Leukemia Research 34 (2010) 1596–1600

Contents lists available at ScienceDirect

Leukemia Research
journal homepage: www.elsevier.com/locate/leukres

MTHFR C677T polymorphisms and childhood acute lymphoblastic leukemia:

A meta-analysis
Jing Wang a , Ping Zhan b , Bing Chen a , Rongfu Zhou a , Yonggong Yang a , Jian Ouyang a,∗
a
Department of Hematology, the Affiliated DrumTower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing 210008, Jiangsu PR China
b
Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing, PR China

a r t i c l e i n f o a b s t r a c t

Article history: To date, case–control studies on the association between methylenetetrahydrofolate reductase (MTHFR)
Received 4 January 2010 C677T and childhood acute lymphoblastic leukemia have provided either controversial or inconclusive
Received in revised form 19 March 2010 results. To clarify the effect of MTHFR C677T on the risk of childhood acute lymphoblastic leukemia,
Accepted 20 March 2010
a meta-analysis of all case–control observational studies was performed. Heterogeneity (I2 = 65%,
Available online 20 April 2010
P < 0.0001) for C677T among the studies was extreme. The random effects (RE) model showed that the
677T allele was not associated with a decreased susceptibility risk of childhood acute lymphoblastic
Keywords:
leukemia compared with the C allele [OR = 0.96, 95% confidence interval (CI) (0.88–1.04), P = 0.34]. The
MTHFR polymorphisms
Acute lymphoblastic leukemia
contrast of homozygotes, recessive model and dominant model produced the same pattern of results
Meta-analysis as the allele contrast. Although MTHFR C677T was associated with increased risks of colorectal cancer,
leukemia, and gastric cancer, our pooled data suggest no evidence for a major role of MTHFR C677T in
the carcinogenesis of childhood acute lymphoblastic leukemia.
© 2010 Elsevier Ltd. All rights reserved.

1. Introduction failed to confirm such an association [10,11]. Moreover, two meta-

Acute lymphoblastic leukemia (ALL) is the most common malig-
nancy affecting children, constituting about 30% of all cancers
among children [1,2]. Although significant improvements in both
ALL diagnosis and treatment have been made over the past decades,
the etiology of most cases of ALL remains unknown due to proba-
ble multifactorial mechanisms of pathogenesis [3]. Pediatric acute
leukemias are likely influenced by both the genetic background and
the environment of the patient [4,5].
analyses [12,13] investigating the same hypothesis, quite similar
in methods and performed almost at the same time, yielded
different conclusions. The exact relationship between genetic
polymorphisms of MTHFR C677T and susceptibility to childhood
ALL has not been entirely established. To clarify the effect of
MTHFR C677T on the risk of childhood ALL, our study undertakes a
meta-analysis of all published case–control observational studies.
2. Methods

Methylenetetrahydrofolate reductase (MTHFR) plays an 2.1. Publication search

important role in folate metabolism by catalyzing the irre-
versible conversion of 5,10-methylenetetrahydrofolate to
5-methyltetrahydrofolate [4]. A common polymorphism at
the nucleotide 677, C677T (Ala → Val), in the gene for the enzyme
MTHFR, results in a less stable version of the enzyme [6]. MTHFR
C677T has been associated with an increased risk of colorectal
cancer, leukemia, and gastric cancer [7]. The role of MTHFR
polymorphisms in the development of childhood ALL has been
investigated in the past decade, with conflicting results. Sev-
eral studies have previously suggested an association between
the MTHFR C677T polymorphism and a decreased risk of acute
lymphoblastic leukemia (ALL) [8,9]. However, other studies have
The electronic databases PubMed, Embase, Web of Science, and CNKI (China
National Knowledge Infrastructure) were searched for studies to include in the
present meta-analysis, using the terms: “Methylenetetrahydrofolate Reductase,”
“genotype,” “Leuk(a)emia,” “Acute lymphocytic,” “Acute lymphoblastic,” “Child-
hood,” “P(a)ediatric,” “polymorphism,” “MTHFR,” “C677T,” “folate,” and “mutation.”
An upper date limit of August 30, 2009 was applied; we used no lower date limit. The
search was conducted without any restrictions on language but focused on stud-
ies that had been conducted on human subjects. We also reviewed the Cochrane
Library for relevant articles. The reference lists of reviews and retrieved articles
were hand-searched simultaneously. Only published studies with full text articles
were included. When more than one instance of the same patient population was
included in several publications, only the most recent or complete study was used
in this meta-analysis.

2.2. Data extraction

The following information was extracted from each study: first author, year
∗ Corresponding author. Tel.: +86 25 83105211; fax: +86 25 83105211. of publication, ethnicity of study population, genotyping method, and the num-
E-mail address: ouyang211@hotmail.com (J. Ouyang). ber of cases and controls for the C677T genotype. We did not define any

0145-2126/$ – see front matter © 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.leukres.2010.03.034
 J. Wang et al. / Leukemia Research 34 (2010) 1596–1600 1597

Table 1
Study characteristics.

Study first author Country Source of controls No. of cases/controls Leukemia characteristics

Franco et al. [8] Brazil Population 71/71 77% B-ALL and 23% T-ALL
Wiemels et al. [10] United Kingdom Population 216/200 36% were TEL-AML1 and 64% were hyperdiploid leukemias
Balta et al. [11] Turkey Population 142/185 52% B-ALL, 28% non-B-ALL, and 20% undetermined
Karjinovic et al. [14] Canada Hospital 270/300 85% pre B-ALL, 11% T-ALL, and 4% undetermined
Jiang et al. [9] China Population 29/67 Immunophenotype not described
Chatzidakis et al. [18] Greece Population 52/88 87% B-ALL and 13% T-ALL
Oliveira et al. [16] Portugal Population 103/111 Immunophenotype not described
Schnakenberg et al. [17] Germany Population 443/379 77.7% B-ALL, 18.3% T-ALL, 0.9% biphenotype, and 3.2% undetermined
Thirumaran et al. [15] Germany Population 453/1448 Immunophenotype not described
Zanrosso et al. [19] Brazil Population 165/198 94.9% B-ALL and 5.1% T-ALL
Kim et al. [22] Korea Population 66/100 Immunophenotype not described
Reddy et al. [21] India Population 135/142 Immunophenotype not described
Yu et al. [20] China Population 51/53 72.5% B-ALL and 27.5% T-ALL
Petra et al. [24] Slovenia Hospital 68/258 75% B-ALL, 11.8% T-ALL, 13.2% biphenotype, and 3.2% undetermined
Kamel et al. [23] Egypt Population 88/311 B-ALL
Giovannetti et al. [25] Indonesia Population 71/44 Immunophenotype not described
Alcasabas et al. [26] Philippines Population 189/394 Immunophenotype not described
Liu et al. [27] China Population 83/83 Immunophenotype not described
de Jonge et al. [28] Netherlands Population 243/496 75% B-ALL and 25% T-ALL
Kim et al. [29] Korea Population 107/1700 Immunophenotype not described
Yeoh et al. [30] Singapore Population 318/345 89.4% B-ALL, 7.8% T-ALL and 2.8% infant ALL

Three studies [9–11] were excluded from this meta-analysis

minimum number of patients as a criterion for a study’s inclusion in our meta- a statistically significant publication bias). All calculations were performed using
analysis. ReviewManage 5.0.

2.3. Statistical analysis

The meta-analysis examined the overall association for the allele contrasts, the
contrast of homozygotes, and the recessive and dominant models. The effect of the
association was indicated as an odds ratio (OR) with its corresponding 95% confi-
dence interval (CI). Pooled OR was estimated using fixed effects and random effects
models. Heterogeneity between studies was tested using the Q statistic. Such het-
erogeneity was considered statistically significant if P < 0.10. Heterogeneity was
quantified using the I2 metric, which is independent of the number of studies in
the meta-analysis (I2 < 25% no heterogeneity; I2 = 25–50% moderate heterogene-
ity; I2 > 50% large or extreme heterogeneity). An estimate of potential publication
bias was carried out by the funnel plot, in which the standard error of log (OR)
of each study was plotted against its log (OR). An asymmetric plot suggests a
possible publication bias. Funnel plot asymmetry was assessed by the method
of Egger’s linear regression test, a linear regression approach for measuring fun-
nel plot asymmetry on the natural logarithm scale of the OR. The significance of
the intercept was determined by the t-test suggested by Egger (P < 0.05 indicated
3. Results
3.1. Study characteristics
We found 21 published articles addressing the relation-
ship between MTHFR C677T and childhood acute lymphoblastic
leukemia (Table 1). The studies were published between 1999 and
2009. In all studies, the cases were histologically confirmed, and
the control groups were free of ALL and were matched for age
and gender. Studies were conducted in various populations of dif-
ferent ethnicities: nine were conducted in populations of Asian
regions [9,20–22,25–27,29,30], and eight studies looked at Euro-
peans [10,11,15–18,24,28].

Table 2
Distribution of methylenetetrahydrofolate reductase (MTHFR) C677T genotypes and allelic frequency.

Study first author (year) Distribution of C677T MTHFR genotype Frequency of C677T MTHFR alleles Hardy–Weinberg
equilibrium (HWE) P
CC CT TT C T value
Cases, n Controls, n Cases, n Controls, n Cases, n Controls, n Cases, n Controls, n Cases, n Controls, n

Franco et al. (2001) [8] 36 22 28 36 6 13 100 80 40 62 0.796

Wiemels et al. (2001) [10] 98 89 91 79 27 32 287 257 145 143 0.047
Balta et al. (2004) [11] 71 90 60 87 11 8 202 267 82 103 0.020
Karjinovic et al. (2004) [14] 112 126 127 128 31 46 351 380 189 220 0.159
Jiang et al. (2004) [9] 15 18 14 41 0 8 44 77 14 57 0.039
Chatzidakis et al. (2005) [18] 31 32 18 47 3 9 80 111 24 65 0.169
Oliveira et al. (2005) [16] 48 45 50 57 5 9 141 147 60 75 0.120
Schnakenberg et al. (2005) [17] 195 184 201 152 47 43 591 520 304 238 0.179
Thirumaran et al. (2005) [15] 199 600 195 681 59 167 593 1881 313 1015 0.210
Yu et al. (2006) [20] 30 20 14 23 7 10 74 63 28 43 0.466
Zanrosso et al. (2006) (W) [19] 43 59 35 50 8 10 121 168 51 70 0.896
Zanrosso et al. (2006) (nW) [19] 53 37 21 32 5 10 127 106 31 52 0.462
Kim et al. (2006) [22] 17 24 38 55 11 21 72 103 60 97 0.313
Reddy et al. (2006) [21] 51 79 77 58 7 5 179 216 91 68 0.148
Petra et al. (2007) [24] 30 112 33 110 5 36 93 334 43 182 0.287
Kamel et al. (2007) [23] 39 156 42 135 7 20 120 447 56 175 0.195
Liu et al. (2008) [27] 34 38 23 36 26 9 91 112 75 54 0.914
Giovannetti et al. (2008) [25] 51 26 11 6 3 0 113 58 17 6 0.558
Alcasabas et al. (2008) [26] 145 322 41 66 3 6 331 710 47 78 0.227
de Jonge et al. (2009) [28] 130 219 93 223 22 54 353 661 137 331 0.805
Kim et al. (2009) [29] 29 540 51 863 27 297 109 1943 105 1457 0.132
Yeoh et al. (2009) [30] 184 163 111 150 23 32 479 476 157 214 0.765
1598 J. Wang et al. / Leukemia Research 34 (2010) 1596–1600
Fig. 1. Forest plot of the OR of T allele vs. C allele. The size of the squares reflects each study’s relative weight and the diamond (♦) represents the aggregate OR and 95% CI.
The studies provided 3358 cases and 6961 controls for C677T.
The variant genotype and allele frequencies of C677T in the indi-
vidual studies are shown in Table 2. For case groups, the frequency
of C677T polymorphism among CC-homozygous individuals was
48.9%; while 40.9% of CT-heterozygous individuals and 10.2% of
TT-homozygous individuals displayed C677T polymorphism. In
control groups, the frequencies of C677T polymorphism among
CC-homozygous individuals, CT-heterozygous individuals, and TT-
homozygous individuals were 43.1%, 45.0%, and 12.1%, respectively.
The 677T allelic frequencies in the case and control groups were
30.8% and 34.5%, respectively. In three studies [9–11] of the C677T
polymorphism, the distribution of genotypes in the control group
was not in HWE (P < 0.05), indicating genotyping errors and/or pop-
ulation stratification (Table 2). These three studies were excluded
from this meta-analysis to clarify the effect of MTHFR C677T on the
risk of childhood ALL.
3.2. Meta-analysis results
Table 3 lists the main results of this meta-analysis. Overall,
the 677T allele was not associated with the risk of childhood ALL
compared with the C allele (OR = 0.93; 95% CI = 0.82–1.07, Fig. 1).
Contrasting homozygotes (TT vs. CC), the recessive model, and the
dominant model produced the same pattern of results as the allele
contrast. In the analysis stratified by ethnicity and region, no sig-
nificant associations were found between childhood ALL and the
various genetic models. There was extreme heterogeneity (I2 = 65%,
P < 0.0001) among the 18 studies. To eliminate heterogeneity, we
divided the 18 studies into subgroups as far as possible; subse-
quently, heterogeneity only decreased for subgroups of white and
European subjects, which revealed that most of the studies could
not be grouped helpfully according to ethnicity and region.
3.3. Publication bias
Begg’s funnel plot and Egger’s test were performed to assess
the publication bias of literatures. Evaluation of publication bias
for 677T allele versus C allele showed that the Egger test was not
significant (P = 0.346). These results did not indicate a potential for
publication bias. For TT versus CC, the publication bias was also not
found (P = 0.356).
4. Discussion
It is well recognized that individual susceptibility to the same
kind of cancer can vary, even with identical environmental expo-
sures. Host factors, including polymorphism in the genes involved
in carcinogenesis may account for this difference. Therefore,
genetic susceptibility to cancer has been the focus of research in
the scientific community. Recently, genetic variants of the MTHFR
gene have been subject to increasing attention in the etiology of
leukemia. This meta-analysis summarized all the available data
on the association between MTHFR C677T and childhood acute
lymphoblastic leukemia, including a total of 3358 cases and 6961
controls. Our results indicated no evidence for a major protective
role of MTHFR C677T in the carcinogenesis of childhood acute lym-
phoblastic leukemia. Additionally, white ethnicity and European
region were not found to be significantly associated with any of
the genetic models. Although in Caucasians, no significant associa-
tions were found for the genetic models examined, heterogeneity
disappeared when that population was viewed as a separate group,
which suggested that the effect of T allele on the risk of pediatric
ALL may differ by ethnicity. Population stratification is an area of
concern, and it can lead to spurious evidence for the association
between the genetic marker and the disease, suggesting a possible
role of ethnic differences in genetic backgrounds and environments
[31].
In an effort to shed some light on the impact of MTHFR C677T on
pediatric ALL, data was pooled from available published trials for
meta-analysis. However, two previous meta-analyses [12,13] per-
formed almost at the same time came to different conclusions from
one another. One of these previously published meta-analyses [12]
drew on four fewer publications than the other [13]. Of these four
missed/excluded publications, two examined adult ALL [32,33] and
two evaluated childhood ALL [15,19]. In fact, electronic searches
by Zintzaras et al. were carried out solely using Medline [12]. The
use of this database alone is not sufficient for literature searches
[34]. Previous research assessing different electronic databases has
 J. Wang et al. / Leukemia Research 34 (2010) 1596–1600 1599

Table 3
Odds ratios (ORs) and heterogeneity results for the genetic contrasts of MTHFR gene C677T polymorphisms for childhood acute lymphoblastic leukemia.

Population OR I2 (%) P value Q test

Fixed effects (95% CI) Random effects (95% CI)

All 0.95 (0.89–1.02) 0.93 (0.82–1.07) 65 <0.0001

Non-White 1.02 (0.91–1.15) 1.03 (0.80–1.31) 73 0.0001
White 0.91 (0.84–1.00) 0.87 (0.76–1.01) 51 0.04
Alleles (T vs. C)
European 0.93 (0.84–1.03) 0.89 (0.75–1.05) 54 0.05
Asian 1.05 (0.92–1.20) 1.09 (0.83–1.43) 72 0.0007
East Asiana 0.96 (0.82–1.11) 0.97 (0.68–1.39) 79 0.0007

All 0.91 (0.78–1.07) 0.87 (0.68–1.11) 44 0.02

Non-White 1.08 (0.82–1.42) 1.05 (0.67–1.67) 55 0.02
White 0.84 (0.68–1.02) 0.80 (0.62–1.02) 21 0.25
TT to CC
European 0.88 (0.70–1.10) 0.85 (0.65–1.12) 17 0.30
Asian 1.18 (0.88–1.58) 1.20 (0.72–2.01) 57 0.02
East Asian 1.11 (0.81–1.52) 1.07 (0.56–2.06) 72 0.006

All 0.98 (0.84–1.14) 0.95 (0.76–1.18) 38 0.05

Non-White 1.19 (0.93–1.54) 1.16 (0.78–1.72) 48 0.04
White 0.87 (0.72–1.06) 0.87 (0.72–1.07) 3 0.41
TT to (CT + CC)
European 0.93 (0.75–1.15) 0.94 (0.76–1.17) 0 0.43
Asian 1.26 (0.96–1.65) 1.25 (0.80–1.96) 52 0.04
East Asian 1.24 (0.93–1.64) 1.20 (0.68–2.14) 71 0.009

All 0.93 (0.84–1.02) 0.91 (0.76–1.08) 65 <0.0001

Non-White 1.00 (0.85–1.16) 1.00 (0.73–1.38) 72 0.0002
White 0.89 (0.79–1.00) 0.84 (0.69–1.03) 55 0.02
TT + CT to CC
European 0.89 (0.78–1.02) 0.85 (0.67–1.07) 59 0.03
Asian 1.03 (0.86–1.22) 1.07 (0.75–1.53) 72 0.0008
East Asian 0.82 (0.67–1.01) 0.85 (0.58–1.23) 60 0.04
a
East Asian is composed of Chinese and Korean.

demonstrated that a single search engine does not provide all of
the pertinent articles, and combining more databases yields greater
coverage of possible articles [35]. Conference proceedings and jour-
nal supplements should also be searched to ensure that relevant
remaining reports are identified. However, additional assessments
of databases other than PubMed and EMBASE should be analyzed
with caution, due to a potential lack of quality in study design.
Although the other meta-analysis included more publications in
its analysis, one study may not suitable for the subgroup analysis
according to age [36]. In this study, cases and controls were not
matched for age and gender (P < 0.05).
Krajinovic et al. found a protective effect of MTHFR polymor-
phisms in children born before 1996 (about the time that Health
Canada recommended folate supplementation during pregnancy)
but not in children born later [14]. More conceivable would be the
relation between folate status and genotype in adult ALL, where
folate status might be more conditional on the subject’s own geno-
type and folate intake. In studies of breast cancer risk, high folate
intake may be more protective in women with the polymorphism
than in those with the wild type [37,38]. These findings demon-
strate that the risks associated with the MTHFR 677 TT genotype
vary depending on folate status. Genetic and/or environmental
exposures are required for cancer to develop. None of the studies to
date has assessed dietary folate intake to evaluate whether overall
folate status may have modified the relation between having the
MTHFR genotype and one’s risk of developing leukemia. We cannot
rule out the possibility that the C677T variant plays a major role in
risk modulation in pediatric ALL for populations with inadequate
folate intake.
Considering some limitations of this meta-analysis, our results
should be interpreted with caution. Firstly, heterogeneity is
a potential problem when interpreting the results from any
meta-analysis. We minimized the likelihood of encountering het-
erogeneity problems by performing a careful search for published
studies and using explicit criteria for study inclusion, precise
data extraction, and strict data analysis. Significant between-study
heterogeneity existed in almost each comparison. Heterogene-
ity can result from study differences in the selection of controls,
age distribution, lifestyle factors, and so on. There are major
differences of genetic background within the Asian population
studied, and it should be stratified to add more flavor to the
subject. Secondly, only published studies were included in this
meta-analysis. The presence of publication bias indicates that non-
significant or negative findings may be unpublished. Lastly, our
results were based on unadjusted estimates, while a more pre-
cise analysis should be conducted using individual data if they
were available, which would allow researchers to adjust covari-
ates including age, ethnicity, family history, environmental factors,
and lifestyle.
In conclusion, although studies investigating the association
between MTHFR C667T polymorphism and the risk of childhood
ALL arrive at different conclusions, this meta-analysis suggests
that MTHFR C667T polymorphism is not associated with childhood
ALL.
Conflict of interest
We declare that we have no financial and personal relationships
with other people or organizations that can inappropriately influ-
ence our work, there is no professional or other personal interest of
any nature or kind in any product, service and company that could
be construed as influencing the position presented in, or the review
of, the manuscript.
Acknowledgements
Contributions. JW, PZ and JO conceived and designed the study.
JW, PZ and BC did the electronic search, data collection, abstrac-
tion, hand-search of journals, and data entry; RZ and YY were
responsible for the quality assessment of trials and quality scores;
JW and PZ were statistical advisers; JW, BC, RZ and JO were
responsible for the overall direction of the text and discus-
sion.
1600 J. Wang et al. / Leukemia Research 34 (2010) 1596–1600
References
[1] Chen CL, Liu Q, Pui CH, Rivera GK, Sandlund JT, Ribeiro R, et al. Higher frequency
of glutathione Stransferase deletions in black children with acute lymphoblas-
tic leukemia. Blood 1997;89(5):1701–7.
[2] Sinnett D, Krajinovic M, Labuda D. Genetic susceptibility to childhood acute
lymphoblastic leukemia. Leuk Lymphoma 2000;38(5–6):447–62.
[3] Gilliland DG. Molecular genetics of human leukemia. Leukemia 1998;12(Suppl.
1):S7–12.
[4] Smith MT, McHale CM, Wiemels JL, Zhang L, Wiencke JK, Zheng S, et al. Molec-
ular biomarkers for the study of childhood leukemia. Toxicol Appl Pharmacol
2005;206(2):237–45.
[5] Cnattingius S, Zack MM, Ekbom A, Gunnarskog J, Kreuger A, Linet M, et al.
Prenatal and neonatal risk factors for childhood lymphatic leukemia. J Natl
Cancer Inst 1995;87(12):908–14.
[6] Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, et al. A
candidate genetic risk factor for vascular disease: a common mutation in
methylenetetrahydrofolate reductase. Nat Genet 1995;10(1):111–3.
[7] Dong LM, Potter JD, White E, Ulrich CM, Cardon LR, Peters U. Genetic sus-
ceptibility to cancer: the role of polymorphisms in candidate genes. JAMA
2008;299(20):2423–36.
[8] Franco RF, Simões BP, Tone LG, Gabellini SM, Zago MA, Falcão RP. The
methylenetetrahydrofolate reductase C677T gene polymorphism decreases
the risk of childhood acute lymphocytic leukaemia. Br J Haematol
2001;115(3):616–8.
[9] Jiang H, Gu LJ, Xue HL. Methylenetetrahydrofolate reductase gene polymor-
phism of childhood acute lymphocytic leukaemia. Zhonghua Xue Ye Xue Za
Zhi 2004;25(7):439–40.
[10] 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
USA 2001;98(7):4004–9.
[11] Balta G, Yuksek N, Ozyurek E, Ertem U, Hicsonmez G, Altay C, et al. Character-
ization of MTHFR, GSTM1, GSTT1, GSTP1, and CYP1A1 genotypes in childhood
acute leukemia. Am J Hematol 2003;73(3):154–60.
[12] Zintzaras E, Koufakis T, Ziakas PD, Rodopoulou P, Giannouli S, Voulgarelis M.
A meta-analysis of genotypes and haplotypes of methylenetetrahydrofolate
reductase gene polymorphisms in acute lymphoblastic leukemia. Eur J Epi-
demiol 2006;21(7):501–10.
[13] Pereira TV, Rudnicki M, Pereira AC, Pombo-de-Oliveira MS, Franco RF.
5,10-Methylenetetrahydrofolate reductase polymorphisms and acute lym-
phoblastic leukemia risk: a meta-analysis. Cancer Epidemiol Biomark Prev
2006;15(10):1956–63.
[14] Krajinovic M, Lamothe S, Labuda D, Lemieux-Blanchard E, Theoret Y, Moghrabi
A, et al. Role of MTHFR genetic polymorphisms in the susceptibility to childhood
acute lymphoblastic leukemia. Blood 2004;103(1):252–7.
[15] Thirumaran RK, Gast A, Flohr T, Burwinkel B, Bartram C, Hemminki K, et al.
MTHFR genetic polymorphisms and susceptibility to childhood acute lym-
phoblastic leukemia. Blood 2005;106(7):2590–1.
[16] Oliveira E, Alves S, Quental S, Ferreira F, Norton L, Costa V, et al. The MTHFR
C677T and A1298C polymorphisms and susceptibility to childhood acute lym-
phoblastic leukemia in Portugal. J Pediatr Hematol Oncol 2005;27(8):425–9.
[17] Schnakenberg E, Mehles A, Cario G, Rehe K, Seidemann K, Schlegelberger B,
et al. Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and
susceptibility to pediatric acute lymphoblastic leukemia in a German study
population. BMC Med Genet 2005;6:23.
[18] Chatzidakis K, Goulas A, Athanassiadou-Piperopoulou F, Fidani L, Koliouskas D,
Mirtsou V. Methylenetetrahydrofolate reductase C677T polymorphism: asso-
ciation with risk for childhood acute lymphoblastic leukemia and response
during the initial phase of chemotherapy in Greek patients. Pediatr Blood Can-
cer 2006;47(2):147–51.
[19] Zanrosso CW, Hatagima A, Emerenciano M, Ramos F, Figueiredo A, Félix TM,
et al. The role of methylenetetrahydrofolate reductase in acute lymphoblastic
leukemia in a Brazilian mixed population. Leuk Res 2006;30(4):477–81.
[20] Yu H, Jin RM, Bai Y. The relationship between the methylenetetrahydrofo-
late reductase C677T gene polymorphism and acute lymphocytic leukemia in
children. Lin Chuang Xue Ye Xue Za Zhi 2006;19(4):205–9.
[21] Reddy H, Jamil K. Polymorphisms in the MTHFR gene and their possible associ-
ation with susceptibility to childhood acute lymphocytic leukemia in an Indian
population. Leuk Lymphoma 2006;47(7):1333–9.
[22] Kim NK, Chong SY, Jang MJ, Hong SH, Kim HS, Cho EK, et al. Associa-
tion of the methylenetetrahydrofolate reductase polymorphism in Korean
patients with childhood acute lymphoblastic leukemia. Anticancer Res
2006;26(4B):2879–81.
[23] Kamel AM, Moussa HS, Ebid GT, Bu RR, Bhatia KG. Synergistic effect of methyl-
tetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphism as risk
modifiers of pediatric acute lymphoblastic leukemia. J Egypt Natl Canc Inst
2007;19(2):96–105.
[24] Petra BG, Janez J, Vita D. Gene–gene interactions in the folate metabolic path-
way influence the risk for acute lymphoblastic leukemia in children. Leuk
Lymphoma 2007;48(4):786–92.
[25] Giovannetti E, Ugrasena DG, Supriyadi E, Vroling L, Azzarello A, de Lange D,
et al. Methylenetetrahydrofolate reductase (MTHFR) C677T and thymidylate
synthase promoter (TSER) polymorphisms in Indonesian children with and
without leukemia. Leuk Res 2008;32(1):19–24.
[26] Alcasabas P, Ravindranath Y, Goyette G, Haller A, Del Rosario L, Lesaca-Medina
MY, et al. 5,10-Methylenetetrahydrofolate reductase (MTHFR) polymorphisms
and the risk of acute lymphoblastic leukemia (ALL) in Filipino children. Pediatr
Blood Cancer 2008;51(2):178–82.
[27] Liu JX, Chen JP, Lin DX. Polymorphisms in the MTHFR gene and their possible
association with susceptibility to acute lymphocytic leukemia. Jie Fang Jun Za
Zhi 2008;33(11):1291–3.
[28] de Jonge R, Tissing WJ, Hooijberg JH, Jansen G, Kaspers GJ, Lindemans J, et al.
Polymorphisms in folate-related genes and risk of pediatric acute lymphoblas-
tic leukemia. Blood 2009;113(10):2284–9.
[29] Kim HN, Kim YK, Lee IK, Yang DH, Lee JJ, Shin MH, et al. Association between
polymorphisms of folate-metabolizing enzymes and hematological malignan-
cies. Leuk Res 2009;33(1):82–7.
[30] Yeoh AE, Lu Y, Chan JY, Chan YH, Ariffin H, Kham SK, et al. Genetic sus-
ceptibility to childhood acute lymphoblastic leukemia shows protection in
Malay boys: results from the Malaysia–Singapore ALL Study Group. Leuk Res
2010;34(3):276–83.
[31] Hirschhorn JN, Lohmueller K, Byrne E. A comprehensive review of genetic asso-
ciation studies. Genet Med 2002;4:45–61.
[32] Deligezer U, Akisik E, Dalay N. Genotyping of the MTHFR gene polymor-
phism, C677T in patients with leukemia by melting curve analysis. Mol Diagn
2003;7(3–4):181–5.
[33] Gemmati D, Ongaro A, Scapoli GL, Della Porta M, Tognazzo S, Serino ML, 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 2004;13(5):787–
94.
[34] Shuman AL. For literature searches, is Medline enough? Perception of an ade-
quate literature search. Lab Anim (NY) 2004;33(2):15–6.
[35] Brand-de Heer DL. A comparison of the coverage of clinical medicine provided
by PASCAL BIOMED and MEDLINE. Health Info Libr J 2001;18(2):110–6.
[36] Chiusolo P, Reddiconto G, Cimino G, Sica S, Fiorini A, Farina G, et al.
Methylenetetrahydrofolate reductase genotypes do not play a role in acute
lymphoblastic leukemia pathogenesis in the Italian population. Haematologica
2004;89(2):139–44.
[37] Chen J, Gammon MD, Chan W, Palomeque C, Wetmur JG, Kabat GC, et al. One-
carbon metabolism, MTHFR polymorphisms, and risk of breast cancer. Cancer
Res 2005;65(4):1606–14.
[38] Shrubsole MJ, Gao YT, Cai Q, Shu XO, Dai Q, Hébert JR, et al. MTHFR poly-
morphisms, dietary folate intake, and breast cancer risk: results from the
Shanghai Breast Cancer Study. Cancer Epidemiol Biomark Prev 2004;13(2):
190–6.