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Sequence variants of the Axin gene in hepatoblastoma
Jiangyong Miao1, Takeshi Kusafuka, Yuko Udatsu
1Department of Pediatric Surgery, Osaka University Medical School, 2-2 Yamadaoka, Suita, 565-0871, Osaka, Japan
Abstract:
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.
Insights
Mutations in the Axin gene may contribute to hepatoblastoma development by affecting beta-catenin accumulation. This study identified a potential germline mutation in Axin in a subset of childhood hepatoblastoma cases.
Area of Science:
- Molecular Biology
- Oncology
- Developmental Biology
Background:
- The Wnt signaling pathway is crucial for embryonic development and tumorigenesis.
- Aberrant Wnt signaling, particularly beta-catenin accumulation, is implicated in hepatoblastoma.
- Previous studies noted APC or beta-catenin alterations in hepatoblastoma, but Axin remained less explored.
Purpose of the Study:
- To investigate the role of the Axin gene in beta-catenin accumulation in hepatoblastoma.
- To identify potential mutations in the Axin gene associated with childhood hepatoblastoma.
Main Methods:
- Analysis of the Axin gene's coding region in 22 hepatoblastoma samples and paired normal tissues.
- Polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) was used for mutation screening.
- Direct sequencing was performed on samples with aberrant band patterns.
Main Results:
- Identified eight exonic and four intronic nucleotide substitutions in the Axin gene.
- Seven exonic variants were silent mutations.
- One non-silent mutation (Thr95Met) was found in a hepatoblastoma sample and confirmed as a germline mutation.
Conclusions:
- Axin gene mutations may play a role in the tumorigenesis of a subset of childhood hepatoblastomas.
- The identified germline mutation suggests a potential inherited predisposition in some cases.
- Further research is warranted to elucidate the precise mechanism of Axin's involvement in hepatoblastoma.