Deciphering the genetic origin of childhood liver cancer

Hepatoblastoma (HB) represents the most common malignant liver tumor in infancy and is assumed to arise from immature liver progenitor cells by aberrant activation of genes important in embryonic development. The only recurrent genetic alteration described up to now is activating mutation of the beta-catenin gene in approx. 80% of HB cases, the key molecule of the Wnt signaling pathway. However, modeling constitutive Wnt activation in the mouse is not sufficient to drive liver tumorigenesis. To extend the understanding of the genetic basis of HB, whole exome sequencing of 8 HB patients was performed using Illumina HiSeq 2000 technology. Besides the well-described beta-catenin mutation, no other recurrent mutations could be identified. The overall mutation rate was very low, with only 3.9 mutations per tumor. However, many mutations were found in genes encoding components of the epigenetic machinery, including histones, histone deacetylases (HDAC) and demethylases, HDAC-binding corepressors, and transcription factors. These findings suggest that epigenetic misregulation rather than genetic alterations appears to be responsible for the formation of embryonal liver tumors on a beta-catenin mutated background.