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Original research
Recurrent chromosomal rearrangements of ROS1, FRK and IL6 activating JAK/STAT pathway in inflammatory hepatocellular adenomas
  1. Quentin Bayard1,
  2. Stefano Caruso1,
  3. Gabrielle Couchy1,
  4. Sandra Rebouissou1,
  5. Paulette Bioulac Sage2,3,
  6. Charles Balabaud3,
  7. Valerie Paradis4,5,
  8. Nathalie Sturm6,
  9. Anne de Muret7,
  10. Catherine Guettier8,
  11. Benjamin Bonsang9,
  12. Christiane Copie9,
  13. Eric Letouzé1,
  14. Julien Calderaro9,
  15. Sandrine Imbeaud1,
  16. Jean-Charles Nault1,10,11,
  17. Jessica Zucman-Rossi1,12
  1. 1 Centre de Recherche des Cordeliers, Sorbonne Université, Inserm,Université de Paris, Université Paris 13, Functional Genomics of Solid Tumors laboratory, F-75006 Paris, France
  2. 2 Service de Pathologie, Hôpital Pellegrin, CHU de Bordeaux, F 33076 Bordeaux, France
  3. 3 Université Bordeaux, UMR1053 Bordeaux Research in Translational Oncology, BaRITOn, F-33076 Bordeaux, France
  4. 4 Service d’anatomopathologie, Hôpital Beaujon, Assistance-Publique Hôpitaux de Paris, Clichy, France
  5. 5 INSERM U1149, Clichy, France
  6. 6 Service d’anatomopathologie, CHU, Grenoble, France
  7. 7 Service d’anatomopathologie, CHU, Tours, France
  8. 8 Service d’anatomopathologie, CHU Bicètre, Assistance-Publique Hôpitaux de Paris, Bicètre, France, Bicètre, France
  9. 9 Service d’anatomopathologie, Hôpital Henri Mondor; Université Paris Est, Inserm U955, Team 18, Institut Mondor de Recherche Biomédicale, France, Créteil, France
  10. 10 Service d’hépatologie, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bondy, France
  11. 11 Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris 13, Communauté d’Universités et Etablissements Sorbonne Paris Cité, Paris, France, Paris, France
  12. 12 Hôpital Européen Georges Pompidou, F-75015, Assistance Publique-Hôpitaux de Paris, Paris, France
  1. Correspondence to Dr Jean-Charles Nault, INSERM UMR 1338, INSERM, Paris 93140, France; naultjc{at}gmail.com; Professor Jessica Zucman-Rossi; jessica.zucman-rossi{at}inserm.fr

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.

  • hepatocellular carcinoma
  • inflammation
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Footnotes

  • J-CN and JZ-R are joint senior authors.

  • Twitter @naultjc, @Zucmanrossi

  • Contributors Author contributions to manuscript—study design: J-CN, JZ-R; generation of experimental data: QB, GC, SC, J-CN, BB, CB, JZ-R; analysis and interpretation of data: QB, GC, SC, J-CN, SI, EL, SR, JZ-R; collection of samples and related histological and clinical data: PBS, CB, VP, NS, AdM, CG, J-CN; drafting of the manuscript: QB, SC, EL, J-CN, JZ-R; revision of the manuscript and approval of the final version of the manuscript: all the authors. J-CN, JZ-R: these authors shared the last authorship.

  • Funding This work was supported by Institut National du Cancer (INCa) with the International Cancer Genome Consortium (ICGC LICA-FR project), INSERM with the ‘Cancer et Environnement’ (plan Cancer) and MUTHEC projects (INCa). The group is supported by the Ligue Nationale contre le Cancer (Equipe Labellisée), Labex OncoImmunology (investissement d’avenir), grant IREB, Coup d’Elan de la Fondation Bettencourt-Schueller, the SIRIC CARPEM, Raymond Rosen Award from the Fondation pour le Recherche Médicale, Prix René and Andrée Duquesne Comité de Paris Ligue Contre le Cancer and Fondation Mérieux.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval Paris Saint-Louis Institutional Review Board committee approved this study (Paris Saint-Louis, 2004; INSERM IRB 2010; the French Liver Biobanks network—AFAQ NF S96-900 and Hepatobio bank)

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available in a public, open access repository.

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