Accelerated age-related CpG island methylation in ulcerative colitis

J. P J Issa, Nita Ahuja, M. Toyota, M. P. Bronner, T. A. Brentnall

Research output: Contribution to journalArticle

Abstract

CpG island hypermethylation is a mechanism of gene silencing that can be usurped by neoplastic cells to inactivate undesirable genes. In the colon, hypermethylation often starts in normal mucosa as a function of age and is markedly increased in cancer. To test the hypothesis that subjects at increased risk of colon cancer have higher levels of methylation in their nonneoplastic mucosa, we studied methylation patterns of five genes in the normal and dysplastic mucosa of patients with ulcerative colitis (UC), a condition associated with a marked increased risk of colon cancer. One gene (Mlh1) was unmethylated in all tissues examined. All four remaining genes had low but detectable levels of methylation in the epithelium of UC patients without evidence of dysplasia, and this methylation was not different from non-UC controls. By contrast, all four genes were highly methylated in dysplastic epithelium from high-grade dysplasia (HGD)/cancer patients with UC; methylation in HGD versus controls averaged 40.0% versus 7.4% (P = 0.00003) for ER, 44.0% versus 3.0% (P <0.00003) for MYOD, 9.4% versus 2.4% (P = 0.03)for p16 exon 1, and 57.5% versus 30.6% (P = 0.01) for CSPG2. Importantly, three of the four genes were also highly methylated in the normal appearing (nondysplastic) epithelium from these same HGD/cancer patients, indicating that methylation precedes dysplasia and is widespread in these patients. Compared with controls, methylation averaged 20.1% versus 7.2% (P = 0.07) for ER, 18.4% versus 3.0% (P <0.008) for MYOD, and 7.9% versus 2.4% (P = 0.007) for p16 exon 1. These results are consistent with the hypothesis that age-related methylation marks (and may lead to) the field defect that reflects acquired predisposition to colorectal neoplasia. Furthermore, the data suggest that chronic inflammation is associated with high levels of methylation, perhaps as a result of increased cell turnover, and that UC can be viewed as resulting in premature aging of colorectal epithelial cells.

Original languageEnglish (US)
Pages (from-to)3573-3577
Number of pages5
JournalCancer Research
Volume61
Issue number9
StatePublished - May 1 2001

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CpG Islands
Ulcerative Colitis
Methylation
Genes
Mucous Membrane
Epithelium
Colonic Neoplasms
Exons
Neoplasms
Premature Aging
Gene Silencing
Colitis
Colon
Epithelial Cells
Inflammation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Issa, J. P. J., Ahuja, N., Toyota, M., Bronner, M. P., & Brentnall, T. A. (2001). Accelerated age-related CpG island methylation in ulcerative colitis. Cancer Research, 61(9), 3573-3577.

Accelerated age-related CpG island methylation in ulcerative colitis. / Issa, J. P J; Ahuja, Nita; Toyota, M.; Bronner, M. P.; Brentnall, T. A.

In: Cancer Research, Vol. 61, No. 9, 01.05.2001, p. 3573-3577.

Research output: Contribution to journalArticle

Issa, JPJ, Ahuja, N, Toyota, M, Bronner, MP & Brentnall, TA 2001, 'Accelerated age-related CpG island methylation in ulcerative colitis', Cancer Research, vol. 61, no. 9, pp. 3573-3577.
Issa JPJ, Ahuja N, Toyota M, Bronner MP, Brentnall TA. Accelerated age-related CpG island methylation in ulcerative colitis. Cancer Research. 2001 May 1;61(9):3573-3577.
Issa, J. P J ; Ahuja, Nita ; Toyota, M. ; Bronner, M. P. ; Brentnall, T. A. / Accelerated age-related CpG island methylation in ulcerative colitis. In: Cancer Research. 2001 ; Vol. 61, No. 9. pp. 3573-3577.
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abstract = "CpG island hypermethylation is a mechanism of gene silencing that can be usurped by neoplastic cells to inactivate undesirable genes. In the colon, hypermethylation often starts in normal mucosa as a function of age and is markedly increased in cancer. To test the hypothesis that subjects at increased risk of colon cancer have higher levels of methylation in their nonneoplastic mucosa, we studied methylation patterns of five genes in the normal and dysplastic mucosa of patients with ulcerative colitis (UC), a condition associated with a marked increased risk of colon cancer. One gene (Mlh1) was unmethylated in all tissues examined. All four remaining genes had low but detectable levels of methylation in the epithelium of UC patients without evidence of dysplasia, and this methylation was not different from non-UC controls. By contrast, all four genes were highly methylated in dysplastic epithelium from high-grade dysplasia (HGD)/cancer patients with UC; methylation in HGD versus controls averaged 40.0{\%} versus 7.4{\%} (P = 0.00003) for ER, 44.0{\%} versus 3.0{\%} (P <0.00003) for MYOD, 9.4{\%} versus 2.4{\%} (P = 0.03)for p16 exon 1, and 57.5{\%} versus 30.6{\%} (P = 0.01) for CSPG2. Importantly, three of the four genes were also highly methylated in the normal appearing (nondysplastic) epithelium from these same HGD/cancer patients, indicating that methylation precedes dysplasia and is widespread in these patients. Compared with controls, methylation averaged 20.1{\%} versus 7.2{\%} (P = 0.07) for ER, 18.4{\%} versus 3.0{\%} (P <0.008) for MYOD, and 7.9{\%} versus 2.4{\%} (P = 0.007) for p16 exon 1. These results are consistent with the hypothesis that age-related methylation marks (and may lead to) the field defect that reflects acquired predisposition to colorectal neoplasia. Furthermore, the data suggest that chronic inflammation is associated with high levels of methylation, perhaps as a result of increased cell turnover, and that UC can be viewed as resulting in premature aging of colorectal epithelial cells.",
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