RSPO2 gene rearrangement: a powerful driver of β-catenin activation in liver tumours
| العنوان: | RSPO2 gene rearrangement: a powerful driver of β-catenin activation in liver tumours |
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| المؤلفون: | Volker Endris, Thomas Longerich, Benedikt Brors, Andreas Rosenwald, Beate K. Straub, Mark Kriegsmann, Zahra Abadi, R Pellegrino, Falko Schulze, Olaf Neumann, Ludwig Wilkens, Martina Kirchner, Arianeb Mehrabi, Peter Schirmacher, Stefan Froehling, Jan Budczies, Karl Heinz Weiss, Sebastian Uhrig, Kai Breuhahn, Tim Frederik Weber, Albrecht Stenzinger, Eugen Rempel |
| المصدر: | Gut. 68:1287-1296 |
| بيانات النشر: | BMJ, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Gene expression profiling, Gastroenterology, Cancer research, Wnt signaling pathway, Telomerase reverse transcriptase, Gene rearrangement, HCCS, Biology, RSPO2, Malignant transformation, RSPO2 Gene |
| الوصف: | ObjectiveWe 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).DesignLarge 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.ResultsA 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.ConclusionThe 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. |
| تدمد: | 1468-3288 0017-5749 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_________::fa0f08b77ba05dfece49db5c8a898ab9Test https://doi.org/10.1136/gutjnl-2018-317632Test |
| رقم الانضمام: | edsair.doi...........fa0f08b77ba05dfece49db5c8a898ab9 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14683288 00175749 |
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