Article Text

Download PDFPDF
Original article
RSPO2 gene rearrangement: a powerful driver of β-catenin activation in liver tumours
  1. Thomas Longerich1,2,
  2. Volker Endris1,
  3. Olaf Neumann1,
  4. Eugen Rempel1,
  5. Martina Kirchner1,
  6. Zahra Abadi1,
  7. Sebastian Uhrig3,4,
  8. Mark Kriegsmann1,
  9. Karl Heinz Weiss2,5,
  10. Kai Breuhahn1,
  11. Arianeb Mehrabi2,6,
  12. Tim Frederik Weber2,7,
  13. Ludwig Wilkens8,9,
  14. Beate K Straub10,
  15. Andreas Rosenwald11,
  16. Falko Schulze12,
  17. Benedikt Brors4,
  18. Stefan Froehling13,14,
  19. Rossella Pellegrino1,
  20. Jan Budczies1,
  21. Peter Schirmacher1,2,
  22. Albrecht Stenzinger1
  1. 1 Institute of Pathology, UniversitatsKlinikum Heidelberg, Heidelberg, Germany
  2. 2 Liver Cancer Center Heidelberg, UniversitatsKlinikum Heidelberg, Heidelberg, Germany
  3. 3 Faculty of Bioscience, Ruprecht Karls University Heidelberg, Heidelberg, Germany
  4. 4 Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany
  5. 5 Department of Internal Medicine IV, UniversitatsKlinikum Heidelberg, Heidelberg, Germany
  6. 6 Department of General, Visceral and Transplantation Surgery, UniversitatsKlinikum Heidelberg, Heidelberg, Germany
  7. 7 Diagnostic and Interventional Radiology, University Hospital Heidelberg, Heidelberg, Germany
  8. 8 Institute for Pathology, KRH, Nordstadt Krankenhaus, Hannover, Germany
  9. 9 Institute for Human Genetics, Medical School Hannover, Hannover, Germany
  10. 10 Institute of Pathology, Johannes Gutenberg Universitat Universitatsmedizin, Mainz, Germany
  11. 11 Institute of Pathology, University of Wuerzburg and Comprehensive Cancer Center Mainfranken, Würzburg, Germany
  12. 12 Senckenberg Institute of Pathology, Klinikum der Johann Wolfgang Goethe-Universitat Frankfurt, Frankfurt am Main, Germany
  13. 13 Division of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany
  14. 14 German Cancer Consortium (DKTK), Heidelberg, Germany
  1. Correspondence to Professor Thomas Longerich, Institute of Pathology, UniversitatsKlinikum Heidelberg, Heidelberg 69120, Germany; thomas.longerich{at}


Objective We aimed at the identification of genetic alterations that may functionally substitute for CTNNB1 mutation in ß-catenin-activated hepatocellular adenomas (HCAs) and hepatocellular carcinoma (HCC).

Design Large cohorts of HCA (n=185) and HCC (n=468) were classified using immunohistochemistry. The mutational status of the CTNNB1 gene was determined in ß-catenin-activated HCA (b-HCA) and HCC with at least moderate nuclear CTNNB1 accumulation. Ultra-deep sequencing was used to characterise CTNNB1wild-type and ß-catenin-activated HCA and HCC. Expression profiling of HCA subtypes was performed.

Results A roof plate-specific spondin 2 (RSPO2) gene rearrangement resulting from a 46.4 kb microdeletion on chromosome 8q23.1 was detected as a new morphomolecular driver of β-catenin-activated HCA. RSPO2 fusion positive HCA displayed upregulation of RSPO2 protein, nuclear accumulation of β-catenin and transcriptional activation of β-catenin-target genes indicating activation of Wingless-Type MMTV Integration Site Family (WNT) signalling. Architectural and cytological atypia as well as interstitial invasion indicated malignant transformation in one of the RSPO2 rearranged b-HCAs. The RSPO2 gene rearrangement was also observed in three β-catenin-activated HCCs developing in context of chronic liver disease. Mutations of the human telomerase reverse transcriptase promoter—known to drive malignant transformation of CTNNB1-mutated HCA—seem to be dispensable for RSPO2 rearranged HCA and HCC.

Conclusion The RSPO2 gene rearrangement leads to oncogenic activation of the WNT signalling pathway in HCA and HCC, represents an alternative mechanism for the development of b-HCA and may drive malignant transformation without additional TERT promoter mutation.

  • molecular genetics
  • hepatocellular carcinoma
  • adenoma
  • molecular carcinogenesis

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.


  • PS and AS contributed equally.

  • Contributors TL: experimental design, data interpretation, study supervision, drafting and critical revision of the manuscript; VE and RP: experimental design, data acquisition, data analysis and interpretation and revision of the manuscript; ON and MK: data acquisition, data analysis and revision of the manuscript; ER, SU and ZA: data analysis and interpretation and revision of the manuscript; MK, KHW, KB, AM, TFW, LW, BKS, AR and FS: data acquisition and revision of the manuscript; BB and SF: critical revision of the manuscript; JB: experimental design, data analysis and interpretation and drafting of the manuscript, PS and AS: experimental design, data analysis and interpretation, study supervision and critical revision of the manuscript.

  • Funding This work was supported by the Deutsche Forschungsgemeinschaft (LO 1676/2-1, LO 1676/4-1, SFB/TR209 project B08, to TL) and the German Cancer Consortium (DKTK, to PS and AS).

  • Competing interests None declared.

  • Ethics approval The retrospective study was approved by the local ethics committee of the University Hospital Heidelberg (S-346/2018).

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

  • Patient consent for publication Not required.

Linked Articles