Recurrent chromosomal rearrangements of , and activating JAK/STAT pathway in inflammatory hepatocellular adenomas.

Background: Inflammatory hepatocellular adenomas (IHCAs) are benign liver tumours characterised by an activation of the janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway caused by oncogenic activating mutations. However, a subset of IHCA lacks of identified mutation explaining the inflammatory phenotype.

Methods: 657 hepatocellular adenomas developed in 504 patients were analysed for gene expression of 17 genes and for mutations in seven genes by sequencing. 22 non-mutated IHCAs were analysed by whole-exome and/or RNA sequencing.

Results: We identified 296 IHCA (45%), 81% of them were mutated in either (61%), (8%), (5%), (3%) or (2%). Among non-mutated IHCA, RNA sequencing identified recurrent chromosome rearrangement involving or genes. fusions were identified in 8 IHCA, involving C-terminal part of genes highly expressed in the liver (, , ) fused with exon 33-35 to 43 of including the tyrosine kinase domain. In two cases a truncated transcript from exon 36 to 43 was identified. rearrangements were validated by fluorescence in situ hybridisation (FISH) and led to overexpression. Among the 5 IHCA with rearrangements, 5 different partners were identified (, , , ) fused to a common region in that included exon 3-8. No overexpression of transcript was detected but the predicted chimeric proteins lacked the auto-inhibitory SH2-SH3 domains. In two IHCA, we identified truncated 3'UTR of associated with overexpression of the transcript.

Conclusion: Recurrent chromosomal alterations involving , or genes lead to activation of the JAK/STAT pathway in IHCAs.