AJTR Copyright © 2009-All rights reserved. Published by e-Century Publishing Corporation, Madison, WI 53711
Am J Transl Res 2010;2(1):105-118

Review Article
Molecular genetics of hepatocellular neoplasia

Shilpa Jain, Shashideep Singhal, Peng Lee, Ruliang Xu

Department of Pathology and Urology, New York University School of Medicine, New York Harbor Healthcare
System, New York, NY and Department of Medicine, The Brooklyn Hospital Center, Brooklyn, NY

Received January 12, 2010; accepted January 18; available online: January 23, 2010

Abstract: 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 α gene,
those with mutant β–catenin, and those without mutations in either of these loci. Hepatic adenomas with β-
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-β) 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 multikinase
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..(AJTR201001002).

Key words: Hepatocellular carcinoma, molecular genetics, HSP70, CAP2, glypican 3, glutamine synthetase,

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Address all correspondence to:
Ruliang Xu, MD, PhD
Department of Pathology
New York University School of Medicine
560 First Avenue, New York, NY 10010
Tel: (212)-263-0728, Fax: (212)-263