PT  - JOURNAL ARTICLE
AU  - Thomas Longerich
AU  - Volker Endris
AU  - Olaf Neumann
AU  - Eugen Rempel
AU  - Martina Kirchner
AU  - Zahra Abadi
AU  - Sebastian Uhrig
AU  - Mark Kriegsmann
AU  - Karl Heinz Weiss
AU  - Kai Breuhahn
AU  - Arianeb Mehrabi
AU  - Tim Frederik Weber
AU  - Ludwig Wilkens
AU  - Beate K Straub
AU  - Andreas Rosenwald
AU  - Falko Schulze
AU  - Benedikt Brors
AU  - Stefan Froehling
AU  - Rossella Pellegrino
AU  - Jan Budczies
AU  - Peter Schirmacher
AU  - Albrecht Stenzinger
TI  - <em>RSPO2</em> gene rearrangement: a powerful driver of β-catenin activation in liver tumours
AID  - 10.1136/gutjnl-2018-317632
DP  - 2019 Jul 01
TA  - Gut
PG  - 1287--1296
VI  - 68
IP  - 7
4099  - http://gut.bmj.com/content/68/7/1287.short
4100  - http://gut.bmj.com/content/68/7/1287.full
SO  - Gut2019 Jul 01; 68
AB  - 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.