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Point/Counterpoint
Folate and Cancer Prevention—Where to Next?
Counterpoint
Cornelia M. Ulrich
Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, Washington
It is an interesting task to write a ‘‘counterpoint’’ to
Dr. Kim’s article on folate and cancer prevention (1). We
both agree that there are positive and negative aspects to
the B-vitamin folate in cancer prevention and the terms
‘‘Janus-head’’ and ‘‘double-edged sword’’ have been
used. In the broader sense, the folate story reminds us
that as cancer epidemiologists we need to be mindful of
cancer biology and the potentially different roles of an
exposure during the carcinogenic process. In addition,
we may need to consider nonlinear relationships and the
potential for an optimum exposure beyond which one
may not do additional good, but possibly harm. In the
following, I will focus on some key aspects of folate in
carcinogenesis and cancer epidemiology. Because of the
high intakes of synthetic folate (=folic acid) in much of
the population (as part of nutritional supplements,
functional foods, and food fortification), we need to
devise a research agenda that will fill fundamental gaps
in our knowledge. The following will briefly summarize
what is known today about folate and cancer prevention
and suggest some next steps to arrive at responsible
public health recommendations.
Biological Mechanisms—Does Folate Status
Mediate Carcinogenesis via Epigenetic Effects?
Folate biochemistry is generally very well understood: all
major enzymes are described and both cytosolic and
mitochondrial folate metabolism is well defined (2, 3).
The connection of folate to carcinogenesis is probably
attributed to a large degree to its role in nucleotide
synthesis; experimental studies unequivocally link folate
deficiency to decreased synthesis of both thymidylate
and purines, with subsequent DNA damage and
inadequate repair (4). Recent studies suggest that
enzymes of folate-mediated one-carbon metabolism that
are critical for nucleotide synthesis exist not only in the
cytosol but also directly in the nucleus (5). This is an
active area of research.
However, folate is also critical for the provision of
methyl groups, including for DNA methylation, which is
Cancer Epidemiol Biomarkers Prev 2008;17(9):2226 – 30
Received 12/31/07; accepted 4/8/08.
Grant support: NIH grants CA 105437 (C.M. Ulrich), CA 59045 (J.D. Potter), and CA
105145 (C.M. Ulrich).
Requests for reprints: Cornelia M. Ulrich, Cancer Prevention Program, Fred
Hutchinson Cancer Research Center, Seattle, WA 98109. Phone: 206-667-7617;
Fax: 206-667-7850. E-mail: [email protected]
Copyright D 2008 American Association for Cancer Research.
doi:10.1158/1055-9965.EPI-07-2952
an important epigenetic mode of gene silencing. The
connection between DNA methylation and cancer risk is
complicated: DNA methylation can occur at known gene
promoters as well as in repetitive genomic sequences;
currently, the processes that initiate and regulate DNA
methylation at these different sites are poorly understood, although BRAF mutations may play a role (6).
During carcinogenesis, both global hypomethylation at
repetitive sequences and promoter-specific hypermethylation with associated gene silencing are observed. The
capacity of folate status to affect global genomic
methylation is fairly well supported by both human
and experimental data (7-11). However, data are sparse
and conflicting on whether folate status affects promoter
methylation of specific genes or the CpG island methylator phenotype, which characterizes tumors with widespread hypermethylation of gene promoters (12-18).
Thus, more epidemiologic and experimental studies
evaluating the effects of folate deficiency and folate
excess on epigenetic biomarkers are looked for, ideally
involving epigenetic assays in target tissues (e.g., the
gastrointestinal tract). It is important to note that
lymphocytes, which have been used as easily accessible
source of DNA, have a short life span and do not
necessarily reflect methylation patterns of the tissue of
interest (e.g., the colon or breast).
Where Are Gaps in the Cancer Epidemiology of
Folate and One-Carbon Nutrients?
The role of folate in nucleotide synthesis suggests that an
adequate intake is most critical for tissues with regularly
replicating cells or tissues that are undergoing periods of
growth. Indeed, antifolate drugs (discussed in more
detail below) can have severe toxicities affecting the
gastrointestinal tract (which is constantly self-renewing)
as well as the hematopoietic system, both of which are
sites of active cellular replication. The epidemiologic
evidence on folate and cancer is consistent with this
biological mechanism of an adequate supply of folate
being vital for nucleotide synthesis and reduction of
mutations in replicating tissues. The body of epidemiologic literature can perhaps be summarized as reflecting
consistent inverse associations between higher folate
intakes and colorectal cancer (19), a possible role of low
folate increasing the risk of breast cancer, most likely in
conjunction with high alcohol intakes (20), and some
evidence for inverse associations with other gastrointestinal cancers, cervical cancer and pancreatic cancer.
There are several key questions that still need to be
addressed with regard to the epidemiology of folate and
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cancer. First, are the dose-response relationships linear,
or do we observe a flattening out with higher intakes
and, perhaps, even increases in risk with excessive
intakes (20)? Second, what are the associations between
dietary and supplemental folate intakes and hematopoietic cancers? These have been strongly associated with
genetic polymorphisms (21-23), yet studies on diet have
been sparse. Third, to what extent do epidemiologic
associations differ, depending on the source of folate (i.e.,
the natural form from foods, versus the synthetic form,
folic acid, from supplements or fortified foods)? Folic
acid has greater bioavailability and thus epidemiologic
studies of diet should use the composite ‘‘dietary folate
equivalents’’ to account for both dietary folate and
synthetic folic acid from fortified foods or supplements
(24) to obtain a more accurate exposure measure. In
addition, other nutrients that are important in onecarbon metabolism, particularly, vitamin B6 or methionine, may be linked to cancer risk (25, 26) and this area
deserves further investigation.
What Is the Importance of Genetic Variability in
Folate Metabolism?
There are common genetic polymorphisms that affect
both folate homeostasis and the risks of several types of
cancer (27-30). The ‘‘poster child polymorphism’’ in this
regard is the MTHFR C677T variant, which shows a
fairly consistent, and biochemically supported, pattern
of gene-diet interaction in relation to cancer risk. In
addition, the thymidylate synthase promoter variant that
clearly reduces thymidylate synthase gene expression
has also been associated with cancer risk. These polymorphisms may also affect mutation patterns and
tumor characteristics (31, 32). The fact that these polymorphisms are associated with cancer risk, particularly
of the gastrointestinal and hematopoietic systems,
strongly implicates folate status as causally related to
disease. However, most studies to date have focused
only on selected candidate polymorphisms. Because of
the well-supported significance of folate and folaterelated polymorphisms to health outcomes, we should
undertake a comprehensive assessment of genetic
variability (with sufficient power and appropriate biomarkers) in relation to multiple cancer types. Subsequently, we will face the challenge of devising
appropriate statistical analysis tools for pathway-based
analyses; folate metabolism is a promising starting point
for such analyses: the biochemical relationships are well
defined and several nonlinear interactions have been
described. Our group’s efforts have focused on integrating mathematical modeling of the biochemistry of folate
metabolism in the statistical data analysis (33, 34);
however, many other important approaches to pathway-based analyses are getting developed and are
critical to support molecular epidemiologic studies of
candidate pathways.
Is Folate A Cancer Chemopreventive Agent?
The results of the Aspirin/Folate Polyp Prevention Trial
have added yet another complexity to the picture of folate
and cancer (35). This first randomized, controlled trial of
folic acid for chemoprevention of colorectal polyps
included about 1,000 participants with a history of
colorectal adenomas who were randomly assigned to
1 mg/d folic acid F aspirin. Follow-up colonoscopies
took place f3 years after the initial endoscopy and
supplementation continued until a second surveillance
exam. Folic acid clearly did not prevent the recurrence of
colorectal adenomas at 3 years (rate ratio, 1.04) and at the
second follow-up (rate ratio, 1.13; 0.93-1.37). In fact, at the
second follow-up, the intervention group experienced a
67% increased risk of advanced lesions (rate ratio, 1.67;
1.00-2.80), along with a more than 2-fold increased risk of
having at least three adenomas (rate ratio, 2.32; 1.23-4.35).
How should one interpret the unexpected results of this
study? The most likely explanation for the increased risk
of advanced and multiple adenomas in the intervention
group is that early precursor lesions were present in the
mucosa of these patients and not detected during
endoscopy and that folic acid promoted growth of these
lesions (36). This is consistent with the notion that
patients with adenoma are at increased risk of a second
adenoma. Thus, the trial was designed to investigate the
secondary prevention on colorectal adenoma, rather than
the primary prevention. Based on the epidemiologic
picture overall, higher folate status seems protective
against colon cancer (19), although apparently not in
individuals with precursor lesions. So what should be our
next steps after this trial? Do we need to give up on folate
as a cancer-preventive agent entirely? Should we attribute
the discrepancy between the epidemiologic and trial data
simply to faulty epidemiologic data, perhaps pointing to
confounding by other substances in fruits and vegetables,
or health behaviors associated with fruits and vegetables?
The strong experimental evidence and the associations
with genetic polymorphisms in genes of this pathway
argue against this interpretation. Rather, the trial results
should be interpreted in light of our knowledge today,
about the different effects of folate during the process of
carcinogenesis (Fig. 1). The trial results also point toward
several critical avenues of research.
We know that many cancers respond to chemotherapy
with agents that target folate metabolism, such as
5-fluorouracil and methotrexate (37). These drugs result
in reduced nucleotide synthesis with subsequent DNA
damage and apoptosis (37). Further, tumors are known
to up-regulate folate receptors and enzymes in nucleotide synthesis (38-44), consistent with a greater need for
folate to support DNA synthesis and tumor growth. The
experimental evidence from studies in rats and mice [as
reviewed by Kim (1, 45)] implicates folate as supporting
the growth of early neoplastic lesions. Thus, the
interpretation that folate supplementation in the Aspirin/Folate Polyp Prevention Trial increased the growth
of undetected precursor lesions in individuals at high
risk of recurring adenomas is well supported. The trial
raises yet several important questions: First, what are the
net effects of folate supplementation on colon cancer
rates in the population? Is there a ‘‘biological switch’’
after which supplementation may be harmful? Data by
Mason et al. (46) suggest a potential increase with the
initiation of folate fortification in both the United States
and Canada. In addition to this ecologic study, our group
has used an established model of colon cancer development (47) to mimic the dual role of folate in carcinogenesis (48). Findings from this modeling suggest that the
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Figure 1. Possible dual roles of folate in the prevention and promotion of carcinogenesis, as suggested by prior investigations (59, 60).
Although higher folate status prevents an accumulation of mutations and genomic instability, it may also foster the growth of early
preneoplastic lesions.
effects of folate on colon carcinogenesis are indeed age
and dose dependent, with predominantly harm if the
amount of folate given were to increase cellular
replication rates by 20%. However, this modeling also
illustrated the shortcomings in the current literature on
quantitative estimates of the response of tissues or cancer
precursors to folate or folic acid supplementation. To
better estimate risks to the population, it will be essential
that such data are obtained experimentally.
Can Folate Promote the Growth of Cancer
Precursors in Humans?
An interrelated question is what the effects of folate
supplementation may be on existing colorectal polyps? In
the Aspirin/Folate Polyp Prevention Trial, the study
design with repeated colonoscopies ensured that no
colons contained polyps. Yet, in the general U.S. population, only about a third of adults over age 50 have had an
endoscopic examination in the previous 5 years (49). It
has been estimated that f30% of individuals over age 60
carry a prevalent colorectal polyp (50). Use of folic acid –
containing supplements is particularly common in this
age group (51). Studying the effects of folic acid
supplementation on unresected colorectal polyps is
unethical in humans; thus, we need to rely on animal
experiments, perhaps incorporating new technologies,
such as mouse endoscopy (52). Incorporating results
from such studies may then be used to inform mathematical modeling of the opposing effects of folic acid on
cancer in humans.
Is There a Safe Dose of Folic Acid?
Most recently, results from the ukCAP trial, which
parallels the Aspirin/Folate Polyp Prevention Trial, have
become available (53). Here, 853 European individuals
with a prior history of adenoma were randomized to
500 Ag folic acid or aspirin (in a similar 2 2 factorial
design). Follow-up colonoscopies were targeted at
3 years, yet sometimes completed earlier. The trial
showed relative risks of 1.07 (0.85-1.34) for the occurrence of any adenoma in the folic acid intervention arm
and 0.98 (0.68-1.40) for advanced adenoma and, again, no
evidence for cardiovascular protection. Does this suggest
that a dose of 500 Ag does not have tumor-promoting
effects? This conclusion would be premature because the
relative risks from the ukCAP trial are consistent with
those of the Aspirin/Folate Polyp Prevention Trial at its
first 3-year follow-up (e.g., 1.07 versus 1.04 for any
adenoma), and in the Aspirin/Folate Polyp Prevention
Trial, the elevated risks did not emerge until the second
follow-up after 6 to 8 years, which is largely consistent
with the time frame for development of a larger
colorectal polyp. The ukCAP trial took place in countries
that have not (yet) introduced folic acid fortification,
which reduced participants’ background folic acid
intakes by about 150 to 200 Ag/d. Finally, polyp
multiplicity was not assessed, which was increased most
prominently in the Aspirin/Folate Polyp Prevention
Trial. Hopefully, the intervention period of the ukCAP
trial can be extended or participants followed further to
provide insight into the long-term effects of the 500 Ag
folic acid intervention in a nonfortified population.
What Are the Effects of Folate Supplements on
Cancer Prognosis?
Another research priority ought to be studying the effects
of folate supplementation among cancer patients. Cancer
patients generally consume more supplements than
healthy individuals, frequently without knowledge of
the treating physicians (54). A significant proportion of
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cancer patients will exceed the recommended upper
intake level of synthetic folic acid of 1,000 mg/d (55).
Such intakes can be easily achieved by use of multivitamins (f400 Ag folic acid), health drinks or bars (up to
400 Ag folic acid), breakfast cereals (up to 400 Ag folic acid
per serving), and folic acid fortification (in average
100-200 Ag/d). Considering the potential of folate to
support or enhance the growth of tumors, we urgently
should initiate studies of the effects of folate supplement
use on cancer progression and recurrence. Studying the
role of folate status in cancer prognosis is particularly
relevant, given that methotrexate and 5-fluorouracil are
commonly used chemotherapeutic drugs that target
enzymes in folate metabolism. Initial research suggests
that their efficacy and toxicity can be related to genetic
polymorphisms in folate metabolism (56, 57). However,
the role of folate supplementation during chemotherapy
and radiation therapy has been insufficiently explored
(58). Considering the multiple components of folate
status in cancer patients, including folate-related characteristics of the tumor, the patient, chemotherapy, and
supplement use, an integrated and interdisciplinary
approach to prognostic studies of folate and cancer will
be most successful.
Finally, the Aspirin/Folate Polyp Prevention Trial has
reported an increased risk of cancers other than
colorectal cancer in the intervention group, largely
attributable to prostate cancer cases (35). Although the
number of cases was small, the potential public health
effect of an increase in the progression of prostate cancers
with folic acid is significant and requires rigorous followup studies.
Summary and Recommendations
In summary, the recently completed Aspirin/Folate
Polyp Prevention Trial has added an important chapter
to the story of folate and cancer: the results raise concerns
about the use of folic acid in older individuals who may
harbor cancer precursors, as well as cancer patients. The
exposure of the public to synthetic folic acid is high,
particularly among consumers of supplements and
fortified health foods. Thus, it is critical that we continue
research on the effects of folate on carcinogenesis in the
context of our knowledge of cancer biology. A dual role
of folate in carcinogenesis is the most likely explanation
for the somewhat contradictory research findings from
epidemiology and the cancer prevention trial. Yet, we
still need better quantitative experimental data on the
growth-promoting effects of folate in carcinogenesis of
the colon and other tissues to clarify the potential of
adverse effects of folate at varied doses. A research
agenda on folate and cancer should aim to fill gaps in
understanding the biological mechanisms (especially
effects of folate status on epigenetics) and cancer etiology
(dose response, genetic variability, and noncolon cancers). Yet, particularly important from a public health
perspective are studies on the effects of high or excessive
folate intakes in patients with cancer precursors or
cancer, and the effects of these high intakes on their
prognosis.
In the absence of these important data to inform our
decision making, what should be the current public
health recommendations? First, as a safeguard, clinicians
should inquire about the use of supplements among
cancer patients and caution them against high intakes of
folic acid from supplements, particularly when their
nutritional intake in general is adequate or good. Second,
countries that are currently considering mandatory
fortification with folic acid (such as Australia and several
European countries) may be best advised to defer
decisions until more is known about the potential
cancer-promoting effects of added folic acid.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Acknowledgments
I thank Dr. John D. Potter and my other colleagues working on
folate and carcinogenesis for their valuable insights.
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Cancer Epidemiol Biomarkers Prev 2008;17(9). September 2008
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Folate and Cancer Prevention−−Where to Next?
Counterpoint
Cornelia M. Ulrich
Cancer Epidemiol Biomarkers Prev 2008;17:2226-2230.
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