Hepatoblastoma is the most common liver cancer in children. However, the hereditary predisposition and acquired molecular aberrations related to the clinicopathological diversity of this cancer are not well understood. Therefore, researchers in Japan have performed integrative genomic profiling of paediatric liver tumours to identify the genetic and epigenetic basis of hepatoblastoma liver cancer diversity.
Hepatoblastoma is the most common malignant paediatric solid liver tumour and one of the fastest-rising cancers in children under the age of 5. Hepatoblastoma is thought to be derived from hepatic precursor cells.
It is not yet known why hepatoblastoma develops more commonly in infants. However, previous research has indicated that genetic conditions, such as Bechwith-Wiedemann syndrome (BWS) and Aicardi syndrome, are associated with increased risk of embryonal tumours including hepatoblastoma. Very low birth weight has also been associated with a significantly increased risk of hepatoblastoma. However, the underlying mechanisms of this currently remains unknown.
Despite these previous findings and recent large-scale genomic analyses, hepatoblastoma is recognised as the tumour with the fewest somatic mutations among all paediatric solid tumours. Therefore, it is critical for researchers to explore the key genetic and epigenetic drivers of this malignancy as well as explore the ‘cell of origin’.
Identifying drivers of hepatoblastoma diversity
To identify the molecular markers and genetic drivers of hepatoblastoma malignancy, the researchers behind this study, published in Nature Communications, performed integrative genomic profiling of 163 paediatric liver tumours. The team used data from the JPLT-2 (Japanese study group for Pediatric Liver Tumours-2) cohort study. This previous study was conducted between 2000 and 2012 and collected the 5-year event-free survival (EFS) rates of patients with early- and late-stage hepatoblastoma.
Age and hepatoblastoma liver cancer diversity
In this study, researchers carried out whole-genome and whole-exome analysis of 163 histologically confirmed tumours. The findings revealed that the landscape of genomic aberrations in hepatoblastoma was closely associated with the age at diagnosis. Most hepatoblastomas in this study were characterised by mutations in the CTNNB1 and TERT genes.
Somatic mutations or deletions of CTNNB1 exon 3 were observed in more than 80% of hepatoblastoma patients younger than 8 years of age. Whereas promoter mutations of TERT were mostly seen in the pre-teen hepatoblastoma cases. These findings suggest that there are two distinct pathways of this particular childhood hepatic malignancy.
DNA methylation and hepatoblastoma liver cancer diversity
DNA methylation profiling through genome-wide methylation analysis revealed that classical hepatoblastomas are characterised by specific hypomethylated enhancers, which are enriched with binding sites for ASCL2. ASCL2 is a regulatory transcription factor involved in maintaining Lgr5-positive intestinal stem cells.
While ASCL2 is involved in definitive endoderm and digestive systems, it is not expressed during hepatocyte maturation. Transcriptional upregulation of ASCL2 has been frequently observed in human gastrointestinal cancers, but not in human hepatocellular carcinomas. Hepatocellular carcinoma is another form of liver cancer, which is usually seen in older children and adolescents. It can therefore be assumed that sharing the feedback upregulation of Wnt-targeted genes with colorectal cancer could explain the unique features of Wnt activation in hepatoblastoma rather than in hepatocellular carcinoma. Moreover, this may imply that the ‘cell of origin’ of hepatoblastoma is derived from ASCL2-positive premature hepatoblasts, similar to intestinal epithelial cells, which have high proliferative potential.
Overall, this study describes a comprehensive molecular analysis of hepatoblastoma, using data from the JPLT-2 cohort. Systematic molecular profiling of hepatoblastoma is essential for understanding the genetic and epigenetic driver events that occur during hepatoblast carcinogenesis, which is necessary for risk stratification in precision medicine.
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