Genomic and transcriptomic profiling of hepatocellular carcinoma in patients with Fontan-associated liver disease

BACKGROUND AND AIMS: Fontan-associated liver disease (FALD) could lead to liver cirrhosis and hepatocellular carcinoma (HCC). The prognosis of FALD patients is worse when HCC develops. Therefore, a better understanding of the mechanisms of FALD hepatocarcinogenesis is critical. We investigated the genomic and transcriptomic signatures of FALD HCC. APPROACH AND RESULTS: Ten patients with FALD HCCs, 2 patients with non-Fontan congenital heart surgery (CHS) HCC, and 1 patient with FALD focal nodular hyperplasia (FNH) were enrolled. Whole-genome sequencing and transcriptome sequencing were performed, and the results were compared with other etiology-related HCCs in common databases. FALD HCCs exhibited comparable tumor mutation burdens to those of HCCs in the databases, as well as mutation signatures related to DNA double-strand break repair deficiency. These features were shared by non-Fontan CHS HCCs and FALD FNH, suggesting that postoperative stress has an impact on genomic alterations. Of note, FALD and non-Fontan CHS HCCs showed a higher amount of copy number alterations and structural variants, including short deletions and translocations, which were rarely detected in FALD FNH. These structural variants were implicated in frequently altered genes of HCC, suggesting a possible trigger of hepatocarcinogenesis. Transcriptome analysis revealed that individual FALD and non-Fontan CHS HCCs were grouped into the reported HCC subclasses, namely progenitor phenotype, rather than an uncommon HCC subclass. CONCLUSIONS: Genomic mutational profiles of FALD and non-Fontan CHS HCCs are distinct from HCCs with other etiologies. Copy number alterations and transcriptional profiles in FALD HCCs classified these into a poor-prognosis group of HCCs.