RESEARCH ARTICLE Open Access
Methylenetetrahydrofolate reductase C677T
polymorphism in patients with lung cancer in a
Lian-Hua Cui1, Min-Ho Shin2*, Hee Nam Kim3, Hye-Rim Song2, Jin-Mei Piao2,6, Sun-Seog Kweon2,4, Jin-Su Choi2,
Woo-Jun Yun2, Young-Chul Kim5, In-Jae Oh5, Kyu-Sik Kim5
Background: This study was designed to investigate an association between methylenetetrahydrofolate reductase
(MTHFR) C677T polymorphism and the risk of lung cancer in a Korean population.
Methods: We conducted a large-scale, case-control study involving 3938 patients with newly diagnosed lung
cancer and 1700 healthy controls. Genotyping was performed with peripheral blood DNA for MTHFR C677T
polymorphisms. Statistical significance was estimated by logistic regression analysis.
Results: The MTHFR C677T frequencies of CC, CT, and TT genotypes were 34.5%, 48.5%, and 17% among lung cancer
patients, and 31.8%, 50.7%, and 17.5% in the controls, respectively. The MTHFR 677CT and TT genotype showed a weak
protection against lung cancer compared with the homozygous CC genotype, although the results did not reach
statistical significance. The age- and gender-adjusted odds ratio (OR) of overall lung cancer was 0.90 (95% confidence
interval (CI), 0.77-1.04) for MTHFR 677 CT and 0.88 (95% CI, 0.71-1.07) for MTHFR 677TT. However, after stratification
analysis by histological type, the MTHFR 677CT genotype showed a significantly decreased risk for squamous cell
carcinoma (age- and gender-adjusted OR, 0.78; 95% CI, 0.64-0.96). The combination of 677 TT homozygous with 677 CT
heterozygous also appeared to have a protection effect on the risk of squamous cell carcinoma. We observed no
significant interaction between the MTHFR C677T polymorphism and age and gender or smoking habit.
Conclusions: This is the first reported study focusing on the association between MTHFR C677T polymorphisms
and the risk of lung cancer in a Korean population. The T allele was found to provide a weak protective association
with lung squamous cell carcinoma.
Lung cancer is the leading cause of cancer-related death
worldwide. The incidence and mortality of lung cancer
have been significantly and constantly increasing over
the past two decades in Korea [1-3]. According to the
Korean National Cancer Registry, the age-standardized
incidence rate for lung cancer of Korean population was
47.5/100,000 for men and 13.3/100,000 for women in
2007 , it has become the second most common
malignant tumor following gastric cancer. The reason
for this increase in lung cancer has not been clearly
explained. Although it is well known that cigarette
smoking is the major cause of lung cancer, only 10-20%
of lifetime smokers are known to develop lung cancer.
Additionally, lung cancer is a multicellular and multi-
stage process involving a number of genetic changes in
oncogenes, suggesting that genetic factors may play an
important role in its development [4-6].
Methylenetetrahydrofolate reductase (MTHFR) is an
important enzyme in folate metabolism. A common
mutation of the MTHFR gene is the C to T transition at
nucleotide 677, which converts alanine to valine, results
in a thermo-labile enzyme with decreased activity .
The heterozygote and homozygous variant of C677T
were shown to have 65 and 30% of the enzyme activity,
respectively . The low enzymatic activity of the
* Correspondence: firstname.lastname@example.org
2Department of Preventive Medicine, Chonnam National University Medical
School, Gwangju, South Korea
Full list of author information is available at the end of the article
Cui et al. BMC Medical Genetics 2011, 12:28
© 2011 Cui et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
MTHFR C677T genotypic variant is associated with
DNA hypomethylation, which may induce genomic
instability or the derepression of proto-oncogenes.
To date, several studies have shown that the MTHFR
C677T polymorphism are associated with either
increased [9-12] or decreased [13-15] risk of lung cancer,
whereas others observed no association between the
MTHFR C677T genotype and genetic susceptibility to
lung cancer [16-18]. Small sample size, various ethnic
groups, diet, environment, and methodologies may be
responsible for the discrepancy. Therefore, a larger single
study is required to evaluate MTHFR C677T polymorph-
isms and the lung cancer risk in a specific population.
Additionally, to our knowledge, no previous report has
examined the effect of MTHFR C677T polymorphisms
on the risk of lung cancer in a Korean population. In the
present study, we performed a large population based
case-control study involving 3938 lung cancer patients
and 1700 healthy controls to evaluate whether MTHFR
C677T polymorphism was associated with lung cancer
risk in a Korean population. Additionally, we investigated
whether MTHFR C677T plays an interactive role in the
lung cancer risk in relation to histological subtypes and
The study population consisted of 3938 patients with
newly diagnosed lung cancer and 1700 population-based
controls. All enrolled patients were pathologically con-
firmed at Chonnam National University Hwasun Hospi-
tal between January 2000 and August 2010. Cases with
secondary or recurrent tumors were excluded.
The control group (n = 1700) consisted of participants
in the Thyroid Disease Prevalence Study , conducted
from July 2004 to January 2006 in the Yeonggwang and
Muan Counties of Jeollanam-do Province and in Namwon
City of Jeollabuk-do, Korea. A total of 4018 subjects were
randomly selected by 5-year age strata and sex. Of the
total number, 3486 were eligible subjects. Of those eligible,
1699 (48.8% of the eligible subjects; 820 men and 879
women), underwent clinical examinations. At the time of
their peripheral blood collections, all control subjects pro-
vided their informed consent to participate in this study.
This study was approved by the Institutional Review
Board of the Chonnam National University Hwasun Hos-
pital in Hwasun, South Korea. At the time of their periph-
eral blood collections, all case and control subjects
provided their informed consent to participate in this
blood using a QIAamp DNA Blood Mini Kit (Qiagen,
DNAwasextracted from peripheral
Valencia, CA, USA) according to the manufacturer’s
protocol. Genotyping was performed by polymerase
chain reaction-restriction fragment length polymorphism
(PCR-RFLP) or real-time PCR. The genotyping protocol
for PCR-RFLP was adapted from Frosst et al. . After
HinfI (Takara, Tokyo, Japan) restriction enzyme diges-
tion, samples were run on a 10% polyacrylamide gel
(19:1) using Microtitre Array Diagonal Gel Electrophor-
esis (MADGE; MadgeBio, Grantham and Southampton,
UK). Genotyping by real-time PCR was performed by
allelic discrimination using dual-labeled probes contain-
ing locked nucleic acids (LNA) in a real-time PCR assay.
PCR primers and LNA probes were designed and
synthesized by Integrated DNA Technologies (IDT, Cor-
alville, IA, USA). Primers producing a 104-bp amplicon
were as follows: forward, 5’-CTTTGAGGCTGACCT-
GAAGC-3’ and reverse, 5’-TCACAAAGCGGAAGAA
TGTG-3’. Dual-labeled LNA hybridization probes were
5’-FAM-ATG GcT ccc-BHQ1-3’ for the C allele and
5’-cy5-cgA CTc cCg C-BHQ2-3’ for the T allele (LNA
bases are denoted in upper case, and single nucleotide
polymorphisms are underlined). Real-time PCR was per-
formed using a Rotor-Gene 3000 multiplex system (Cor-
bett Research, Sydney, Australia) in a 10-μL reaction
volume containing 200 nM PCR primer, 10-10 nM each
probe, 0.5 U f-taq polymerase (Solgent, Daejeon, Korea),
and 40 ng of genomic DNA. In 24 subjects, the results
of PCR-RFLP were compared with those from real-time
PCR, and the resulting concordance rate was 100%.
The statistical significance of differences between the
patient and control groups was estimated by logistic
regression analysis. Adjusted odds ratios (OR) were cal-
culated with a logistic regression model that controlled
for gender and age and are given with 95% confidence
intervals (CI). Subjects with the wild-type genotypes
(MTHFR 677CC) were considered to be at baseline risk.
The expected frequency of control genotypes was
checked by the Hardy-Weinberg equilibrium test. The
heterogeneity was tested by multivariate logistic regres-
sion model. Subjects for whom there were missing data
for smoking or histological type were excluded in inter-
action and subgroup analyses related to these variables.
All analyses were performed using the Statistical Pack-
age for the Social Sciences software (ver. 13.0; SPSS,
Chicago, IL, USA).
The characteristics of the study population are pre-
sented in Table 1. In total, 3938 cases and 1700 controls
were included in these analyses. The 3938 lung cancer
cases consisted of 1523 adenocarcinomas, 1519 squa-
mous cell carcinomas, 574 small cell carcinomas, and
Cui et al. BMC Medical Genetics 2011, 12:28
Page 2 of 6
322 other types, including 75 large cell cancers and 247
mixed types. The mean age of patients with lung cancer
was significantly higher than the control group. A statis-
tically significant gender difference was also found
between patients with lung cancer and healthy controls;
the control group had more females. The proportion of
smokers in lung cancer cases was higher than in the
Table 2 shows the genotype distributions for MTHFR
C677T and their ORs and 95% CIs in lung cancer. The
distribution of the MTHFR C677T gene polymorphisms
in the controls was calculated by the Hardy-Weinberg
equilibrium. The MTHFR C677T frequencies of CC,
CT, and TT genotypes were 34.5%, 48.5%, and 17.0% in
lung cancer, and 31.8%, 50.7%, and 17.5% in the con-
trols, respectively. The frequencies of combination for
677 CT heterozygous and 677 TT homozygous were
observed 65.4% in lung cancer and 68.2% in the con-
trols. Compared with the MTHFR 677 CC genotype, the
TT and CT genotypes showed a protective effect for the
risk of lung cancer when adjustments were made for age
and gender, overall TT versus CC (OR = 0.88; 95% CI =
0.71-1.07) and overall CT versus CC (OR = 0.90; 95%
CI = 0.77-1.04); however, the results did not reach sta-
Table 3 shows subgroup analysis by gender, age and
histological type for the MTHFR C677T polymorphisms.
When the MTHFR 677CC genotype was used as the
reference group, the MTHFR 677 CT genotype were
associated with a significantly reduced risk in squamous
cell carcinoma (OR = 0.78; 95% CI = 0.64- 0.96), the
combined variant genotypes (677 CT + TT) also showed
a protect effect on the risk of squamous cell carcinoma
(OR = 0.79; 95% CI = 0.65- 0.95), while there was no
significant association in other histological types of lung
cancer. There were no heterogeneities among subgroups
of gender (male, female), age (age ≤65, age > 65), smok-
ing (never smoker, ever smoker), histological type (ade-
nocarcinoma, squamous cell carcinoma, small cell
carcinoma, other types). Nor did we find evidence for
an interaction between the MTHFR C677T polymorph-
isms and age and gender or smoking habit.
The current study represents the largest sample (3938
lung cancer patients and 1700 controls) of a single
population reported to evaluate a possible association
between MTHFR C677T gene polymorphism and sus-
ceptibility to lung cancer. To our knowledge, this is also
the first report to examine the association between
MTHFR C677T polymorphisms and susceptibility to
lung cancer in a Korean population. We found that the
MTHFR 677 CT and TT showed weak protection for
overall lung cancer, although the results were not statis-
tically significant. However, by histological subtype, we
found significant protection of the MTHFR CT geno-
type for squamous cell carcinoma risk.
The combination of 677 TT homozygous with 677 CT
heterozygous also appeared to have a protection effect
on the risk of squamous cell carcinoma. We observed
no significant interactions between the MTHFR C677T
polymorphism and smoking, gender, or age.
Results of several studies examining the role of the
MTHFR C677T polymorphism in lung cancer suscept-
ibility have been inconsistent. Liu et al.  and Jeng
et al.  in Taiwan and Suzuki et al.  in Japan
showed that the MTHFR 677 TT genotype was asso-
ciated with a decreased risk of lung cancer. However,
Siemianowicz et al.  in Poland, Hung et al.  in
Central Europe, and Shen et al.  in China showed
that individuals with MTHFR TT genotype had an
increased risk of lung cancer versus those with the wild-
type homozygous variant, while a recent meta-analysis
by Mao et al.  based on eight case-control study
suggested no evidence for a major role of the MTHFR
C677T polymorphisms in carcinogenesis of lung cancer.
Table 1 General characteristics of subjects
CharacteristicsCases n (%) Controls n (%)
Age(mean ± SD)*
> 65 years
64.8 ± 9.6
52.2 ± 14.3
SD, standard deviation; ADC, adenocarcinoma; SQC, squamous cell carcinoma;
SCLC, small cell lung cancer; others, large cell carcinoma and mixed types;
*, p < 0.01.
Table 2 Distribution of MTHFR C677T and their
association with lung cancer risk
MTHFR C677T Lung cancer n (%)Control n (%) ORa
aAdjusted for age, gender; OR, odds ratio; CI, confidence interval.
Cui et al. BMC Medical Genetics 2011, 12:28
Page 3 of 6
Small sample size, various ethnic groups, diet, environ-
ment, and methodologies might be responsible for the
The pathogenesis of adenocarcinoma is considered to
be somewhat different from that of squamous cell carci-
nomas, and whether the effect of MTHFR C677T poly-
morphism differs by lung cancer histology remains
unclear. We performed a stratification analysis by
histological type, which is lacking in most previous stu-
dies, and found that the MTHFR 677 CT genotype was
associated with a significantly decreased risk for lung
squamous cell carcinoma (OR = 0.78, 95%CI = 0.64-
0.96), supporting the potential effect of MTHFR C677T
polymorphism on lung squamous cell carcinoma. In
other histological type of lung cancer, such as adenocar-
cinoma and small cell lung cancer, we found no associa-
tion between C677T MTHFR genotype and lung cancer
risk. A similar result was seen in a Japanese study in
which no effect of MTHFR C677T polymorphism on
the risk of overall lung cancer was evident, but on
histology based analysis, the MTHFR 677T allele was
associated with a reduced risk of squamous/small cell
carcinoma . While Siemianowicz et al.  reported
that the 677TT genotype was associated with a signifi-
cantly higher risk of non-small cell lung cancer.
The role of MTHFR polymorphisms in modulating can-
cer risk is associated with folate status. Under adequate
folate conditions, the protective effect of the 677TT geno-
type turns to a situation of elevated risk of lung cancer
among MTHFR 677TT genotype with low folate intakes.
A recent meta-analysis by Boccia et al. , which
included stratified analysis according to dietary folate
intake, showed an increased risk for individuals with low
folate intake (OR = 1.28, 95% CI = 0.97-1.68 for lung) ver-
sus high folate intake (OR = 0.94, 95% CI = 0.79-1.12 for
lung). Plasma folate level might be relatively high among
Korean adults; the median plasma folate was 22.7 nmol/L
in our population based controls, which is higher than
that in Chinese population , and also higher than that
in populations from15 European countries (folate status
ranged from 6.3 to 20.1 nmol/L) . In addition, folate
intake seems also fairly high among Korean population;
the average of folate intake in Korea is about 347 μg/day
. This level is higher than the average intake in most
European countries, except for United Kingdom . This
might provide a partial explanation why the MTHFR 677
mutations were found to protect against lung cancer, espe-
cially in lung squamous cell carcinoma in our study.
Moreover, our recent study found a protective effect of
MTHFR 677 T allele on the risk of gastric and colorectal
cancer in a Korean population .
In our study, there was no significant gender differ-
ence in the effect of MTHFR C677T polymorphism on
lung cancer risk. Our results seem to differ from those
of the Shi et al.  study in Houston, TX, USA, which
reported that the MTHFR 677TT genotype in women
was associated with a decreased lung cancer risk com-
pared with carriers of the MTHFR 677CC genotype.
Cigarette smoking is a known risk factor for lung can-
cer, and smokers may tend to have lower levels of
serum and produce a localized deficiency of folic acid.
We further examined the effects of MTHFR C677T in
subgroups according to smoking status and found no
interaction between the MTHFR C677T polymorphism
Table 3 Subgroup analysis for the MTHFR C677T polymorphisms
CT vs. CC
TT vs. CC
CT+TT vs. CC
SCLC, small cell lung cancer; SQC, squamous cell carcinoma; ADC, adenocarcinoma; others, large cell carcinoma and mixed types.
ORa: odds ratio adjusted for age and gender, CI, confidence interval.
Pb: p values for heterogeneity.
Cui et al. BMC Medical Genetics 2011, 12:28
Page 4 of 6
and smoking. Our results seem somewhat similar to
the results of Vineis, et al. , which showed that the
MTHFR C677T polymorphism had no any association
in both smokers and nonsmokers. However, a benefi-
cial effect of the MTHFR TT genotype on the risk of
lung cancer was observed in those with heavy smokers;
Suzuki et al.  in Japan found that MTHFR 677T
alleles were associated with reduced risk of squamous/
small cell carcinomas, especially among heavy smokers
with the MTHFR 677T allele. Liu et al.  in Taiwan
observed that smokers carrying the MTHFR 677 T
allele showed a significantly decreased risk of lung
It is well known that familial aggregation of lung cancer
could increase the risk of lung cancer, and a high con-
sumption of vegetables and fruits is associated with a
reduced risk of lung cancer. However, we have no infor-
mation on the accuracy of reported family history of can-
cer, dietary folate intake or detailed data on the
environmental tobacco exposure risk factors for lung can-
cer. Thus, we cannot evaluate the relationship between
gene-environment interactions. Another limitation of the
present study is that the case group was composed of lung
cancer patients who were enrolled from hospital, which
could not be representative the general population.
Our present large case-control study in Korea found a
protective effect of the MTHFR C677T variant genotype
for lung squamous cell carcinoma and suggested that
the effects of MTHFR C677T polymorphism may be
involved in the development of lung cancer for Korean
1Department of Public Health, Qingdao University Medical College, Qingdao,
China.2Department of Preventive Medicine, Chonnam National University
Medical School, Gwangju, South Korea.3Genome Research Center for
Hematopoietic Diseases, Chonnam National University Hwasun Hospital,
Hwasun, Jeollanam-do, South Korea.4Jeonnam Regional Cancer Center,
Chonnam National University Hwasun Hospital, Hwasun, Jeollanam-do,
South Korea.5Lung and Esophageal Cancer Clinic, Chonnam National
University Medical School, Hwasun Hospital, Hwasun, Jeollanam-do, South
Korea.6Yanbian University Medical College, 121 Juzi Street, Yanji, Jilin
MHS planned the analysis. CLH performed in the study design and drafted
the manuscript. HNK and HRS participated in the experiments. JMP
performed data analysis. YCK, IJO and KSK provided clinical material. SSK,
JSC, and WJY participated in its design and coordination. All authors read
and approved the final manuscript.
The authors declare that they have no competing interests.
Received: 15 November 2010 Accepted: 22 February 2011
Published: 22 February 2011
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The pre-publication history for this paper can be accessed here:
Cite this article as: Cui et al.: Methylenetetrahydrofolate reductase
C677T polymorphism in patients with lung cancer in a Korean
population. BMC Medical Genetics 2011 12:28.
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