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 journalArticle

20 Citations (Scopus)

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 1 2012

Fingerprint

CpG Islands
Inflammatory Bowel Diseases
Methylation
Colorectal Neoplasms
Phenotype
Neoplasms
Genome
Mutation Rate
Microarray Analysis
Carcinogenesis

Keywords

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

ASJC Scopus subject areas

  • Gastroenterology
  • Immunology and Allergy

Cite this

Olaru, A. V., Cheng, Y., Agarwal, R., Yang, J., David, S., Abraham, J. M., ... Mori, Y. (2012). Unique patterns of CpG island methylation in inflammatory bowel disease-associated colorectal cancers. Inflammatory Bowel Diseases, 18(4), 641-648. https://doi.org/10.1002/ibd.21826

Unique patterns of CpG island methylation in inflammatory bowel disease-associated colorectal cancers. / Olaru, Alexandru V.; Cheng, Yulan; Agarwal, Rachana; Yang, Jian; David, Stefan; Abraham, John M.; Yu, Wayne; Kwon, John H.; Lazarev, Mark; Brant, Steven R.; Marohn, Michael R.; Hutcheon, David F.; Harpaz, Noam; Meltzer, Stephen J.; Mori, Yuriko.

In: Inflammatory Bowel Diseases, Vol. 18, No. 4, 01.04.2012, p. 641-648.

Research output: Contribution to journalArticle

Olaru, AV, Cheng, Y, Agarwal, R, Yang, J, David, S, Abraham, JM, Yu, W, Kwon, JH, Lazarev, M, Brant, SR, Marohn, MR, Hutcheon, DF, Harpaz, N, Meltzer, SJ & Mori, Y 2012, 'Unique patterns of CpG island methylation in inflammatory bowel disease-associated colorectal cancers', Inflammatory Bowel Diseases, vol. 18, no. 4, pp. 641-648. https://doi.org/10.1002/ibd.21826
Olaru, Alexandru V. ; Cheng, Yulan ; Agarwal, Rachana ; Yang, Jian ; David, Stefan ; Abraham, John M. ; Yu, Wayne ; Kwon, John H. ; Lazarev, Mark ; Brant, Steven R. ; Marohn, Michael R. ; Hutcheon, David F. ; Harpaz, Noam ; Meltzer, Stephen J. ; Mori, Yuriko. / Unique patterns of CpG island methylation in inflammatory bowel disease-associated colorectal cancers. In: Inflammatory Bowel Diseases. 2012 ; Vol. 18, No. 4. pp. 641-648.
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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.",
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author = "Olaru, {Alexandru V.} and Yulan Cheng and Rachana Agarwal and Jian Yang and Stefan David and Abraham, {John M.} and Wayne Yu and Kwon, {John H.} and Mark Lazarev and Brant, {Steven R.} and Marohn, {Michael R.} and Hutcheon, {David F.} and Noam Harpaz and Meltzer, {Stephen J.} and Yuriko Mori",
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T1 - Unique patterns of CpG island methylation in inflammatory bowel disease-associated colorectal cancers

AU - Olaru, Alexandru V.

AU - Cheng, Yulan

AU - Agarwal, Rachana

AU - Yang, Jian

AU - David, Stefan

AU - Abraham, John M.

AU - Yu, Wayne

AU - Kwon, John H.

AU - Lazarev, Mark

AU - Brant, Steven R.

AU - Marohn, Michael R.

AU - Hutcheon, David F.

AU - Harpaz, Noam

AU - Meltzer, Stephen J.

AU - Mori, Yuriko

PY - 2012/4/1

Y1 - 2012/4/1

N2 - 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.

AB - 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.

KW - Colorectal cancer

KW - Crohn's disease

KW - DNA methylation microarray

KW - Inflammatory bowel disease

KW - Ulcerative colitis

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