Unique phenotype of hepatocellular cancers with exon-3 mutations in beta-catenin gene.
Wnt/beta-catenin signaling plays an important role in liver development and regeneration. Its aberrant activation, however, is observed in a subset of primary hepatocellular cancers (HCCs). In the current study, we compare and contrast the tumor characteristics of HCC in the presence or absence of mutations in the beta-catenin gene (CTNNB1). Frozen HCCs (n = 32), including five fibrolamellar (FL) variants, and control livers (n = 3) from Health Sciences Tissue Bank and Department of Surgery at the University of Pittsburgh Medical Center, were examined for mutations in CTNNB1, protein levels of beta-catenin, tyrosine-654-phosphorylated-beta-catenin (Y654-beta-catenin), and glutamine synthetase (GS). Missense mutations in the exon-3 of CTNNB1were identified in 9/32 HCCs. Total beta-catenin levels were higher than controls in most tumors; however, GS was exclusively increased in HCCs with mutations. Phenotypically, greater percentages of mutated HCCs showed macrovascular and microvascular invasion. Also, the tumor size was greater than double in mutated HCCs. High levels of total beta-catenin protein were observed in multinodular tumors independent of beta-catenin mutations. In addition, significant cases with mutations showed absence of cirrhosis. Finally, the highest levels of Y654-beta-catenin were exclusively observed in fibrolamellar (FL)-HCC cases.


CONCLUSIONS
Thus, HCCs that harbor missense mutations in exon-3 of CTNNB1 exhibit, histologically, a more aggressive phenotype. Also, CTNNB1 mutations might lead to HCC in the absence of cirrhosis. Finally, FL-HCC cases display a unique up-regulation of tyrosine-phosphorylated-beta-catenin, suggesting robust receptor tyrosine kinase signaling in this tumor type.
Cieply
Benjamin
B
Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15261, USA.
Zeng
Gang
G
Proverbs-Singh
Tracy
T
Geller
David A
DA
Monga
Satdarshan P S
SP
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000918:Antibody Specificity; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology*; D016022:Case-Control Studies; D005091:Exons / Q000235:genetics; D005260:Female; D005974:Glutamate-Ammonia Ligase / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D010641:Phenotype; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics* / Q000276:immunology
D051176:beta Catenin; D020794:Receptor Protein-Tyrosine Kinases; D005974:Glutamate-Ammonia Ligase