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

Abstract

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

CONCLUSION:

Recurrent chromosomal alterations involving ROS1, FRK or IL6 genes lead to activation of the JAK/STAT pathway in IHCAs.

• Authors: Quentin Bayard, Stefano Caruso, Gabrielle Couchy, Sandra Rebouissou, Paulette Bioulac Sage, Charles Balabaud, Valerie Paradis, Nathalie Sturm, Anne de Muret, Catherine Guettier, Benjamin Bonsang, Christiane Copie, Eric Letouzé, Julien Calderaro, Sandrine Imbeaud, Jean-Charles Nault, Jessica Zucman-Rossi
• Journal: Gut (Gut) Vol. 69 Issue 9 Pg. 1667-1676 (09 2020) ISSN: 1468-3288 [Electronic] England
• PMID: 31907296 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Chemical References

• IL6ST protein, human
• Neoplasm Proteins
• Proto-Oncogene Proteins
• STAT Transcription Factors
• Cytokine Receptor gp130
• Protein-Tyrosine Kinases
• ROS1 protein, human
• FRK protein, human
• Janus Kinases

Topics

• Adenoma, Liver Cell (genetics, immunology, pathology)
• Adult
• Cytokine Receptor gp130 (genetics)
• Female
• Gene Expression Profiling (statistics & numerical data)
• Gene Rearrangement (immunology)
• Humans
• Inflammation (genetics)
• Janus Kinases (metabolism)
• Liver Neoplasms (genetics, immunology, pathology)
• Male
• Mutation
• Neoplasm Proteins (genetics)
• Protein-Tyrosine Kinases (genetics)
• Proto-Oncogene Proteins (genetics)
• STAT Transcription Factors (metabolism)
• Signal Transduction (genetics, immunology)