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Unique phenotype of hepatocellular cancers with exon‐3 mutations in beta‐catenin gene
Author(s) -
Cieply Benjamin,
Zeng Gang,
ProverbsSingh Tracy,
Geller David A.,
Monga Satdarshan P. S.
Publication year - 2009
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.22695
Subject(s) - hccs , missense mutation , cancer research , beta catenin , exon , biology , hepatocellular carcinoma , cirrhosis , catenin , mutation , phenotype , pathology , wnt signaling pathway , gene , medicine , microbiology and biotechnology , genetics
Wnt/β‐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 β‐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 β‐catenin, tyrosine‐654‐phosphorylated‐β‐catenin (Y654‐β‐catenin), and glutamine synthetase (GS). Missense mutations in the exon‐3 of CTNNB1 were identified in 9/32 HCCs. Total β‐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 β‐catenin protein were observed in multinodular tumors independent of β‐catenin mutations. In addition, significant cases with mutations showed absence of cirrhosis. Finally, the highest levels of Y654‐β‐catenin were exclusively observed in fibrolamellar (FL)‐HCC cases. Conclusion: 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‐β‐catenin, suggesting robust receptor tyrosine kinase signaling in this tumor type. (H EPATOLOGY 2009.)