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Hepatocellular carcinoma (HCC) is the most rapidly increasing cause of cancer mortality with poor prognosis (5-year survival <12%) in the United States.1 Although it is known that advanced liver fibrosis/cirrhosis is the high-risk condition that rationalizes regular HCC surveillance, the extremely high prevalence of cirrhosis (1%-2% of the general population) as well as other factors such as immigration from developing world make it difficult to adhere to the surveillance protocol: only 17% of new HCC cases were diagnosed through regular surveillance.2, 3 On the other hand, whereas annual cancer incidence in cirrhotic patients is very high (1%-7%), a certain proportion of patients with cirrhosis do not develop HCC during their lifetime.4 In addition, there is great diversity in the clinical course of HCC. However, our ability to predict these outcomes is still limited or lacking, especially in patients with early stage disease. A great expectation has been placed on molecular biomarkers to fill this unmet need and enable effective, personalized patient management with limited medical resources. Furthermore, such biomarkers will help HCC prevention strategies by enriching at-risk patients for clinical trials as well as by predicting and monitoring treatment response.

HCC development is a multistep process that involves establishment of chronic liver injury, progressive liver fibrosis that results in cirrhosis, initiation of neoplastic clone, and stepwise malignant transformation and dissemination of the clone (Fig. 1). Molecular mechanisms involved in each of the steps have been studied extensively with a goal of identifying the key drivers and gatekeepers, yielding many candidates of biomarkers and/or therapeutic targets.5

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Figure 1. Multistep process of HCC development in chronic liver disease. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

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Molecular Risk Factors of HCC Development

  1. Top of page
  2. Abstract
  3. Molecular Risk Factors of HCC Development
  4. Molecular Subclasses of Aggressive HCC Tumor
  5. Clinical Translation of Molecular Indicators of HCC risk and Poor Prognosis
  6. References

To date, numerous genetic polymorphisms have been reported as host genetic factors that determine susceptibility to HCC development (Table 1).6 Large-scale case-control or cohort studies, as well as systematic reviews, have identified HCC-associated single-nucleotide polymorphisms in genes involved in immune response (TNF, IL10), oxidative stress (GSTM1, GSTT1), growth signaling (EGF), cell cycle (MDM2), DNA damage repair (XPC), and iron metabolism (HFE) in viral hepatitis– or alcohol-related HCC.7-14 Recent genome-wide association studies have identified the DEPDC5 gene as well as MICA and 1p36.22 regions as risk loci in viral hepatitis–related HCC.15-17 These associations are generally modest (odds or hazard ratios below 2), and therefore the combination of multiple loci representing independent mechanisms may yield a more powerful polygenic signature of HCC risk variants. A panel of seven variants in immune-related genes has been tested for its association with fibrosis progression, but not yet for HCC development.18 One caveat is that the case-control design employed in most of these studies often failed to control several key confounding factors. Gene expression signatures in stromal liver tissue, another class of biological information assumed to capture functional molecular deregulation, were shown to be predictive of disseminative or de novo HCC recurrence after surgical resection.19, 20 Etiological agent–related molecular factors could also influence HCC risk. A high serum hepatitis B virus (HBV) DNA level, which is indicative of increased viral replication, is associated with elevated risk of HCC.21 Some studies have suggested that HBV genotype could affect HCC risk.22, 23

Table 1. Molecular Risk Factors of HCC Development
Molecular FeatureType of InformationBiological PathwayEtiologyReference
  1. Case-control or cohort studies enrolling >500 cases are included.

  2. Abbreviations: SNP, single-nucleotide polymorphism; GWAS, genome-wide association study; HCV, hepatitis C virus; GH, genetic hemochromatosis.

TNF, G308ASNPImmune responseHBV, HCV7
IL10, A592CSNPImmune responseHBV, HCV8
GSTM1/GSTT1DeletionOxidative stressHBV, HCV9
EGF, A61GSNPGrowth signalingHBV, HCV, alcohol10, 11
MDM2, G309TSNPCell cycleHBV, HCV12
XPC, L939GSNPDNA damage repairHBV, HCV, aflatoxin13
HFE, C282YSNPIron metabolismAlcohol, GH14
DEPDC5SNPGWASHCV15
MICASNPGWASHCV16
1p36.22SNPGWASHBV17
Th1/Th2 signatureGene expressionVenous metastasisHBV19
186-Gene signatureGene expressionField effectHCV, HBV20

Molecular Subclasses of Aggressive HCC Tumor

  1. Top of page
  2. Abstract
  3. Molecular Risk Factors of HCC Development
  4. Molecular Subclasses of Aggressive HCC Tumor
  5. Clinical Translation of Molecular Indicators of HCC risk and Poor Prognosis
  6. References

Genomics technology has revealed heterogeneous molecular features of HCC tumors associated with biological aggressiveness and poorer clinical outcome, especially early recurrence after surgical or ablative therapies (Table 2). Recurrent TP53 inactivation mutations and CTNNB1 activation mutations have been observed in multiple patient cohorts24, 25 and were recently confirmed by next-generation sequencing together with other relatively frequent mutations in chromatin regulator genes such as ARID.26-28 Global transcriptional profiling identified subsets of HCC tumors characterized by progenitor cell–like features, transforming growth factor-β activation, Myc activation, Met activation, and poor prognosis (Fig. 2).24, 29-36 MicroRNA expression adds another layer of molecular prognostic information.37 These data will collectively provide the basis for the identification and establishment of etiology-specific or independent driver events and prognostic biomarkers.29 Future discovery of molecular-targeted therapies may lead to treatment-based molecular classification of HCC tumors.

Table 2. Molecular Subclasses and Signatures of HCC Tumor
Molecular FeatureClinical OutcomeEtiologyReference
  1. Abbreviations: TGF, transforming growth factor; HBV, hepatitis B virus; HCV, hepatitis C virus.

TP53 mutationsPoor prognosisHBV, HCV, Alcohol25, 26
CTNNB1 mutationsGood prognosisHBV, HCV, Alcohol25, 26
Hepatoblast signaturePoor survivalHBV, HCV, Alcohol30
EpCAM signaturePoor survivalHBV35
TGF-β signaturePoor survivalHBV, HCV, Alcohol31, 33
Met signaturePoor survivalHBV, HCV, Alcohol36
Meta-analysis transcriptome subclassEarly recurrenceHBV, HCV31
153-Gene signaturePoor survivalHBV32
65-Gene signaturePoor survivalHBV34
Low miR-26 expressionPoor survivalHBV37
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Figure 2. Molecular subclasses of HCC. Abbreviation: TGF-β, transforming growth factor-β. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

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Clinical Translation of Molecular Indicators of HCC risk and Poor Prognosis

  1. Top of page
  2. Abstract
  3. Molecular Risk Factors of HCC Development
  4. Molecular Subclasses of Aggressive HCC Tumor
  5. Clinical Translation of Molecular Indicators of HCC risk and Poor Prognosis
  6. References

The clinical use and applicability of molecular information remain to be determined in future clinical studies. The establishment of a framework and resources for such evaluation will be the key issue, given that very few of the molecular prognostic factors in the literature have had successful validation for clinical deployment.38 Biomolecules involved in any of the steps of chronic liver disease progression (e.g., viral life cycle, fibrogenesis, and cellular transformation), could theoretically be considered as markers or targets of HCC prevention. A clinical framework to evaluate antiviral or fibrotic therapies (which may have unsatisfactory antiviral or fibrotic effects) in the context of HCC prevention will accelerate the development of HCC prevention therapies. Furthermore, preclinical animal models recapitulating a broader spectrum of the natural history of HCC development in cirrhosis will greatly enhance our capability to test the antiviral or fibrotic targets in the context of HCC prevention.

References

  1. Top of page
  2. Abstract
  3. Molecular Risk Factors of HCC Development
  4. Molecular Subclasses of Aggressive HCC Tumor
  5. Clinical Translation of Molecular Indicators of HCC risk and Poor Prognosis
  6. References
  • 1
    El-Serag HB. Hepatocellular carcinoma. N Engl J Med 2011; 365: 1118-1127.
  • 2
    Friedman SL. Evolving challenges in hepatic fibrosis. Nat Rev Gastroenterol Hepatol 2010; 7: 425-436.
  • 3
    Davila JA, Morgan RO, Richardson PA, Du XL, McGlynn KA, El-Serag HB. Use of surveillance for hepatocellular carcinoma among patients with cirrhosis in the United States. Hepatology 2010; 52: 132-141.
  • 4
    Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet 2012; 379: 1245-1255.
  • 5
    Hoshida Y, Fuchs BC, Tanabe KK. Prevention of hepatocellular carcinoma: potential targets, experimental models, and clinical challenges. Curr Cancer Drug Targets. In press.
  • 6
    Yu XJ, Fang F, Tang CL, Yao L, Yu L. dbHCCvar: a comprehensive database of human genetic variations in hepatocellular carcinoma. Hum Mutat 2011; 32: E2308-E2316.
  • 7
    Wei Y, Liu F, Li B, Chen X, Ma Y, Yan L, et al. Polymorphisms of tumor necrosis factor-alpha and hepatocellular carcinoma risk: a HuGE systematic review and meta-analysis. Dig Dis Sci 2011; 56: 2227-2236.
  • 8
    Wei YG, Liu F, Li B, Chen X, Ma Y, Yan LN, et al. Interleukin-10 gene polymorphisms and hepatocellular carcinoma susceptibility: a meta-analysis. World J Gastroenterol 2011; 17: 3941-3947.
  • 9
    Wang B, Huang G, Wang D, Li A, Xu Z, Dong R, et al. Null genotypes of GSTM1 and GSTT1 contribute to hepatocellular carcinoma risk: evidence from an updated meta-analysis. J Hepatol 2010; 53: 508-518.
  • 10
    Abu Dayyeh BK, Yang M, Fuchs BC, Karl DL, Yamada S, Sninsky JJ, et al. A functional polymorphism in the epidermal growth factor gene is associated with risk for hepatocellular carcinoma. Gastroenterology 2011; 141: 141-149.
  • 11
    Tanabe KK, Lemoine A, Finkelstein DM, Kawasaki H, Fujii T, Chung RT, et al. Epidermal growth factor gene functional polymorphism and the risk of hepatocellular carcinoma in patients with cirrhosis. JAMA 2008; 299: 53-60.
  • 12
    Jin F, Xiong WJ, Jing JC, Feng Z, Qu LS, Shen XZ. Evaluation of the association studies of single nucleotide polymorphisms and hepatocellular carcinoma: a systematic review. J Cancer Res Clin Oncol 2011; 137: 1095-1104.
  • 13
    Long XD, Ma Y, Zhou YF, Ma AM, Fu GH. Polymorphism in xeroderma pigmentosum complementation group C codon 939 and aflatoxin B1-related hepatocellular carcinoma in the Guangxi population. Hepatology 2010; 52: 1301-1309.
  • 14
    Jin F, Qu LS, Shen XZ. Association between C282Y and H63D mutations of the HFE gene with hepatocellular carcinoma in European populations: a meta-analysis. J Exp Clin Cancer Res 2010; 29: 18.
  • 15
    Miki D, Ochi H, Hayes CN, Abe H, Yoshima T, Aikata H, et al. Variation in the DEPDC5 locus is associated with progression to hepatocellular carcinoma in chronic hepatitis C virus carriers. Nat Genet 2011; 43: 797-800.
  • 16
    Kumar V, Kato N, Urabe Y, Takahashi A, Muroyama R, Hosono N, et al. Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma. Nat Genet 2011; 43: 455-458.
  • 17
    Zhang H, Zhai Y, Hu Z, Wu C, Qian J, Jia W, et al. Genome-wide association study identifies 1p36.22 as a new susceptibility locus for hepatocellular carcinoma in chronic hepatitis B virus carriers. Nat Genet 2010; 42: 755-758.
  • 18
    Marcolongo M, Young B, Dal Pero F, Fattovich G, Peraro L, Guido M, et al. A seven-gene signature (cirrhosis risk score) predicts liver fibrosis progression in patients with initially mild chronic hepatitis C. Hepatology 2009; 50: 1038-1044.
  • 19
    Budhu A, Forgues M, Ye QH, Jia HL, He P, Zanetti KA, et al. Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment. Cancer Cell 2006; 10: 99-111.
  • 20
    Hoshida Y, Villanueva A, Kobayashi M, Peix J, Chiang DY, Camargo A, et al. Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N Engl J Med 2008; 359: 1995-2004.
  • 21
    Chen CJ, Yang HI, Su J, Jen CL, You SL, Lu SN, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006; 295: 65-73.
  • 22
    Yang HI, Yeh SH, Chen PJ, Iloeje UH, Jen CL, Su J, et al. Associations between hepatitis B virus genotype and mutants and the risk of hepatocellular carcinoma. J Natl Cancer Inst 2008; 100: 1134-1143.
  • 23
    Hoshida Y. Risk of recurrence in hepatitis B-related hepatocellular carcinoma: impact of viral load in late recurrence. J Hepatol 2009; 51: 842-844.
  • 24
    Hoshida Y, Toffanin S, Lachenmayer A, Villanueva A, Minguez B, Llovet JM. Molecular classification and novel targets in hepatocellular carcinoma: recent advancements. Semin Liver Dis 2010; 30: 35-51.
  • 25
    Villanueva A, Newell P, Chiang DY, Friedman SL, Llovet JM. Genomics and signaling pathways in hepatocellular carcinoma. Semin Liver Dis 2007; 27: 55-76.
  • 26
    Guichard C, Amaddeo G, Imbeaud S, Ladeiro Y, Pelletier L, Maad IB, et al. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat Genet 2012; 44: 694-698.
  • 27
    Li M, Zhao H, Zhang X, Wood LD, Anders RA, Choti MA, et al. Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma. Nat Genet 2011; 43: 828-829.
  • 28
    Fujimoto A, Totoki Y, Abe T, Boroevich KA, Hosoda F, Nguyen HH, et al. Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators. Nat Genet 2012; 44: 760-764.
  • 29
    Hoshida Y, Moeini A, Alsinet C, Kojima K, Villanueva A. Gene signatures in the management of hepatocellular carcinoma. Semin Oncol 2012; 39: 473-485.
  • 30
    Lee JS, Heo J, Libbrecht L, Chu IS, Kaposi-Novak P, Calvisi DF, et al. A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells. Nat Med 2006; 12: 410-416.
  • 31
    Hoshida Y, Nijman SM, Kobayashi M, Chan JA, Brunet JP, Chiang DY, et al. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res 2009; 69: 7385-7392.
  • 32
    Roessler S, Jia HL, Budhu A, Forgues M, Ye QH, Lee JS, et al. A unique metastasis gene signature enables prediction of tumor relapse in early-stage hepatocellular carcinoma patients. Cancer Res 2010; 70: 10202-10212.
  • 33
    Coulouarn C, Factor VM, Thorgeirsson SS. Transforming growth factor-beta gene expression signature in mouse hepatocytes predicts clinical outcome in human cancer. Hepatology 2008; 47: 2059-2067.
  • 34
    Kim SM, Leem SH, Chu IS, Park YY, Kim SC, Kim SB, et al. Sixty-five gene-based risk score classifier predicts overall survival in hepatocellular carcinoma. Hepatology 2012; 55: 1443-1452.
  • 35
    Yamashita T, Forgues M, Wang W, Kim JW, Ye Q, Jia H, et al. EpCAM and alpha-fetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma. Cancer Res 2008; 68: 1451-1461.
  • 36
    Kaposi-Novak P, Lee JS, Gomez-Quiroz L, Coulouarn C, Factor VM, et al. Met-regulated expression signature defines a subset of human hepatocellular carcinomas with poor prognosis and aggressive phenotype. J Clin Invest 2006; 116: 1582-1595.
  • 37
    Ji J, Shi J, Budhu A, Yu Z, Forgues M, Roessler S, et al. MicroRNA expression, survival, and response to interferon in liver cancer. N Engl J Med 2009; 361: 1437-1447.
  • 38
    D'Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol 2006; 44: 217-231.