Wnt signaling and telomerase activation of hepatoblastoma: correlation with chemosensitivity and surgical resectability

Purpose: Recently, it became apparent that telomerase directly modulated Wnt signaling as a cofactor in a beta-catenin transcriptional complex. In this study, we investigated Wnt/beta-catenin signaling and telomerase activation in hepatoblastoma (HBL). Methods: Tumors derived from 56 HBL cases treated with the Japanese Study Group for Pediatric Liver Tumors (JPLT) Protocol-2 were analyzed for oncogenic mutations (missense mutations and interstitial deletions in the third exon) of the CTNNB1 gene-encoding beta-catenin and for the expression levels of telomerase reverse transcriptase (TERT). Results: Oncogenic mutations of CTNNB1 were detected in 42 cases (75%). The expression levels of TERT were significantly higher in 14 cases without mutation (P < .05) and in 8 cases with metastasis (P < .01). Interestingly, Wnt/beta-catenin target genes were significantly activated in the tumors without mutations (P = .013). In cases with mutations, preoperative chemotherapy was more effective (P = .008), and complete resection rate was higher (P = .034). Consequently, 2 patients with mutations and 4 patients without mutations died of disease (P = .013). High expression of TERT was detected in all tumors of these dead patients. Conclusions: Wnt/beta-catenin signaling in the HBLs without CTNNB1 mutations was activated by high expression of TERT. The clinical courses in HBLs without CTNNB1 mutations seemed to be unfavorable because of chemoresistance and low rates of resectability. (C) 2011 Elsevier Inc. All rights reserved.