Genomic and transcriptomic profile of HNF1A-mutated adenomas: molecular signature and potential therapeutic implications

Background: Hepatocellular adenomas (HAs) are tumors that can develop under different conditions, including in patients harboring a germline mutation in HNF1A. However, little is known about the pathogenesis of such disease. This work aims at better defining what mechanisms lie under the development of this condition. Results: 6 HAs were sampled from the liver of a 17-year-old male affected by diabetes and multiple hepatic adenomatosis harboring the heterozygous pathogenic germline variant c.815G>A, p.(Arg272His) in HNF1A which has a dominant negative effect. All HAs were molecularly characterized and four of them were shown to harbor a second somatic HNF1A variant, one had a mutation in the ARID1A gene while no additional somatic changes were found in the remaining HA and in normal parenchyma. A transcriptomic profile of the same HA samples was also performed. HNF1A biallelic mutations were associated with the up-regulation of several pathways including tricarboxylic acid cycle, the metabolism of fatty acids and mTOR signaling while angiogenesis, endothelial and vascular proliferation, cell migration/adhesion, and immune response were down-regulated. Contrariwise, in the tumor harboring the ARID1A variant, angiogenesis was up-modulated while fatty acid metabolism was down-modulated. Histological analyses confirmed the molecular data. Independently of the second mutation, energetic processes and cholesterol metabolism were up-modulated while immune response was down-modulated. Conclusions: this work provides a complete molecular signature of HNF1A-associated HAs, analyzing the association between specific HNF1A variants and the development of HA, while identifying potential new therapeutic targets for non-surgical treatment.