Recurrent chromosomal rearrangements of <i>ROS1</i>, <i>FRK</i> and <i>IL6</i> activating JAK/STAT pathway in inflammatory hepatocellular adenomas.

Abstract

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. 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. We identified 296 IHCA (45%), 81% of them were mutated in either <i>IL6ST</i> (61%), <i>FRK</i> (8%), <i>STAT3</i> (5%), <i>GNAS</i> (3%) or <i>JAK1</i> (2%). Among non-mutated IHCA, RNA sequencing identified recurrent chromosome rearrangement involving <i>ROS1, FRK</i> or <i>IL6</i> genes. <i>ROS1</i> fusions were identified in 8 IHCA, involving C-terminal part of genes highly expressed in the liver (<i>PLG</i>, <i>RBP4</i>, <i>APOB</i>) fused with exon 33-35 to 43 of <i>ROS1</i> including the tyrosine kinase domain. In two cases a truncated <i>ROS1</i> transcript from exon 36 to 43 was identified. <i>ROS1</i> rearrangements were validated by fluorescence in situ hybridisation (FISH) and led to <i>ROS1</i> overexpression. Among the 5 IHCA with <i>FRK</i> rearrangements, 5 different partners were identified (<i>MIA3</i>, <i>MIA2</i>, <i>LMO7</i>, <i>PLEKHA5, SEC16B</i>) fused to a common region in <i>FRK</i> that included exon 3-8. No overexpression of <i>FRK</i> transcript was detected but the predicted chimeric proteins lacked the auto-inhibitory SH2-SH3 domains. In two IHCA, we identified truncated 3'UTR of <i>IL6</i> associated with overexpression of the transcript. Recurrent chromosomal alterations involving <i>ROS1</i>, <i>FRK</i> or <i>IL6</i> genes lead to activation of the JAK/STAT pathway in IHCAs.