Table 1.

Key preclinical and clinical studies of dietary folate intake and colorectal cancer

Preclinical Studies
Authors	Title	Year	Model System	Intervention	Primary Findings
Cravo ML, et al.	Folate deficiency enhances the development of colonic neoplasia in dimethylhydrazine-treated rats.	1992	Sprague-Dawley rats (DMH 20mg/kg s.c.)	Diet containing either 0 or 8 mg/kg folic acid (FA)	Rats given 0 mg/kg FA diet had significantly increased incidence of dysplaia and carcinoma
Kim YI, et al.	Dietary folate protects against the development of macroscopic colonic neoplasia in a dose responsive manner in rats.	1996	Sprague-Dawley rats (DMH 44mg/kg s.c.)	Diet containing 0, 2, 8 or 20 mg/kg folic acid (FA)	Inverse relationship between FA intake and tumor incidence up to 8 mg/kg, no additional benefit from 20 mg/kg
Le Leu RK, et al.	Folate deficiency reduces the development of colorectal cancer in rats.	2000	Sprague-Dawley rats (AOM 15 mg/kg s.c.)	Diet containing either 0 or 8 mg/kg folic acid (FA)	Rats given 0 mg/kg FA had significantly decreased incidence of colonic adenocarcinoma
Song J, et al.	Effects of dietary folate on intestinal tumorigenesis in the apcMin mouse.	2000	ApcMin/+ mice	Diet containing 0, 2, 8 or 20 mg/kg folic acid (FA)	After 3 mo., inverse relationship between FA intake and ileal polyp incidence. After 6 mo. 62-76% reduction in ileal polyp incidence in 0 mg/kg FA group.
Lawrance AK, et al.	Genetic and nutritional deficiencies in folate metabolism influence tumorigenicity in Apcmin/+ mice.	2007	ApcMin/+ mice haploinsufficient for either folate carrier 1 (Rfc1+/−) or methionine synthase (Mtr+/−)	Diet containing either 0.2 or 2 mg/kg folic acid (FA)	Reduction in adenoma burden in Rfc1+/− mice compared to WT. No effect on adenoma burden in Rfc1+/− mice due to 0.2 mg/kg FA compared to 2 mg/kg. In Mtr+/− mice, 0.2 mg/kg FA diet significantly increase adenoma burden compared to 2 mg/kg.
Ventrella-Lucente LF, et al.	Folate deficiency provides protection against colon carcinogenesis in DNA polymerase beta haploinsufficient mice.	2010	C57BL/6 WT and polymerase beta haploinsufficient mice (β-pol+/−) (DMH 30 mg/kg i.p.)	Diet containing 0 or 2 mg/kg folic acid (FA)	Long term 0 mg/kg FA diet increases ACF and tumor incidence in WT, but decreases ACF incidence and blocks tumorigenesis in β-pol+/− mice .
Kadaveru K, et al.	Dietary methyl donor depletion protects against intestinal tumorigenesis in Apc(Min/+) mice.	2012	ApcMin/+ mice	Methyl donor deficient (MDD) diet containing 0 mg/kg folic acid, methionine, choline and vitamin B12	80-96% reduction in intestinal polyp incidence in MDD diet-fed group.

Clinical Studies
Authors	Title	Year	Study Population	Intervention	Primary Findings
Cole BF and Baron JA, et al.	Folic acid for the prevention of colorectal adenomas: a randomized clinical trial.	2007	1021 men and women with recent history of adenoma enrolled in AFPPS	1 mg/d folic acid or placebo	1 mg/d folic acid does not reduce incidence of colorectal adenoma, and may increase the risk of future neoplaia
Logan, et al.	Aspirin and folic acid for the prevention of recurrent colorectal adenomas.	2008	945 men and women with adenoma removed in the 6 mo. prior to enrollment in ukCAP	Either one or both of 300 mg/d aspirin or 0.5 mg/d folic acid	0.5 mg/d folic acid does not reduce recurrence of colorectal adenoma
Wu K, et al.	A randomized trial on folic acid supplementation and risk of recurrent colorectal adenoma.	2009	672 men and women withrecent history of adenoma enrolled in NHS/HPFS	1 mg/d folic acid or placebo	1 mg/d folic acid reduces incidence of recurrent adenoma in individuals with low baseline serum folate. No effect on incidence in individuals with high baseline serum folate, no overall protective effect.