Deleted in Malignant Brain Tumors 1 (DMBT1) is differentially expressed in cholangiocarcinogenesis and shows influence on patient survival

B Goeppert; L Frauenschuh; M Zucknick; S Roessler; A Stenzinger; A Warth; C End; J Mollenhauer; M Vogel; A Mehrabi; M Hafezi; P Schirmacher; W Weichert; M Renner

doi:10.1055/s-0033-1360958

Zeitschrift für Gastroenterologie, Inhaltsverzeichnis

Deleted in Malignant Brain Tumors 1 (DMBT1) is differentially expressed in cholangiocarcinogenesis and shows influence on patient survival

B Goeppert ¹, L Frauenschuh ¹, M Zucknick ², S Roessler ¹, A Stenzinger ¹, A Warth ¹, C End ³, J Mollenhauer ⁴, M Vogel ⁵, A Mehrabi ⁶, M Hafezi ⁶, P Schirmacher ¹, W Weichert ¹, M Renner ¹

¹University Hospital Heidelberg, Institute of Pathology, Heidelberg, Germany
²German Cancer Research Center (DKFZ), Department of Biostatistics, Heidelberg, Germany
³German Cancer Research Center (DKFZ), Division of Molecular Analysis, Heidelberg, Germany
⁴University of Southern Denmark, Medical Biotechnology Center, Odense, Denmark
⁵University Hospital Heidelberg, Department of Neuroradiology, Heidelberg, Germany
⁶University Hospital Heidelberg, Department of General Visceral and Transplantation Surgery, Heidelberg, Germany

Abstract

Aims: The secreted scavenger receptor cysteine-rich (SRCR) protein DMBT1 is differentially expressed in various cancer types and has been proposed to play a critical role in epithelial cell growth and cell differentiation. In biliary tract cancers (BTC) several risk factors, including cholangiolithiasis, liver fluke infection, and anatomical abnormalities, all associated with inflammation of the biliary tract, have been described. Therefore, the aim of the study was to analyze the expression of DMBT1 in BTC and to correlate the expression with clinicopathological data including patient survival.

Methods: Tissue microarrays containing tissue specimens of 205 BTC patients (79 intrahepatic (ICC), 83 extrahepatic cholangiocarcinomas (ECC), and 43 gallbladder adenocarcinomas (GBAC)), 57 premalignant lesions (high grade biliary intraepithelial neoplasia, BilIN 3), and 72 non-neoplastic biliary epithelium samples of BTC patients were stained immunohistochemically for DMBT1. The DMBT1 expression was evaluated semi-quantitatively using the Remmele-score and correlation with clinicopathological data was performed.

Results: Compared to non-malignant intrahepatic large and small bile ducts, DMBT1 expression was significantly increased in BilIN 3 (p < 0.001) and significantly decreased in BTC (invasive carcinomas) (p < 0.001). Existence of DMBT1 expression in non-malignant biliary epithelial cells of BTC-patients was associated with improved survival (log-rank test, p = 0.027). DMBT1 expression was positively correlated with high MHC class I expression in tumor cells (p < 0.04). Correlation of DMBT1 expression with age identified a significant higher expression in older patients (p < 0.001). DMBT1 expression showed no significant correlation with the amount of tumor infiltrating immune cells (CD4, FOXP3, CD8, CD20, and CD68).

Conclusions: Our data suggest that DMBT1 plays a diverse role in chronic inflammation of bile ducts and in cholangiocarcinogenesis dependent on spatiotemporal expression. DMBT1 expression might be of importance in the progression of BTC and ultimately have an influence on the outcome of BTC-patients.