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MET is an oncogene that encodes the tyrosine kinase receptor for hepatocyte growth factor HGF located on chromosome 7qq A subset of human HCCs with deregulated Met expression shows aggressive phenotype and poor prognosis [ ]. Gene expression profiling of HCC: Recently developed technology, such as DNA microarrays and other molecular profiling techniques, has provided new insights into the molecular genetics of HCC [ - ]. Moreover, gene expression profiling data confirm that HCV-related HCCs have different molecular genetics from those associated with HBV-related HCCs [ , ], supporting the theory that these disease processes are driven by different pathophysiological mechanisms of hepatocarcinogenesis.
These genes or gene products may be used as potential tumor markers that can be readily detected by serological or molecular tests. In addition, some gene profiling or signature genes have been found to be associated with greater potential for metastasis and recurrence [ , , ]. Aberrant expression of MicroRNAs: Up-regulation of mir and mir could reduce tumor apoptosis and lead to angiogene-sis and invasion [ ]. Results may lead to cell growth, survival, motility, invasion, and metastasis [ - ]. A miRNA signature has been found to be associated with HCC venous invasion and could also correlate with disease free and overall survival time [ ].
In general, these classification or staging systems can provide useful information for the management of patients, prognostication, and to some extent, therapy, but their clinical relevance and accuracy are debatable. It has been advocated that molecular approaches, such as gene expression microarray and SNP array, should be used to develop a new classification system for HCCs that better predicts clinical outcome and facilitates targeted molecular therapy [ - ]. Expression signatures found via global gene expression profiling can stratify HCCs into several clinically relevant groups. Class A, a low survival subclass overall survival time In comparison, Class B, a high survival subclass overall survival time Furthermore, gene expression profiles of nontu-moral liver tissue from paraffin-embedded specimens can be used to subclassify HCC patients into different survival groups [ ].
Each subgroup has unique clinical and genetic characteristics based upon chromosome stability status: G1-G3 are chromosome unstable and G4-G5 are chromosome stable. Since each group of tumors has specific pathway activations i. Whole-genomic array CGH analysis of 87 HCCs revealed two groups of tumors clusters A and B with significant differences in chromosomal alteration profiles and clinical outcomes. Cluster A's progression is more malignant than cluster B, shows exclusive chromosomal amplifications on 1q, 6p, and 8q, and has chromosomal losses on 8p.
Cluster B has a low frequency of chromosomal alterations and tends to harbor limited numbers of chromosomal alterations. Since HCC is composed of several genetically homogeneous subclasses with characteristic genetics, these data have illuminated the opportunity for using targeted molecular therapy according to specific genetic background [ ]. Treatment options for early or small HCC include liver transplantation, resection, or local radiation therapy, which significantly improve patient survival.
However, because patients with HCC are usually diagnosed at advanced stages of disease, the above treatment modalities and chemotherapy are rarely effective. Furthermore, there is significant clinical and genetic heterogeneity among HCCs of different etiologies, thus one or a few standard treatments may not work for all HCCs. Recently introduced molecular targeted therapies are specific for groups of HCCs with similar genetics. The targeted therapy aims to inactivate activated oncogenes, recover tumor suppressor genes, or repair other genes and molecules related to HCC development, thereby correcting abnormal genes or functions as well as biological behavior.
Recently, many candidate genome-based drug targets have been discovered via microarray technology, whole-genome epigenetic aberration analysis using promoter arrays, ChlP-chip analysis, and high-throughput sequencing systems. Moreover, some of these targeted therapies, such as monoclonal antibodies, small molecules and antisense drugs, have reached phase II and III clinical trials for therapeutic use, and many have been shown to be effective. Sorafenib, an oral multikinase inhibitor of vascular endothelial growth factor receptor VEGFR and Ras kinase, has been approved by the FDA as a molecularly targeted anticancer agent [ , ].
Some other agents targeting similar genes or molecules are being tested in preclinical and clinical trials for HCC. Results are summarized below and partially listed in Table 1. Monoclonal antibodies against EGFR, such as Cetuximab, and small molecule tyrosine kinase inhibitors, such as Gefitinib and Erlotinib, have shown therapeutic effects in both cell culture and in patients in a phase II study [ ].
Anti-vascular endothelial growth factor antiangiogenesis: It is one of the putative targets of Sorafenib, an oral inhibitor of the VEGF receptor and other kinases [ ]. Bevaci zumab, a recombinant, humanized monoclonal antibody, inhibits VEGF and also decreases the permeability of tumor vessels and relieves ele vated tumor interstitial pressure, thus poten tially enhancing the effectiveness of chemother apy [ , ].
Many reagents target multiple sites of pathways or multiple genes or products. It has shown anti-HCC activity in both xenograft models and in a phase II clinical trial in patients with unresectable or metastatic HCC [ - ]. In summary, targeted therapy has proven to be an effective treatment for certain groups of HCC patients who might not respond to conventional therapeutic modalities.
With a better understanding of the molecular mechanisms of hepa-tocarcinogenesis, more therapeutic options will be offered to cure or alleviate the symptoms of HCC. National Center for Biotechnology Information , U. Am J Transl Res. Author information Article notes Copyright and License information Disclaimer. Please address correspondence to: Received Jan 12; Accepted Jan This article has been cited by other articles in PMC. Abstract Hepatocellular carcinoma HCC is the sixth most common malignancy and the third leading cause of cancer deaths worldwide.
Hepatic Adenoma Hepatic adenoma predominantly occurs in younger women who are of child-bearing age, with or without prolonged use of oral contraception or abnormal carbohydrate metabolism i. Molecular basis of pathogenesis The molecular mechanisms by which an adenoma arises from hepatocytes are not well understood. Molecular diagnosis and classification While the diagnosis of hepatic adenoma can generally be made histologically, with or without radiological correlation, understanding the molecular genetics of hepatic adenomas may be clinically relevant.
Hepatocellular carcinoma Hepatocellular carcinoma is the sixth most common malignancy and the third most common cause of cancer deaths world wide. Molecular basis of pathogenesis HCC is a heterogeneous group of carcinomas, with largely diverse molecular alterations associated with different etiologies. Molecular genetics of HCC Chromosomal abnormalities: Molecular therapeutic targets of HCC Treatment options for early or small HCC include liver transplantation, resection, or local radiation therapy, which significantly improve patient survival.
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