INTRODUCTION
The etiology of pediatric cancer is largely unknown [1]. Despite
intensive research, gaps remain in our understanding of the genetic
landscape of pediatric cancer susceptibility. It is assumed that
germline mutations in cancer-predisposing genes (CPGs) in children and
adolescents are rare events [2–4]. However, the genetic
predisposition to childhood cancer is most likely underidentified. Most
investigations have focused on known CPGs and sequenced patients without
parental samples, an approach that impairs a broad evaluation of the
full range of genetic mechanisms underlying pediatric cancer risk, such
as de novo mutations and the identification of new candidate
CPGs. Recent studies of large cohorts of pediatric cancer patients have
confirmed that approximately 8-18% of patients carry a germline
pathogenic variant in a broad spectrum of known CPGs [3, 5–10].
These studies also highlighted that isolated factors, such as tumor type
and a positive family history of cancer, have low predictive power for
the presence of germline CPG mutations.
Hepatoblastoma (HB) is the most common malignant liver tumor in the
pediatric population [11], although it is considered an ultrarare
disease, accounting for only 1% of all pediatric tumors [12–14].
In Brazil, collected data on HB are concordant with the worldwide
incidence of 0.5 to 1.5 cases per million [15, 16]. Most cases are
diagnosed before the age of 4 years, and a male preponderance is
reported [17]. Nongenetic factors known to be associated with HB
risk are related to very low birth weight (<1500 g), including
preterm birth (<33 weeks), small for gestational age, and
multiple birth pregnancies[11, 18]. A slow increase in HB incidence
is observed in North America and Europe [19], which can be partly
due to the increased survival of children with low birth weight
[20]. An increased risk for HB development has been reported in
association with a few specific genetic conditions, including
Beckwith-Wiedemann syndrome [21, 22], familial adenomatous polyposis
(APC gene) [23], Li-Fraumeni syndrome (TP53 gene)
[24], Aicardi syndrome [25], and trisomy 18 [26].
Here, we investigated the germline exome of 30 children who developed
HB, 13 of whom (43%) exhibited additional clinical signs. Our analysis
provides a framework for investigating candidate genes involved in HB
predisposition, as well as the tumor association with specific birth
defects.