Low
folate status is a risk factor for colon
carcinogenesis; mechanisms proposed to account for this relationship include
uracil misincorporation into
DNA and global
DNA hypomethylation. We investigated whether such
biomarkers are related to
folate status in isolated colonocytes from colonoscopy patients. In cases with
adenomatous polyps (n = 40) or hyperplastic
polyps (n = 16), colonocytes were isolated from biopsies from the
polyp, from a site adjacent to the
polyp, and from normal mucosa 10-15 cm distal to the
polyp. In
polyp-free controls (n = 53), biopsies were taken from ascending, transverse, and descending areas of colon. Within
adenoma cases, there was a trend (P-trend < 0.001) of decreasing colonocyte
folate (pg/10⁵ cells, mean ± CI) from the site distal to the
polyp (16.9 ± 2.4), to the site adjacent to the
polyp (14.7 ± 2.3), to the
polyp (12.8 ± 2.0). Correspondingly, there were increases in
uracil misincorporation (P-trend < 0.001) and global
DNA hypomethylation (P-trend = 0.012) across the 3 sites. Colonocyte
folate concentrations were significantly correlated with RBC
folate concentrations, but only in individuals with generally lower (≤484 μg/L) RBC
folate status (r = 0.54; P = 0.006; n = 24), and were also significantly lower in normal mucosa of cases with
adenomatous polyps than in controls matched for colonic segment. In conclusion, localized
folate deficiency in specific areas of colon might create carcinogenic fields and affect the development of colorectal
polyps through
uracil misincorporation and
DNA hypomethylation; alternatively, the
polyp itself might deplete
folate in the surrounding tissue.
Folate supplementation trials aimed at
colon cancer prevention should target individuals with suboptimal
folate status.