title: Unique patterns of CpG island methylation in inflammatory bowel disease-associated colorectal cancers.
abstract: BACKGROUND
  CpG island (CGI) hypermethylation at discrete loci is a prevalent cancer-promoting abnormality in sporadic colorectal carcinomas (S-CRCs). We investigated genome-wide CGI methylation in inflammatory bowel disease (IBD)-associated CRCs (IBD-CRCs).
  
  
  METHODS
  Methylation microarray analyses were conducted on seven IBD-CRCs, 17 S-CRCs, and eight normal control colonic tissues from patients without CRC or IBD. CGI methylator phenotype (CIMP), a surrogate marker for widespread cancer-specific CGI hypermethylation, was examined in 30 IBD-CRCs and 43 S-CRCs.
  
  
  RESULTS
  The genome-wide CGI methylation pattern of IBD-CRCs was CIMP status-dependent. Based on methylation array data profiling of all autosomal loci, CIMP(+) IBD-CRCs grouped together with S-CRCs, while CIMP(-) IBD-CRCs grouped together with control tissues. CIMP(-) IBD-CRCs demonstrated less methylation than did age-matched CIMP(-) S-CRCs at autosomal CGIs (z-score -0.17 vs. 0.09, P = 3 × 10(-3)) and CRC-associated hypermethylation target CGIs (z-score -0.43 vs. 0.68, P = 1 × 10(-4)). Age-associated hypermethylation target CGIs were significantly overrepresented in CGIs that were hypermethylated in S-CRCs (P = 1 × 10(-192)), but not in CGIs that were hypermethylated in IBD-CRCs (P = 0.11). In contrast, KRAS mutation prevalence was similar between IBD-CRCs and S-CRCs. Notably, CIMP(+) prevalence was significantly higher in older than in younger IBD-CRC cases (50.0 vs. 4.2, P = 0.02), but not in S-CRC cases (9.7 vs. 16.7, P = 0.92).
  
  
  CONCLUSIONS
  Cancer-specific CGI hypermethylation and age-associated CGI hypermethylation are diminished in IBD-CRCs relative to S-CRCs, while the KRAS mutation rate is comparable between these cancers. CGI hypermethylation appears to play only a minor role in IBD-associated carcinogenesis. We speculate that aging, rather than inflammation per se, promotes CIMP(+) CRCs in IBD patients.
authors.affiliation: Department of Medicine, Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Alexandru V
authors.initials: AV
authors.lastname: Olaru
authors.forename: Yulan
authors.initials: Y
authors.lastname: Cheng
authors.forename: Rachana
authors.initials: R
authors.lastname: Agarwal
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.forename: Stefan
authors.initials: S
authors.lastname: David
authors.forename: John M
authors.initials: JM
authors.lastname: Abraham
authors.forename: Wayne
authors.initials: W
authors.lastname: Yu
authors.forename: John H
authors.initials: JH
authors.lastname: Kwon
authors.forename: Mark
authors.initials: M
authors.lastname: Lazarev
authors.forename: Steven R
authors.initials: SR
authors.lastname: Brant
authors.forename: Michael R
authors.initials: MR
authors.lastname: Marohn
authors.forename: David F
authors.initials: DF
authors.lastname: Hutcheon
authors.forename: Noam
authors.initials: N
authors.lastname: Harpaz
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Meltzer
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Mori
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002277:Carcinoma / Q000209:etiology / Q000235:genetics*; D003106:Colon / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000209:etiology / Q000235:genetics*; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000150:complications / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins