In conclusion, although much is still unknown, Gpr49 may be critically involved in the development of HCCs with beta-catenin mutations and has the potential to be a new therapeutic target in the treatment of HCC.
Recently, beta-catenin, one of the key components of the Wnt signaling pathway, has been found to be mutated in about 20% of HCCs, suggesting a role of the Wnt pathway in their development.
As β-catenin is mutated in a wide variety of tumors, including up to 10% of all sporadic colon carcinomas and 20% of hepatocellular carcinomas, it has been considered a promising target for therapeutic interventions.
A number of recently published NGS studies on HCCs have not only confirmed previously known mutations in CTNNB1 and TP53 in HCC, but also identified novel genetic alterations in HCC including mutations in genes involved in epigenetic regulation.
E-cadherin signaling plays an important role in hepatocellular carcinoma (HCC) initiation and progression considering the highly mutated frequency of CTNNB1 (27%).
HCCs with extensive methylation harbor frequent beta-catenin mutations, whereas HCCs with high levels of CIN are associated with p53 mutations, suggesting the presence of two independent pathways for the pathogenesis of HCC.
However, simultaneous induction of an additional mutation in the beta-catenin gene causes a clonal expansion of such dysplastic cells, followed by nodular formation and development of hepatocellular carcinoma.
In this study, we found that 34.8% of human HCC samples with FAK amplification also show β-catenin mutations, suggesting a co-occurrence of FAK overexpression and β-catenin mutations in HCC.
TP53 and CTNNB1 are the next most prevalent mutations, affecting 25%-30% of HCC patients, that, in addition to low-frequency mutated genes (eg, AXIN1, ARID2, ARID1A, TSC1/TSC2, RPS6KA3, KEAP1, MLL2), help define some of the core deregulated pathways in HCC.
Activating β-catenin mutations occur in a variety of liver tumors, including hepatocellular carcinoma (HCC), but no specific therapies are available to treat these tumor subsets.
To ascertain the prevalence of deregulating mutations of beta-catenin gene, and to correlate this with the occurrence of 249(serine) p53 gene mutation and hepatitis B virus infection in southern African Blacks with hepatocellular carcinoma.
In the genome-based molecular classification, CTNNB-1 mutated HCC shows a less aggressive nature, while CK19/EpCAM positive HCC and macrotrabecular massive HCC show an aggressive one.
Two cases (one nodule-in-nodule case and another case with closely attached HCC and HGDN) showed several overlapped driver mutations (CTNNB1 and CEBPA) and CNAs (losses of CDKN2A, RB1, and TP53) between HGDNs and HCCs, suggesting their roles in the early HCC development.
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.
Inactivation of the p16INK4a (p16) tumor suppressor gene by promoter hypermethylation and mutation within exon 3 of beta-catenin represent two of the more common gene alterations in human hepatocellular carcinoma (HCC).