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Identification and Characterization of Differentially Methylated CpG Islands in Pancreatic Carcinoma¹

Departments of Pathology [T. U., K. M. W., R. H. H., M. G.], Oncology [M. T., R. H. H., M. G.], Surgery [C. J. Y.], Epidemiology [H. S.], and Medicine [M. G.], Johns Hopkins School of Medicine and the Johns Hopkins School of Public Health, Baltimore, Maryland 21205, and the Department of Leukemia of University of Texas at MD Anderson Cancer Center, Houston, Texas 77030 [J-P. J. I.]

To identify CpG islands differentially methylated in pancreatic adenocarcinoma, we used methylated CpG island amplification (MCA) coupled with representational difference analysis. Of 42 CpG islands identified by MCA/representational difference analysis, 7 CpG islands [methylated in carcinoma of the pancreas (MICP)] were differentially methylated in a panel of eight pancreatic cancer cell lines compared with normal pancreas. In a larger panel of 75 pancreatic adenocarcinomas, these 7 MICPs (ppENK, Cyclin G, ZBP, MICP25, 27, 36, and 38) were methylated in 93, 3, 9, 15, 48, 19, and 41% of cancers, respectively, by methylation-specific PCR but not in any of 15 normal pancreata. In pancreatic cancer cell lines, methylation of ppENK, a gene with known growth suppressive properties, was associated with transcriptional silencing that was reversible with 5-aza-2'-deoxycytidine treatment. Relationships between the methylation patterns of pancreatic adenocarcinomas and their clinicopathological features were also determined. Larger pancreatic cancers and those from older patients (P = 0.017) harbored more methylated loci than smaller tumors and those from younger patients (P = 0.017). ppENK, MICP25, and 27 were variably methylated in normal gastric, duodenal, and colonic mucosae.

These data indicate that aberrant methylation of ppENK and its transcriptional repression is a common event in pancreatic carcinogenesis.

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