Hepatocellular carcinoma (HCC) is the sixth most common
malignancy and the third leading cause of
cancer deaths worldwide. Proper classification and early identification of HCC and precursor lesions is essential to the successful treatment and survival of HCC patients. Recent molecular genetic, pathologic, and clinical data have led to the stratification of hepatic
adenomas into three subgroups: those with mutant TCF1/HNF1 alpha gene, those with mutant
beta-catenin, and those without mutations in either of these loci. Hepatic
adenomas with
alpha-catenin mutations have a significantly greater risk for malignant transformation in comparison with the other two subgroups. Telangiectatic
focal nodular hyperplasia has now been reclassified as telangiectatic
adenoma due to the presence of non-random methylation patterns, consistent with the monoclonal origin which is similar to hepatic
adenoma and HCC. HCC precursor lesions demonstrate unique molecular alterations of HSP70, CAP2,
glypican 3, and
glutamine synthetase that have proven useful in the histologic diagnosis of early HCC. Though specific genetic alterations depend on HCC etiology, the main
proteins affected include cell membrane receptors (in particular
tyrosine kinase receptors) as well as
proteins involved in cell signaling (specifically Wnt/
beta-catenin, Ras/Raf/
MEK/ERK and PI3K/Akt/mTOR pathways), cell cycle regulation (i.e. p53, p16/INK4,
cyclin/cdk complex), invasiveness (EMT,
TGF-beta) and
DNA metabolism. Advances in gene expression profiling have provided new insights into the molecular genetics of HCC. HCCs can now be stratified into two clinically relevant groups: Class A, the low survival subclass (overall survival time 30.3+/- 8.02 months), shows strong expression signatures of cell proliferation and antiapoptosis genes (such as PNCA and cell cycle regulators CDK4, CCNB1, CCNA2, and CKS2) as well as genes involving ubiquitination and sumoylation; Class B, the high survival subclass (overall survival time 83.7 +/-10.3 months), does not have the above expression signature. In fact, insights into HCC-specific alterations of signal transduction pathways and
protein expression patterns have led to the development of new therapeutic agents with molecular targets such as EGFR,
VEGF, or other multi-
kinase inhibitors. In the future, these specific molecular alterations in HCC can potentially serve as diagnostic tools, prognostic markers, and/or therapeutic targets with the potential to alter clinical outcomes.