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Departments of a Epidemiology and b Nutrition, Harvard School of Public Health, c The Harvard Center for Cancer Prevention, and d Channing Laboratory, Department of Medicine, Brigham and Woman's Hospital, Harvard Medical School, Boston, MA 02115
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHYL-REPLETE DIETS AND...METHYLENETETRAHYDROFOLATE...MTHFR-NUTRIENT INTERACTIONS AND...SIGNIFICANCE OF STUDYING GENE...ADVANTAGES AND LIMITATIONSREFERENCES |
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T, ala
val) in the methylenetetrahydrofolate reductase (MTHFR) gene
with colorectal cancer but not with colorectal adenomas. The inverse
association of methionine and adverse association of alcohol with
colorectal cancer were stronger among val/val individuals.
These interactions were not present in studies of colorectal adenomas.
Our studies illustrate that studying gene-environment interactions in
relation to cancer can be of importance in clarifying cancer etiology
as well as pointing to preventive dietary modifications.
KEY WORDS: • MTHFR polymorphism • colorectal cancer • colorectal adenomas • methyl diet
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHYL-REPLETE DIETS AND...METHYLENETETRAHYDROFOLATE...MTHFR-NUTRIENT INTERACTIONS AND...SIGNIFICANCE OF STUDYING GENE...ADVANTAGES AND LIMITATIONSREFERENCES |
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); up to 90% of these malignancies can be
attributed to environmental factors, including diet (Doll and Peto 1981
). Genes that interact with environmental or dietary exposures may
play a large role in colorectal carcinogenesis. The attributable risk
for functional polymorphisms in a common nutrient- or
carcinogen-metabolizing gene with a relatively modest relative risk
(e.g., relative risk of 2.0) may be higher than that of rare mutations
in a major proto-oncogene or tumor-suppressor gene with much higher
relative risk. In addition, studying gene-environment interactions in
relation to risk of cancer may be valuable because positive findings
would clearly implicate the substrates with which the gene interacts as
disease-causing exposures, clarify cancer etiology and point to
preventive dietary and other environmental modifications. In this paper, we present our studies on interactions of a folate-metabolizing gene polymorphism and dietary intake in colorectal tumorigenesis to illustrate the potential importance of studying interactions between genotype and environmental exposure in relation to cancer risk.
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METHYL-REPLETE DIETS AND COLORECTAL CARCINOGENESIS |
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TOPABSTRACTINTRODUCTIONMETHYL-REPLETE DIETS AND...METHYLENETETRAHYDROFOLATE...MTHFR-NUTRIENT INTERACTIONS AND...SIGNIFICANCE OF STUDYING GENE...ADVANTAGES AND LIMITATIONSREFERENCES |
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). In a prospective study of 47,931 male health
professionals in the U.S. (Giovannucci et al. 1995
), folate and
methionine intakes were each weakly inversely associated with risk of
colon cancer. Current intake of more than two alcoholic drinks daily
doubled risk of colon cancer; past drinkers also had twice the risk.
Combinations of high alcohol and low methionine and folate intake
yielded more than a threefold increase in risk of colon cancer. A
methyl-replete diet was also inversely related to risk of colon
adenomas in the same population of male health professionals as well as
in another prospective study of 88,756 women (Giovannucci et al. 1993
);
those in the highest quintile of folate intake had a 35% reduction in
risk of adenomas compared with those in the lowest quintile of intake.
Those drinking >30 g of alcohol per day (~2 drinks) had a
significant 80% elevation in risk compared with those who did not
consume alcohol. Combinations of alcohol, folate and methionine were
formed to examine the joint influence on risk of adenomas. High intake
of alcohol and low intake of folate and methionine constituted a strong
risk factor for adenomas, especially adenomas <1 cm, resulting in
close to a threefold increase in risk compared with individuals with
high intake of folate and methionine and low or no alcohol intake.
Consistent with these findings, other epidemiologic studies have
reported that individuals with high folate intake have a reduced risk
of colorectal carcinoma and adenoma (Benito et al. 1991 and 1993
,
Ferraroni et al. 1994
, Freudenheim et al. 1991
). The majority of
studies also indicate an association between alcohol intake and higher
risk of colorectal adenoma (Landler et al. 1993
) as well as large bowel
cancer (Kune and Vitetta 1992
), especially cancers in the distal
colorectum (Klatsky et al. 1988
). Moreover, indirect evidence
implicates the benefit of a methyl-replete diet; fruits and vegetables,
major sources of folate, as well as chicken and fish, major sources of
methionine, are associated with decreased risk of colorectal cancer and
adenomas (Giovannucci et al. 1992
, Willett et al. 1992
).
In light of this evidence indicating a protective effect of methyl-replete diet against colon cancer, it is reasonable to hypothesize that functional polymorphisms in genes associated with methyl metabolism, such as the methylenetetrahydrofolate reductase (MTHFR)5gene, may confer differential susceptibility to colorectal cancer.
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METHYLENETETRAHYDROFOLATE REDUCTASE POLYMORPHISM |
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TOPABSTRACTINTRODUCTIONMETHYL-REPLETE DIETS AND...METHYLENETETRAHYDROFOLATE...MTHFR-NUTRIENT INTERACTIONS AND...SIGNIFICANCE OF STUDYING GENE...ADVANTAGES AND LIMITATIONSREFERENCES |
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). Severe
hyperhomocysteinemia due to MTHFR deficiency causes neurological
abnormalities, mental retardation, arteriosclerosis and thrombosis
(Rosenblatt 1989
). Mild hyperhomocysteinemia is considered to be an
independent risk factor for arterial diseases such as myocardial
infarction (Stampfer et al. 1992
).
A common 677CT (ala val) polymorphism, presumably at
the folate-binding region of the gene, was found to decrease the
activity and enhance the thermolability of the enzyme (Frosst et al. 1995
). The variant homozygous genotype is associated with a significant
elevation in plasma homocysteine levels as well as a significant
decrease in plasma folate levels (Ma et al.1996
, van der Put et al.1995
). The polymorphism appears to be a risk factor for neural-tube
defects (van der Put et al. 1995
) and endometrial cancer (Esteller et al. 1997
).
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MTHFR-NUTRIENT INTERACTIONS AND RISK OF COLORECTAL CARCINOMA AND ADENOMAS |
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TOPABSTRACTINTRODUCTIONMETHYL-REPLETE DIETS AND...METHYLENETETRAHYDROFOLATE...MTHFR-NUTRIENT INTERACTIONS AND...SIGNIFICANCE OF STUDYING GENE...ADVANTAGES AND LIMITATIONSREFERENCES |
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val)
polymorphism and risk of colorectal carcinoma and adenoma; additional
prospective data are available from the Physicians' Health Study
(PHS). The HPFS in men and NHS in women are population-based cohort
studies on the association of nutritional and environmental factors and
risk of cancer and other chronic diseases; PHS is a randomized trial of
aspirin in the reduction of cardiovascular mortality and ß-carotene
in the reduction of cancer incidence in men. The association of the
MTHFR polymorphism with colorectal cancer in HPFS (Chen et al. 1996
)
and PHS (Ma et al. 1997
) as well as colorectal adenomas in NHS (Chen et al. 1998
) was investigated.
An inverse association of the val/val genotype with risk of
colorectal cancer was observed in both the HPFS and the PHS
(Table 1
).The inverse association of methionine and adverse association of
alcohol with colorectal cancer was stronger among val/val
individuals in HPFS (Fig. 1
).The benefit of the MTHFR polymorphism was diminished by high alcohol
and low methionine consumption. The relation of folate consumption to
colon cancer followed a similar trend to that of methionine; however,
the association was not as strong and was not significant. In the PHS,
in which plasma folate level was measured, the inverse association of
val/val genotype and colorectal cancer was more profound
among people with adequate plasma folate status; folate deficiency
abolished the protective effect of the MTHFR polymorphism. The stronger
adverse association of alcohol and colorectal cancer among
val/val individuals was also observed in this population (Ma et al. 1997
). When we examined the relation of the MTHFR polymorphism
and risk of colorectal adenomas, we did not observe any significant
association between val/val genotype and risk of adenomas
(Table 1)
, nor did we observe any significant difference with respect
to folate and methionine intake among individuals with a
val/val genotype compared with those with ala/ala
or val/ala genotypes (Fig. 1)
. The lack of a plausible
biological explanation suggests that the U-shaped association across
three alcohol consumption levels is likely to be a chance finding.
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SIGNIFICANCE OF STUDYING GENE-ENVIRONMENT INTERACTIONS |
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TOPABSTRACTINTRODUCTIONMETHYL-REPLETE DIETS AND...METHYLENETETRAHYDROFOLATE...MTHFR-NUTRIENT INTERACTIONS AND...SIGNIFICANCE OF STUDYING GENE...ADVANTAGES AND LIMITATIONSREFERENCES |
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), suggesting that individuals with
this variant genotype are especially sensitive to the carcinogenic
effect of alcohol. Similarly, if the effect of a dietary exposure is
limited to a genetically predisposed subset, evaluation of the exposure
without genetic information may lead to it being dismissed as a cause
of disease because the overall effect may be diluted when susceptible
and nonsusceptible individuals are combined.
In addition, studying gene-environment interactions may be useful
in clarifying pathogenic pathways in cancer etiology. The mechanism by
which the methyl-replete diet exerts an anticarcinogenic effect is not
well understood. It has been hypothesized that low methyl diets reduce
levels of SAM, which is required for DNA methylation; DNA
hypomethylation has been linked with the formation of colon adenomas
and cancer (Goelz et al. 1985
). The cancer-enhancing effect of alcohol
may be due to an adverse impact on methyl-group metabolism (Barak et al. 1987
). On the other hand, folate/methyl deficiency may also
interrupt DNA repair, leading to enhanced mutagenesis and apoptosis in
hamster cells (James et al. 1994
) as well as DNA strand breaks and
hypomethylation of p53 in rats (Kim et al. 1997
). In a recent study by
Blount et al. (1997)
, folate deficiency in humans resulted in deficient
methylation of dUMP to dTMP, causing misincorporation of uracil into
DNA and subsequent chromosomal breaks.
Our findings that val/val individuals experienced a lower risk of colorectal cancer and were more sensitive to dietary methyl intake may shed light on the mechanism of colon cancer pathogenesis, suggesting that both DNA methylation and synthesis are critical processes that depend on the methyl supply in the diet. When dietary methyl supply is high, MTHFR val/val individuals are at reduced risk of colorectal cancer probably because higher levels of 5,10-methylenetetrahydrofolate may prevent imbalances of nucleotide pools during DNA synthesis. In contrast, when the methyl content in dietary intake is low or depleted by alcohol consumption, val/val individuals may be less able to compensate, leading to potentially oncogenic alterations in DNA methylation; the protective association of the MTHFR polymorphism is thus eliminated.
We did not observe any material association between the MTHFR polymorphism and risk of colorectal adenomas, nor did we observe an interaction between this polymorphism and the consumption of folate, methionine and alcohol. Because of the relatively low val/val genotype frequency and limited sample size, it is possible that a very modest association could exist but was not detected because of the limited power of the study.
However, the absence of these associations, if confirmed in other
studies, seems to suggest that MTHFR may play a role only in a late
stage (adenoma carcinoma) of colorectal tumorigenesis. Even though
the observation of a protective association between a methyl-replete
diet and risk of colorectal adenomas supports the notion that
methylation is an early event in the colorectal tumorigenesis, our data
suggest that the MTHFR polymorphism may protect against potential
defects in DNA synthesis, which might be more crucial toward a later
stage. The protective effect of this polymorphism in DNA synthesis may
be abolished once the optimal methylation is challenged. We speculate
that as adenomas progress to carcinoma, colorectal epithelial cells
divide faster and are more likely to be prone to nucleotide pool
imbalances. In particular, dUMP may replace dTMP, the limiting
nucleotide for DNA synthesis, and its misincorporation into DNA may
result in strand break–induced genomic instability (Blount et al. 1997
). This mechanism may be less crucial in the early stage of
tumorigenesis when cells divide less often. Another possibility is that
the MTHFR val/val polymorphism is protective only in a
subset of colorectal adenomas that have potential to progress to
malignant tumors. It has been shown that the cumulative incidence of
colorectal cancer among patients with an adenoma 
10 mm was only 10%
over 15 y of follow-up (Morson 1984
), indicating that only a
fraction of adenomas undergo metastatic progression to cancer. If the
benefit of the MTHFR val/val genotype were limited to a
small subset of premalignant adenomas, then an overall association with
adenomas would be difficult to detect.
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ADVANTAGES AND LIMITATIONS |
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TOPABSTRACTINTRODUCTIONMETHYL-REPLETE DIETS AND...METHYLENETETRAHYDROFOLATE...MTHFR-NUTRIENT INTERACTIONS AND...SIGNIFICANCE OF STUDYING GENE...ADVANTAGES AND LIMITATIONSREFERENCES |
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). Second, in such a
study setting, biological specimens are obtained from subjects already
part of a prospective study; recall bias in the exposure assessment is
thus eliminated because all exposure information is obtained before
disease. This type of study design minimizes the major problems of
conventional case-control studies and provides unbiased estimates of
interaction between genetic markers and environmental exposure in
relation to disease outcomes. The major limitation of this study, like most other prospective studies on gene-environment interactions, is the relatively poor power to test for interactions when the number of incident cases is low, or the genotype frequency or the prevalence of exposure is also low. This is an inherent limitation of many prospective studies in genetic epidemiology because of the expense of obtaining the blood or other samples needed. However, for relating common outcomes, adequate power can be reached to detect interactions of substantial public health significance in a way that should be free of both selection and recall bias.
In summary, studies of gene-environment interaction merit attention because of their potential importance in clarifying cancer etiology as well as pointing to preventable cancer risk factors.
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FOOTNOTES |
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1 Presented at the symposium "Interactions of Diet
and Nutrition with Genetic Susceptibility in Cancer" as part of
Experimental Biology 98, April 18–22, 1998, San Francisco, CA. The
symposium was sponsored by the American Society for Nutritional
Sciences. Published as a supplement to The Journal of
Nutrition. Guest editors for the symposium publication were Jo L.
Freudenheim, State University of New York, Buffalo, NY and Rashmi
Sinha, National Cancer Institute, Bethesda, MD.
2 Some of these data have been published as follows:
Chen, J., Giovannucci, E., Kelsey, K., Rimm, E. B., Stampfer,
M. J., Colditz, G. A., Spiegelman, D., Willett, W. C. &
Hunter, D. J. (1996) A methylenetetrahydrofolate
reductase polymorphism and the risk of colorectal cancer. Cancer Res.
56: 4862–4864; Chen, J., Giovannucci, E., Hankinson, S. E., Ma,
J., Willett, W. C., Spiegelman, D., Kelsey, K. T. & Hunter,
D. J. (1998) A prospective study of
methylenetetrahydrofolate reductase and methionine synthase gene
polymorphism and risk of colorectal adenoma. Carcinogenesis (in press);
Ma, J., Stampfer, M. J., Giovannucci, E., Artigas, C., Hunter,
D. J., Fuchs, C., Willett, W. C., Selhub, J., Hennekens
C. H. & Rozen, R. (1997) Methylenetetrahydrofolate
reductase polymorphism, dietary interactions, and risk of colorectal
cancer. Cancer Res. 57: 1098–1102.
3 Supported by National Institutes of Health grants
CA55075, CA40365, CA42182 and CA70817. J.C. is supported by a training
grant ES07069 from the National Institute for Environmental Health
Sciences. D.J.H. is partially supported by an American Cancer Society
Faculty Research Award (FRA-455).
4 Abbreviations used: HPFS, Health Professional's
Follow-up Study; MTHFR, methylenetetrahydrofolate reductase; NHS,
Nurses' Health Study; OR, odds ratio; PHS, Physicians' Health Study;
SAM, S-adenosylmethionine.
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0.05.