Unique patterns of CpG island methylation in inflammatory bowel disease-associated colorectal cancers

Alexandru V. Olaru, Yulan Cheng, Rachana Agarwal, Jian Yang, Stefan David, John M. Abraham, Wayne Yu, John H. Kwon, Mark Lazarev, Steven R. Brant, Michael R. Marohn, David F. Hutcheon, Noam Harpaz, Stephen J. Meltzer, Yuriko Mori

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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 SCRCs, 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.

Original languageEnglish (US)
Pages (from-to)641-648
Number of pages8
JournalInflammatory bowel diseases
Volume18
Issue number4
DOIs
StatePublished - Apr 2012

Keywords

  • Colorectal cancer
  • Crohn's disease
  • DNA methylation microarray
  • Inflammatory bowel disease
  • Ulcerative colitis

ASJC Scopus subject areas

  • Immunology and Allergy
  • Gastroenterology

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