Oncogene (2006) 25, 3778–3786. doi:10.1038/sj.onc.1209547

Genetics of hepatocellular tumors

P Laurent-Puig1,2 and J Zucman-Rossi3,4

  1. 1Inserm, U775, Bases Moléculaires de la réponse aux xénobiotiques, Paris, France
  2. 2Université Paris 5, Paris, France
  3. 3Inserm, U674, Génomique fonctionnelle des tumeurs solides, Paris, France
  4. 4Université Paris 7 Denis Diderot, Institut Universitaire d'Hématologie, CEPH, Paris, France

Correspondence: Dr J Zucman-Rossi, Inserm, U674, Génomique fonctionnelle des tumeurs solides, 27 rue Juliette Dodu, Paris 75010, France.



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 1alpha (HNF1alpha) 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/beta-catenin pathway through CTNNB1/beta-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 beta-catenin activated. These classifications have clinical relevance as genetic alterations may also be related to prognosis.


hepatocellular carcinoma, hepatocellular adenoma, chromosome instability, gene mutation, tumor suppressor gene



Cancer is a DNA disease owing to the accumulation of genetic alterations and more specifically of genes that control cell cycle and cell proliferation. Some of the observed genetic alterations are widely shared among the different tumor types; however, the association of the recurrent genetic alterations is highly specific of a tumor type. Therefore, the comprehensive knowledge of a broad field of genetic alterations in a tumor type and the study of the correlation between these alterations and the different clinical and histological parameters allow to refine the tumor classification and the understanding of the multistep carcinogenesis process.

Dysplastic cirrhotic nodules are considered to be precursors of hepatocellular carcinoma (HCC) because of their frequent association with the HCC occurrence (Furuya et al., 1988; Terada et al., 1993). Overall, HCC development is closely associated with cirrhosis and more than 90% of the tumors are found in a chronic hepatitis or a cirrhotic background (Edmondson and Peters, 1983). The various risk factors that are associated with the development of these lesions are well known. They mainly include infection with the hepatitis B virus (HBV) or hepatitis C virus (HCV), heavy alcohol intake, prolonged dietary exposure to aflatoxin B1 (AFB1) or vinyl chloride and primary hemochromatosis. In 90% of the HCC cases, at least one of these risk factors can be identified, either alone or in combination (detailed in Donato et al., in this issue) and the presence of each risk factor among patients varies according to the geographical origin of the patients (detailed in Seef et al., in this issue). However, in less than 10% of the cases, HCC are observed in non-cirrhotic liver and even without inflammatory lesions. These HCC developed in an otherwise normal liver are usually found in patients without well-established risk factors. Some of these cases may correspond to the malignant transformation of liver adenoma that are rare benign hepatocellular tumors found in young women taking oral contraception for more than 3 years (Edmondson et al., 1976). Hepatoblastoma is another particular case of primary hepatocellular tumor developed in otherwise normal liver parenchyma. Hepatoblastoma is a rare embryonic tumors (1:1 000 000 births), but it represents the most frequent liver tumors in children under the age of 3 years (Weinberg and Finegold, 1983). These tumors histologically differ from HCC as they are composed of immature epithelial cells with sometimes immature mesenchymal or teratomatous elements (Weinberg and Finegold, 1983).

The HCC as well as precursor benign lesions have been extensively studied in terms of genetic alteration in the past 10 years and our knowledge has dramatically increased in this field leading to the definition of the different altered pathways in hepatocarcinogenesis. As in other solid tumors, a large number of genetic alterations are accumulated during the carcinogenetic process. Indeed, genetic and epigenetic alterations have been observed in cirrhotic nodules and half of them have been found to have a monoclonal origin by examining the X-chromosome methylation pattern (Piao et al., 1997; Paradis et al., 1998; Yeh et al., 2001). Chromosome aberrations with loss of alleles are found in half of cirrhotic nodules and more frequently in nodules with small cell dysplasia (Yeh et al., 2001). However, structural alterations of specific gene, that is, activating mutations of oncogene and inactivating mutations of tumor suppressor genes have not been described in cirrhosis and were only found in HCC and liver cell adenomas. Overall, a very large number of genetic alterations have been described in primary liver tumors, and in this review, we will describe the different somatic genetic alterations acquired by the hepatocytes to be fully transformed in tumor cells. These genetic alterations can be divided in specific or nonspecific aberrations to the HCC etiological factors. Relationship between gene alterations and clinical features such as prognostic and genetic susceptibility will be analysed.


Genetic alterations specific to etiological factors

Genetic alterations and hepatitis B virus infection

Hepatitis B virus infection can promote carcinogenesis by at least three different mechanisms. First, integration of the viral DNA in the host genome can induce chromosome instability (Aoki et al., 1996). Second, insertional mutations have been described in which HBV integration at specific sites activates endogenous genes such as retinoic acid beta-receptor (Dejean et al., 1986), cyclin A (Wang et al., 1990) and mevalonate kinase (Graef et al., 1994). More recently, 15 new genes were found to be altered by an HBV integration in tumors, suggesting that viral integration in the vicinity of genes controlling cell proliferation, viability and differentiation is a mechanism frequently involved in HBV hepatocarcinogenesis (Ferber et al., 2003; Horikawa and Barrett, 2003; Paterlini-Brechot et al., 2003). All of these integration events are unique, except for the human telomerase reverse transcriptase (hTERT) and the inositol 1,4,5-triphosphate receptor (IPR) genes that have been observed to have site-specific HBV integrations in independent tumors (Ferber et al., 2003; Horikawa and Barrett, 2003; Paterlini-Brechot et al., 2003). Insertional mutagenesis seems to be implicated in 20–40% of the HCC cases related to HBV infection. The third mechanism of carcinogenesis linked to HBV infection is based on the expression of viral protein, in particular HBX, to modulate cell proliferation and viability (Andrisani and Barnabas, 1999; Diao et al., 2001). Moreover, HBX binds to p53 and inactivates p53-dependent activities, including p53-mediated apoptosis (Feitelson et al., 1993).

In endemic HBV area, familial aggregations of HCC were observed. Although this clustering of familial HBV is mainly owing to perinatal transmission of HBV infection, some evidences suggest that genetic susceptibility may also be involved (Yu et al., 2000). Furthermore, segregation analysis suggested that this familial aggregation could be owing to a gene with an autosomal mode of inheritance that may act with HBV to increase the risk of HCC (Shen et al., 1991; Cai et al., 2003).

Exposure to aflatoxin B1 leads to specific TP53 mutation in hepatocellular carcinoma

Aflatoxin B1 requires metabolic conversion to its exo-8,9-epoxide in order to damage DNA and proteins and various adducts are formed in vitro and in vivo (Essigmann et al., 1977; Martin and Garner, 1977; Miller, 1978; Groopman et al., 1981). After an exposure to AFB1, mainly in sub-tropical regions, an accumulation of DNA adducts are found in the liver, as a result of conversion of the AFB1 to its active metabolites. Aflatoxin B1 is a very potent mutagen and the AFB1 epoxide reacts with guanine in DNA, leading to genetic changes. The most frequently induced mutation is the GC right arrow TA transversion. The mutational spectrum of TP53 (tumor protein p53) gene in HCC from Qidong and Mozambique, where AFB1 exposure level is high, revealed G right arrow T transversion at codon 249 in more than 50% of the cases (Bressac et al., 1991). This mutation at codon 249 of TP53, leading to the amino-acid substitution R249S, is exceptionally found in HCC from geographical regions without AFB1 exposure. In general, the frequency of the R249S mutation paralleled the estimated level of AFB1 exposure, supporting the hypothesis that the carcinogen has a causative role in hepatocarcinogenesis. Molecular mechanisms of AFB1–DNA binding and mutagenesis have been elucidated in human tumors, animal models and in vitro (see for a review Smela et al., 2001).

There is evidence that the carcinogenic potential of AFB1 may vary between individuals, as for the same exposition not all patients will develop HCC. The variation is likely owing to the individual capacity to detoxify the aflatoxin 8,9 epoxide, the mutagenic metabolite of AFB1. A part of this inter-individual variability is owing to different efficacy of the enzymes to metabolize this carcinogene compound. Among the enzymes implicated in the detoxification process, the glutathion transferase GSTM1 and GSTT1 and the epoxide hydrolase (EPHX) have been shown to play an important role. In the human population, these enzymes are polymorphic and some of these polymorphisms have functional consequences. For GSTM1 and GSTT1, the main polymorphism is owing to a gene deletion, which leads to a null allele. Patients are grouped according to the presence or the absence of non-null allele. For the EPHX, the main functional polymorphism is owing to the substitution of a histidine in position 113 by a tyrosine decreasing the EPHX activity of 40%. For GSTM1 and H113T EPHX polymorphisms, there was a statistically significant relationship with detectable levels of AFB1–albumin adducts in the serum. In a case–control study, it has been shown that patients with one EXPH 113 Tyr allele have an increased risk of developing HCC; furthermore, a synergistic effect exists with HBV infection leading to a risk ratio of 77 of developing HCC when patients bearing the at-risk EPHX allele (i.e. one 113 Tyr allele) are infected by HBV. The risk was 15 for HBV patients with no EPHX risk allele and three for patients with the at-risk allele but not infected by HBV (McGlynn et al., 1995). A more recent publication showed that either GSTM1 and GSTT1 homozygous null allele patients are at risk of developing HCC when exposed to AFB1 (Sun et al., 2001). In addition, the effect of aflatoxin exposure on HCC risk was more pronounced among chronic hepatitis B surface antigen carriers with the GSTT1 null genotypes (odds ratio 3.3, confidence interval 95% 1.5–9.3). These results demonstrate the importance of gene–environment interaction in the development of HCC.

KRAS mutations are associated with vinyl chloride exposure in hepatocellular carcinoma

Vinyl chloride is a carcinogen associated with the development of liver angiosarcomas and rarely with HCC. Recently, the presence of KRAS2 mutations was observed in 33% of 18 vinyl chloride-associated HCCs and three mutations were found in adjacent non-neoplastic liver tissue (Weihrauch et al., 2001). The KRAS mutations observed were probably caused by chloroethylene oxide, a carcinogenic metabolite of vinyl chloride. Because KRAS mutations are rarely observed in HCCs that are not associated with vinyl chloride exposure, these results strongly suggest that KRAS2 mutations play an important role in the carcinogenetic pathway linked to vinyl chloride exposure.

Specific genetic alterations associated with liver cell adenomas

Recently, biallelic mutation of the transcription factor 1 (TCF1) gene, coding for hepatocyte nuclear factor 1alpha (HNF1alpha), were identified in 60% of a sample of liver cell adenoma cases (Bluteau et al., 2002b) (Figure 1). Hepatocyte nuclear factor 1alpha is a transcription factor that is implicated in hepatocyte differentiation and is required for the liver-specific expression of several genes, including beta-fibrinogen, albumin and alpha1-antitrypsin (Frain et al., 1989; Baumhueter et al., 1990; Cereghini et al., 1990; Chouard et al., 1990). Heterozygous germline mutations of TCF1/HNF1alpha have been linked to the occurrence of MODY3 (maturity onset diabetes of the young, OMIM no. 600496) in humans (Yamagata et al., 1996). MODY3 is a rare, dominantly inherited subtype of non-insulin-dependent diabetes mellitus characterized by early onset, usually before the age of 25, and a primary defect in insulin secretion. In liver cell adenomas, inactivation of both TCF1/HNF1alpha alleles is normally observed; in 90% of the cases both mutations are somatic. However in the other cases, corresponding to MODY3 patients, one mutation is germ line and the second allele inactivation is a somatic event observed only in the tumor (Bluteau et al., 2002b; Bacq et al., 2003). Furthermore, two well-differentiated HCC occurring in normal liver contained somatic biallelic TCF1/HNF1alpha mutations in a sample of 30 HCCs screened. These results indicate that inactivation of HNF1alpha, whether sporadic or associated with MODY3, is an important genetic event in the occurrence of human liver adenoma and may be an early step in the development of some HCCs (Bluteau et al., 2002b). In a recent study including 96 adenomas, we showed that HNF1alpha-mutated adenoma represented the most common type of adenoma which is phenotypically characterized by marked steatosis (Zucman-Rossi et al., 2006).

Figure 1.
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Transcription factor 1 (TCF1) mutations in liver cell adenoma tumorigenesis (Bluteau et al., 2002b).

Full figure and legend (15K)

Genetic predisposition to hepatoblastoma

Most of the hepatoblastoma are sporadic, but they can also occur in the Beckwith–Wiedemann syndrome (BWS) or in the familial adenomatous polyposis (FAP), two cancers predispositions. The last predisposition is owing to adenomatosis polyposis coli (APC) germline mutation. Immunohistochemical analysis of beta-catenin has demonstrated nuclear/cytoplasmic accumulation of the protein in most hepatoblastomas and sequence analysis of the beta-catenin N-terminal domain has revealed interstitial deletions or missense mutations in the GSK3beta phosphorylation motif in 48–67% of sporadic hepatoblastoma tumors (Koch et al., 1999; Wei et al., 2000; Buendia, 2002). In some hepatoblastoma cases, activation of the WNT/beta-catenin pathway may be related to AXIN2 (axis inhibition protein 2) mutations (Koch et al., 2004). However, in a series of five FAP patients with hepatoblastoma, Cetta et al. (2003) noted that neither beta-catenin and allelic losses were found at APC locus, suggesting that in patients with germline APC mutation, activation of the Wnt pathway occurs in the absence of beta-catenin mutations in the exon 3.


Global study of the molecular alterations in hepatocellular carcinoma

Genomewide analysis of genetic alterations in hepatocellular carcinoma

Genetic alterations accumulated in HCC are numerous with more than 20 different genes involved altering at least four different signaling pathways. To understand relations existing between these different genetic alterations, we recently analysed a large number of genetic alterations in the same series of tumors (Laurent-Puig et al., 2001) (Figure 3). A series of 137 HCC was collected in France in which the different etiological factors were equally represented with alcohol abuse found in 37% of the cases, HBV and HCV infection each in one-third of the cases. Tumors were analysed using high-density allelotyping to search for LOH on the entire genome and gene mutations were sought in TP53, AXIN1 and CTNNB1/beta-catenin genes. Loss of heterozygosity was the most frequent genetic alteration observed because only seven tumors showed no loss of any chromosome arms. According to the other studies, most frequently deleted chromosome arms were 8p (48%), 17p (45%), 4q (38%), 1p (33%), 13q (30%), 6q (29%), 16p (24%) and 9p (20%). Activation of the Wnt pathway was found in 28% of the case either by activation CTNNB1/beta-catenin mutations (19% of the cases) or by AXIN1 inactivation (9% of the cases). Alteration of the TP53 pathway was found at the same frequency with a TP53 gene mutation identified in 26% of the cases. To test associations between genetic alterations, correlations were sought by analysing TP53, AXIN1 and CTNNB1/beta-catenin mutations together with the 10 most frequently deleted chromosomes and the FAL index measuring the number of chromosomes deleted per tumor. Half of the tumors showed LOH on more than five chromosome arms (FAL index>0.12), reflecting a chromosomal instability as described by Cahill et al. (1998) in colon cancer. Genetic alterations associated with chromosome instability were LOH at chromosome 1p, 4q, 13q and 16, and mutation of the axin1 and TP53 genes. In the other half of the HCC, tumors were chromosome stable, LOH at the short arm of chromosome 8 and beta-catenin mutations were most frequently observed. Thus, this study enabled the definition of two mechanisms of hepatocarcinogenesis. In the first, genetic alterations are accumulated through a chromosome instability, and in the second, activation of the Wnt pathway by CTNNB1/beta-catenin mutation was predominant (Laurent-Puig et al., 2001).

Figure 3.
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Major hepatocarcinogenesis pathways defined by genetic alterations and their relations with clinical parameters. Lines joining boxes indicate significant correlation (Laurent-Puig et al., 2001).

Full figure and legend (20K)

Correlations between etiological factors and molecular alterations

Associations between etiological factors of HCC and genetic alterations in tumors have been found in several studies. In our series analysing 137 French HCC, chromosome instability together with TP53 and AXIN1 mutations were closely related to HBV infection (Laurent-Puig et al., 2001). This relationship could explain the variation of FAL index values observed in different published series. In contrast, the second hepatocarcinogenesis pathway defined by CTNNB1/beta-catenin mutation associated with chromosome 8p deletion in a context of chromosome stability is significantly associated with the absence of HBV infection. This last group of tumors includes HCV and alcohol-related tumors without genetic alteration specifically associated with the alcohol abuse. 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).

Correlations between other clinical parameters and molecular alterations

Globally, the number of genetic alterations in HCC tumors is inversely proportional to its degree of differentiation (Nishida et al., 1992). Positive relations were observed between a poor differentiation of the tumor and chromosome losses at 4q (Okabe et al., 2000), 16q (Tsuda et al., 1990; Nishida et al., 1992; Kuroki et al., 1995; Okabe et al., 2000), 17p (Kuroki et al., 1995; Laurent-Puig et al., 2001), 8p (Kuroki et al., 1995; Okabe et al., 2000) and 13q (Nishida et al., 1992; Kuroki et al., 1995; Okabe et al., 2000; Laurent-Puig et al., 2001). Similarly, TP53 mutations are most frequently observed in poorly differentiated tumors (Tanaka et al., 1993; Teramoto et al., 1994; Laurent-Puig et al., 2001). These results suggest that chromosome LOH at 4q, 16q, 17p and 13q, and TP53 mutations may be late genetic alterations accumulated at the end of hepatocarcinogenesis progression.

Apart from TCF1/HNF1alpha mutations found in two cases of HCC developed in otherwise normal liver, no specific molecular alteration have been found in this group of tumors (Bluteau et al., 2002a). In our series analysing 137 French tumors, we found that tumors developed in non-cirrhotic liver had significantly most frequent chromosome 8p and 13q LOH (Laurent-Puig et al., 2001). However, this result has to be confirmed in a second study. Finally, beta-catenin-activating mutations were found most frequently in large sized (Laurent-Puig et al., 2001; Wong et al., 2001) and well-differentiated tumors (Mao et al., 2001). Although the pathological tumor-node-metastasis staging has been applied clinically to HCC patients, this system is inadequate for predicting recurrence in individuals who undergo hepatic resection. In our analysis of 137 resected HCC, we found that chromosome instability and more specifically chromosome 9p and 6q losses were associated with poor prognosis (Laurent-Puig et al., 2001). In other studies, different new variables have been suggested to have a prognostic value (Okabe et al., 2001; Shirota et al., 2001; Xu et al., 2001). In the future, additional studies using larger prospective series of patients should clarify the prognostic value of these new molecular markers.



Characterization of the genetic alterations associated with HCC tumors is an essential step to increase our knowledge of hepatocarcinogenesis. Systematic search for these alterations in series of tumors, including all grade, stages, etiologies and also pre-neoplastic lesions, will enable to find a chronological order in the accumulation of the genetic alterations during tumor progression. Systematic transcriptome and proteome analyses may also contribute to identify new carcinogenetic pathways altered in these tumors. Finally, comprehensive studies may find clinical application to identify markers useful to early detection of tumors, to predict prognosis or to find new therapeutic targets.



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This work was supported by the Inserm and the Fondation de France.