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Methylation of estrogen receptor and mutL homolog 1 in normal colonic mucosa: association with folate and vitamin B-12 status in subjects with and without colorectal neoplasia^1,2

¹ From the Nutritional Sciences Research Division, King's College London, London, United Kingdom

Background: Greater promoter methylation in some tumor-suppressor genes underlies most sporadic colorectal cancers and increases with age in the colon.

Objective: We tested the hypothesis that biomarkers of folate and vitamin B-12 status are associated with estrogen receptor (ER) and mutL homolog 1 (MLH1) promoter methylation in subjects with and without neoplasia.

Design: Biopsies of normal-appearing colorectal mucosa from 156 subjects with and without colorectal neoplasia (disease free, n = 76; cancer, n = 28; adenoma, n = 35; hyperplastic polyps, n = 17) were obtained at colonoscopy and used to evaluate methylation in 7 CpG sites in the ER promoter and 13 CpG sites in the MLH1 promoter. Blood samples were obtained for the measurement of serum and red cell folate, serum vitamin B-12, and plasma homocysteine concentrations. Methylation indexes were generated to reflect an average methylation value across all CpG dinucleotides in both ER and MLH1.

Results: The methylation indexes for ER and MLH1 generally were significantly (P < 0.05) higher in subjects with neoplasia than in disease-free subjects. The ER methylation index correlated negatively with serum vitamin B-12 (r = –0.239, P = 0.003) and positively with plasma homocysteine (r = 0.188, P = 0.021). Disease status (P < 0.005), age (P < 0.001), and serum vitamin B-12 concentrations (P = 0.006) were independent determinants of ER promoter methylation. Serum and red cell folate concentrations had no influence on ER promoter methylation.

Conclusion: Serum vitamin B-12 but not folate status may be associated with ER promoter methylation in normal-appearing colorectal mucosa.

Key Words: Folate • vitamin B-12 • homocysteine • DNA methylation • estrogen receptor • ER • mutL homolog 1 • MLH1 • colorectal cancer • colorectal adenoma • hyperplastic polyps

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				M. S. Ally, R. Al-Ghnaniem, and M. Pufulete The Relationship between Gene-Specific DNA Methylation in Leukocytes and Normal Colorectal Mucosa in Subjects with and without Colorectal Tumors Cancer Epidemiol. Biomarkers Prev., March 1, 2009; 18(3): 922 - 928. [Abstract] [Full Text] [PDF]