Sequence variants of the Axin gene in hepatoblastoma.

The Wnt signaling pathway plays critical roles in the embryonic development and tumorigenesis. As a part of the Wnt signal transduction, the function of Axin complex is inhibited, leading to accumulation of beta-catenin. In hepatoblastomas, loss of APC (adenomatous polyposis coli) function or activation of beta-catenin that are the other two components involving in Wnt signaling has been demonstrated. Because hepatoblastoma shows immunohistochemical positivity of beta-catenin more often than its mutation frequency, we analyzed the Axin gene as a candidate to lead beta-catenin accumulation in hepatoblastoma. The coding region of the Axin gene was examined by PCR-SSCP using 24 sets of the primers in 22 hepatoblastomas and some paired normal tissues. Samples revealing aberrant band patterns were subjected to direct sequencing analysis. We identified totally eight variants in the exons and four intronic nucleotide substitutions. Seven variants in the exons were silent mutations, however, the remaining variant at codon 95 (ACG-->ATG) found in one hepatoblastoma predicted to result in an amino acid change from threonine to methionine. The paired peripheral blood DNAs from this patient also showed the same change; we suggested that it was a germline mutation of Axin gene. Our results suggest that mutation of the Axin gene may have a tumorigenic function in a subset of childhood hepatoblastomas.