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

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.

journal_name

Gut

journal_title

Gut

authors

Longerich T,Endris V,Neumann O,Rempel E,Kirchner M,Abadi Z,Uhrig S,Kriegsmann M,Weiss KH,Breuhahn K,Mehrabi A,Weber TF,Wilkens L,Straub BK,Rosenwald A,Schulze F,Brors B,Froehling S,Pellegrino R,Budczies J,Schirmac

doi

10.1136/gutjnl-2018-317632

subject

Has Abstract

pub_date

2019-07-01 00:00:00

pages

1287-1296

issue

7

eissn

0017-5749

issn

1468-3288

pii

gutjnl-2018-317632

journal_volume

68

pub_type

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