Mutational spectrum of β-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas

Abstract

Activation of Wnt signaling through beta-catenin mutations contributes to the development of hepatocellular carcinoma (HCC) and hepatoblastoma (HB). To explore the contribution of additional Wnt pathway molecules to hepatocarcinogenesis, we examined beta-catenin, AXIN1 and AXIN2 mutations in 73 HCCs and 27 HBs. beta-catenin mutations were detected in 19.2% (14 out of 73) HCCs and 70.4% (19 out of 27) HBs. beta-catenin mutations in HCCs were primarily point mutations, whereas more than half of the HBs had deletions. AXIN1 mutations occurred in seven (9.6%) HCCs and two (7.4%) HBs. The AXIN1 mutations included seven missense mutations, a 1 bp deletion, and a 12 bp insertion. The predominance of missense mutations found in the AXIN1 gene is different from the small deletions or nonsense mutations described previously. Loss of heterozygosity at the AXIN1 locus was present in four of five informative HCCs with AXIN1 mutations, suggesting a tumor suppressor function of this gene. AXIN2 mutations were found in two (2.7%) HCCs but not in HBs. Two HCCs had both AXIN1 and beta-catenin mutations, and one HCC had both AXIN2 and beta-catenin mutations. About half the HCCs with AXIN1 or AXIN2 mutations showed beta-catenin accumulation in the nucleus, cytoplasm or membrane. Overall, these data indicate that besides the approximately 20% of HCCs and 80% of HBs with beta-catenin mutations contributing to hepatocarcinogenesis, AXIN1 and AXIN2 mutations appear to be important in an additional 10% of HCCs and HBs.

Sporadic childhood hepatoblastomas show activation of β-catenin, mismatch repair defects and p53 mutations

“…[5][6][7] Our results are in agreement with the studies of Koch et al, 5,27 who detected b-catenin point mutations in 22 and 25% of their sporadic hepatoblastoma cases, while Taniguchi et al reported a slightly higher percentage (33%) of mutated cases. 28 As reported by Takayasu et al, 25 we observed that the hepatoblastoma cases with b-catenin protein accumulation were much more numerous than the cases with identified b-catenin mutations. In this respect it should be noted that we could not investigate large b-catenin gene deletions, which are known to occur in hepatoblastoma.…”

“…5,27,28 Furthermore, we cannot exclude alterations in Wnt regulators acting upstream of b-catenin, 29 such as AXIN1 and AXIN2, implicated in hepatoblastoma cases negative for mutations in the b-catenin gene but positive for b-catenin protein accumulation. 28,30 With regard to correlations with histology, it is noteworthy that b-catenin immunostaining tended to be more evident in embryonal and in mesenchymal areas in epithelial and in mixed epithelial/ mesenchymal hepatoblastoma, respectively. This is concordant with evidence suggesting that b-catenin activation interferes with developmental signals regulating early stages of hepatic differentiation.…”

Dysregulation of growth factor signaling in human hepatocellular carcinoma

“…In addition, mutational inactivation by deletions, missense and nonsense mutations has been described for axin-1 (5-14%), predominantly in the region responsible for b-catenin and GSK-3b interactions (Satoh et al, 2000;Ishizaki et al, 2004). Equally, axin-2 (Conductin), which also contains binding sites for b-catenin and GSK-3b, exhibits mutations in 3-10% of the HCCs (Taniguchi et al, 2002;Ishizaki et al, 2004).…”

Disruption of transforming growth factor-β signaling through β-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation

“…Activation of the Wnt signaling pathway with b-catenin mutations is observed in 17-40% of HCCs and axin-2 inactivation in 3-10% of cases (Taniguchi et al, 2002;Ishizaki et al, 2004). Cyclin D1, Cdk4 and c-Myc levels are raised in approximately 50% of HCCs (Tiniakos et al, 1993;Ito et al, 1999).…”