beta-Catenin mutation and overexpression in hepatocellular carcinoma: clinicopathologic and prognostic significance.
BACKGROUND
beta-Catenin has been recognized as a critical member of the Wnt signaling pathway, and inappropriate activation of this pathway has been implicated in carcinogenesis.


METHODS
To determine the clinical significance of beta-catenin in hepatocellular carcinoma (HCC), we performed mutational analysis at exon 3 of the gene, investigated the subcellular protein expression, and analyzed their clinicopathologic and prognostic significance in 60 patients with resected primary HCC.


RESULTS
By direct DNA sequencing, somatic mutations of the beta-catenin gene were detected in 7 (12%) HCCs. All the mutations were found at the region (exon 3) responsible for phosphorylation and ubiquitination, therefore likely to result in stabilization of free cytoplasmic beta-catenin. Nuclear accumulation of the beta-catenin protein, similar to the response to the Wnt signal, was found in 10 (17%) HCCs and was closely associated with gene mutation (P < 0.001). In the remaining cases, nonnuclear type overexpression, that is, overexpression in the cytoplasm and/or cytoplasmic membrane, was observed in 31 (62%) HCCs, thus suggesting that the mechanisms leading to beta-catenin overexpression may be heterogeneous. HCCs with a nonnuclear type of beta-catenin overexpression were more frequently larger than 5 cm in diameter (P = 0.022) and had poorer cellular differentiation (P = 0.037), and the patients had significantly shorter disease-free survival lengths (P = 0.041). Review of the data from previous studies in HCC showed that beta-catenin mutations were more frequent in HCV-associated HCC than in HBV-associated ones.


CONCLUSIONS
beta-catenin mutation and deregulation may play an important role in hepatocarcinogenesis. Nonnuclear type beta-catenin overexpression appeared to have pathologic and prognostic significance.
Wong
C M
CM
Department of Pathology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
Fan
S T
ST
Ng
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D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000235:genetics*; D004247:DNA / Q000032:analysis; D004252:DNA Mutational Analysis; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D006509:Hepatitis B / Q000150:complications; D006515:Hepatitis B virus; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D011379:Prognosis; D017386:Sequence Homology, Amino Acid; D016019:Survival Analysis; D015534:Trans-Activators; D051176:beta Catenin
D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D005819:Genetic Markers; D015534:Trans-Activators; D051176:beta Catenin; D004247:DNA