Drs. Mason and Levesque thoroughly review data from intervention
trials and epidemiologic studies that suggest a role for folate
in preventing cancer of the colorectum and, to a lesser degree,
cancers of the uterine cervix, lung, esophagus, and stomach. The
authors also provide a comprehensive discussion of the possible
mechanisms by which folate may prevent cancer, in particular,
the relationship between folate status and DNA methylation.
The article begins with a historical perspective that relates
the development of megaloblastosis and possibly dysplasia resulting
from folate deficiency. Perhaps the most interesting of the early
accounts linking folate deficiency to megaloblastic anemia is
the experiment by Herbert, in which he deprived himself of dietary
folate. However, as Mason and Levesque indicate, the observations
linking megaloblastosis to dysplasia are a priori evidence. Although
there is a strong link between folate deficiency and hypomethylation
and a link between hypomethylation of specific genes and cancer,
the connection between folate-deficient diets and dysplasia is
The notion that folate deficiency functions as a cocarcinogen
is supported by the observation that an increase in cervical cancer
was evident only in folate-deficient patients who had a concurrent
human papilloma virus-16 (HPV-16) infection. If this notion is
accurate and folate deficiency is manifested as dysplasia only
when specific organisms are present or in the context of a specific
biochemical environment, there is a very definite need to conduct
studies to determine the exact nature of these corequirements
How Much Folate? Is More Better?
The authors correctly state that results from epidemiologic studies
do not establish a cause-and-effect relationship between folate
status and cancer. To take this one step further, results from
studies that depend on dietary recall or that do not standardize
food preparation do not take into account the fact that food preparation
and cooking substantially influence the amount of folate actually
The authors describe the results of two rat studies coauthored
by Dr. Mason (one of which is in press) that support the contention
that increased dietary folate intake decreases the incidence of
colorectal cancer. To our knowledge, these are the only studies
in which the relationship between colorectal cancer and folate
status has been examined in animals. In rats, a folate-deficient
diet decreases the incidence of mammary cancer, but results from
an older study suggests that folate causes regression of mammary
tumors in mice.[3,4]
As alluded to by the authors, the cancer chemopreventive effect
of folate may be specific to certain organs, but one cannot dismiss
the possibility that increasing dietary consumption of folate
may have less beneficial or perhaps even harmful effects in some
tissues or organs. It seems irrefutable that other dietary components
will interact with folate to influence the development of dysplasia
and that this interaction may also be organ-specific.
A particularly interesting point made by the authors is that lower
red blood cell (RBC) folate levels that are within the conventional
normal range are associated with a higher incidence of colorectal
and uterine cancer than are higher folate levels. As discussed
by McNulty, the currently recommended dietary allowances of folate
in both the United Kingdom and the United States have been lowered,
presumably in response to a lack of evidence that a higher intake
is necessary or beneficial. In view of the aforementioned results,
further study is required to determine whether a reevaluation
of the current dietary allowances may be needed.
With regard to gender, race, and socioeconomic status, it would
be informative to know whether folate or its metabolites have
different effects depending on the indicator. For example, American
whites consume significantly more folate than do African-Americans,
but it is not known to what extent, if any, this accounts for
the observed racial differences in the incidence of various cancers.
Alcohol, Tobacco, and Folates
The interaction among alcohol, tobacco, and folate as it influences
colorectal cancer is an area in which there are more questions
than answers. As the authors note, high alcohol consumption coupled
with a low folate diet translates into a fourfold higher incidence
of colorectal cancer. Collectively, the data supporting an association
between alcohol and colorectal cancer are unconvincing and are
most compelling with regard to beer drinking and rectal cancer.
Interestingly, beer accounts for 10% of the total folate intake
by adults in the United Kingdom. Given that a small decrease in
RBC folate levels appears to result in a higher incidence of colorectal
cancer, encouraging temperance, at least with regard to beer,
would lower folate levels, producing a net effect that would not
necessarily be beneficial!
As mentioned earlier, perhaps folate deficiency functions as a
cocarcinogen with alcohol in the colon. In one study, a methyl-deficient
(low-methionine, low-folate) diet in conjunction with high alcohol
intake has been associated with a higher risk of human colorectal
cancer. In this study, smoking was not a confounding factor,
and the most recent report focusing on tobacco and colorectal
cancer does not support a correlation between the two. Although
the data are conflicting, the consensus appears to be that if
smoking does increase the risk of colorectal cancer, it does so
only in those who smoke for more than 35 years, and the risk is
relatively greater for the rectum.
The authors state that chronic use of tobacco is associated with
decreased blood folate levels. Thus, owing to the association
between cancer incidence and folate concentration, it would stand
to reason that chronic smokers would have a higher incidence of
colorectal cancer. This has not been observed, however. A host
of confounding issues enter into this equation, most of which
are just beginning to be approached experimentally or in clinical
The authors detail various potential mechanisms by which folate
may prevent cancer. The role of folate in altering DNA methylation
status is discussed most thoroughly. DNA methylation results from
transfer of a methyl group from S-adenosylmethionine to deoxycytidine
located primarily in CpG islands. The primary dietary sources
of these methyl groups are folate, methionine, and choline.
In general, methylation is a mechanism for regulating gene activity.
DNA hypomethylation is recognized as a very early event in adenoma
formation, specifically in adenomas 0.5 cm.or less It is not
certain how methylation influences carcinogenesis, but it is thought
that a change in chromatin packing enhances the accessibility
of carcinogens to DNA. Alternatively, hypomethylation may lead
to global genomic instability and, consequently, aberrant chromosome
pairing and dysjunction during mitosis.
Interestingly, hypermethylation can also influence tumorigenesis
by downregulating expression of important genes. Both hypomethylation
and hypermethylation may be regional and may greatly influence
the activation state of important oncogenes or tumor-suppressor
genes. The methylation status of specific genes may thereby
determine the outcome of subsequent mutational events. It would
appear that DNA methylation greatly influences tumor formation,
and an important body of work indicates that diet greatly influences
methylation status. This is a highly pertinent area of study that
will continue to generate considerable interest.
There is a growing consensus that chemoprevention will be most
successful through the use of multiple micronutrients. Unfortunately,
as noted by Dr. Frank Meyskens at the most recent AACR meeting,
we currently lack good intermediate biomarkers to assess the efficacy
of dietary interventions in preventing cancer. DNA methylation
status may be a good biomarker, but considerable work remains
to be done to establish its utility in chemoprevention studies.
1. Herbert V: Experimental nutritional folate deficiency in man.
Trans Assoc Am Physicians 75:307-320, 1962.
2. McNulty H: Folate requirements for health in different population
groups. Br J Biomed Sci 52:110-119, 1995.
3. Baggott JE, Vaughn WH, Juliana MM, et al: Effects of folate
deficiency and supplementation on methylnitrosurea-induced rat
mammary tumors. J Natl Cancer Inst 84:1740-1744, 1992.
4. Lewisohn R, Leuchtenberger C, Leuchtenberger R, et al: The
influence of liver L. casei factor on spontaneous breast cancer
in mice. Science 104:436-437, 1946.
5. Giovannucci E, Rimm EB, Ascherio A, et al: Alcohol, low-methionine-low-folate
diets, and risk or colon cancer in men. J Natl Cancer Inst 87:265-273,
6. Nyren O, Bergstrom R, Nystrom L, et al: Smoking and colorectal
cancer: A 20-year follow-up study of Swedish construction workers.
J Natl Cancer Inst 88:1302-1307, 1996.
7. Jennings E: Folic acid as a cancer-preventing agent. Med Hypotheses
8. Nivatvongs S, Dorudi S: Colorectal polyps and their management,
in NS Williams (ed): Colorectal Cancer, pp 39-54. New York, Churchill
9. Baylin SB, Makos M, Wu J, et al: Abnormal patterns of DNA methylation
in human neoplasia: Potential consequences for tumor progression.
Cancer Cells 3:383-390, 1991.
10. Is chemoprevention overrated or underfunded? (commentary).
J Natl Cancer Inst 88:947-949, 1996.