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

Abstract

We aimed at the identification of genetic alterations that may functionally substitute for <i>CTNNB1</i> mutation in ß-catenin-activated hepatocellular adenomas (HCAs) and hepatocellular carcinoma (HCC). Large cohorts of HCA (n=185) and HCC (n=468) were classified using immunohistochemistry. The mutational status of the <i>CTNNB1</i> 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 <i>CTNNB1</i>wild-type and ß-catenin-activated HCA and HCC. Expression profiling of HCA subtypes was performed. A <i>roof plate-specific spondin 2</i> (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. <i>RSPO2</i> 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 <i>RSPO2</i> rearranged b-HCAs. The <i>RSPO2</i> 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 <i>CTNNB1</i>-mutated HCA-seem to be dispensable for <i>RSPO2</i> rearranged HCA and HCC. The <i>RSPO2</i> 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.