Abstract
Hepatoblastoma (HB) is the most common pediatric liver malignancy; however, hereditary predisposition and acquired molecular aberrations related to HB clinicopathological diversity are not well understood. Here, we perform an integrative genomic profiling of 163 pediatric liver tumors (154 HBs and nine hepatocellular carcinomas) based on the data acquired from a cohort study (JPLT-2). The total number of somatic mutations is precious low (0.52/Mb on exonic regions) but correlated with age at diagnosis. Telomerase reverse transcriptase (TERT) promoter mutations are prevalent in the tween HBs, selective in the transitional liver cell tumor (TLCT, > 8 years old). DNA methylation profiling reveals that classical HBs are characterized by the specific hypomethylated enhancers, which are enriched with binding sites for ASCL2, a regulatory transcription factor for definitive endoderm in Wnt-pathway. Prolonged upregulation of ASCL2, as well as fetal-liver-like methylation patterns of IGF2 promoters, suggests their “cell of origin” derived from the premature hepatoblast, similar to intestinal epithelial cells, which are highly proliferative. Systematic molecular profiling of HB is a promising approach for understanding the epigenetic drivers of hepatoblast carcinogenesis and deriving clues for risk stratification.
Highlights
Hepatoblastoma (HB) is the most common pediatric liver malignancy; hereditary predisposition and acquired molecular aberrations related to HB clinicopathological diversity are not well understood
In Japan, the JPLT-2 study was conducted between 2000–2012, and the 5-year event-free survival (EFS) rate of patients with early stages was more than 80%, but those with advanced stages were under 60%6,7
Whole-genome and whole-exome analysis revealed that the landscape of genomic aberrations in HB is closely associated with the age at diagnosis
Summary
Hepatoblastoma (HB) is the most common pediatric liver malignancy; hereditary predisposition and acquired molecular aberrations related to HB clinicopathological diversity are not well understood. The mutation or deletion of the ß-catenin gene (CTNNB1) exon 3 is frequently detected in HB, suggesting activation of the wingless/WNT signal pathway[12] While this plays an important role in the pathogenesis of HB, it is not considered a predictive molecular marker for distinguishing high-risk tumors from other tumors[11,13]. Very low birth weight is associated with a significantly increased risk of HB, but the underlying mechanism remains unknown[14,15] Despite these previous findings and recent large-scale genomic analyses[16], HB has been recognized as the tumor with the fewest somatic mutations among all pediatric solid tumors. In this work, using pre-treatment samples in this clinical trial cases, we elucidate the molecular mechanism during hepatoblast carcinogenesis and identify the useful molecular biomarkers for HB risk stratification by comprehensive genomic, epigenomic, and transcriptomic analyses including whole-genome-sequencing and exome-sequencing, RNA sequencing, SNP array, and DNA methylation array
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