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.
- molecular genetics
- hepatocellular carcinoma
- molecular carcinogenesis
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PS and AS contributed equally.
Contributors TL: experimental design, data interpretation, study supervision, drafting and critical revision of the manuscript; VE and RP: experimental design, data acquisition, data analysis and interpretation and revision of the manuscript; ON and MK: data acquisition, data analysis and revision of the manuscript; ER, SU and ZA: data analysis and interpretation and revision of the manuscript; MK, KHW, KB, AM, TFW, LW, BKS, AR and FS: data acquisition and revision of the manuscript; BB and SF: critical revision of the manuscript; JB: experimental design, data analysis and interpretation and drafting of the manuscript, PS and AS: experimental design, data analysis and interpretation, study supervision and critical revision of the manuscript.
Funding This work was supported by the Deutsche Forschungsgemeinschaft (LO 1676/2-1, LO 1676/4-1, SFB/TR209 project B08, to TL) and the German Cancer Consortium (DKTK, to PS and AS).
Competing interests None declared.
Ethics approval The retrospective study was approved by the local ethics committee of the University Hospital Heidelberg (S-346/2018).
Provenance and peer review Not commissioned; externally peer reviewed.
Patient consent for publication Not required.
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