title: Identification and characterization of differentially methylated CpG islands in pancreatic carcinoma.
abstract: 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.
authors.affiliation: Department of Pathology, Johns Hopkins School of Medicine and the Johns Hopkins School of Public Health, Baltimore, Maryland 21205, USA.
authors.forename: T
authors.initials: T
authors.lastname: Ueki
authors.forename: M
authors.initials: M
authors.lastname: Toyota
authors.forename: H
authors.initials: H
authors.lastname: Skinner
authors.forename: K M
authors.initials: KM
authors.lastname: Walter
authors.forename: C J
authors.initials: CJ
authors.lastname: Yeo
authors.forename: J P
authors.initials: JP
authors.lastname: Issa
authors.forename: R H
authors.initials: RH
authors.lastname: Hruban
authors.forename: M
authors.initials: M
authors.lastname: Goggins
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001374:Azacitidine / Q000494:pharmacology; D018899:CpG Islands; D056746:Cyclin G; D056766:Cyclin G1; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D019175:DNA Methylation; D004745:Enkephalins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011498:Protein Precursors / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000964:Antimetabolites, Antineoplastic; C534702:CCNG1 protein, human; D056746:Cyclin G; D056766:Cyclin G1; D016213:Cyclins; D004745:Enkephalins; D011498:Protein Precursors; C033660:preproenkephalin; D001374:Azacitidine