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.