Introduction: Patients born with congenital porto-systemic shunts have been shown to have a high risk of benign and malignant liver tumors in otherwise healthy livers. This study aimed to evaluate the genetic landscape of liver tumors in patients with congenital porto-systemic shunts (CPSS) and correlate genotype with histological findings.

Methods: Nodules from patients with CPSS and sporadic pediatric focal nodular hyperplasia (FNH) or FNH-like nodules were evaluated histologically and sequenced for a panel of 50 genes using next-generation sequencing.

Results: Thirty-eight nodules from 17 patients with CPSS were histologically classified as hepatoblastomas (n = 2), hepatocellular carcinomas (n = 4), HNF-1α-inactivated hepatocellular adenomas (HCAs) (n = 2), β-catenin-activated HCAs (n = 5), unclassified HCAs (n = 9), and FNH-like nodules (n = 16). CTNNB1 variants were detected in 26/38 nodules (68%) across different histological categories (2/2 hepatoblastomas, 4/4 HCCs, 10/16 HCAs, 10/16 FNH-like nodules), but not in sporadic FNH or FNH-like nodules (0/10). Less frequent variants were identified in APOB , GNAS , HNF1A , SERPINA1 , MAML2 , PTCH1 , G6PC , KMT2C , DICER1 , AXIN1 , IL6ST and the promoter region of TERT . Germline variants were identified in AXIN1 , HFE , SERPINA1 , and ZNF521 . CTNNB1 variants affecting amino acid positions 32 and 33 are more common in malignant tumors. Multiple CTNNB1 variants were identified in 6/7 (86%) of patients with multiple nodules, but no intratumoral variation was found.

Discussion: CPSS is strongly associated with nodules containing variants in CTNNB1 , irrespective of the histological category. Areas in background liver containing these variants were also identified, and different variants could be identified in individual patients. The high proportion of CTNNB1 variants may explain the higher malignant potential of benign tumors found in CPSS.