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RSPO2 gene rearrangement: a powerful driver of β-catenin activation in liver tumours

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 immunohistochemi...

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Main Authors: Longerich, Thomas (Author) , Endris, Volker (Author) , Neumann, Olaf (Author) , Rempel, Eugen (Author) , Kirchner, Martina (Author) , Abadi, Zahra (Author) , Kriegsmann, Mark (Author) , Weiss, Karl Heinz (Author) , Breuhahn, Kai (Author) , Mehrabi, Arianeb (Author) , Weber, Tim (Author) , Fröhling, Stefan (Author) , Pellegrino, Rossella (Author) , Budczies, Jan (Author) , Schirmacher, Peter (Author) , Stenzinger, Albrecht (Author)
Format: Article (Journal)
Language:English
Published: 2 February 2019
In: Gut
Year: 2019, Volume: 68, Issue: 7, Pages: 1287-1296
ISSN:1468-3288
DOI:10.1136/gutjnl-2018-317632
Online Access:Verlag, Pay-per-use, Volltext: http://dx.doi.org/10.1136/gutjnl-2018-317632
Verlag, Pay-per-use, Volltext: https://gut.bmj.com/content/68/7/1287.long
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Author Notes:Thomas Longerich, Volker Endris, Olaf Neumann, Eugen Rempel, Martina Kirchner, Zahra Abadi, Sebastian Uhrig, Mark Kriegsmann, Karl Heinz Weiss, Kai Breuhahn, Arianeb Mehrabi, Tim Frederik Weber, Ludwig Wilkens, Beate K Straub, Andreas Rosenwald, Falko Schulze, Benedikt Brors, Stefan Froehling, Rossella Pellegrino, Jan Budczies, Peter Schirmacher, Albrecht Stenzinger
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Summary: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.
Item Description:Published online first 2 February 2019
Gesehen am 23.10.2019
Physical Description:Online Resource
ISSN:1468-3288
DOI:10.1136/gutjnl-2018-317632

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