|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
NEOPLASIA
From the NFCR Center for Genomics and Nutrition, School
of Public Health, and the Department of Nutritional Sciences,
University of California, Berkeley, CA; the Leukaemia Research Fund
Centre for Clinical Epidemiology, Leeds, and the Department of
Haematology, University of Leeds, United Kingdom.
We previously reported that 2 polymorphisms in the
5,10-methylenetetrahydrofolate reductase (MTHFR) gene at positions
C677T and A1298C were associated with lower risk of adult acute
lymphocytic leukemia (ALL). In the present study, we have examined
whether polymorphisms in other folate-metabolizing genes play a role in ALL susceptibility. Polymorphisms in methionine synthase (MS A2756G), cytosolic serine hydroxymethyltransferase (SHMT1 C1420T), and a double
(2R2R) or triple (3R3R) 28-bp tandem repeat in the promoter region of
thymidylate synthase (TS) were studied and found to modulate ALL risk. In a univariate analysis, SHMT1 1420CT individuals exhibited a 2.1-fold decrease in ALL risk (odds ratio [OR] = 0.48; 95% confidence interval [CI], 0.25-0.91), whereas the 1420TT
genotype conferred a 3.3-fold reduction in risk (OR = 0.31; 95% CI,
0.10-0.90). Similarly, TS 2R3R individuals exhibited a 2.8-fold
reduction in ALL risk (OR = 0.36; 95% CI: 0.16-0.83), while the TS
3R3R genotype conferred an even greater level of protection
(OR = 0.25; 95% CI, 0.08-0.78). However, no significant associations
were evident for the MS 2756AG polymorphism (OR = 0.79; 95% CI,
0.38-1.7). In addition, potential interactions between the
SHMT1 and TS or MS genes were
observed. TS 3R3R individuals who were SHMT1 1420CT/TT had a 13.9-fold
decreased ALL risk (OR = 0.072; 95% CI, 0.0067-0.77). Further, MS
2756AG individuals who were SHMT1 1420CT/TT had a 5.6-fold reduction in
ALL risk (OR = 0.18; 95% CI, 0.05-0.63). This study suggests an
important role for uracil misincorporation and resultant chromosomal
damage in the pathogenesis of ALL, and that genetic interactions
involving low penetrance polymorphisms in folate-metabolizing genes
may increase ALL risk.
(Blood. 2002;99:3786-3791) Although the clinical and pathologic aspects of
leukemia are well documented, little is known about the genes that
influence susceptibility to this disease. While highly penetrant
inherited mutations in DNA account for a small number of leukemia
cases, the majority of cases likely involve variations in several genes encoding diverse proteins that can interact to define a high-risk phenotype. These gene-gene interactions, as well as their interplay with diet, other environmental exposures, and individual immune function, may be major determinants in leukemia susceptibility. We
previously reported an association between polymorphic variants at
positions C677T and A1298C in the folate-metabolizing gene 5,10-methylenetetrahydrofolate reductase (MTHFR), and a
decreased risk of adult acute lymphocytic leukemia (ALL).1
Similar findings in childhood leukemia have recently been
reported.2 We propose that this protective effect is due
to an increase in the flux of 5,10-methylenetetrahydrofolate
(methyleneTHF) available for DNA synthesis and subsequent reductions of
uracil in DNA (Figure 1). Accumulation of
uracil in DNA and the removal of this abnormal base during excision
repair processes could result in DNA double-strand breaks, essential
for the formation of chromosomal translocations and deletions. This
chromosomal damage may be sufficient to initiate ALL progression
through the malignant transformation and clonal expansion of
lymphopoeitic progenitor cells.
To confirm our previous findings of the role of the folate pathway in
leukemia susceptibility and to further test the significance of the DNA
synthesis pathway in ALL risk, we examined polymorphisms in 3 additional genes involved in various branches of folate metabolism. Thymidylate synthase (TS), located on chromosome 18p11.32,
plays a critical role in maintaining a balanced supply of
deoxynucleotides required for DNA synthesis (Figure 1). Impairments of
the TS enzyme have been associated with chromosome damage and fragile
site induction.3,4 TS has a unique tandem
repeat sequence in the 5' untranslated region (UTR) immediately
upstream of the ATG codon initiation start site that has been shown to
be polymorphic, containing either 2 or 3 28-bp repeats.5
The presence of the triple versus double 28-bp repeat was shown to
enhance gene expression in in vitro and in vivo
studies.6,7 This enhanced expression may increase the
conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP), reducing the level of uracil that might otherwise
be incorporated into DNA. Theoretically, this could limit DNA damage in
rapidly dividing tissues that have the greatest requirement for DNA
such as those involved in hematopoeisis, and afford some protection in
leukemia risk.
Serine hydroxymethyltransferase (SHMT) encodes a vitamin
B6-dependent enzyme8 that catalyzes the reversible
conversion of serine and tetrahydrofolate (THF) to glycine and
methyleneTHF (Figure 1). There are 2 distinct SHMT isoenzymes:
one in the cytosol localized to the SHMT1 gene on chromosome
17p11.2, and the other is in the mitochondrion localized to the
SHMT2 gene on chromosome 12q13.2.9 SHMT1 plays
a pivotal role in providing one-carbon units for purine, thymidylate,
and methionine synthesis, in addition to other metabolic
functions.10 Recently, a C1420T polymorphism in
SHMT1 numbered from the start ATG codon of the open
reading frame or at position C1444T numbered from the start of the
5'-UTR has been described11 that results in reduced plasma
and red blood cell folate levels in 1420CC individuals. Based on the
role of SHMT in the provision of one-carbon units for multiple folate pathways, disturbances in protein expression or enzyme activity due to
this polymorphism could mimic a folate deficiency by reducing the
one-carbon moieties available for both remethylation of homocysteine and DNA synthesis, making this an ideal gene candidate to study.
Methionine synthase (MS), located on chromosome 5p15.3-15.2,
encodes a vitamin B12-dependent enzyme that catalyzes the
remethylation of homocysteine to methionine (Figure 1). An A-to-G
transition at position 2756 in the open reading frame of the
MS gene that converts an aspartic acid to a glycine residue
(D919G) has recently been described.12,13 This
polymorphism is predicted to alter enzyme activity since it is located
in the domain involved in methylation and reactivation of the B12
cofactor.14 Previous studies have shown that the 2756G
allele is associated with decreased plasma homocysteine
levels15,16 and a higher proportion of formylated
folates,17 the latter of which could result in the increased production of downstream folates favoring purine and pyrimidine synthesis. In addition, lower rates of colorectal cancer have been observed in MS 2756GG versus 2756AA individuals with low
alcohol intakes.18 These studies suggest that the MS 2756G allele may be associated with an increased flux of one-carbon moieties
available for DNA synthesis and repair. We predicted that if
compromised DNA synthesis was a likely mechanism involved in the
chromosomal damage associated with susceptibility to ALL, we would
expect to observe a higher proportion of ALL cases than controls with
the TS 2R2R, SHMT 1420CC, and MS 2756AA genotypes. To test this
hypothesis, we examined the same ALL case-control population as in our
previous study of MTHFR polymorphisms1 and performed a
multivariate analysis of the data obtained in both studies.
Study population and sample collection
Human subjects concerns
Analysis of the TS 2R Analysis of the SHMT1 C1420T genotypes Genotyping for the SHMT1 variants was first carried out using a standard restriction fragment length polymorphism method and restriction enzyme analysis. The following primers were used to amplify a 292-bp fragment containing the loci of interest: 5'-GTG TGG GGT GAC TTC ATT TGT G-3' (forward) and 5'-GGA GCA GCT CAT CCA TCT CTC-3' (reverse). Restriction enzyme digestion was carried out using EAR1 which cuts the wild-type sequence into 113-bp and 179-bp fragments. However, we found that the EAR1 enzyme was not efficient in cutting at the restriction site, leading to incomplete digestion and inaccurate allele frequencies. We therefore performed allelic discrimination to detect the SHMT1 C1420T polymorphism using fluorogenic 3'-minor groove binding probes in a real-time PCR assay.20 The PCR was conducted in an ABI Prism 7700 thermocycler (Applied Biosystems, Foster City, CA) using fluorescently labeled wild type (5'-FAM-CGC CTC TCT CTT C-MGB-3') and mutant (5'-VIC-CGC CTC TTT CTT C-MGB-3') allele probes. Each 15-µL reaction contained 200 nM of each probe, 900 nM each of forward primer 5'-CAG AGC CAC CCT GAA AGA GTT C-3' and reverse primer 5'-AGT GGG CCC GCT CCT TTA-3', 1X Taqman Universal PCR Master Mix (Applied Biosystems), and 12 ng DNA. PCR cycling conditions consisted of one 2-minute cycle at 50°C, one 10-minute cycle at 95°C, followed by 38 cycles of 92°C for 15 seconds and 62°C for 1 minute.Analysis of the MS A2756G genotypes This A-to-G base pair substitution in the MS gene creates a HaeIII restriction site. Genotyping for the detection of the MS A2756G polymorphism was analyzed by PCR using 0.5 µg to 1.0 µg of human genomic DNA and 0.2 µM each of an exonic forward primer (5'-TGT TCC CAG CTG TTA GAT GAA AAT C-3') and an intronic reverse primer (5'-GAT CCA AAG CCT TTT ACA CTC CTC-3'). These primers generate a 211-bp fragment spanning the polymorphism. PCR thermal cycling conditions were a 2-minute denaturation period at 94°C, and 40 cycles of the following: 94°C for 30 seconds, 60°C for 30 seconds, and 72°C for 30 seconds. This was followed by a 5-minute extension at 72°C. Restriction digestion was carried out using 1.3 µL buffer and 20 units HaeIII restriction enzyme (New England Biolabs, MA) added to 12 µL of PCR product and incubated at 37°C for at least 2 hours. Digestion products were visualized after electrophoresis on a 3% agarose gel with ethidium bromide. Wild types (2756AA) produced a singlet band at 211 bp. Heterozygotes (2756AG) produced 211-bp, 131-bp, and 80-bp fragments. Homozygous mutants (2756GG) produced 2 fragments of 80-bp and 131-bp.Quality control samples were included in all analyses and laboratory personnel were blinded as to case and control status. Statistical analysis Because the data were matched, analyses were carried out using conditional logistic regression to obtain ORs and 95% CIs to estimate relative risks; note that the rate of ALL in the adult population is low (less than one case per 100 000 persons annually), and thus the estimates of the ORs generated by conditional logistic regression are approximations of relative risks. Initially, we examined the possible association of each individual polymorphism and leukemia risk univariately. This was done first categorically and then by treating the number of mutant alleles as a continuous variable (0 = wild type, 1 = heterozygous, or 2 = homozygous mutant) to increase our power to detect trends (referred to as a trend test). For the categorical analyses, we report both the individual ORs and CIs of the non-wild-type (wild type is baseline), as well as the overall likelihood ratio test ( 2) of association. For the trend
test, we report only the P value of the trend (association)
test. In addition, we also examined potential statistical interactions
between genes. Again, both categorical and continuous (number of mutant
alleles) analyses were performed, and, as in the univariate analyses,
we report the ORs for the categorical analyses (stratified by
polymorphisms in each gene) and the likelihood ratio test of
interaction, but only the test of interaction for the trend test. The
expected frequency of genotypes is a simple application of the
Hardy-Weinberg law. Maximum likelihood estimates for the expectation
were calculated and tested against the observed counts using a standard
likelihood ratio test (against 2). Maximum likelihoods
were also calculated for cases given the Hardy-Weinberg equilibrium of
the controls. All analyses were performed using the statistical program
Stata (Stata, College Station, TX).
Univariate analyses of the TS 2R TS 2R SHMT1 C1420T. For SHMT1 C1420T, the frequency of the T allele was 23.9% in the cases and 38.2% in the controls. The 1420CC genotype was observed among 57.8% of the cases and 39.5% of the controls, the 1420CT allelic variant in 36.6% of the cases and 44.7% of the controls, and the 1420TT genotype was observed in 5.6% of the cases and 15.8% of the controls. We found that when using SHMT1 1420CC as baseline, 1420CT individuals had a 2.1-fold decrease in ALL risk (OR = 0.48; 95% CI, 0.25-0.91; P = .024), whereas those with the 1420TT genotype exhibited a 3.3-fold decrease in risk of leukemia (OR = 0.31; 95% CI, 0.10-0.90; P = .031). The trend test yielded a significant P value of .008. MS A2756G. The overall mutant allele frequency of the MS A2756G polymorphism was 17% in the controls and 15% in the cases, within the range of what has been previously reported.15,18,23-25 The MS A2756G genotype frequencies for AA, AG, and GG were 65.8%, 34.2%, and 0% in the controls, and 71.4%, 27.1%, and 1.4%, in the cases, respectively. One case was not successfully genotyped for MS A2756G. Since there was only one homozygous variant (2756GG) found in our data set, all analyses were performed excluding MS 2756 GG. We did not find that the MS A2756G polymorphism affected ALL risk when comparing heterozygotes (2756AG) to wild types (2756AA) (OR = 0.79; 95% CI, 0.38-1.7). Because essentially only 2 polymorphisms were available in the data, a trend test was irrelevant. Stratifying the ALL cases according to ALL-B and ALL-T immunophenotypes led to small numbers in each group, resulting in nonsignificant differences in TS 2R 3R, SHMT1 C1420T, and MS A2756G genotype frequencies between groups (data not shown). Therefore, all ALL cases
were considered as a single group for this analysis.
Bivariate (interaction) analyses Following this univariate analysis, we next investigated possible gene-gene interactions using multiplicative interaction terms in a conditional logistic regression model. Here we observed potential statistical interaction between the SHMT1 C1420T and TS 2R3R and MS
A2756G genotypes (Table 2, Table
3). To measure effects of interaction
between the SHMT1 and TS genes and to gain power
in our analyses, we collapsed the SHMT1 1420CT and 1420TT genotype
groups since there were no cases within the combined SHMT1 1420TT-TS
3R3R genotype. An interesting observation was that the relative risk of
leukemia in SHMT1 1420CT/TT versus 1420CC individuals varied over
levels of the TS tandem repeat. Namely, individuals with the
TS 3R3R genotype who were SHMT1 1420CT/TT versus 1420CC had a 13.9-fold
decrease in ALL risk (OR = 0.072; 95% CI, 0.0067-0.77;
P = .03). This estimated reduction in risk was
considerably reduced among TS 2R3R variants (OR = 0.39; 95% CI,
0.15-0.99; P = .048), whereas among TS 2R2R genotypes, no significant difference in risk between SHMT1 1420CT/TT and 1420CC individuals was found (OR = 1.1; 95% CI, 0.35-3.7;
P = .84). The likelihood ratio test of the existence of
multiplicative interaction resulted in a marginal P value
of .10.
Potential interaction was also detected between the MS A2756G and SHMT1 C1420T polymorphisms. Specifically, among individuals with the MS 2756AG variant, the relative risk of SHMT1 CT/TT versus 1420CC was 0.18 (OR = 0.18; 95% CI, 0.05-0.63; P = .008), whereas among MS 2756AA individuals, the same relative risk (1420CT/TT versus 1420CC) was 0.59 (OR = 0.59; 95% CI, 0.28-1.2; P = .15). As above, the P value of the likelihood ratio test of no interaction was marginal at .10. Although the large variation in the estimated ORs among strata implies possible interaction, the study did not have the power to detect this magnitude of interaction statistically; no tests of statistical interaction among the trend tests were close to statistical significance. Using our previously published data on the MTHFR 677 and 1298 polymorphisms, we next tested whether statistical interaction existed between MTHFR and TS, SHMT1, or MS in our conditional logistic regression model. We found no evidence of statistical interaction in these analyses (data not shown). Due to small sample sizes, the combined effects of more than 2 genotypes (ie, 3-way interactions) could not be examined using conditional logistic regression. Table 1 shows that for TS and
SHMT1, the population-based controls were in Hardy-Weinberg
equilibrium. Further, applying the control allele frequency
distribution to the cases shows that the case distribution is
significantly different to the control distribution. However, the
controls are not in Hardy-Weinberg equilibrium for MS
(P = .035), although the deficit amounts to only 3 persons, which does not suggest a significant departure from
Hardy-Weinberg. Further, there is no significant departure when
comparing cases to controls.
Previously, we have reported that polymorphisms at positions C677T and A1298C of the MTHFR gene are associated with reduced susceptibility to ALL. We postulated that this protective effect was due to increased levels of the methyl group donor methyleneTHF available for DNA synthesis, thereby reducing levels of incorporation of the abnormal base uracil instead of thymidine into DNA. Uracil misincorporation has been shown to cause DNA double-strand breaks,26 presumably through the deficient methylation of dUMP to dTMP. Failure to repair DNA double-strand breaks could result in the formation of chromosome translocations and deletions common in leukemia. This case-control study provides further support of the role of folate deficiency in leukemia risk, and adds greater insight into a proposed biologic mechanism of the relationship between perturbations in one-carbon metabolism and ALL. The results of our current study support the theory of enhanced availability of methyleneTHF for DNA synthesis and repair through the identification of polymorphisms in 2 important DNA-synthesizing genes, TS and SHMT1, and their significant impact on leukemia risk. Specifically, a higher distribution of TS 2R3R or 3R3R versus 2R2R variants was observed among the controls than among the cases, conferring a significant 64% (OR = 0.36; 95% CI, 0.16-0.83) and 75% (OR = 0.25; 95% CI, 0.08-0.78) decrease in risk of ALL among these individuals, respectively. Furthermore, the SHMT1 1420 T allele afforded similar levels of protection. We observed a 52% reduction in ALL risk among individuals with the SHMT1 1420CT genotype (OR = 0.48; 95% CI, 0.25-0.91), and a 69% lower risk in those with the 1420TT variant (OR = 0.31; 95% CI, 0.10-0.90). However, no significant differences in MS A2756G genotypes among
the patients and controls were observed. This may be the result of the
small number of MS 2756GG variants in our study population, reducing
the power necessary to detect differences. In testing for statistical
interaction between the TS 2R TS binds methyleneTHF, which serves as a hydroxymethyl donor in the conversion of dUMP to dTMP in the DNA synthesis pathway.27 Reductions in TS gene expression could likely affect the balanced supply of deoxynucleotides required for normal DNA synthesis, particularly in rapidly proliferating cells such as those found in blood-forming tissues. Horie et al28 have recently characterized the human TS promoter region, identifying several potential mechanisms for gene regulation. These studies found that the TS 28-bp triple repeat found in the 5'-UTR near the ATG start site led to gene expression that was 2.6 times greater than that found in the double repeat in a transient expression assay.6 Moreover, at least one set of the repeated sequence and its complementary sequence is necessary for efficient expression of the human TS gene. Possible mechanisms for the enhancing effect of the repeat could be an unknown nuclear factor that binds to the region, or the formation of stem loops in the 5'-terminal region of TS mRNA influencing gene expression.7 These studies may explain the protective effect against ALL that we observed among individuals with at least one TS triple tandem repeat allele and further substantiates the basis that enhanced flux of methyleneTHF in the DNA synthesis pathway may attenuate cancer risk. During folate stress or as a result of TS inhibition, high levels of uracil accumulate in DNA, which has been previously demonstrated in a number of in vivo studies,26,29,30 resulting in the degradation of newly synthesized DNA due to an active excision repair pathway.31 Early investigations established that high levels of uracil misincorporation followed by extensive repair by uracil DNA glycosylase increase double-strand DNA breaks that may contribute to chromosomal instability,32 translocations,33 and chromosome aberrations,34 factors that may contribute to leukemia risk. At this time, the functional role of cytosolic SHMT is not fully
understood since mitochondrial SHMT can also supply the one-carbon units required for cytosolic folate metabolism.35 In the
cytosol, SHMT catalyzes 2 reactions; one involves the reversible
interconversion of serine to glycine to form methyleneTHF, the crucial
intermediate at the branch point of 3 key pathways involved in
thymidylate, purine, and methionine synthesis.36 Cytosolic
SHMT also catalyzes the irreversible conversion of
methenyltetrahydrofolate (methenylTHF) to 5-formyltetrahydrofolate
(5-formylTHF), in what has been termed the "futile
cycle"35 (Figure 2). Until
recently, the role of 5-formylTHF has been poorly understood, although
previous studies identified it as a potent inhibitor of cytosolic
SHMT.37 According to recent studies, however, the
formation of 5-formylTHF may be critical in maintaining
one-carbon homeostasis, particularly during rapid proliferative
stages of development.10 Thus, inhibition of cytosolic
SHMT may be a mechanism to prevent an unnecessary accumulation of
5-methylTHF (committed to methionine and SAM synthesis) at the expense
of depriving one-carbon units for thymidylate and purine
formation.10 We speculate that the SHMT1 C1420T
polymorphism may influence the flux of one-carbon moieties toward
thymidylate synthesis either through increasing formation of
5-formylTHF or by enhancing interactions between SHMT1 and
other genes involved in DNA synthesis such as TS or
dihydrofolate reductase (DHFR). SHMT1 and
TS play crucial roles in the synthesis of DNA that may involve protein-protein interactions in the production of methyleneTHF catalyzed by cytosolic SHMT, the subsequent formation of dihydrofolate (DHF) and thymidylate catalyzed by TS, and the reconversion of DHF to
tetrahydrofolate (THF) catalyzed by DHFR (Figure 1).38 Furthermore, TS and cytosolic SHMT may share a common translational autoregulatory process that could couple the control of their expression, providing a mechanism to tightly regulate thymidylate and
DNA synthesis.39 Our observation of statistical
interaction between the TS and SHMT1 genes may
relate to some factor that varies between the SHMT1 1420 C and T
alleles that affects its biologic interaction with TS and
ultimately affects thymidylate synthesis. However, whether the SHMT1
C1420T polymorphism really affects its interaction with the
TS gene cannot be concluded from this study, and requires
further biochemical analyses.
In conclusion, this research reveals an association between aberrations in folate metabolic pathways which affect thymidylate synthesis and lymphocytic leukemia risk that may underscore the widespread importance of compromised DNA fidelity and insufficient folate pools in the pathogenesis of adult ALL. DNA integrity is critically dependent on the bioavailability of deoxynucleotides, particularly in cells with high replication rates such as those found in the hematopoietic system and epithelium. Even minor imbalances in pyrimidine synthesis in these cells can greatly increase the level of DNA double-strand breaks that can lead to point mutations, chromosomal translocations, and other preneoplastic alterations. Moreover, low intakes of folic acid and the folate cofactors, vitamins B2, B6, and B12, may exacerbate ALL risk in individuals with "high risk" genotypes. A combination of unfavorable genotypes, diet, and vitamin B status may conceivably be the key factor in susceptibility to adult ALL that may also hold true for certain subtypes of childhood ALL.40 Continued research in this area may help establish how dietary and nutritional modifications in susceptible individuals may alter individual ALL risk.
Submitted September 28, 2001; accepted January 10, 2002.
Supported by the Leukaemia Research Fund of Great Britain (G.J.M., R.A.C, E.R., G.R.L.), National Institutes of Health (NIH) grant HL58991 (B.S), the National Foundation for Cancer Research (M.T.S.), and NIH grant P30ES01896 from the National Institute of Environmental Health Sciences (M.T.S.).
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Martyn T. Smith, Division of Environmental Health Sciences, School of Public Health, 216 Earl Warren Hall, University of California, Berkeley, CA 94720-7360; e-mail: martynts{at}uclink4.berkeley.edu.
1.
Skibola CF, Smith MT, Kane E, et al.
Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults [see comments].
Proc Natl Acad Sci U S A.
1999;96:12810-12815
2.
Wiemels JL, Smith RN, Taylor GM, Eden OB, Alexander FE, Greaves MF.
Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia.
Proc Natl Acad Sci U S A.
2001;98:4004-4009 3. Hori T, Ayusawa D, Glover TW, Seno T. Expression of fragile site on the human X chromosome in somatic cell hybrids between human fragile X cells and thymidylate synthase-negative mouse mutant cells. Jpn J Cancer Res. 1985;76:977-983[Medline] [Order article via Infotrieve].
4.
Hori T, Ayusawa D, Shimizu K, Koyama H, Seno T.
Chromosome breakage induced by thymidylate stress in thymidylate synthase-negative mutants of mouse FM3A cells.
Cancer Res.
1984;44:703-709
5.
Kaneda S, Takeishi K, Ayusawa D, Shimizu K, Seno T, Altman S.
Role in translation of a triple tandemly repeated sequence in the 5'-untranslated region of human thymidylate synthase mRNA.
Nucleic Acids Res.
1987;15:1259-1270 6. Horie N, Aiba H, Oguro K, Hojo H, Takeishi K. Functional analysis and DNA polymorphism of the tandemly repeated sequences in the 5'-terminal regulatory region of the human gene for thymidylate synthase. Cell Struct Funct. 1995;20:191-197[Medline] [Order article via Infotrieve]. 7. Kawakami K, Omura K, Kanehira E, Watanabe Y. Polymorphic tandem repeats in the thymidylate synthase gene is associated with its protein expression in human gastrointestinal cancers. Anticancer Res. 1999;19:3249-3252[Medline] [Order article via Infotrieve]. 8. Shane B, Stokstad E. Vitamin B12-folate interrelationships. Annu Rev Nutr. 1985;5:115-141[CrossRef][Medline] [Order article via Infotrieve].
9.
Schirch L, Peterson D.
Purification and properties of mitochondrial serine hydroxymethyltransferase.
J Biol Chem.
1980;255:7801-7806
10.
Girgis S, Suh JR, Jolivet J, Stover PJ.
5-Formyltetrahydrofolate regulates homocysteine remethylation in human neuroblastoma.
J Biol Chem.
1997;272:4729-4734 11. Heil SG, Van der Put NM, Waas ET, den Heijer M, Trijbels FJ, Blom HJ. Is mutated serine hydroxymethyltransferase (shmt) involved in the etiology of neural tube defects? Mol Genet Metab. 2001;73:164-172[CrossRef][Medline] [Order article via Infotrieve].
12.
Leclerc D, Campeau E, Goyette P, et al.
Human methionine synthase: cDNA cloning and identification of mutations in patients of the cblG complementation group of folate/cobalamin disorders.
Hum Mol Genet.
1996;5:1867-1874
13.
Chen LH, Liu ML, Hwang HY, Chen LS, Korenberg J, Shane B.
Human methionine synthase: cDNA cloning, gene localization, and expression.
J Biol Chem.
1997;272:3628-3634 14. Shane B. Folate metabolism. In: Picciano M,Stokstad E,Gregory J, eds. Folic Acid Metabolism in Health and Disease. New York, NY: Wiley-Liss; 1990:65-78. 15. Harmon DL, Shields DC, Woodside JV, et al. Methionine synthase D919G polymorphism is a significant but modest determinant of circulating homocysteine concentrations. Genet Epidemiol. 1999;17:298-309[CrossRef][Medline] [Order article via Infotrieve]. 16. Chen J, Stampfer MJ, Ma J, Selhub J, Malinow MR, Hennekens CH, Hunter DJ. Influence of methionine synthase (D919G) polymorphism on plasma homocysteine and folate levels and relation to risk of myocardial infarction. Atherosclerosis. 2001;154:667-672[CrossRef][Medline] [Order article via Infotrieve].
17.
Lucock M, Daskalakis I, Briggs D, Yates Z, Levene M.
Altered folate metabolism and disposition in mothers affected by a spina bifida pregnancy: influence of 677c
18.
Ma J, Stampfer MJ, Christensen B, et al.
A polymorphism of the methionine synthase gene: association with plasma folate, vitamin B12, homocyst(e)ine, and colorectal cancer risk.
Cancer Epidemiol Biomarkers Prev.
1999;8:825-829 19. Kane EV, Roman E, Carwright RA, Parker J, Morgan G. Tobacco and the risk of acute leukemia in adults. Br J Cancer. 1999;81:1228-1233[CrossRef][Medline] [Order article via Infotrieve].
20.
Kutyavin IV, Afonina IA, Mills A, et al.
3'-minor groove binder-DNA probes increase sequence specificity at PCR extension temperatures.
Nucleic Acids Res.
2000;28:655-661 21. Marsh S, Ameyaw MM, Githang'a J, Indalo A, Ofori-Adjei D, McLeod HL. Novel thymidylate synthase enhancer region alleles in African populations. Hum Mutat. 2000;16:528[Medline] [Order article via Infotrieve]. 22. Marsh S, Collie-Duguid ES, Li T, Liu X, McLeod HL. Ethnic variation in the thymidylate synthase enhancer region polymorphism among Caucasian and Asian populations. Genomics. 1999;58:310-312[CrossRef][Medline] [Order article via Infotrieve]. 23. Conroy JM, Trivedi G, Sovd T, Caggana M. The allele frequency of mutations in four genes that confer enhanced susceptibility to venous thromboembolism in an unselected group of New York State newborns. Thromb Res. 2000;99:317-324[CrossRef][Medline] [Order article via Infotrieve].
24.
Chen J, Giovannucci E, Hankinson SE, et al.
A prospective study of methylenetetrahydrofolate reductase and methionine synthase gene polymorphisms, and risk of colorectal adenoma.
Carcinogenesis.
1998;19:2129-2132
25.
van der Put NM, van der Molen EF, Kluijtmans LA, et al.
Sequence analysis of the coding region of human methionine synthase: relevance to hyperhomocysteinaemia in neural-tube defects and vascular disease.
Quarterly Journal of Medicine.
1997;90:511-517
26.
Blount BC, Mack MM, Wehr CM, et al.
Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage.
Proc Natl Acad Sci U S A.
1997;94:3290-3295 27. Kamb A, Finer-Moore J, Calvert AH, Stroud RM. Structural basis for recognition of polyglutamyl folates by thymidylate synthase. Biochemistry. 1992;31:9883-9890[CrossRef][Medline] [Order article via Infotrieve].
28.
Horie N, Takeishi K.
Identification of functional elements in the promoter region of the human gene for thymidylate synthase and nuclear factors that regulate the expression of the gene.
J Biol Chem.
1997;272:18375-18381
29.
James SJ, Miller BJ, Basnakian AG, Pogribny IP, Pogribna M, Muskhelishvili L.
Apoptosis and proliferation under conditions of deoxynucleotide pool imbalance in liver of folate/methyl deficient rats.
Carcinogenesis.
1997;18:287-293
30.
Duthie SJ, Hawdon A.
DNA instability (strand breakage, uracil misincorporation, and defective repair) is increased by folic acid depletion in human lymphocytes in vitro.
FASEB Journal.
1998;12:1491-1497 31. Ingraham HA, Dickey L, Goulian M. DNA fragmentation and cytotoxicity from increased cellular deoxyuridylate. Biochemistry. 1986;25:3225-3230[CrossRef][Medline] [Order article via Infotrieve]. 32. Melnyk S, Pogribna M, Miller BJ, Basnakian AG, Pogribny IP, James SJ. Uracil misincorporation, DNA strand breaks, and gene amplification are associated with tumorigenic cell transformation in folate deficient/repleted Chinese hamster ovary cells. Cancer Lett. 1999;146:35-44[CrossRef][Medline] [Order article via Infotrieve]. 33. Kunz BA. Mutagenesis and deoxyribonucleotide pool imbalance. Mutat Res. 1988;200:133-147[Medline] [Order article via Infotrieve].
34.
Tommerup N, Poulsen H, Brøndum-Nielsen K.
5-Fluoro-2'-deoxyuridine induction of the fragile site on Xq28 associated with X linked mental retardation.
J Med Genet.
1981;18:374-376 35. Girgis S, Nasrallah IM, Suh JR, et al. Molecular cloning, characterization and alternative splicing of the human cytoplasmic serine hydroxymethyltransferase gene. Gene. 1998;210:315-324[CrossRef][Medline] [Order article via Infotrieve].
36.
Stover P, Schirch V.
5-Formyltetrahydrofolate polyglutamates are slow tight binding inhibitors of serine hydroxymethyltransferase.
J Biol Chem.
1991;266:1543-1550 37. Stover P, Kruschwitz H, Schirch V. Evidence that 5-formyltetrahydropteroylglutamate has a metabolic role in one-carbon metabolism. Adv Exp Med Biol. 1993;338:679-685[Medline] [Order article via Infotrieve]. 38. Snell K. Enzymes of serine metabolism in normal, developing and neoplastic rat tissues. Adv Enzyme Regul. 1984;22:325-400[CrossRef][Medline] [Order article via Infotrieve]. 39. Snell K, Baumann U, Byrne PC, et al. The genetic organization and protein crystallographic structure of human serine hydroxymethyltransferase. Adv Enzyme Regul. 2000;40:353-403[CrossRef][Medline] [Order article via Infotrieve]. 40. Thompson JR, Gerald PF, Willoughby ML, Armstrong BK. Maternal folate supplementation in pregnancy and protection against acute lymphoblastic leukaemia in childhood: a case-control study. Lancet. 2001;358:1935-1940[CrossRef][Medline] [Order article via Infotrieve].
© 2002 by The American Society of Hematology.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
|
 |
|
  S. M. Collin, C. Metcalfe, L. Zuccolo, S. J. Lewis, L. Chen, A. Cox, M. Davis, J. A. Lane, J. Donovan, G. D. Smith, et al. Association of Folate-Pathway Gene Polymorphisms with the Risk of Prostate Cancer: a Population-Based Nested Case-Control Study, Systematic Review, and Meta-analysis Cancer Epidemiol. Biomarkers Prev., September 1, 2009; 18(9): 2528 - 2539. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. de Jonge, W. J. E. Tissing, J. H. Hooijberg, G. Jansen, G. J. L. Kaspers, J. Lindemans, G. J. Peters, and R. Pieters Polymorphisms in folate-related genes and risk of pediatric acute lymphoblastic leukemia Blood, March 5, 2009; 113(10): 2284 - 2289. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. T. Pullarkat, K. Danley, L. Bernstein, R. K. Brynes, and W. Cozen High Lifetime Incidence of Adult Acute Lymphoblastic Leukemia among Hispanics in California Cancer Epidemiol. Biomarkers Prev., February 1, 2009; 18(2): 611 - 615. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Ulrich Folate and Cancer Prevention--Where to Next? Counterpoint Cancer Epidemiol. Biomarkers Prev., September 1, 2008; 17(9): 2226 - 2230. [Full Text] [PDF]
|
|
|
|
 |
|
 C. F. Woeller, D. D. Anderson, D. M. E. Szebenyi, and P. J. Stover Evidence for Small Ubiquitin-like Modifier-dependent Nuclear Import of the Thymidylate Biosynthesis Pathway J. Biol. Chem., June 15, 2007; 282(24): 17623 - 17631. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Gemmati, A. Ongaro, S. Tognazzo, L. Catozzi, F. Federici, E. Mauro, M. Della Porta, D. Campioni, A. Bardi, G. Gilli, et al. Methylenetetrahydrofolate reductase C677T and A1298C gene variants in adult non-Hodgkin's lymphoma patients: association with toxicity and survival Haematologica, April 1, 2007; 92(4): 478 - 485. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Lim, S. S. Wang, P. Hartge, W. Cozen, L. E. Kelemen, S. Chanock, S. Davis, A. Blair, M. Schenk, N. Rothman, et al. Gene-nutrient interactions among determinants of folate and one-carbon metabolism on the risk of non-Hodgkin lymphoma: NCI-SEER Case-Control Study Blood, April 1, 2007; 109(7): 3050 - 3059. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Niclot, Q. Pruvot, C. Besson, D. Savoy, E. Macintyre, G. Salles, N. Brousse, B. Varet, P. Landais, P. Taupin, et al. Implication of the folate-methionine metabolism pathways in susceptibility to follicular lymphomas Blood, July 1, 2006; 108(1): 278 - 285. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Zhang, X. An, K. Yang, D. L. Perlstein, L. Hicks, N. Kelleher, J. Stubbe, and M. Huang Nuclear localization of the Saccharomyces cerevisiae ribonucleotide reductase small subunit requires a karyopherin and a WD40 repeat protein PNAS, January 31, 2006; 103(5): 1422 - 1427. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. J. Lightfoot, C. F. Skibola, E. V. Willett, D. R. Skibola, J. M. Allan, F. Coppede, P. J. Adamson, G. J. Morgan, E. Roman, and M. T. Smith Risk of Non-Hodgkin Lymphoma Associated with Polymorphisms in Folate-Metabolizing Genes Cancer Epidemiol. Biomarkers Prev., December 1, 2005; 14(12): 2999 - 3003. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 Z. Zhang, Y. Xu, J. Zhou, X. Wang, L. Wang, X. Hu, J. Guo, Q. Wei, and H. Shen Polymorphisms of thymidylate synthase in the 5'- and 3'-untranslated regions associated with risk of gastric cancer in South China: a case-control analysis Carcinogenesis, October 1, 2005; 26(10): 1764 - 1769. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 U. Lim, K. Peng, B. Shane, P. J. Stover, A. A. Litonjua, S. T. Weiss, J. M. Gaziano, R. L. Strawderman, F. Raiszadeh, J. Selhub, et al. Polymorphisms in Cytoplasmic Serine Hydroxymethyltransferase and Methylenetetrahydrofolate Reductase Affect the Risk of Cardiovascular Disease in Men J. Nutr., August 1, 2005; 135(8): 1989 - 1994. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. de Jonge, J. H. Hooijberg, B. D. van Zelst, G. Jansen, C. H. van Zantwijk, G. J. L. Kaspers, F. G. J. Peters, Y. Ravindranath, R. Pieters, and J. Lindemans Effect of polymorphisms in folate-related genes on in vitro methotrexate sensitivity in pediatric acute lymphoblastic leukemia Blood, July 15, 2005; 106(2): 717 - 720. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Fenech The Genome Health Clinic and Genome Health Nutrigenomics concepts: diagnosis and nutritional treatment of genome and epigenome damage on an individual basis Mutagenesis, July 1, 2005; 20(4): 255 - 269. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
Q. Shi, Z. Zhang, A. S. Neumann, G. Li, M. R. Spitz, and Q. Wei Case-control analysis of thymidylate synthase polymorphisms and risk of lung cancer Carcinogenesis, March 1, 2005; 26(3): 649 - 656. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Zhang, Y. Cui, G. Kuang, Y. Li, N. Wang, R. Wang, W. Guo, D. Wen, L. Wei, F. Yu, et al. Association of the thymidylate synthase polymorphisms with esophageal squamous cell carcinoma and gastric cardiac adenocarcinoma Carcinogenesis, December 1, 2004; 25(12): 2479 - 2485. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Zhang, Q. Shi, E. M. Sturgis, M. R. Spitz, W. K. Hong, and Q. Wei Thymidylate Synthase 5'- and 3'-Untranslated Region Polymorphisms Associated with Risk and Progression of Squamous Cell Carcinoma of the Head and Neck Clin. Cancer Res., December 1, 2004; 10(23): 7903 - 7910. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. F. Skibola, M. S. Forrest, F. Coppede, L. Agana, A. Hubbard, M. T. Smith, P. M. Bracci, and E. A. Holly Polymorphisms and haplotypes in folate-metabolizing genes and risk of non-Hodgkin lymphoma Blood, October 1, 2004; 104(7): 2155 - 2162. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. H. Wilson and K. Olden The Environmental Genome Project: Phase I and Beyond Mol. Interv., June 1, 2004; 4(3): 147 - 156. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Gemmati, A. Ongaro, G. L. Scapoli, M. Della Porta, S. Tognazzo, M. L. Serino, E. Di Bona, F. Rodeghiero, G. Gilli, R. Reverberi, et al. Common Gene Polymorphisms in the Metabolic Folate and Methylation Pathway and the Risk of Acute Lymphoblastic Leukemia and non-Hodgkin's Lymphoma in Adults Cancer Epidemiol. Biomarkers Prev., May 1, 2004; 13(5): 787 - 794. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-H. Pui, M. V. Relling, and J. R. Downing Acute Lymphoblastic Leukemia N. Engl. J. Med., April 8, 2004; 350(15): 1535 - 1548. [Full Text] [PDF]
|
|
|
|
 |
|
 L. Hagmar, U. Stromberg, S. Bonassi, I.-L. Hansteen, L. E. Knudsen, C. Lindholm, and H. Norppa Impact of Types of Lymphocyte Chromosomal Aberrations on Human Cancer Risk: Results from Nordic and Italian Cohorts Cancer Res., March 15, 2004; 64(6): 2258 - 2263. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Sharp and J. Little Polymorphisms in Genes Involved in Folate Metabolism and Colorectal Neoplasia: A HuGE Review Am. J. Epidemiol., March 1, 2004; 159(5): 423 - 443. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Uchida, K. Hayashi, K. Kawakami, S. Schneider, J. M. Yochim, H. Kuramochi, K. Takasaki, K. D. Danenberg, and P. V. Danenberg Loss of Heterozygosity at the Thymidylate Synthase (TS) Locus on Chromosome 18 Affects Tumor Response and Survival in Individuals Heterozygous for a 28-bp Polymorphism in the TS Gene Clin. Cancer Res., January 15, 2004; 10(2): 433 - 439. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. V. Mandola, J. Stoehlmacher, S. Muller-Weeks, G. Cesarone, M. C. Yu, H.-J. Lenz, and R. D. Ladner A Novel Single Nucleotide Polymorphism within the 5' Tandem Repeat Polymorphism of the Thymidylate Synthase Gene Abolishes USF-1 Binding and Alters Transcriptional Activity Cancer Res., June 1, 2003; 63(11): 2898 - 2904. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
K. A. Zanetti and P. J. Stover Pyridoxal Phosphate Inhibits Dynamic Subunit Interchange among Serine Hydroxymethyltransferase Tetramers J. Biol. Chem., March 14, 2003; 278(12): 10142 - 10149. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|||||||
 |
 |
 |
 |
 |
 |
 |
 |
||
| Copyright © 2002 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
Top
Abstract
Introduction
2 years), and race as the patient. Cases
were considered ineligible if they were diagnosed with acute leukemia
within 6 months of being diagnosed with a prior hematologic malignancy
or within 2 years of any other cancer. This ineligibility criterion was
likewise applied to controls. With their physician's permission, all
study subjects were asked to be interviewed and to give a blood sample
that was collected by venipuncture. DNA was isolated using a proteinase
K treatment, followed by phenol-chloroform extraction and ethanol
precipitation. Of the 71 ALL cases, 50 were diagnosed with B-cell ALL,
11 with T-cell ALL, and for 10 cases, the immunophenotype could not be specified. Since the prevalence of the polymorphisms under study may
vary with race and the number of nonwhite cases included in the study
was small, this analysis was restricted to 71 Caucasian cases and their
114 matched Caucasian controls.
