These findings suggested the activation of the Wnt pathway in HB, which was confirmed by immunohistochemical staining of the β-catenin in 42 HB tumors.
Whole-exome sequencing identified HB as a genetically very simple tumour (2.9 mutations per tumour) with recurrent mutations in ß-catenin (CTNNB1) (12/15 cases) and the transcription factor NFE2L2 (2/15 cases).
The current observation of a somatic CTNNB1 mutation in a hepatoblastoma from a patient with a germline GPC3 mutation supports the notion that the mutation in GPC3 may influence one of the initial steps in tumorigenesis and the progression to hepatoblastoma.
In conclusion, our data clearly identify protein stabilizing mutations of the β-catenin gene as a common feature of nested stromal epithelial tumors of the liver, similarly as in hepatoblastomas.
A further investigation using N- and C-terminal-specific β-catenin antibodies on human hepatoblastomas revealed a correlation between full-length versus truncated β-catenin and differentiation status, with embryonal hepatoblastomas expressing full-length β-catenin and fetal hepatoblastomas expressing β-catenin lacking its N terminus.
Presuming that the HB in the two siblings was the first manifestation of FAP we performed APC mutation analysis in DNA from archived tumour tissue of his sister and in blood samples of both parents.
We and others have previously shown that the overexpression of insulin-like growth factor 2 (IGF2), loss of imprinting at the IGF2/H19 locus, and amplification of pleomorphic adenoma gene 1 (PLAG1) are common features in HB, suggesting a critical role of the IGF axis in hepatoblastomagenesis.
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 β-catenin and for the expression levels of telomerase reverse transcriptase (TERT).
Our results also revealed a large subset of HB, 83%, with cytoplasmic expression of tyrosine654-phosphorylated beta-catenin and 30% showing additional nuclear accumulation.
Among human cancers tightly linked to abnormal Wnt/β-catenin signaling, hepatoblastoma (HB) presents with the highest rate (50-90%) of β-catenin mutations.
Could APC gene screening be useful in children with hepatoblastoma? Early onset of adenocarcinoma in a child with familial adenomatous polyposis and hepatoblastoma.
We studied the activation status of the Wnt and Notch pathways and the differential expression of hepatocyte nuclear factor 4alpha, EGFR, and IGF2 genes, relevant to liver development and malignant transformation in histologic variants of hepatoblastoma.
Deregulation of the APC/beta-catenin pathway occurs in a consistent fraction of hepatoblastomas, with mutations in the APC and beta-catenin genes implicated in familial adenomatous polyposis-associated and sporadic hepatoblastomas, respectively.
This study confirms that beta-catenin deregulation is involved in sporadic hepatoblastoma and also suggests that mismatch repair defects and p53 mutations contribute to this rare liver cancer.
We investigated a series of 21 sporadic paraffin-embedded hepatoblastoma cases for mutations in the p53 (exons 5-8) and beta-catenin (exon 3) genes, loss of heterozygosity at APC, microsatellite instability and immunohistochemical expression of beta-catenin and of the two main mismatch repair proteins, MLH1 and MSH2.
beta-catenin mutation and RASSF1A methylation were found in 22 (56.4%) and 15 (38.5%) of 39 hepatoblastomas, respectively, but SFRPs methylation was not found in any of them.
Changes in the antioxidant defense and hepatic drug metabolizing enzyme and isoenzyme levels, 8-hydroxydeoxyguanosine formation and expressions of c-raf.1 and insulin-like growth factor II genes during the stages of development of hepatocellular carcinoma in rats.
Overexpression of Tbx3 is closely associated with the mutational status of beta-catenin in murine liver tumors induced by Myc as well as in human hepatocellular carcinomas and hepatoblastomas.