title: Genome-wide CpG island profiling of intraductal papillary mucinous neoplasms of the pancreas.
abstract: OBJECTIVE
  Intraductal papillary mucinous neoplasms (IPMN) are precursors to infiltrating pancreatic ductal adenocarcinomas. Widespread epigenetic alterations are characteristic of many cancers, yet few studies have systematically analyzed epigenetic alterations of neoplastic precursors. Our goal was to conduct genome-wide CpG island methylation profiling to identify aberrantly methylated loci in IPMNs.
  
  
  METHODS
  We compared the CpG island methylation profiles of six IPMNs to normal primary pancreatic duct samples using methylation CpG island amplification (MCA) and Agilent CpG island microarray (MCAM) analysis. When selected 13 genes identified as differentially methylated by MCAM for methylation-specific PCR (MSP) analysis in an independent set of IPMNs and normal pancreas samples and conducted expression analysis of selected genes.
  
  
  RESULTS
  We identified 2,259 loci as differentially methylated in at least one of six IPMNs including 245 genes hypermethylated in IPMNs with high-grade dysplasia compared with normal pancreatic duct samples. Eleven of 13 genes evaluated by MSP were more commonly methylated in 61 IPMNs than in 43 normal pancreas samples. Several genes (BNIP3, PTCHD2, SOX17, NXPH1, EBF3) were significantly more likely to be methylated in IPMNs with high-grade than with low-grade dysplasia. One gene, SOX17, showed loss of protein expression by immunohistochemistry in 22% (19 of 88) of IPMNs. The most specific marker, BNIP3, was not methylated in any IPMNs with low-grade dysplasia or in normal pancreas samples.
  
  
  CONCLUSIONS
  IPMNs undergo extensive aberrant CpG island hypermethylation. The detection of genes selectively methylated in high-grade IPMNs such as BNIP3 may have use in the clinical evaluation of IPMNs.
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA.
authors.forename: Seung-Mo
authors.initials: SM
authors.lastname: Hong
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Omura
authors.forename: Audrey
authors.initials: A
authors.lastname: Vincent
authors.forename: Ang
authors.initials: A
authors.lastname: Li
authors.forename: Spencer
authors.initials: S
authors.lastname: Knight
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
authors.forename: Michael
authors.initials: M
authors.lastname: Goggins
mesh_terms: D002288:Adenocarcinoma, Mucinous / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000368:Aged; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C090121:BNIP3 protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins