RSPO2 gene rearrangement: a powerful driver of ß-catenin activation in liver tumours.
Gut
; 68(7): 1287-1296, 2019 07.
Article
en En
| MEDLINE
| ID: mdl-30901310
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 ß-catenin-activated HCA. RSPO2 fusion positive HCA displayed upregulation of RSPO2 protein, nuclear accumulation of ß-catenin and transcriptional activation of ß-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 ß-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.Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Reordenamiento Génico
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Adenoma de Células Hepáticas
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Carcinoma Hepatocelular
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Péptidos y Proteínas de Señalización Intercelular
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Beta Catenina
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Neoplasias Hepáticas
Tipo de estudio:
Etiology_studies
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Incidence_studies
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Observational_studies
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Prognostic_studies
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Risk_factors_studies
Límite:
Adolescent
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Adult
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Aged
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Child
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Año:
2019
Tipo del documento:
Article