The ultrarare hepatoblastoma is the most common pediatric liver cancer. HB risk is related to a few rare syndromes, and the molecular bases remain elusive for most cases. We investigated the burden of rare damaging germline variants in 30 Brazilian patients with HB. A high frequency of prematurity (20%) and birth defects (37%), especially craniofacial (17%, including craniosynostosis) and kidney (7%) anomalies, was observed. Pathogenic or likely pathogenic variants mapped to 10 cancer predisposition genes (APC, CHEK2, DROSHA, ERCC5, FAH, MSH2, MUTYH, RPS19, TGFBR2 and VHL,) were detected in 33% of the patients, only 40% of them with a family history of cancer. These findings showed a predominance of CPGs with a known link to gastrointestinal/colorectal and renal cancer risk. A remarkable feature was an enrichment of rare damaging variants affecting different classes of DNA repair genes, particularly those known as Fanconi anemia genes. Moreover, several damaging rare variants mapped to genes impacting liver functions were observed. To our knowledge, this is the first comprehensive assessment of rare germline variants in HB patients, contributing to elucidating the genetic architecture of HB risk.

Background: Hepatoblastoma (HB) treatment has improved over time with established chemotherapy (Qtx) protocols, and liver resection or liver transplantation (LT). However, the right timing for LT and adequate patient selection are key to achieve acceptable disease-free survival rates in patients with unresectable HB. Few groups have reported such factors in the setting of living donor liver transplantation (LDLT). Procedure: This single-center retrospective analysis of 28 children with HB submitted to LDLT aimed at determining the pre-transplant factors associated with worse post-transplant event-free survival. Results: Patients were divided in groups according to the occurrence of the event (recurrence/death) after LDLT – 10 patients in the event-yes and 18 patients in the event-no. Probability of 5-y event-free survival was 63.9%. Alpha-fetoprotein (AFP) reduction post-Qtx > 70% had a good performance for the occurrence of the event, with a calculated AUC of 0.8. A scoring system was derived from the pre-transplant risk factors (AFP reduction < 70%, time from diagnosis to LDLT > 12 months, rescue LT) for the probability of the event: no risk factor present (15.4%), one risk factor present (33.3%), and > 2 risk factors present (66.7%), (p=0.02). Conclusion: LDLT for HB is the preferred treatment option for unresectable HB, with no distant metastasis and adequate response to Qtx. The pre-transplant factors composing the risk score should be critically evaluated in order to move forward with the LDLT. However, due to the limited number of patients in this study, a larger number of patients is required to corroborate these findings.