditions. Specifically, pX expression sensitizes the less-differentiated 4pX-1 hepatocyte cell ...

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“…42 We were the first to demonstrate MSI in cases of cirrhosis, 24 as previously shown in pancreatitis 43 or in ulcerative colitis, 44 and confirmed in cirrhosis. 45,46 However, we may have been too hasty in suggesting MSI with alterations in the MMR genes. The dinucleotide slippage observed in HCC and adjacent liver tissue probably could rather reflect the clonal expansion of tumor cells [47][48][49] or result from the underlying inflammatory process in tumors developing in a cirrhotic liver, mainly associated with HBV infection.…”

Section: Genetic Alterations According To Whether the Primary Tumor Wmentioning

confidence: 98%

Analysis of chromosomal instability in pulmonary or liver metastases and matched primary hepatocellular carcinoma after orthotopic liver transplantation

Gross‐Goupil

Riou

Émile³

et al. 2003

Intl Journal of Cancer

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To investigate the genetic mechanism of metastatic spread in hepatocellular carcinoma (HCC), we analyzed genomic changes in lung or liver metastases and the corresponding primary tumors (83 tumor samples) in 18 patients who underwent orthotopic liver transplantation. We studied the incidence of microsatellite instability (MSI) and loss of heterozygosity (LOH) involving 8 highly polymorphic microsatellite markers and the polyA tract, Bat26. We also sought alterations of p53 and ␤-catenin gene mutations. High MSI (>30 -40% of the loci analyzed) was found only in primary tumors (11%), whereas LOH was observed in 50% of primary and in 39% of recurrent tumors. p53 mutations were found in 2 cases of primary HCC but not in the corresponding metastases. P53 was overexpressed in 4 primary HCC (22%) and 7 metastases (39%). The percentage of ␤-catenin gene mutations was low (6%). Lung metastases retained the D16S402 microsatellite abnormalities observed in the primary tumors, whereas recurrent liver tumor did not (p ‫؍‬ 0.02). In conclusion, LOH and P53 protein overexpression, rather than mutations in the p53 or ␤-catenin genes or MSI, seem to be involved in the spreading of HCC, suggesting the presence of metastasis suppressor genes in the vicinity of the chromosomal loci in question. The recurrence of cancers remains a major problem despite advances in diagnostic procedures and changes in operative management. The poor outcome may result from an inappropriate choice of treatment at the time of tumor diagnosis. In hepatocellular carcinoma (HCC), the overall survival rate after resection is just 35-50%. [1][2][3][4][5] The prognostic criteria are related to the general status of the patient and to the characteristics of the tumor, such as vascular invasion or portal vein tumor thrombus, the number and maximum diameter of nodules and the infiltration of the capsule. 6 -8 However, these prognostic criteria remain controversial, and neither biologic markers of the tumor nor genetic changes have proved to be efficient prognostic tools for use at the time of diagnosis.About 20 genes carrying somatic mutations have now been identified in HCC. 9 -18 The genetic changes can be divided into at least 4 different pathways, although each pathway appears to be involved in a limited number of tumors. 16,19 -21 These are 1) the p53 pathway involved in the DNA damage response, 2) the retinoblastoma pathway involved in the control of the cell cycle, 3) the transforming growth factor-␤ (TGF-␤) pathway involved in growth inhibition and apoptosis, and 4) the antigen-presenting cell (APC)/␤-catenin pathway implicated in cell-cell adhesion and signal transduction. A recent study by Laurent-Puig et al. 16 detected loss of heterozygosity (LOH) on all chromosome arms and mutations in p53, ␤-catenin and axin and suggested 2 main pathways depending on whether the chromosomal instability was associated with alterations of specific genes or not.The genetic alterations that are the most implicated in the metastatic process of HCC are not yet known. M...

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Quantitative evaluation of genomic instability as a possible predictor for development of hepatocellular carcinoma: Comparison of loss of heterozygosity and replication error

Cited by 64 publications

References 15 publications

Tumor suppressor genes FHIT and WWOX are deleted in primary effusion lymphoma (PEL) cell lines

Tumor suppressor genes FHIT and WWOX are deleted in primary effusion lymphoma (PEL) cell lines

Hepatitis B Virus X Protein Increases the Cdt1-to-Geminin Ratio Inducing DNA Re-replication and Polyploidy

Analysis of chromosomal instability in pulmonary or liver metastases and matched primary hepatocellular carcinoma after orthotopic liver transplantation

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