Z Gastroenterol 2019; 57(01): e64
DOI: 10.1055/s-0038-1677216
4. Tumors
Georg Thieme Verlag KG Stuttgart · New York

RSPO2 gene rearrangement – a new cancer driver in the liver

T Longerich
1   Institute of Pathology, University Hospital Heidelberg, Germany
2   Liver Cancer Center Heidelberg, Germany
,
V Endris
1   Institute of Pathology, University Hospital Heidelberg, Germany
,
O Neumann
1   Institute of Pathology, University Hospital Heidelberg, Germany
,
E Rempel
1   Institute of Pathology, University Hospital Heidelberg, Germany
,
S Uhrig
3   Division of Applied Bioinformatics, German Cancer Research Center and National Center for Tumor Diseases (NCT) Heidelberg, Germany
,
M Kriegsmann
1   Institute of Pathology, University Hospital Heidelberg, Germany
,
KH Weiss
2   Liver Cancer Center Heidelberg, Germany
4   Internal Medicine IV, University Hospital Heidelberg
,
A Mehrabi
2   Liver Cancer Center Heidelberg, Germany
5   Department of General and Transplant Surgery, University Hospital Heidelberg, Heidelberg
,
TF Weber
2   Liver Cancer Center Heidelberg, Germany
6   Diagnostic and Interventional Radiology, University Hospital Heidelberg, Heidelberg
,
BK Straub
7   Institute of Pathology, University Medicine, Johannes Gutenberg-University Mainz
,
A Rosenwald
8   Institute of Pathology, University of Würzburg and Comprehensive Cancer Center (CCC) Mainfranken, Würzburg, Germany
,
F Schulze
9   Senckenberg Institute of Pathology, University Hospital Frankfurt, Frankfurt, Germany
,
J Budczies
1   Institute of Pathology, University Hospital Heidelberg, Germany
,
P Schirmacher
1   Institute of Pathology, University Hospital Heidelberg, Germany
2   Liver Cancer Center Heidelberg, Germany
,
A Stenzinger
1   Institute of Pathology, University Hospital Heidelberg, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
04 January 2019 (online)

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Hepatocellular tumours in adults can be divided in hepatocellular adenomas (HCA) and hepatocellular carcinomas (HCC). While HCA comprise a group of benign liver tumours that mainly develop in females without pre-existing liver disease in the context of oral contraception, HCC has a male predilection and occurs in the setting of chronic liver diseases. Activating mutations of the CTNNB1 gene are among the most frequent somatic alterations in human HCC, and additionally characterize ß-catenin-activated (b-HCA), which carry an increased risk of malignant transformation to HCC.

All HCAs diagnosed at our institution between 2008 and 2018 were reviewed and subtyped using immunohistochemistry. The mutational status of the CTNNB1 gene was determined in b-HCA and an ultra-deep sequencing panel covering 161 cancer driver genes (incl. gene fusions) was used to characterize CTNNB1 wildtype, b-HCAs.

A Roof plate-specific spondin 2 (RSPO2) gene rearrangement resulting from a 46.4 kb microdeletion on chromosome 8q23.1 was detected in CTNNB1 wildtype, b-HCAs. RSPO2 fusion positive HCA showed RSPO2 protein overexpression as determined by immunohistochemistry and remarkable nuclear accumulation of β-catenin, indicating strong activation of WNT signalling. In addition, malignant transformation to HCC was recorded in one of the RSPO2 rearranged b-HCAs. Furthermore, the RSPO2 gene rearrangement was also detected in a CTNNB1-wildtype HCCs due to hepatitis B-induced liver cirrhosis.

In summary, an RSPO2 gene rearrangement drives oncogenic activation of WNT signalling in b-HCA and HCC. As an inhibitor of WNT secretion was able to induce tumour clearance in a RSPO2 rearranged colon cancer model, this rearrangement might be a promising target for the treatment of hepatic RSPO2 activated tumours as well. Our molecular diagnostic approach could be used as companion diagnostic to select HCC patients that may benefit from such a precision medicine concept.