CLINICAL STUDY

5,10-Methylenetetrahydrofolate reductase (MTHFR), methioninesynthase (MTRR), and methionine synthase reductase (MTR) genepolymorphisms and adult meningioma risk

Jun Zhang • Yan-Wen Zhou • Hua-Ping Shi •

Yan-Zhong Wang • Gui-Ling Li • Hai-Tao Yu •

Xin-You Xie

Received: 13 January 2013 / Accepted: 4 August 2013 / Published online: 20 August 2013

� Springer Science+Business Media New York 2013

Abstract The causes of meningiomas are not well under-

stood. Folate metabolism gene polymorphisms have been

shown to be associated with various human cancers. It is still

controversial and ambiguous between the functional poly-

morphisms of folate metabolism genes 5,10-methylenete-

trahydrofolate reductase (MTHFR), methionine synthase

(MTRR), and methionine synthase reductase (MTR) and risk

of adult meningioma. A population-based case–control study

involving 600 meningioma patients (World Health Organi-

zation [WHO] Grade I, 391 cases; WHO Grade II, 167 cases;

WHO Grade III, 42 cases) and 600 controls was done for the

MTHFR C677T and A1298C, MTRR A66G, and MTR

A2756G variants in Chinese Han population. The folate

metabolism gene polymorphisms were determined by using a

polymerase chain reaction–restriction fragment length poly-

morphism assay. Meningioma cases had a significantly lower

frequency of MTHFR 677 TT genotype [odds ratio

(OR) = 0.49, 95 % confidence interval (CI) 0.33–0.74;

P = 0.001] and T allele (OR = 0.80, 95 % CI 0.67–0.95;

P = 0.01) than controls. A significant association between

risk of meningioma and MTRR 66 GG (OR = 1.41, 95 % CI

1.02–1.96; P = 0.04) was also observed. When stratifying by

the WHO grade of meningioma, no association was found.

Our study suggested that MTHFR C677T and MTRR A66G

variants may affect the risk of adult meningioma in Chinese

Han population.

Keywords Methylenetetrahydrofolate reductase �Methionine synthase �Methionine synthase reductase �Meningioma � Gene polymorphism

Introduction

Meningioma is now the most common brain/central nervous

system tumor type in the US [1]. It is also a common brain

tumor in China [2, 3]. Many meningiomas are benign (WHO

Grade I), but up to 20 % of all meningiomas are assigned to

the WHO Grades II (atypical) and III (anaplastic/malignant

meningiomas) [4]. Despite their largely benign histology,

these tumors can cause serious morbidity by virtue of their

intracranial location [5, 6]. The 5 year survival rate of

patients with meningioma could be 81.8 % [7]. The causes

of meningiomas are not well understood. Most cases are

sporadic, appearing randomly, while some are familial. Few

studies have examined the risk factors associated with a

diagnosis of meningioma with two categories of exposure,

hormones (both endogenous and exogenous) and radiation,

most strongly associated with meningioma risk [8–10].

Evidence from prior epidemiologic studies, although

inconsistent, suggests a possible association between the risk

of meningioma and some gene polymorphisms [8, 11].

Folate metabolism genes 5,10-methylenetetrahydrofolate

reductase (MTHFR), methionine synthase (MTRR), and

methionine synthase reductase (MTR) play important and

interrelated roles in the folate metabolic pathway [12]. The

MTHFR gene, located on chromosome 1 (1p36.3), encodes for

methylenetetrahydrofolate reductase enzyme, which plays an

J. Zhang � Y.-W. Zhou � H.-P. Shi � Y.-Z. Wang � G.-L. Li �H.-T. Yu � X.-Y. Xie (&)

Clinical Laboratory, Sir Run Run Show Hospital, School of

Medicine, Zhejiang University, No. 3 QingChun East Road,

Hangzhou 310016, China

e-mail: xiexyx@hotmail.com

J. Zhang � Y.-W. Zhou � G.-L. Li � H.-T. Yu � X.-Y. Xie

Key Laboratory of Biotherapy of Zhejiang Province,

Hangzhou 310016, China

H.-P. Shi

Hangzhou Red Cross Hospital, Hangzhou 310003, China

123

J Neurooncol (2013) 115:233–239

DOI 10.1007/s11060-013-1218-z

important role in folate metabolism [13–15]. It has been

demonstrated that the C677T and A1298C are two common

polymorphisms in the MTHFR gene affecting enzyme activity

[16–18]. The polymorphisms of MTR A2756G and MTRR

A66G result in homocysteine elevation and DNA hypome-

thylation [19]. Folate metabolism gene polymorphisms have

been shown to be associated with various human cancers.

Compared with other cancer types, the role of polymor-

phic variants of the folate metabolism genes as risk factors

for meningioma has received comparatively little attention

[4, 20, 21]. One small case–control study comprised of 74

patients with histologically-verified primary brain tumors

and 98 cancer-free control subjects suggested that the

MTHFR C667T polymorphism was not associated with

meningioma patients [21]. A case-controlled, monocenter

association study included 290 patients of Caucasian origin

undergoing surgical resection for intracranial meningioma

(WHO Grade I, 190 cases; WHO Grade II, 82 cases; WHO

Grade III, 18 cases) and 287 age- and sex-matched local

controls revealed an association of the MTR A2756G variant

with meningioma WHO Grade III [4]. Another case–control

study comprised of 1,005 glioma cases, 631 meningioma

cases, and 1,101 controls suggested that the MTHFR C667T

and MTRR A66G polymorphisms were associated with

meningioma [20]. It is still controversial and ambiguous

between the functional polymorphisms of folate metabolism

genes (MTHFR, MTRR, and MTR) and risk of adult menin-

gioma [4, 20]. The purpose of this study was to examine the

effect of folate metabolism gene polymorphisms on adult

meningioma risk in Chinese Han population.

Materials and methods

Study subjects

This is a population-based case–control study involving

600 meningioma patients and 600 controls during the years

2008 to 2012 in Chinese Han population from the Sir Run

Run Show Hospital of Zhejiang University, China. All

histological diagnoses were made in the Sir Run Run Show

Hospital of Zhejiang University. Controls were randomly

selected from the population registry continuously

throughout the study period, stratified on sex, age, and

catchment area. In addition, similar to the cases they were

all required to be born in China to native Chinese parents.

The controls were recruited in parallel to the cases; each

time a new meningioma patient was included in the study

we sought a control meeting the matching criteria. It was

also required that this control subjects was in sufficiently

good condition to provide a blood sample. The study was

approved by the local ethics committee. All participants

gave informed written consent.

Genotyping

DNA was extracted from leukocytes using the phenol–

chloroform method [22, 23]. The MTHFR C677T and

A1298C, MTRR A66G, and MTR A2756G were deter-

mined by using a polymerase chain reaction–restriction

fragment length polymorphism (PCR–RFLP) assay. Based

on the GenBank reference sequence, the PCR primers were

listed in Table 1. When digested with HinfI, MTHFR

677CC produced one band of 198 bp and MTHFR 677TT

produced two bands of 175 and 23 bp. When digested with

MboII, MTHFR 1298AA produced three bands of 182, 28

and 27 bp, MTHFR 1298CC produced two bands of 210

and 27 bp. When digested with HaeIII, MTR 2756AA

produced one 211 bp band, MTR 2756GG produced two

bands of 131 and 80 bp. When digested with NdeI, MTRR

66AA produced two bands of 124 and 27 bp, MTRR 66GG

produced one 151 bp band. The digestion products were

then subjected to electrophoresis in 3 % agarose gel, and

alleles were evaluated according to band size. Control

samples were always used from homozygous and hetero-

zygous individuals during the RFLP procedures.

Statistical analysis

The allele and genotype frequencies of folate metabolism

gene in patients were compared to controls using the v2 test.

The Hardy–Weinberg equilibrium was tested for goodness-

of-fit Chi square test with one degree of freedom to compare

the observed genotype frequencies among the subjects with

the expected genotype frequencies. Data were analyzed using

the SPSS statistical package software version 17 (SPSS Inc.,

Chicago, IL, USA). Comparisons between groups were made

with v2 test (nominal data) or Student t test (interval data). A

P-value was considered significant at a level of\0.05.

Results

Characteristics of participants

Characteristics of meningioma cases and controls were

showed in Table 2. The mean age was 53.3 (±9.7) years

for the meningioma cases and 52.9 (±9.4) years for the

controls. The 62.5 % meningioma cases were female for

the meningioma cases and 58.3 % for the controls. We

found no significant differences in the smoking status

(P = 0.32), drinking (P = 0.39), or family history of

cancer (P = 0.37) when the groups were compared. Six

hundred meningioma cases were enrolled, 391 cases with

WHO Grade I, 167 with WHO Grade II, and 42 with WHO

Grade III. The genotype frequencies were in agreement

with the Hardy–Weinberg equilibrium.

234 J Neurooncol (2013) 115:233–239

123

MTHFR C677T polymorphism and adult meningioma

Meningioma cases had a significantly lower frequency of

MTHFR 677 TT genotype [odds ratio (OR) = 0.49, 95 %

confidence interval (CI) 0.33–0.74; P = 0.001] and T

allele (OR = 0.80, 95 % CI 0.67–0.95; P = 0.01) than

controls (Table 3). When stratifying by the WHO grade of

meningioma, no association was found (Table 4).

MTHFR A1298C polymorphism and adult meningioma

We found no significant association between risk of

meningioma and MTHFR A1298C polymorphism

(Table 3). When stratifying by the WHO grade of menin-

gioma, no association was found (Table 4).

MTRR A66G polymorphism and adult meningioma

A significant association between risk of meningioma and

MTRR 66 GG (OR = 1.41, 95 % CI 1.02–1.96; P = 0.04)

was also observed (Table 3). When stratifying by the WHO

grade of meningioma, no association was found (Table 4).

MTR A2756G polymorphism and adult meningioma

We found no significant association between risk of

meningioma and MTR A2756G polymorphism (Table 3).

When stratifying by the WHO grade of meningioma, no

association was found (Table 4).

Discussion

We analyzed the MTHFR C677T and A1298C, MTRR

A66G, and MTR A2756G polymorphisms in 600 meningi-

oma patients and 600 controls. Meningioma cases had a

significantly lower frequency of MTHFR 677 TT genotype

and T allele than controls. A significant association between

risk of meningioma and MTRR 66 GG was also observed.

When stratifying by the WHO grade of meningioma, no

association was found. These results differ from previous

study [20]. A gene and gene or gene and environment

interaction makes sense to explain our difference in results,

since Chinese Han population have different genetic and

environmental backgrounds against which this variant is

exerting its influence. Of course, false positives by our study,

others, or both could also explain these results.

There is increasing evidence investigating the association

between genetic polymorphisms and risk of meningiomas.

Dobbins et al. [11] conducted a genome-wide association

study (GWAS) and identified a new susceptibility locus for

meningioma at 10p12.31 (MLLT10, rs11012732). But no

GWAS be conducted in Chinese Han population. A case-

controlled, monocenter association study included 290

patients of Caucasian origin undergoing surgical resection

for intracranial meningioma and 287 age- and sex-matched

Table 1 Restriction enzyme and primer sequences of folate metabolism gene

Gene and SNP SNP ID Restriction

enzyme

Forward primer Reverse primer

MTHFR C677T rs1801133 HinfI 50-TGAAGGAGAAGGTGTCTGCGGGA-30 50-AGGACGGTGCGGTGAGAGTG-30

MTHFR A1298C rs1801131 MboII 50-AAGGAGGAGCTGCTGAAGATG-30 50-CTTTGCCATGTCCACAGCATG-30

MTRR A66G rs1801394 NdeI 50-CAGGCAAAGGCCATCGCAGAAGA

CAT-3050-CACTTCCCAACCAAAATTCTTCA

AAG-30

MTR A2756G rs1805087 HaeIII 50-TGTTCCCAGCTGTTAGATGAAAATC-30 50-GATCCAAAGCCTTTTACAC

TCCTC-30

Table 2 Characteristics of meningioma cases and controls

Meningioma

(n = 600)

Controls

(n = 600)

P value

Age, mean (SD) year 53.3 (9.7) 52.9 (9.4) 0.47

Sex 0.14

Male 225 (37.5) 250 (41.7)

Female 375 (62.5) 350 (58.3)

Smoking status

(male/female)

0.32

Never 460 (90/370) 445 (101/344)

Ever 140 (135/5) 155 (149/6)

Drinking 0.39

Never 443 (73.8) 456 (76.0)

Ever 157 (26.2) 144 (24.0)

Family history of cancer 0.37

Yes 118 (19.7) 106 (17.7)

No 482 (80.3) 494 (82.3)

WHO Grade

I 391 (65.2)

II 167 (27.8)

III 42 (7.0)

J Neurooncol (2013) 115:233–239 235

123

local controls suggested that genetic variants of methionine

metabolism were associated with meningioma formation [4].

The association between the folate metabolism gene

polymorphisms and other cancer types was much studied.

Meta-analysis suggested that the MTHFR 677T allele was a

low-penetrant risk factor for developing breast cancer [24,

25]. A meta-analysis suggested that MTHFR 677T allele

might provide protection against colorectal cancer in world-

wide populations, while MTRR 66G allele might increase the

risk of colorectal cancer in Caucasians [26, 27]. Prospective

case–control studies suggested that the MTHFR 677TT

genotype appears to increase ovarian cancer risk and worsen

its prognosis in a Chinese population [28, 29]. A matched

hospital-based case–control study with 155 esophageal cancer

and 310 non-cancer controls supported the hypothesis that

MTHFR C667T polymorphisms played a role in pathogenesis

of esophageal cancer in the Chinese population [30]. A meta-

analysis of 75,000 cases and 93,000 controls suggested that

MTHFR C667T homozygosity associated with increased risk

of esophagus and gastric cancer, and with decreased risk of

colorectal cancer [31]. A case–control study with 620 oral

cancer patients and 620 non-cancer controls suggested that

MTHFR C677T genotype may have joint effects with smok-

ing on oral carcinogenesis, and may be a useful biomarker for

prediction and prognosis of oral cancer [32]. A multicenter

case–control study enrolled 927 Korean women suggested

that the MTHFR C677T genotype may increase cervical

intraepithelial neoplasia and cervical cancer risk in women

with low folate or vitamin B12 status [33]. A case–control

study suggested that the heterozygote CT genotype and the

677T allele of the MTHFR polymorphism might be associated

with an decreased prostate cancer risk [34]. A meta-analysis

including 27 case–control studies suggested that C677T and

A1298C polymorphisms in the MTHFR gene were associated

with bladder cancer risk and prognosis [35]. A case–control

study comprised of 462 lung cancer cases and 379 controls in a

Japanese population suggested that MTHFR C677T poly-

morphism was significantly associated with lung cancer risk

[36]. A nested case–control study within the Nurses’ Health

Study suggests a possible role of the polymorphisms in

MTHFR gene (C677T and A1298C) and VDR gene (Fok1,

Bsm1 and Cdx2) interacting with dietary intakes of folate and

vitamin D in skin cancer development, especially for squa-

mous cell carcinoma [37]. A hospital-based, case–control

study of 1,035 lung cancer cases and 1,148 controls of non-

Hispanic whites provided evidence supporting the association

between the MTR A2756G and MTRR A66G polymorphisms

and lung cancer risk [38]. A hospital-based case–control study

showed that the GG genotype of MTRR A66G is a risk factor

for colorectal cancer in Japanese [39].

Table 3 Genotype frequencies

of folate metabolism gene in

meningioma cases and controls

Genotype Cases (%) Controls (%) OR (95 %CI) P

MTHFR C677T (rs1801133)

CC 298 (49.7) 278 (46.3) 1.00 (reference)

CT 259 (43.2) 241 (40.2) 1.00 (0.79–1.27) 0.98

TT 43 (7.1) 81 (13.5) 0.49 (0.33–0.74) 0.001

C allele frequency 855 (71.3) 797 (66.4) 1.00 (reference)

T allele frequency 345 (28.7) 403 (33.6) 0.80 (0.67–0.95) 0.01

MTHFR A1298C (rs1801131)

AA 283 (47.2) 289 (48.2) 1.00 (reference)

AC 241 (40.2) 245 (40.8) 1.01 (0.79–1.28) 0.97

CC 76 (12.6) 66 (11.0) 1.18 (0.81–1.70) 0.39

A allele frequency 807 (67.2) 823 (68.6) 1.00 (reference)

C allele frequency 393 (32.8) 377 (31.4) 1.06 (0.90–1.26) 0.48

MTRR A66G (rs1801394)

AA 209 (34.8) 225 (37.5) 1.00 (reference)

AG 269 (44.8) 282 (47.0) 1.03 (0.80–1.32) 0.84

GG 122 (20.4) 93 (15.5) 1.41 (1.02–1.96) 0.04

A allele frequency 687 (57.2) 732 (61.0) 1.00 (reference)

G allele frequency 513 (42.8) 468 (39.0) 1.17 (0.99–1.38) 0.06

MTR A2756G (rs1805087)

AA 347 (57.8) 361 (60.2) 1.00 (reference)

AG 198 (33.0) 190 (31.7) 1.08 (0.85–1.39) 0.52

GG 55 (9.2) 49 (8.1) 1.17 (0.77–1.76) 0.46

A allele frequency 892 (74.3) 912 (76.0) 1.00 (reference)

G allele frequency 308 (25.7) 288 (24.0) 1.09 (0.91–1.32) 0.35

236 J Neurooncol (2013) 115:233–239

123

Ta

ble

4S

trat

ifica

tio

nan

aly

sis

of

fola

tem

etab

oli

smg

ene

po

lym

orp

his

ms

and

WH

Og

rad

eo

fm

enin

gio

ma

WH

OG

rad

eC

ases

XX

XY

YY

n(%

)O

R(9

5%

CI)

Pn

(%)

OR

(95

%C

I)P

n(%

)O

R(9

5%

CI)

P

MT

HF

RC

67

7T

(rs1

80

11

33

)6

00

29

8(4

9.7

)1

(ref

eren

ce)

25

9(4

3.2

)1

(ref

eren

ce)

43

(7.1

)1

(ref

eren

ce)

I3

91

19

7(5

0.4

)1

.01

(0.8

1–

1.2

7)

0.9

01

65

(42

.2)

0.9

8(0

.77

–1

.23

)0

.85

29

(7.4

)1

.04

(0.6

4–

1.6

9)

0.8

9

II1

67

80

(47

.9)

0.9

7(0

.71

–1

.30

)0

.81

76

(45

.5)

1.0

5(0

.78

–1

.43

)0

.74

11

(6.6

)0

.92

(0.4

6–

1.8

2)

0.8

1

III

42

21

(50

.0)

1.0

1(0

.59

–1

.73

)0

.98

18

(42

.9)

0.9

9(0

.56

–1

.76

)0

.98

3(7

.1)

1.0

0(0

.30

–3

.35

)0

.99

MT

HF

RA

12

98

C(r

s18

01

13

1)

60

02

83

(47

.2)

1(r

efer

ence

)2

41

(40

.2)

1(r

efer

ence

)7

6(1

2.6

)1

(ref

eren

ce)

I3

91

18

4(4

7.1

)0

.99

(0.7

9–

1.2

5)

0.9

81

57

(40

.1)

1.0

0(0

.78

–1

.26

)0

.99

50

(12

.8)

1.0

1(0

.69

–1

.47

)0

.96

II1

67

79

(47

.3)

1.0

0(0

.74

–1

.35

)0

.98

67

(40

.1)

0.9

9(0

.72

–1

.37

)0

.99

21

(12

.6)

0.9

9(0

.59

–1

.65

)0

.97

III

42

20

(47

.6)

1.0

1(0

.58

–1

.75

)0

.97

17

(40

.5)

1.0

0(0

.56

–1

.80

)0

.97

5(1

1.9

)0

.94

(0.3

6–

2.4

4)

0.8

9

MT

RR

A6

6G

(rs1

80

13

94

)6

00

20

9(3

4.8

)1

(ref

eren

ce)

26

9(4

4.8

)1

(ref

eren

ce)

12

2(2

0.4

)1

(ref

eren

ce)

I3

91

13

5(3

4.5

)0

.99

(0.7

7–

1.2

7)

0.9

41

76

(45

.0)

1.0

0(0

.79

–1

.26

)0

.97

80

(20

.5)

1.0

0(0

.73

–1

.37

)0

.96

II1

67

59

(35

.3)

1.0

1(0

.72

–1

.41

)0

.93

74

(44

.3)

0.9

8(0

.72

–1

.34

)0

.94

34

(20

.4)

1.0

0(0

.66

–1

.51

)0

.99

III

42

15

(35

.7)

1.0

2(0

.55

–1

.88

)0

.93

19

(45

.2)

1.0

0(0

.57

–1

.76

)0

.97

8(1

9.1

)0

.93

(0.4

2–

2.0

4)

0.8

7

MT

RA

27

56

G(r

s18

05

08

7)

60

03

47

(57

.8)

1(r

efer

ence

)1

98

(33

.0)

1(r

efer

ence

)5

5(9

.2)

1(r

efer

ence

)

I3

91

22

6(5

7.8

)0

.99

(0.8

1–

1.2

3)

0.9

91

29

(33

.0)

1.0

0(0

.77

–1

.29

)0

.99

36

(9.2

)1

.00

(0.6

5–

1.5

5)

0.9

8

II1

67

97

(58

.1)

1.0

0(0

.75

–1

.33

)0

.97

55

(32

.9)

0.9

9(0

.70

–1

.40

)0

.99

15

(9.0

)0

.98

(0.5

4–

1.7

7)

0.9

4

III

42

24

(57

.2)

0.9

8(0

.58

–1

.66

)0

.96

14

(33

.3)

1.0

1(0

.54

–1

.88

)0

.97

4(9

.5)

1.0

3(0

.35

–3

.00

)0

.94

Ab

bre

via

tio

ns

X/Y

for

C/T

of

MT

HF

RC

67

7T

,A

/Co

fM

TH

FR

A1

29

8C

,A

/Go

fM

TR

RA

66

G,

A/G

of

MT

RA

27

56

G

J Neurooncol (2013) 115:233–239 237

123

The mechanisms of folate metabolism genes polymor-

phisms as a risk factor of meningioma are still unclear. It has

been demonstrated that the 677T allele of the MTHFR gene is

associated with a decrease in enzymatic activity [40]. Given

that studies have shown that the MTHFR 677TT genotype can

be associated with decreased global DNA methylation and

promoter-specific methylation in tumors [41], it is entirely

plausible that the variants we have studied will affect the risk

of meningioma. Although the functional effects of MTRR

A66G have not been fully established, in vitro experiments

suggest that variant MTRR enzyme restores MTR activity less

efficiently than wild-type, and the MTRR A66G genotype has

been shown to influence plasma homocysteine levels and

DNA hypomethylation in humans [19, 42, 43].

Strength of this study was a relatively large sample size.

Some shortcomings of this study should be noted. Firstly,

this study only considers a Chinese population that may

limit the application of these findings to other ethnic pop-

ulations. Secondly, although we and other epidemiologic

studies suggested statistically significant interactions

between folate metabolism genes polymorphisms and

meningioma risk, more biological background data are

needed to explain our results. Thirdly, the current finding

might involve gene-to-environment interactions, which

were not explored in the present study.

In conclusion, to the best of our knowledge this is the first

report of an association between folate metabolism genes

polymorphisms and meningiomas in Chinese Han popula-

tion. Our study suggested that MTHFR C677T and MTRR

A66G variants may affect the risk of adult meningioma. No

associations were found between folate polymorphisms and

meningioma after stratifying by WHO grade, which suggests

that meningioma risk is influenced by MTHFR C677T and

MTRR A66G variants but not necessarily tumor grade.

However it is highly desirable that our findings are validated

through replication in other case–control series.

Acknowledgments This study was supported by the grants from

National Natural Science Foundation of China (81271914), Zhejiang

Provincial Natural Science Foundation (LY12H16025), Science

Foundation of Health Bureau of Zhejiang Province (2011KYA081),

Science Foundation of Education Bureau of Zhejiang Province

(Y201121182) and Funds for Key Program of the Science Technol-

ogy Department Zhejiang Province (2012C13019-2).

Conflict of interest The authors declare that they have no conflict

of interests.

References

1. Dolecek TA, Propp JM, Stroup NE, Kruchko C (2012) CBTRUS

statistical report: primary brain and central nervous system

tumors diagnosed in the United States in 2005–2009. Neuro-

oncology 14(Suppl 5):v1–49

2. Li R, Wang R, Li Y, Li X, Feng Y, Li Y, Jiang C (2013)

Association study on MTHFR polymorphisms and meningioma in

northern China. Gene 516:291–293

3. Hu J, Little J, Xu T, Zhao X, Guo L, Jia X, Huang G, Bi D, Liu R

(1999) Risk factors for meningioma in adults: a case-control

study in northeast China. Int J Cancer 83:299–304

4. Semmler A, Simon M, Moskau S, Linnebank M (2008) Poly-

morphisms of methionine metabolism and susceptibility to

meningioma formation: laboratory investigation. J Neurosurg

108:999–1004

5. Kousi E, Tsougos I, Fountas K, Theodorou K, Tsolaki E, Fezo-

ulidis I, Kapsalaki E (2012) Distinct peak at 3.8 ppm observed by

3T MR spectroscopy in meningiomas, while nearly absent in

high-grade gliomas and cerebral metastases. Mol Med Rep

5:1011–1018

6. Zhang B, Zhao G, Yang HF, Wang D, Yu JL, Huang HY (2011)

Assessment of risk factors for early seizures following surgery for

meningiomas using logistic regression analysis. J Int Med Res

39:1728–1735

7. Weber DC, Schneider R, Goitein G, Koch T, Ares C, Geismar JH,

Schertler A, Bolsi A, Hug EB (2012) Spot scanning-based proton

therapy for intracranial meningioma: long-term results from the

Paul Scherrer Institute. Int J Radiat Oncol Biol Phys 83:865–871

8. Hosking FJ, Feldman D, Bruchim R, Olver B, Lloyd A, Vijaya-

krishnan J, Flint-Richter P, Broderick P, Houlston RS, Sadetzki S

(2011) Search for inherited susceptibility to radiation-associated

meningioma by genomewide SNP linkage disequilibrium map-

ping. Br J Cancer 104:1049–1054

9. Flint-Richter P, Mandelzweig L, Oberman B, Sadetzki S (2011)

Possible interaction between ionizing radiation, smoking, and gen-

der in the causation of meningioma. Neuro-oncology 13:345–352

10. Flint-Richter P, Sadetzki S (2007) Genetic predisposition for the

development of radiation-associated meningioma: an epidemio-

logical study. Lancet Oncol 8:403–410

11. Dobbins SE, Broderick P, Melin B, Feychting M, Johansen C,

Andersson U, Brannstrom T, Schramm J, Olver B, Lloyd A, Ma

YP, Hosking FJ, Lonn S, Ahlbom A, Henriksson R, Schoemaker

MJ, Hepworth SJ, Hoffmann P, Muhleisen TW, Nothen MM,

Moebus S, Eisele L, Kosteljanetz M, Muir K, Swerdlow A,

Simon M, Houlston RS (2011) Common variation at 10p12.31

near MLLT10 influences meningioma risk. Nat Genet

43:825–827

12. Cai D, Ning L, Pan C, Liu X, Bu R, Chen X, Wang K, Cheng Y,

Wu B (2010) Association of polymorphisms in folate metabolic

genes and prostate cancer risk: a case–control study in a Chinese

population. J Genet 89:263–267

13. Algasham A, Ismail H, Dewaidar M, Settin AA (2009) Methy-

lenetetrahydrofolate reductase and angiotensin-converting

enzyme gene polymorphisms among Saudi population from

Qassim region. Genet Test Mol Biomarkers 13:817–820

14. Ziva Cerne J, Stegel V, Gersak K, Novakovic S (2011) Lack of

association between methylenetetrahydrofolate reductase genetic

polymorphisms and postmenopausal breast cancer risk. Mol Med

Rep 4:175–179

15. Kristensen MH, Pedersen PL, Melsen GV, Ellehauge J, Mejer J

(2010) Variants in the dihydropyrimidine dehydrogenase,

methylenetetrahydrofolate reductase and thymidylate synthase

genes predict early toxicity of 5-fluorouracil in colorectal cancer

patients. J Int Med Res 38:870–883

16. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews

RG, Boers GJ, den Heijer M, Kluijtmans LA, van den Heuvel LP

et al (1995) A candidate genetic risk factor for vascular disease: a

common mutation in methylenetetrahydrofolate reductase. Nat

Genet 10:111–113

17. Weisberg I, Tran P, Christensen B, Sibani S, Rozen R (1998) A

second genetic polymorphism in methylenetetrahydrofolate

238 J Neurooncol (2013) 115:233–239

123

reductase (MTHFR) associated with decreased enzyme activity.

Mol Genet Metab 64:169–172

18. Kang SY, Lee SJ, Hong SH, Chung YK, Oh HS, Kim SW, Yim

DJ, Kim NK (2010) Polymorphisms of 5,10-methylenetetrahy-

drofolate reductase and thymidylate synthase in squamous cell

carcinoma and basal cell carcinoma of the skin. Mol Med Rep

3:741–747

19. Leclerc D, Campeau E, Goyette P, Adjalla CE, Christensen B,

Ross M, Eydoux P, Rosenblatt DS, Rozen R, Gravel RA (1996)

Human methionine synthase: cDNA cloning and identification of

mutations in patients of the cblG complementation group of

folate/cobalamin disorders. Hum Mol Genet 5:1867–1874

20. Bethke L, Webb E, Murray A, Schoemaker M, Feychting M,

Lonn S, Ahlbom A, Malmer B, Henriksson R, Auvinen A, Kiuru

A, Salminen T, Johansen C, Christensen HC, Muir K, McKinney

P, Hepworth S, Dimitropoulou P, Lophatananon A, Swerdlow A,

Houlston R (2008) Functional polymorphisms in folate metabo-

lism genes influence the risk of meningioma and glioma. Cancer

Epidemiol Biomarkers Prev 17:1195–1202

21. Kafadar AM, Yilmaz H, Kafadar D, Ergen A, Zeybek U, Bozkurt

N, Kuday C, Isbir T (2006) C677T gene polymorphism of

methylenetetrahydrofolate reductase (MTHFR) in meningiomas

and high-grade gliomas. Anticancer Res 26:2445–2449

22. Chomczynski P, Sacchi N (1987) Single-step method of RNA

isolation by acid guanidinium thiocyanate–phenol–chloroform

extraction. Anal Biochem 162:156–159

23. Chomczynski P, Sacchi N (2006) The single-step method of RNA

isolation by acid guanidinium thiocyanate-phenol-chloroform

extraction: twenty-something years on. Nat Protoc 1:581–585

24. Zhang J, Qiu LX, Wang ZH, Wu XH, Liu XJ, Wang BY, Hu XC

(2010) MTHFR C677T polymorphism associated with breast

cancer susceptibility: a meta-analysis involving 15,260 cases and

20,411 controls. Breast Cancer Res Treat 123:549–555

25. Qi X, Ma X, Yang X, Fan L, Zhang Y, Zhang F, Chen L, Zhou Y,

Jiang J (2010) Methylenetetrahydrofolate reductase polymor-

phisms and breast cancer risk: a meta-analysis from 41 studies

with 16,480 cases and 22,388 controls. Breast Cancer Res Treat

123:499–506

26. Zhou D, Mei Q, Luo H, Tang B, Yu P (2012) The polymorphisms

in methylenetetrahydrofolate reductase, methionine synthase,

methionine synthase reductase, and the risk of colorectal cancer.

Int J Biol Sci 8:819–830

27. Yang Z, Zhang XF, Liu HX, Hao YS, Zhao CL (2012) MTHFR

C677T polymorphism and colorectal cancer risk in Asians, a

meta-analysis of 21 studies. Asian Pac J Cancer Prev 13:

1203–1208

28. Zhang L, Liu W, Hao Q, Bao L, Wang K (2012) Folate intake and

methylenetetrahydrofolate reductase gene polymorphisms as

predictive and prognostic biomarkers for ovarian cancer risk. Int J

Mol Sci 13:4009–4020

29. Gao S, Liu N, Ma Y, Ying L (2012) Methylenetetrahydrofolate

reductase gene polymorphisms as predictive and prognostic

biomarkers in ovarian cancer risk. Asian Pac J Cancer Prev

13:569–573

30. Zhao P, Lin F, Li Z, Lin B, Lin J, Luo R (2011) Folate intake,

methylenetetrahydrofolate reductase polymorphisms, and risk of

esophageal cancer. Asian Pac J Cancer Prev 12:2019–2023

31. Zacho J, Yazdanyar S, Bojesen SE, Tybjaerg-Hansen A, Nor-

destgaard BG (2011) Hyperhomocysteinemia, methylenetetrahy-

drofolate reductase c.677C[T polymorphism and risk of cancer:

cross-sectional and prospective studies and meta-analyses of

75,000 cases and 93,000 controls. Int J Cancer 128:644–652

32. Tsai CW, Hsu CF, Tsai MH, Tsou YA, Hua CH, Chang WS, Lin

CC, Bau DT (2011) Methylenetetrahydrofolate reductase

(MTHFR) genotype, smoking habit, metastasis and oral cancer in

Taiwan. Anticancer Res 31:2395–2399

33. Tong SY, Kim MK, Lee JK, Lee JM, Choi SW, Friso S, Song ES,

Lee KB, Lee JP (2011) Common polymorphisms in methylenete-

trahydrofolate reductase gene are associated with risks of cervical

intraepithelial neoplasia and cervical cancer in women with low

serum folate and vitamin B12. Cancer Causes Control 22:63–72

34. Kucukhuseyin O, Kurnaz O, Akadam-Teker AB, Narter F, Yil-

maz-Aydogan H, Isbir T (2011) Effects of the MTHFR C677T

polymorphism on prostate specific antigen and prostate cancer.

Asian Pac J Cancer Prev 12:2275–2278

35. Kouidhi S, Rouissi K, Khedhiri S, Ouerhani S, Cherif M,

Benammar-Elgaaied A (2011) MTHFR gene polymorphisms and

bladder cancer susceptibility: a meta-analysis including race,

smoking status and tumour stage. Asian Pac J Cancer Prev

12:2227–2232

36. Kiyohara C, Horiuchi T, Takayama K, Nakanishi Y (2011)

Methylenetetrahydrofolate reductase polymorphisms and inter-

action with smoking and alcohol consumption in lung cancer risk:

a case–control study in a Japanese population. BMC Cancer

11:459

37. Han J, Colditz GA, Hunter DJ (2007) Polymorphisms in the

MTHFR and VDR genes and skin cancer risk. Carcinogenesis

28:390–397

38. Shi Q, Zhang Z, Li G, Pillow PC, Hernandez LM, Spitz MR, Wei

Q (2005) Polymorphisms of methionine synthase and methionine

synthase reductase and risk of lung cancer: a case-control anal-

ysis. Pharmacogenet Genomics 15:547–555

39. Matsuo K, Hamajima N, Hirai T, Kato T, Inoue M, Takezaki T,

Tajima K (2002) Methionine synthase reductase gene A66G

polymorphism is associated with risk of colorectal cancer. Asian

Pac J Cancer Prev 3:353–359

40. dos Santos PA, Longo D, Brandalize AP, Schuler-Faccini L

(2010) MTHFR C677T is not a risk factor for autism spectrum

disorders in South Brazil. Psychiatr Genet 20:187–189

41. Paz MF, Avila S, Fraga MF, Pollan M, Capella G, Peinado MA,

Sanchez-Cespedes M, Herman JG, Esteller M (2002) Germ-line

variants in methyl-group metabolism genes and susceptibility to

DNA methylation in normal tissues and human primary tumors.

Cancer Res 62:4519–4524

42. Gaughan DJ, Kluijtmans LA, Barbaux S, McMaster D, Young IS,

Yarnell JW, Evans A, Whitehead AS (2001) The methionine

synthase reductase (MTRR) A66G polymorphism is a novel

genetic determinant of plasma homocysteine concentrations.

Atherosclerosis 157:451–456

43. Olteanu H, Munson T, Banerjee R (2002) Differences in the

efficiency of reductive activation of methionine synthase and

exogenous electron acceptors between the common polymorphic

variants of human methionine synthase reductase. Biochemistry

41:13378–13385

J Neurooncol (2013) 115:233–239 239

123