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Vitamin and Carcinogenesis Program, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONFolate in Nucleic Acid...Candidate Mechanisms for Folate...Methylenetetrahydrofolate...REFERENCES |
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KEY WORDS: • folate • carcinogenesis • DNA methylation • DNA integrity • MTHFR gene
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONFolate in Nucleic Acid...Candidate Mechanisms for Folate...Methylenetetrahydrofolate...REFERENCES |
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Epidemiologic studies have observed that diminished folate status is
associated with cancer of the cervix, colorectum, lung, esophagus,
brain, pancreas, and breast. Among these, epidemiologic support for
such a relationship is clearly most compelling for colorectal cancer
(1)
. Folate deficiency also has been considered as an
important factor in alcohol-related enhancement of rectal
carcinogenesis because alcohol alters normal folate metabolism in a
variety of ways.
Although some animal studies support the epidemiologic concept
that dietary folate is protective against selected cancers (2
, 3)
, the studies are not entirely consistent (4
5
6)
.
The reasons for these conflicting results are due to several factors:
these include the species, the tumor type and model, the timing, dose,
and length of application of carcinogen, the stage of carcinogenesis,
and the dietary level, and form of folate administered as well as its
chronologic relationship to carcinogen administration.
Human intervention trials, designed to determine whether individuals at
increased risk of cancer have that risk reduced by supraphysiologic
doses of folate, have been performed almost exclusively in regard to
cancer of the uterine cervix and colorectum. The studies in the cervix
have been inconsistent (7
, 8)
and, although the eight
randomized, intervention trials conducted on colorectal neoplasia have
been very promising (reviewed in 1), the small size of the populations
studied and the nature of the endpoints has precluded any definite
statements regarding efficacy of supplementation.
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Folate in Nucleic Acid Metabolism. |
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TOPABSTRACTINTRODUCTIONFolate in Nucleic Acid...Candidate Mechanisms for Folate...Methylenetetrahydrofolate...REFERENCES |
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Methionine is regenerated from homocysteine in a reaction catalyzed by
5-methyltetrahydrofolate(methylTHF):homocysteine methyltransferase:
this is a reaction for which 5-methylTHF serves as both a cofactor and
substrate (Fig. 1
). An alternative mechanism for the regeneration of methionine which
does not require folate also exists-the methylation of homocysteine
by betaine-although the latter reaction seems to only be operative
in the liver and kidney. Methionine, in turn, is converted to SAdoMet
in a reaction catalyzed by methionine adenosyl transferase. SAdoMet
then donates the labile methyl group it derived from 5-methylTHF for
over 80 biological methylation reactions, including an array of
reactions whereby specific sites within DNA and RNA become methylated.
Although the alternative betaine pathway may partially compensate,
dietary folate depletion alone is a sufficient perturbing force to
diminish SAdoMet pools (9)
.
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When the dietary methyl supply is inadequate, such as in folate
depletion, the use of folate coenzymes for biological methylation and
nucleotide synthesis appear to compete. As SAdoMet concentrations
decrease, compensatory mechanisms increase the conversion of
5,10-methyleneTHF to 5-methylTHF, an irreversible reaction, and thereby
compromise folate availability for de novo nucleotide synthesis
(9)
.
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Candidate Mechanisms for Folate Associated Carcinogenesis. Altered DNA methylation. |
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TOPABSTRACTINTRODUCTIONFolate in Nucleic Acid...Candidate Mechanisms for Folate...Methylenetetrahydrofolate...REFERENCES |
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. This decrease in genomic
methylation appears early in carcinogenesis, and appears to precede the
more well described mutation and deletion events that occur
later in the evolution of cancer. Genomic hypomethylation
has also been observed in some animal models of carcinogenesis
(10)
. Gene-specific hypomethylation may occur even in
the absence of genomic hypomethylation and is probably a more important
event in carcinogenesis since the prevailing theories of carcinogenesis
emphasize damage which occurs at critical loci within DNA.
Site-specific aberrancies in DNA methylation within critical genes
are also observed in neoplastic tissues, and include both foci of
hypomethylation and hypermethylation (11)
.
Somewhat surprisingly, the patterns of DNA methylation that are
so religiously guarded by the cell seem to be susceptible in certain
settings to perturbations created merely by altering dietary folate in
both animals and man. The induction of genomic hypomethylation in human
lymphocytic DNA has been demonstrated in healthy human volunteers who
were placed on a long-term folate deficient diet (12)
and this effect was reversible when the deficiency was corrected.
Supportive evidence is available from a recent observational study
(13)
where serum folate levels as well as folate
concentrations in the uterine cervix were significantly correlated with
genomic DNA methylation in a study of cervical intraepithelial
neoplasia. Studies performed in rodents fed diets deficient in folate
generally do not show any changes in genomic DNA methylation, although
it does appear to be feasible with a severe deficiency state or one
deficient in multiple lipotropes such as choline, methionine, vitamin
B-12, and folate (10)
. The resistance to the induction of
genomic methylation in rats may be due to the fact that they have a
more active betaine pathway than humans.
The induction of site-specific hypomethylation may be more critical
to the process of carcinogenesis than genomic effects. In this regard,
folate depletion has been shown to induce hypomethylation of the coding
region of the p53 tumor suppressor gene even in the absence of genomic
hypomethylation (14)
. Conversely, supplemental folate has
been shown to revert the hypomethylation of this region which occurs in
association with chemical carcinogenesis (15)
. Of
particular interest is the fact that this region within the p53 gene
that is particularly susceptible to hypomethylation by folate depletion
or chemical carcinogens (exons 5–8) is precisely that region that is
most frequently mutated in human cancer.
Recent studies reveal why changes in site-specific methylation may
be related to subsequent mutations at that site. 5mC is more unstable
than its unmethylated counterpart. Hydrolytic deamination of 5mC leads
to a G/T mismatch and subsequently, if unrepaired, to a C
T
transition mutation (16)
. This probably explains why sites
of DNA methylation are mutational hotspots in many human tumors.
Paradoxically, unmethylated cytosine can also undergo deamination to
yield uracil, particularly under conditions where intracellular SAdoMet
is low (such as in folate deficiency) (17)
. We have found
(14
, 15)
that dietary folate depletion in rodents produces
diminished methylation in the so-called ‘hypermutable region’ of
the p53 gene (exons 5–8); a region where 24% of reported mutations
occur at CT transitions at CpG dinucleotides. This suggests that the
phenomenon of DNA methylation may contribute to these mutations.
Transcriptional repression by hypermethylation of promoter
sequences has been widely discussed as an alternative means for the
inactivation of tumor-suppressor genes in cancer:
methylation-induced alterations in the local conformation of the
gene can render it inaccessible and transcriptionally inactive and is
the presumptive mechanism involved. Hypermethylation of the promoters
of p16, calcitonin, and estrogen receptor genes have all been observed
in neoplastic tissue (18)
. Early reports suggested this
was due to increased DNA-methyltransferase activity in cancers,
although recent reports suggest that methyltransferase activity is not
truly elevated in neoplastic tissue when the data are corrected for the
proliferation rate of the tissue (19)
. Paradoxically a
lipotrope-deficient diet can induce hypermethylation at selected
sites in the genome. Progressive exon-specific hypomethylation
of the hepatic p53 gene was seen in animals fed a diet deficient in
folate, B12, methionine and choline followed by a rebound
hypermethylation at a later time when neoplastic foci became
histologically evident in the liver (20)
. Direct evidence
that isolated folate deficiency can similarly produce
hypermethylation of critical tumor suppressor gene promoter
regions is lacking.
Altered RNA methylation.
Like DNA, a wide variety of RNA species are methylated at specific
sites by SAdoMet-mediated reactions. In some instances, the
5'-methyl cap of RNA is methylated and in other instances, internal
nucleotide residues are methylated. Although the precise functions of
RNA methylation sites are only now becoming apparent, it appears that
these patterns of methylation in RNA are also judiciously guarded by
the cell and serve important purposes in maintaining stability of the
RNA species and facilitating transport across the nuclear membrane
(21)
. De-methylation of tRNA was shown some years ago
with a severe, methyl deficient diet (22)
. Only recently,
however, has it been shown that folate depletion alone (at least in
cell culture) is sufficient to demethylate some RNA species such as
small nuclear RNA (snRNA) (23)
, a species which is a
critical component of the machinery necessary for maturation of
messenger RNA.
Disruption of DNA integrity.
Folate deficiency induces breaks in chromosomes and such breaks are
associated with an increased risk of cancer in humans. More recently,
folate-deficient conditions in both cell culture and animal
experiments have been shown to create an excess of breaks in the
phosphodiester backbone of DNA, which is presumed to be the molecular
basis for chromosomal breaks (24)
. There are several
mechanisms by which folate deficiency might create such breaks: these
include the incorporation of uracil from the cellular nucleotide pool
into DNA and by in situ deamination of cytosine. Folate deficiency
reduces thymidylate synthesis from deoxyuridylate and the ensuing
nucleotide imbalance increases the misincorporation of uracil bases
into DNA as most DNA polymerases do not effectively distinguish between
deoxyuridylate and thymidylate. Uracil in DNA is excised by a repair
glycosylase, and in the process a transient single-strand break
develops in the DNA. Simultaneous removal and repair of two adjacent
uracil residues on opposite strands can result in a double-strand
DNA break, further exacerbating genetic instability. Unrepaired
double-strand DNA breaks enhance cellular transformation in culture
and increase cancer risk. Excessive DNA uracil content, as well as
increased numbers of chromosomal breaks, are observed in folate
deficient humans, and both defects are reversed by folate
administration (25)
. Folate supplementation above the RDA
was also observed to lessen chromosome breakage below levels observed
in normal, folate-replete individuals (26)
.
In cell culture, folate deficient media enhanced DNA strand breaks
induced by an alkylating agent and 
-irradiation (24)
and in a recent rodent study, a folate deficient diet increased gene
specific DNA strand breaks in the hypermutable region of p53
(14)
. Site-specific hypomethylation was also noted at
this site, thereby supporting the speculation that deamination of
nonmethylated C turns to uracil and removal of uracil induces strand
breaks.
In those instances where cancers are enhanced by particular viruses,
the phenomena of hypomethylation and strand breaks may have an
additional significance. For instance, human papilloma virus 18 is
widely accepted as a risk factor for human cervical neoplasia. It is
incorporated into the human genome at four loci, three of which are in
or near a constitutive ‘fragile site’ that is created by folate
depletion. More recently, integrated Human Polyomavirus JCV DNA
sequences have been identified in human colon cancer DNA, raising the
question as to whether the virus plays an etiologic role
(27)
. Methylation of specific sites is known to block the
integration of certain viruses into the genome and strand breaks are
thought to perhaps enhance integration. Whether the hypomethylation or
strand break sites produced by folate deficiency might enhance the
incorporation of tumorigenic viruses remains a provocative concept.
Disruption of DNA repair.
DNA is constantly damaged by a host of endogenous and exogenous
factors, and therefore sophisticated repair mechanisms are available in
all cells to eliminate such damage. As mentioned above folate
deficiency induces dNTP pool imbalance and uracil misincorporation into
DNA. Such misincorporation results in abnormal DNA replication and
imposes greater dependence on the repair system. Cells grown in
folate-deficient media show various types of chromosomal
aberrations but cells grown in hypoxanthine-supplemented
folate-deficient medium exhibit a significantly lower frequency of
damaged mitotic figures (28)
. Hypoxanthine is a purine
precursor which bypasses the need for folate-dependent purine
biosynthesis. In another cultured cell study, folate deficiency acted
synergistically with alkylating agents to increase somatic mutations
and, with -irradiation, to promote DNA strand breaks, by limiting
DNA repair (24)
. In folate deficient rodents we found that
the DNA excision repair was impaired in folate deficient colonic
mucosal cells compared to normal mucosal cells (29)
.
Supplementation of the colonocytes with hypoxanthine as a purine
precursor and thymidine as a pyrimidine precursor, which together
preclude the need for folate dependent nucleotide synthesis, partially
reversed the impaired excision repair. This suggests that folate
deficiency disrupts excision repair in part by altering the cellular
pool of deoxyribonucleotides. Similarly, diminished DNA repair
capability of human lymphocytes was seen in a folate deficient medium
(30)
. Since the p53 gene product is an important regulator
of DNA repair and the cell cycle, folate deficiency-induced
impairment of DNA repair might feasibly be mediated by its effects on
the p53 gene; this is consistent with animal studies mentioned above in
which folate depletion led to strand breaks within the p53 gene
(14)
. Folate deficiency has also been observed to impair
the other major cellular DNA repair system, mismatch repair, in
ulcerative colitis patients (31)
. It was suggested that
increased microsatellite instability in these patients might translate
into an increased risk for mutations.
Aberrations in normal patterns of DNA methylation, which can be induced
by folate depletion as mentioned above, might adversely impact on the
efficacy of DNA repair systems because DNA methylation plays an
important role in strand discrimination during postreplication mismatch
repair. Therefore, site-selective DNA hypomethylation induced by
folate deficiency might affect the methyl-directed mismatch repair.
Also, methylation of CpG sites in the hMLH1 gene, one of the major
mismatch repair genes, has been associated with microsatellite
instability in colon cancer and stomach cancer (32)
.
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Methylenetetrahydrofolate Reductase Gene and Risk of Colon Cancer. |
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TOPABSTRACTINTRODUCTIONFolate in Nucleic Acid...Candidate Mechanisms for Folate...Methylenetetrahydrofolate...REFERENCES |
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. Among men with adequate folate levels, a
three-fold decrease in risk was observed, but protection associated
with the mutation was largely absent in men with low systemic folate
status. It was suggested that the cancer protective effect of the MTHFR
mutation was related to increased availability of 5,10 methyleneTHF,
and therefore increased ease of nucleotide synthesis. One might
speculate that, under low but not high folate conditions, availability
of 5-methylTHF for biological methylation constitutes a more critical
determinant of whether the cell is pushed down the pathway towards
neoplasia.
Recently Bagley and Selhub (34)
found that human subjects
possessing the homozygous polymorphism have formylated forms of
tetrahydrofolate in their red cells; this compares with wild type
individuals, whose cells contain only methylTHF. In a preliminary
study, we have also found that lymphocytic DNA from subjects with the
MTHFR polymorphism is significantly less methylated than DNA from wild
type subjects (35)
. These observations suggest that the
protective effect of the polymorphism may be conveyed by an alteration
in the forms of folate contained within the cell, and it explains how
the protective effect might be operable even when total folate levels
are normal.
Figure 2
summarizes the molecular effects of folate depletion that are described
in this article and provides a framework of how these phenomena are
interrelated. Although it is an oversimplification, increased DNA
damage without a compensatory increase in DNA repair and alterations in
gene expression are generally agreed upon to be major pathways towards
cancer. The premise of this unified scheme, therefore, is that all
mechanisms described in this paper conspire to enhance carcinogenesis
by either increasing net DNA damage and/or altering the expression of
critical genes. At this point in time, the schema presented in Figure 2
has not been conclusively proven to constitute the means by which
folate depletion enhances cancer; nevertheless, considerable work is
presently underway that should give us a more definitive answer in the
near future.
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FOOTNOTES |
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2 This project has been supported in part by a National Institutes of Health Grant (RO1 CA59005–05S1, JBM), and the Cancer Research Foundation of America (SWC).
4 Author for correspondence and reprint requests.
Manuscript received October 28, 1999.
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TOPABSTRACTINTRODUCTIONFolate in Nucleic Acid...Candidate Mechanisms for Folate...Methylenetetrahydrofolate...REFERENCES |
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A. Y. Jung, E. M. Poole, J. Bigler, J. Whitton, J. D. Potter, and C. M. Ulrich DNA Methyltransferase and Alcohol Dehydrogenase: Gene-Nutrient Interactions in Relation to Risk of Colorectal Polyps Cancer Epidemiol. Biomarkers Prev., February 1, 2008; 17(2): 330 - 338. [Abstract] [Full Text] [PDF]
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M. V Gamble, X. Liu, V. Slavkovich, J R. Pilsner, V. Ilievski, P. Factor-Litvak, D. Levy, S. Alam, M. Islam, F. Parvez, et al. Folic acid supplementation lowers blood arsenic Am. J. Clinical Nutrition, October 1, 2007; 86(4): 1202 - 1209. [Abstract] [Full Text] [PDF]
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M. van den Donk, L. Pellis, J. W. Crott, M. van Engeland, P. Friederich, F. M. Nagengast, J. D. van Bergeijk, S. Y. de Boer, J. B. Mason, F. J. Kok, et al. Folic Acid and Vitamin B-12 Supplementation Does Not Favorably Influence Uracil Incorporation and Promoter Methylation in Rectal Mucosa DNA of Subjects with Previous Colorectal Adenomas J. Nutr., September 1, 2007; 137(9): 2114 - 2120. [Abstract] [Full Text] [PDF]
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U. Ericson, E. Sonestedt, B. Gullberg, H. Olsson, and E. Wirfalt High folate intake is associated with lower breast cancer incidence in postmenopausal women in the Malmo Diet and Cancer cohort Am. J. Clinical Nutrition, August 1, 2007; 86(2): 434 - 443. [Abstract] [Full Text] [PDF]
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X. Xu, M. D. Gammon, H. Zhang, J. G. Wetmur, M. Rao, S. L. Teitelbaum, J. A. Britton, A. I. Neugut, R. M. Santella, and J. Chen Polymorphisms of one-carbon-metabolizing genes and risk of breast cancer in a population-based study Carcinogenesis, July 1, 2007; 28(7): 1504 - 1509. [Abstract] [Full Text] [PDF]
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M. K. Keyes, H. Jang, J. B. Mason, Z. Liu, J. W. Crott, D. E. Smith, S. Friso, and S.-W. Choi Older Age and Dietary Folate Are Determinants of Genomic and p16-Specific DNA Methylation in Mouse Colon J. Nutr., July 1, 2007; 137(7): 1713 - 1717. [Abstract] [Full Text] [PDF]
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M. van den Donk, M. van Engeland, L. Pellis, B. J.M. Witteman, F. J. Kok, J. Keijer, and E. Kampman Dietary Folate Intake in Combination with MTHFR C677T Genotype and Promoter Methylation of Tumor Suppressor and DNA Repair Genes in Sporadic Colorectal Adenomas Cancer Epidemiol. Biomarkers Prev., February 1, 2007; 16(2): 327 - 333. [Abstract] [Full Text] [PDF]
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C. J. Jin, H. K. Park, Y. M. Cho, Y. K. Pak, K.-U. Lee, M. S. Kim, S. Friso, S.-W. Choi, K. S. Park, and H. K. Lee S-Adenosyl-L-Methionine Increases Skeletal Muscle Mitochondrial DNA Density and Whole Body Insulin Sensitivity in OLETF Rats J. Nutr., February 1, 2007; 137(2): 339 - 344. [Abstract] [Full Text] [PDF]
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F. F. Zhang, M. B. Terry, L. Hou, J. Chen, J. Lissowska, M. Yeager, W. Zatonski, S. Chanock, A. Morabia, and W.-H. Chow Genetic Polymorphisms in Folate Metabolism and the Risk of Stomach Cancer Cancer Epidemiol. Biomarkers Prev., January 1, 2007; 16(1): 115 - 121. [Abstract] [Full Text] [PDF]
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R. Poo-Prieto, D. B. Haytowitz, J. M. Holden, G. Rogers, S. F. Choumenkovitch, P. F. Jacques, and J. Selhub Use of the Affinity/HPLC Method for Quantitative Estimation of Folic Acid in Enriched Cereal-Grain Products J. Nutr., December 1, 2006; 136(12): 3079 - 3083. [Abstract] [Full Text] [PDF]
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R. A. Hubner, K. R. Muir, J.-F. Liu, G. S. Sellick, R. F.A. Logan, M. Grainge, N. Armitage, I. Chau, R. S. Houlston, and The United Kingdom Colorectal Adenoma Prevention C Folate metabolism polymorphisms influence risk of colorectal adenoma recurrence. Cancer Epidemiol. Biomarkers Prev., September 1, 2006; 15(9): 1607 - 1613. [Abstract] [Full Text] [PDF]
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D. J McKillop, H. McNulty, J. M Scott, J. M McPartlin, J. Strain, I. Bradbury, J. Girvan, L. Hoey, R. McCreedy, J. Alexander, et al. The rate of intestinal absorption of natural food folates is not related to the extent of folate conjugation Am. J. Clinical Nutrition, July 1, 2006; 84(1): 167 - 173. [Abstract] [Full Text] [PDF]
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S. C. Larsson, E. Giovannucci, and A. Wolk Folate intake and stomach cancer incidence in a prospective cohort of Swedish women. Cancer Epidemiol. Biomarkers Prev., July 1, 2006; 15(7): 1409 - 1412. [Abstract] [Full Text] [PDF]
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L. E Kelemen, J. R Cerhan, U. Lim, S. Davis, W. Cozen, M. Schenk, J. Colt, P. Hartge, and M. H Ward Vegetables, fruit, and antioxidant-related nutrients and risk of non-Hodgkin lymphoma: a National Cancer Institute-Surveillance, Epidemiology, and End Results population-based case-control study Am. J. Clinical Nutrition, June 1, 2006; 83(6): 1401 - 1410. [Abstract] [Full Text] [PDF]
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U. Lim, S. Weinstein, D. Albanes, P. Pietinen, L. Teerenhovi, P. R. Taylor, J. Virtamo, and R. Stolzenberg-Solomon Dietary factors of one-carbon metabolism in relation to non-hodgkin lymphoma and multiple myeloma in a cohort of male smokers. Cancer Epidemiol. Biomarkers Prev., June 1, 2006; 15(6): 1109 - 1114. [Abstract] [Full Text] [PDF]
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H. E Gabriel, J. W Crott, H. Ghandour, G. E Dallal, S.-W. Choi, M. K Keyes, H. Jang, Z. Liu, M. Nadeau, A. Johnston, et al. Chronic cigarette smoking is associated with diminished folate status, altered folate form distribution, and increased genetic damage in the buccal mucosa of healthy adults. Am. J. Clinical Nutrition, April 1, 2006; 83(4): 835 - 841. [Abstract] [Full Text] [PDF]
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S. C. Larsson, N. Hakansson, E. Giovannucci, and A. Wolk Folate intake and pancreatic cancer incidence: a prospective study of Swedish women and men. J Natl Cancer Inst, March 15, 2006; 98(6): 407 - 413. [Abstract] [Full Text] [PDF]
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K. Matsuo, H. Ito, K. Wakai, K. Hirose, T. Saito, T. Suzuki, T. Kato, T. Hirai, Y. Kanemitsu, H. Hamajima, et al. One-carbon metabolism related gene polymorphisms interact with alcohol drinking to influence the risk of colorectal cancer in Japan Carcinogenesis, December 1, 2005; 26(12): 2164 - 2171. [Abstract] [Full Text] [PDF]
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U. Lim, M. Schenk, L. E. Kelemen, S. Davis, W. Cozen, P. Hartge, M. H. Ward, and R. Stolzenberg-Solomon Dietary Determinants of One-Carbon Metabolism and the Risk of Non-Hodgkin's Lymphoma: NCI-SEER Case-Control Study, 1998-2000 Am. J. Epidemiol., November 15, 2005; 162(10): 953 - 964. [Abstract] [Full Text] [PDF]
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C. M. Ulrich, K. Curtin, J. D. Potter, J. Bigler, B. Caan, and M. L. Slattery Polymorphisms in the Reduced Folate Carrier, Thymidylate Synthase, or Methionine Synthase and Risk of Colon Cancer Cancer Epidemiol. Biomarkers Prev., November 1, 2005; 14(11): 2509 - 2516. [Abstract] [Full Text] [PDF]
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A. Chanson, T. Sayd, E. Rock, C. Chambon, V. Sante-Lhoutellier, G. Potier de Courcy, and P. Brachet Proteomic Analysis Reveals Changes in the Liver Protein Pattern of Rats Exposed to Dietary Folate Deficiency J. Nutr., November 1, 2005; 135(11): 2524 - 2529. [Abstract] [Full Text] [PDF]
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C. M. Ulrich Nutrigenetics in Cancer Research--Folate Metabolism and Colorectal Cancer J. Nutr., November 1, 2005; 135(11): 2698 - 2702. [Abstract] [Full Text] [PDF]
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C. M. Ulrich, K. Curtin, W. Samowitz, J. Bigler, J. D. Potter, B. Caan, and M. L. Slattery MTHFR Variants Reduce the Risk of G:C->A:T Transition Mutations within the p53 Tumor Suppressor Gene in Colon Tumors J. Nutr., October 1, 2005; 135(10): 2462 - 2467. [Abstract] [Full Text] [PDF]
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C. M Pfeiffer, S. P Caudill, E. W Gunter, J. Osterloh, and E. J Sampson Biochemical indicators of B vitamin status in the US population after folic acid fortification: results from the National Health and Nutrition Examination Survey 1999-2000 Am. J. Clinical Nutrition, August 1, 2005; 82(2): 442 - 450. [Abstract] [Full Text] [PDF]
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A. M. Eaton, R. Sandler, J. M. Carethers, R. C. Millikan, J. Galanko, and T. O. Keku 5,10-Methylenetetrahydrofolate Reductase 677 and 1298 Polymorphisms, Folate Intake, and Microsatellite Instability in Colon Cancer Cancer Epidemiol. Biomarkers Prev., August 1, 2005; 14(8): 2023 - 2029. [Abstract] [Full Text] [PDF]
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W. Tan, X. Miao, L. Wang, C. Yu, P. Xiong, G. Liang, T. Sun, Y. Zhou, X. Zhang, H. Li, et al. Significant increase in risk of gastroesophageal cancer is associated with interaction between promoter polymorphisms in thymidylate synthase and serum folate status Carcinogenesis, August 1, 2005; 26(8): 1430 - 1435. [Abstract] [Full Text] [PDF]
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C.-X. Yang, K. Matsuo, H. Ito, M. Shinoda, S. Hatooka, K. Hirose, K. Wakai, T. Saito, T. Suzuki, T. Maeda, et al. Gene-environment interactions between alcohol drinking and the MTHFR C677T polymorphism impact on esophageal cancer risk: results of a case-control study in Japan Carcinogenesis, July 1, 2005; 26(7): 1285 - 1290. [Abstract] [Full Text] [PDF]
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M. van den Donk, B. Buijsse, S. W. van den Berg, M. C. Ocke, J. L. Harryvan, F. M. Nagengast, F. J. Kok, and E. Kampman Dietary Intake of Folate and Riboflavin, MTHFR C677T Genotype, and Colorectal Adenoma Risk: A Dutch Case-Control Study Cancer Epidemiol. Biomarkers Prev., June 1, 2005; 14(6): 1562 - 1566. [Abstract] [Full Text] [PDF]
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S. Friso, D. Girelli, E. Trabetti, O. Olivieri, P. Guarini, P. F. Pignatti, R. Corrocher, and S.-W. Choi The MTHFR 1298A>C Polymorphism and Genomic DNA Methylation in Human Lymphocytes Cancer Epidemiol. Biomarkers Prev., April 1, 2005; 14(4): 938 - 943. [Abstract] [Full Text] [PDF]
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J. Chen, M. D. Gammon, W. Chan, C. Palomeque, J. G. Wetmur, G. C. Kabat, S. L. Teitelbaum, J. A. Britton, M. B. Terry, A. I. Neugut, et al. One-Carbon Metabolism, MTHFR Polymorphisms, and Risk of Breast Cancer Cancer Res., February 15, 2005; 65(4): 1606 - 1614. [Abstract] [Full Text] [PDF]
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C. L. Girard, H. Lapierre, J. J. Matte, and G. E. Lobley Effects of Dietary Supplements of Folic Acid and Rumen-Protected Methionine on Lactational Performance and Folate Metabolism of Dairy Cows J Dairy Sci, February 1, 2005; 88(2): 660 - 670. [Abstract] [Full Text] [PDF]
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M. P Hannon-Fletcher, N. C Armstrong, J. M Scott, K. Pentieva, I. Bradbury, M. Ward, J. Strain, A. A Dunn, A. M Molloy, M. A Kerr, et al. Determining bioavailability of food folates in a controlled intervention study Am. J. Clinical Nutrition, October 1, 2004; 80(4): 911 - 918. [Abstract] [Full Text] [PDF]
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G. Zaza, W. Yang, L. Kager, M. Cheok, J. Downing, C.-H. Pui, C. Cheng, M. V. Relling, and W. E. Evans Acute lymphoblastic leukemia with TEL-AML1 fusion has lower expression of genes involved in purine metabolism and lower de novo purine synthesis Blood, September 1, 2004; 104(5): 1435 - 1441. [Abstract] [Full Text] [PDF]
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D. C. Cabelof, J. J. Raffoul, J. Nakamura, D. Kapoor, H. Abdalla, and A. R. Heydari Imbalanced Base Excision Repair in Response to Folate Deficiency Is Accelerated by Polymerase {beta} Haploinsufficiency J. Biol. Chem., August 27, 2004; 279(35): 36504 - 36513. [Abstract] [Full Text] [PDF]
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R. Saffroy, P. Pham, F. Chiappini, M. Gross-Goupil, L. Castera, D. Azoulay, A. Barrier, D. Samuel, B. Debuire, and A. Lemoine The MTHFR 677C > T polymorphism is associated with an increased risk of hepatocellular carcinoma in patients with alcoholic cirrhosis Carcinogenesis, August 1, 2004; 25(8): 1443 - 1448. [Abstract] [Full Text] [PDF]
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C. A. Perry, S. A. Renna, E. Khitun, M. Ortiz, D. J. Moriarty, and M. A. Caudill Ethnicity and Race Influence the Folate Status Response to Controlled Folate Intakes in Young Women J. Nutr., July 1, 2004; 134(7): 1786 - 1792. [Abstract] [Full Text]
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M. E. Martinez, S. M Henning, and D. S Alberts Folate and colorectal neoplasia: relation between plasma and dietary markers of folate and adenoma recurrence Am. J. Clinical Nutrition, April 1, 2004; 79(4): 691 - 697. [Abstract] [Full Text] [PDF]
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S. C. Larsson, E. Giovannucci, and A. Wolk Dietary Folate Intake and Incidence of Ovarian Cancer: The Swedish Mammography Cohort J Natl Cancer Inst, March 3, 2004; 96(5): 396 - 402. [Abstract] [Full Text] [PDF]
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K. Pentieva, H. McNulty, R. Reichert, M. Ward, J. J. Strain, D. J. McKillop, J. M. McPartlin, E. Connolly, A. Molloy, K. Kramer, et al. The Short-Term Bioavailabilities of [6S]-5-Methyltetrahydrofolate and Folic Acid Are Equivalent in Men J. Nutr., March 1, 2004; 134(3): 580 - 585. [Abstract] [Full Text] [PDF]
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K. Curtin, J. Bigler, M. L. Slattery, B. Caan, J. D. Potter, and C. M. Ulrich MTHFR C677T and A1298C Polymorphisms: Diet, Estrogen, and Risk of Colon Cancer Cancer Epidemiol. Biomarkers Prev., February 1, 2004; 13(2): 285 - 292. [Abstract] [Full Text] [PDF]
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C. M. Pfeiffer, Z. Fazili, L. McCoy, M. Zhang, and E. W. Gunter Determination of Folate Vitamers in Human Serum by Stable-Isotope-Dilution Tandem Mass Spectrometry and Comparison with Radioassay and Microbiologic Assay Clin. Chem., February 1, 2004; 50(2): 423 - 432. [Abstract] [Full Text] [PDF]
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E. L. Goode, J. D. Potter, J. Bigler, and C. M. Ulrich Methionine Synthase D919G Polymorphism, Folate Metabolism, and Colorectal Adenoma Risk Cancer Epidemiol. Biomarkers Prev., January 1, 2004; 13(1): 157 - 162. [Abstract] [Full Text] [PDF]
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J. Carrier, A. Medline, K.-J. Sohn, M. Choi, R. Martin, S. W. Hwang, and Y.-I. Kim Effects of Dietary Folate on Ulcerative Colitis-Associated Colorectal Carcinogenesis in the Interleukin 2- and {beta}2-Microglobulin-deficient Mice Cancer Epidemiol. Biomarkers Prev., November 1, 2003; 12(11): 1262 - 1267. [Abstract] [Full Text]
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A. Yokoyama, T. Yokoyama, T. Muramatsu, T. Omori, S. Matsushita, S. Higuchi, K. Maruyama, and H. Ishii Macrocytosis, a new predictor for esophageal squamous cell carcinoma in Japanese alcoholic men Carcinogenesis, November 1, 2003; 24(11): 1773 - 1778. [Abstract] [Full Text] [PDF]
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L. B. Bailey Folate, Methyl-Related Nutrients, Alcohol, and the MTHFR 677C->T Polymorphism Affect Cancer Risk: Intake Recommendations J. Nutr., November 1, 2003; 133(11): 3748S - 3753. [Abstract] [Full Text] [PDF]
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H. Shen, Q. Wei, P. C. Pillow, C. I. Amos, W. K. Hong, and M. R. Spitz Dietary Folate Intake and Lung Cancer Risk in Former Smokers: A Case-Control Analysis Cancer Epidemiol. Biomarkers Prev., October 1, 2003; 12(10): 980 - 986. [Abstract] [Full Text] [PDF]
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M. van Rijnsoever, H. Elsaleh, D. Joseph, K. McCaul, and B. Iacopetta CpG Island Methylator Phenotype Is an Independent Predictor of Survival Benefit from 5-Fluorouracil in Stage III Colorectal Cancer Clin. Cancer Res., August 1, 2003; 9(8): 2898 - 2903. [Abstract] [Full Text] [PDF]
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A. Zijno, C. Andreoli, P. Leopardi, F. Marcon, S. Rossi, S. Caiola, A. Verdina, R. Galati, A. Cafolla, and R. Crebelli Folate status, metabolic genotype, and biomarkers of genotoxicity in healthy subjects Carcinogenesis, June 1, 2003; 24(6): 1097 - 1103. [Abstract] [Full Text] [PDF]
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L. B. Bailey, G. C. Rampersaud, and G. P. A. Kauwell Folic Acid Supplements and Fortification Affect the Risk for Neural Tube Defects, Vascular Disease and Cancer: Evolving Science, J. Nutr., June 1, 2003; 133(6): 1961S - 1968. [Abstract] [Full Text] [PDF]
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 J. Lokk News and Views on Folate and Elderly Persons J. Gerontol. A Biol. Sci. Med. Sci., April 1, 2003; 58(4): M354 - 361. [Abstract] [Full Text] [PDF]
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K. Robien and C. M. Ulrich 5,10-Methylenetetrahydrofolate Reductase Polymorphisms and Leukemia Risk: A HuGE Minireview Am. J. Epidemiol., April 1, 2003; 157(7): 571 - 582. [Abstract] [Full Text] [PDF]
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S.-W. Choi, S. Friso, G. G. Dolnikowski, P. J. Bagley, A. N. Edmondson, D. E. Smith, and J. B. Mason Biochemical and Molecular Aberrations in the Rat Colon Due to Folate Depletion Are Age-Specific J. Nutr., April 1, 2003; 133(4): 1206 - 1212. [Abstract] [Full Text] [PDF]
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J. B. Mason Biomarkers of Nutrient Exposure and Status in One-Carbon (Methyl) Metabolism J. Nutr., March 1, 2003; 133(3): 941S - 947. [Abstract] [Full Text] [PDF]
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H. S. Feigelson, C. R. Jonas, A. S. Robertson, M. L. McCullough, M. J. Thun, and E. E. Calle Alcohol, Folate, Methionine, and Risk of Incident Breast Cancer in the American Cancer Society Cancer Prevention Study II Nutrition Cohort Cancer Epidemiol. Biomarkers Prev., February 1, 2003; 12(2): 161 - 164. [Abstract] [Full Text] [PDF]
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B. Diergaarde, W. L. van Geloof, G. N.P. van Muijen, F. J. Kok, and E. Kampman Dietary factors and the occurrence of truncating APC mutations in sporadic colon carcinomas: a Dutch population-based study Carcinogenesis, February 1, 2003; 24(2): 283 - 290. [Abstract] [Full Text] [PDF]
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G. C. Rampersaud, G. P.A. Kauwell, and L. B. Bailey Folate: A Key to Optimizing Health and Reducing Disease Risk in the Elderly J. Am. Coll. Nutr., February 1, 2003; 22(1): 1 - 8. [Abstract] [Full Text] [PDF]
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T. Marugame, E. Tsuji, C. Kiyohara, H. Eguchi, T. Oda, K. Shinchi, and S. Kono Relation of plasma folate and methylenetetrahydrofolate reductase C677T polymorphism to colorectal adenomas Int. J. Epidemiol., February 1, 2003; 32(1): 64 - 66. [Abstract] [Full Text] [PDF]
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E. P Quinlivan and J. F Gregory III Effect of food fortification on folic acid intake in the United States Am. J. Clinical Nutrition, January 1, 2003; 77(1): 221 - 225. [Abstract] [Full Text] [PDF]
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T. Keku, R. Millikan, K. Worley, S. Winkel, A. Eaton, L. Biscocho, C. Martin, and R. Sandler 5,10-Methylenetetrahydrofolate Reductase Codon 677 and 1298 Polymorphisms and Colon Cancer in African Americans and Whites Cancer Epidemiol. Biomarkers Prev., December 1, 2002; 11(12): 1611 - 1621. [Abstract] [Full Text] [PDF]
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J. R. Whetstine, T. L. Witt, and L. H. Matherly The Human Reduced Folate Carrier Gene Is Regulated by the AP2 and Sp1 Transcription Factor Families and a Functional 61-Base Pair Polymorphism J. Biol. Chem., November 8, 2002; 277(46): 43873 - 43880. [Abstract] [Full Text] [PDF]
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X. Miao, D. Xing, W. Tan, J. Qi, W. Lu, and D. Lin Susceptibility to Gastric Cardia Adenocarcinoma and Genetic Polymorphisms in Methylenetetrahydrofolate Reductase in an At-Risk Chinese Population Cancer Epidemiol. Biomarkers Prev., November 1, 2002; 11(11): 1454 - 1458. [Abstract] [Full Text] [PDF]
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D. Sun, A. Wollin, and A. M. Stephen Moderate Folate Deficiency Influences Polyamine Synthesis in Rats J. Nutr., September 1, 2002; 132(9): 2632 - 2637. [Abstract] [Full Text] [PDF]
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