Gastroenterology

Gastroenterology

Volume 124, Issue 5, May 2003, Pages 1240-1248
Gastroenterology

Rapid communications
Folate status, genomic DNA hypomethylation, and risk of colorectal adenoma and cancer: a case control study

https://doi.org/10.1016/S0016-5085(03)00279-8Get rights and content

Abstract

Background & Aims:

Low folate intake may increase risk for colorectal cancer by inducing DNA hypomethylation. This study reports the influence of folate status, DNA methylation, and polymorphisms of methylenetetrahydrofolate reductase (MTHFR 677C→T and 1298A→C), methionine synthase (MS 2756A→G), and cystathionine-β-synthase (CBS 844ins68) on risk for developing colorectal neoplasia.

Methods:

Thirty-five patients with adenoma, 28 patients with cancer, and 76 controls were recruited for a case control study. Recruitment consent rate was 98%. Blood samples were obtained for determination of blood folates, vitamin B12, homocysteine, DNA methylation, and genotypes. Tissue biopsy samples were obtained at colonoscopy for determination of DNA methylation in colonic mucosa. Folate status was assessed by constructing a score from estimates of dietary intake and serum and erythrocyte folate.

Results:

Cancer patients had 26% lower folate status (95% confidence interval [CI]: 6% to 44%, P = 0.01) and 21% lower serum vitamin B12 concentration (95% CI: −38% to 1%, P = 0.06) compared with controls. [3H] methyl incorporation into colonic DNA was 26% higher in patients with adenoma (95% CI: 8% to 56%, P = 0.009) and 30% higher in patients with cancer (95% CI: −3% to 48%, P = 0.08) compared with controls. High folate status was associated with decreased risk for cancer (P = 0.01 for trend). Colonic and leukocyte DNA hypomethylation were associated with increased risk for adenoma (P = 0.02 and P = 0.01 for trend, respectively) and a nonsignificantly increased risk for cancer (P = 0.09 and P = 0.08 for trend, respectively).

Conclusions:

Low folate status and DNA hypomethylation are associated with colorectal neoplasia.

Section snippets

Patients

Subjects were recruited from all patients referred for colonoscopy by the Department of Colorectal Surgery at King’s College Hospital between August 2000 and May 2001. Patients were recruited on the day of their colonoscopy, before the procedure. All patients underwent a clinically indicated colonoscopy for symptoms including rectal bleeding, change in bowel habit, and weight loss. Exclusion criteria included previous history of colorectal cancer, a strong family history of colorectal cancer

Results

Of the 201 patients approached, 196 patients agreed to participate in the study (98%). Of these, a total of 139 patients aged between 38 and 90 years were found to be suitable for inclusion: 28 patients with cancer, 35 patients with adenoma, and 76 controls. Their characteristics and clinical indications for colonoscopy are shown in Table 1. The most frequent indications for colonoscopy were change in bowel habit and rectal bleeding. Subjects with adenoma and cancer were older on average than

Discussion

The aim of this study was to investigate the hypothesis that genomic DNA methylation and folate status differ between subjects with colorectal adenoma and cancer and those with no colorectal abnormality. A folate status score was calculated for each subject based on 3 markers of folate status (folate intake, serum, and erythrocyte folate). We decided to use a combined score to avoid potential misclassification owing to limitations in both specificity and sensitivity associated with the methods

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