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

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 alpha (ER alpha) 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 alpha 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 alpha and MLH1. Results: The methylation indexes for ER alpha and MLH1 generally were significantly (P < 0.05) higher in subjects with neoplasia than in disease-free subjects. The ER alpha 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 alpha promoter methylation. Serum and red cell folate concentrations had no influence on ER alpha promoter methylation. Conclusion: Serum vitamin B-12 but not folate status may be associated with ER alpha promoter methylation in normal-appearing colorectal mucosa.