RSPO2 gene rearrangement

• Verfasst von: Longerich, Thomas [VerfasserIn]
• Verfasst von: Endris, Volker [VerfasserIn]
• Verfasst von: Neumann, Olaf [VerfasserIn]
• Verfasst von: Rempel, Eugen [VerfasserIn]
• Verfasst von: Kirchner, Martina [VerfasserIn]
• Verfasst von: Abadi, Zahra [VerfasserIn]
• Verfasst von: Kriegsmann, Mark [VerfasserIn]
• Verfasst von: Weiss, Karl Heinz [VerfasserIn]
• Verfasst von: Breuhahn, Kai [VerfasserIn]
• Verfasst von: Mehrabi, Arianeb [VerfasserIn]
• Verfasst von: Weber, Tim [VerfasserIn]
• Verfasst von: Fröhling, Stefan [VerfasserIn]
• Verfasst von: Pellegrino, Rossella [VerfasserIn]
• Verfasst von: Budczies, Jan [VerfasserIn]
• Verfasst von: Schirmacher, Peter [VerfasserIn]
• Verfasst von: Stenzinger, Albrecht [VerfasserIn]
• Titel: RSPO2 gene rearrangement
• Titelzusatz: a powerful driver of β-catenin activation in liver tumours
• Verf.angabe: 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
• E-Jahr: 2019
• Jahr: 2 February 2019
• Umfang: 10 S.
• Fussnoten: Published online first 2 February 2019 ; Gesehen am 23.10.2019
• Titel Quelle: Enthalten in: Gut
• Ort Quelle: London : BMJ Publishing Group, 1960
• Jahr Quelle: 2019
• Band/Heft Quelle: 68(2019), 7, Seite 1287-1296
• ISSN Quelle: 1468-3288
• DOI: doi:10.1136/gutjnl-2018-317632
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 167946342X

Abstract

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.