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Page 2 of 12 Armengol et al. Hepatoma Res 2021;7:50 https://dx.doi.org/10.20517/2394-5079.2021.19

INTRODUCTION
Hepatoblastoma (HB) is the predominant liver tumor in childhood; however, it is a rare tumor with an
[1]
incidence of only approximately one case per million children per year . In contrast to HB, pediatric
hepatocellular carcinoma (HCC) is much more uncommon and has a worse prognosis . The difficulty of
[2]
accessing biological samples from childhood liver cancers has prevented deeper understanding of its
molecular nature, thereby challenging translational research. Because of this, there is an urgent need for
centralized biorepositories of human samples, cell lines, and murine models to be able to move translational
[3]
research of childhood liver cancer forward . Up to now, studies focused on deciphering the molecular
factors driving the oncogenesis and tumor progression of HB have been performed on a restricted number
of in vitro and in vivo models as well as in limited cohorts of patients, who, in some cases, had received
heterogeneous treatments. Nevertheless, despite these limitations, the scientific community has improved
the molecular knowledge of HB and identified its main molecular driver, β-catenin, as well as molecular
prognostic subtypes, all of which provide the basis for precision medicine in the future. The main research
findings in HB research, ranging from its genetics, transcriptomics, and methylomics to the potential
therapeutic strategies, are summarized below.

GENETIC AND GENOMIC STUDIES
In contrast to HCC, the most frequent liver tumor in adults, which develops on a cirrhotic liver background
[4]
usually caused by chronic viral hepatitis B or C infection as well as by alcohol consumption , liver tumors
in children, adolescents, and young adults typically occur on apparently normal liver. In young children,
most primary liver tumors are HB, whereas, in adolescents and young adults, the main histologic subtypes
are fibrolamellar carcinoma and HCC . Hepatic liver tumors with HB and HCC histological features
[5-7]
currently indicated as hepatocellular malignant neoplasms not otherwise specified (HCN-NOS), previously
called transitional liver cell tumors (TLCTs), also occur on normal liver and are typically diagnosed in older
children and young adolescents [8-10] . Several studies have explored patients’ genetic profiles in search of the
genomic hallmarks of hepatoblastoma pathogenesis. The high mutation rate (60%-92%) found in CTNNB1,
which encodes β-catenin, ranks HB among the human tumors with the most frequent constitutive
activation of Wnt/β-catenin/TCF signaling [11-16] . Evidence for this pathway as the genetic driver in HB is also
supported by the increased risk to develop HB for children affected by familial adenomatous polyposis, a
disorder caused by germline mutation of the APC gene involved in β-catenin degradation , and by the
[17]
identification of mutations in AXIN1 and AXIN2, two important Wnt pathway-related players [18,19] .
Additional evidence for the genetic/epigenetic origin of this tumor is provided by increased risk associated
with congenital anomalies, such as Beckwith-Wiedemann syndrome , and by the increased risk for
[20]
children exposed to perinatal and maternal factors such as very low weight at birth and eclampsia during
pregnancy [21,22] . Recent whole-exome sequencing studies have explored the genetic landscape of human HB
and found the lowest mutation burden (2.9 mutations per tumor) among pediatric cancers [14,16,23] .
Deciphering the genetics of HB is strongly contributing to our understanding of tumor biology and
improving patient stratification through the identification of diagnostic, prognostic, and theranostic
biomarkers. At the diagnostic level, evaluation of INI1/SMARCB1 gene status by immunohistochemistry
and/or genetic analysis in pediatric primary liver tumors with low serum alpha-fetoprotein (AFP) allows
discriminating HB, which are all INI1 wildtype, from malignant rhabdoid liver tumors, where this gene is
deleted . Telomerase reverse-transcriptase (TERT) promoter mutation and increased expression have been
[24]
frequently found in HCN-NOS/TLCTs and could be used as diagnostic markers to identify such
tumors [14,25] . Furthermore, nuclear factor and erythroid 2 like 2 gene (NFE2L2, also called NRF2), a key
regulator of antioxidant stress-response, has been found mutated in 9%-10% of HBs and associated with
poor prognosis [14,26,27] . As alteration of the NFE2L2-related pathway is strongly involved in
[28]
chemoresistance , NFE2L2 mutation should be evaluated as a chemotherapy efficacy predictive biomarker.