DNA methyltransferases 1, 3a, and 3b overexpression and clinical significance in gastroenteropancreatic neuroendocrine tumors

• Published in: Human pathology 2010-08, Vol.41 (8), p.1069-1078
• Main Authors: Rahman, Md. Mustafizur, PhD, Qian, Zhi Rong, MD, PhD, Lu Wang, Elaine, MD, PhD, Yoshimoto, Katsuhiko, MD, PhD, Nakasono, Masahiko, MD, PhD, Sultana, Razia, MD, PhD, Yoshida, Tomoyuki, MD, Hayashi, Toshitetsu, MD, PhD, Haba, Reiji, MD, PhD, Ishida, Mitsuaki, MD, PhD, Okabe, Hidetoshi, MD, PhD, Sano, Toshiaki, MD, PhD
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Biological and medical sciences; Cell cycle; Clinical trials; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases - biosynthesis; DNA (Cytosine-5-)-Methyltransferases - genetics; DNA methylation; DNA Methyltransferase 3A; DNA Methyltransferase 3B; DNMT1, DNMT3a, DNMT3b, methylation; Epigenetics; Female; Genes; GEP NET; Humans; Intestinal Neoplasms - enzymology; Intestinal Neoplasms - genetics; Intestinal Neoplasms - pathology; Investigative techniques, diagnostic techniques (general aspects); Labeling; Male; Medical sciences; Middle Aged; Neuroendocrine Tumors - enzymology; Neuroendocrine Tumors - genetics; Neuroendocrine Tumors - pathology; Pancreatic Neoplasms - enzymology; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Stomach Neoplasms - enzymology; Stomach Neoplasms - genetics; Stomach Neoplasms - pathology; Studies; Tumors
• ISSN: 0046-8177; 1532-8392
• DOI: 10.1016/j.humpath.2010.01.011

Summary The alteration of DNA methylation is one of the most common epigenetic changes in human cancers. Three genes, namely, DNA methyltransferase 1, 3a, and 3b, which code for DNA methyltransferases that affect promoter methylation status, are thought to play an important role in the development of cancers and may be good anticancer therapy targets. The methylation of tumor suppressor genes has been reported in gastroenteropancreatic neuroendocrine tumors; however, there have been no studies about DNA methyltransferase protein expression and its clinical significance in gastroenteropancreatic neuroendocrine tumors. In this study, the expression of DNA methyltransferase 1, 3a, and 3b was studied in 63 gastroenteropancreatic neuroendocrine tumors by immunohistochemistry. The expression of DNA methyltransferase 1, 3a, and 3b was frequently detected in gastroenteropancreatic neuroendocrine tumors (87%, 81%, and 75%, respectively). The DNA methyltransferase 3a expression level was significantly higher in poorly differentiated neuroendocrine carcinomas than in well-differentiated neuroendocrine tumors or well-differentiated neuroendocrine carcinomas ( P < .01 and P < .05, respectively). The expression of DNA methyltransferase 1, 3a, and 3b showed significantly higher levels in stage IV tumors than in stage I or II tumors. In addition, the expression levels of DNA methyltransferase 1, 3a, and 3b were positively correlated with the MIB-1 labeling index in gastroenteropancreatic neuroendocrine tumors ( R = 0.293, P = .019; R = 0.457, P = .001; and R = 0.249, P = .049; respectively). In addition, the expression levels and positive immunostaining frequencies of DNA methyltransferase 3a and 3b were significantly lower in midgut neuroendocrine tumors than in foregut or hindgut neuroendocrine tumors. Our findings suggest that the overexpression of DNA methyltransferase 1, 3a, and 3b is related to tumorigenesis and the progression of gastroenteropancreatic neuroendocrine tumors.