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

OBJECTIVE

We aimed at the identification of genetic alterations that may functionally substitute for 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 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 wild-type and ß-catenin-activated HCA and HCC. Expression profiling of HCA subtypes was performed.

RESULTS

A (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. 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 rearranged b-HCAs. The 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 -mutated HCA-seem to be dispensable for rearranged HCA and HCC.

CONCLUSION

The 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.