Hepatocellular carcinoma as extracolonic manifestation of Lynch syndrome indicates SEC63 as potential target gene in hepatocarcinogenesis

Abstract

Objective. Lynch syndrome is a cancer predisposition syndrome caused by germline mutations in DNA mismatch repair (MMR) genes with microsatellite instability (MSI) as its molecular hallmark. Hepatocellular carcinoma (HCC) has not been considered part of the tumor spectrum. The aim was to provide a detailed molecular characterization of an HCC associated with Lynch Syndrome (Muir-Torre variant). Materials and methods. HCC samples were analyzed for MSI, MMR protein expression and coding microsatellite instability (cMSI). Since cMSI also affected SEC63 coding for an endoplasmic reticulum membrane protein with implications for intracellular protein translocation, its impact on hepatocyte growth control was assessed in an established short-term model. Recombinant inbred mouse lines (BXD) showing different basal SEC63 expression levels were treated with the chemocarcinogen diethylnitrosamine (DEN) intraperitoneally. Proliferation and apoptosis of hepatocytes were determined after 48 h using Ki67 and TUNEL assays. Results. The HCC was high-grade microsatellite unstable with loss of MSH2 expression. cMSI was detected in four genes (ASTE1, SEC63, TAF1B, TGFBR2). However, only TGFBR2 is known to be involved in hepatocarcinogenesis. When investigating the impact of SEC63 expression on hepatocyte growth control in the murine model, low hepatic expression correlated significantly (p < 0.05) with a decrease in apoptosis and increased proliferative activity. Conclusions. For the first time, an HCC with characteristic molecular features of association with Lynch syndrome is described. The pro-carcinogenic growth behavior of hepatocytes with low SEC63 expression in the murine model indicates a potential role for SEC63 in hepatocarcinogenesis in general, but this needs further functional validation.

Key Words::

• coding microsatellite instability
• hepatocellular carcinoma
• Lynch syndrome
• Sec63

Acknowledgements

The authors would like to thank Prof. Dr. Richard Zimmermann (Homburg) for critical revision of the manuscript and helpful discussion concerning sec63 and Annika Bohner (Homburg) for technical assistance. This work was supported in part by the EU COST action BM091 SYSGENET “European systems genetics network for the study of complex genetic human diseases using mouse genetic reference populations” (to F.L.).

Declaration of interest: The authors declare that they have no conflict of interest or financial interest related to the manuscript.