DNA Methyltransferases 1, 3a and 3b Overexpression and Clinical Significance in Gastroenteropancreatic Neuroendocrine Tumors
ZR Qian, MM Rahman, EL Wang, M Nakasono, T Hayashi, R Haba, M Ishida, H Okabe, T Sano. Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan; Tsurugi Municipal Handa-Hospital, Tokushima, Japan; Faculty of Medicine, Kagawa University, Kagawa, Japan; Shiga University of Medical Science, Shiga, Japan
Background: Alteration of DNA methylation is one of the most consistent epigenetic changes in human cancers. Three genes, namely DNA methyltransferase (DNMT) 1, 3a, and 3b, coding for DNMTs that affect promoter methylation status are thought to play an important role in the development of cancers and may be good anticancer therapy targets. Methylation of tumor suppressor genes has been reported in gastroenteropancreatic (GEP) neuroendocrine tumors (NETs); however, there are no studies about DNMTs protein expression and their clinical significance in GEP NETs.
Design: In this work, using immunohistochemistry the expression of DNMT1, 3a and 3b were studied in 63 GEP NETs included well-differentiated NET (WNET, of either benign or uncertain behavior; n = 31), well-differentiated neuroendocrine carcinoma (WNEC; n = 16), and poorly-differentiated neuroendocrine carcinoma (PNEC; n = 16).
Results: Expression of DNMT1, 3a and 3b was frequently detected in GEP NETs (87%, 81%, 75%, respectively). DNMT3a expression level was significantly higher in poorly-differentiated neuroendocrine carcinomas than well-differentiated NETs or well-differentiated neuroendocrine carcinoma s (P < 0.01, P < 0.05, respectively). Expression of DNMT1, 3a and 3b showed significantly higher levels in stage IV tumors than stage I and II tumors. In addition, expression of DNMT1, 3a and 3b was positively correlated with MIB-1 labeling index in GEP NETs (R = 0.293, P = 0.019; R = 0.457, P = 0.001; R = 0.249, P = 0.049; respectively). In addition, expression levels and frequencies of positive immunostaining of DNMT3a and 3b were significantly lower in midgut NETs than foregut and hindgut NETs.
Conclusions: These results suggest that DNMTs may have important roles in tumorigenesis and development of GEP NETs and epigenetic therapy directed against DNMTs may be a considerable therapeutic approach.
Monday, March 22, 2010 1:00 PM
Poster Session II # 84, Monday Afternoon