Psofaki V, Kalogera C, Tzambouras N, Stephanou D, Tsianos E, Seferiadis K, Kolios G. Promoter methylation status of hMLH1, MGMT, and CDKN2A/p16 in colorectal adenomas. World J Gastroenterol 2010; 16(28): 3553-3560 [PMID: 20653064 DOI: 10.3748/wjg.v16.i28.3553]
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Georgios Kolios, PhD, Laboratory of Biochemistry, University Hospital of Ioannina, Leoforos S. Niarchou, 45500 Ioannina, Greece. firstname.lastname@example.org
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Vasiliki Psofaki, Laboratory of Clinical Chemistry, University of Ioannina Medical School, 45500 Ioannina, Greece
Chryssoula Kalogera, Konstantin Seferiadis, Georgios Kolios, Laboratory of Biochemistry, University Hospital of Ioannina, Leoforos S. Niarchou, 45500 Ioannina, Greece
Nikolaos Tzambouras, Epameinondas Tsianos, Hepatogastroenterology Unit of Internal Medicine, University Hospital of Ioannina, Leoforos S. Niarchou, 45500 Ioannina, Greece
Dimitrios Stephanou, Laboratory of Pathology, University Hospital of Ioannina, Leoforos S. Niarchou, 45500 Ioannina, Greece
Author contributions: All authors actively participated in the study and read the manuscript; Psofaki V performed the molecular analysis and contributed to the study design, data collection, data analysis, and manuscript writing; Kalogera C participated in planning, design and executing of the study, review, and finalization of the manuscript; Tzambouras N performed the colonoscopies and participated in data collection and interpretation of the histopathological analysis; Stephanou D performed the histopathological analysis and contributed to data collection and interpretation of the results; Tsianos E contributed to data interpretation and final review of the manuscript; Seferiadis K contributed to planning of the study, data interpretation, and final review of the manuscript; Kolios G was the principal investigator of the grant and was responsible for the study design, execution, data management and analysis, as well as manuscript preparation.
Supported by A 2-year grant of the Greek Ministry of Health and Welfare, No. 111K/56
Correspondence to: Georgios Kolios, PhD, Laboratory of Biochemistry, University Hospital of Ioannina, Leoforos S. Niarchou, 45500 Ioannina, Greece. email@example.com
Telephone: +30-26510-99419 Fax: +30-26510-99418
Received: December 19, 2009 Revised: February 3, 2010 Accepted: February 10, 2010 Published online: July 28, 2010
AIM: To investigate aberrant DNA methylation of CpG islands and subsequent low- or high-level DNA microsatellite instability (MSI) which is assumed to drive colon carcinogenesis.
METHODS: DNA of healthy individuals, adenoma (tubular or villous/tubulovillous) patients, and colorectal carcinoma patients who underwent colonoscopy was used for assessing the prevalence of aberrant DNA methylation of human DNA mismatch repair gene mutator L homologue 1 (hMLH1), Cyclin-dependent kinase inhibitor 2A (CDKN2A/p16), and O-6-methylguanine DNA methyltransferase (MGMT), as well as their relation to MSI.
RESULTS: The frequency of promoter methylation for each locus increased in the sequence healthy tissue/adenoma/carcinoma. MGMT showed the highest frequency in each group. MGMT and CDKN2A/p16 presented a statistically significant increase in promoter methylation between the less and more tumorigenic forms of colorectal adenomas (tubular vs tubullovillous and villous adenomas). All patients with tubulovillous/villous adenomas, as well as all colorectal cancer patients, showed promoter methylation in at least one of the examined loci. These findings suggest a potentially crucial role for methylation in the polyp/adenoma to cancer progression in colorectal carcinogenesis. MSI and methylation seem to be interdependent, as simultaneous hMLH1, CDKN2A/p16, and MGMT promoter methylation was present in 8/9 colorectal cancer patients showing the MSI phenotype.
CONCLUSION: Methylation analysis of hMLH1, CDKN2A/p16, and MGMT revealed specific methylation profiles for tubular adenomas, tubulovillous/villous adenomas, and colorectal cancers, supporting the use of these alterations in assessment of colorectal tumorigenesis.