ORIGINAL PAPER

Association between OGG1 gene single nucleotide polymorphismsand risk of pancreatic cancer in Chinese

Chengli Liu • Hui Huang • Cheng Wang •

Yalin Kong • Hui Zhang • Hongyi Zhang

Received: 28 April 2014 / Accepted: 16 May 2014

� Springer Science+Business Media New York 2014

Abstract Previous studies have suggested that the

8-oxoguanine DNA glycosylase gene (OGG1) has poten-

tially influenced the risk of pancreatic cancer. The objec-

tive of this study was to assess the association between

single nucleotide polymorphisms (SNPs) of OGG1 gene

and risk of pancreatic cancer. A case–control study has

been conducted in 370 pancreatic cancer patients and 395

healthy controls. Genotypes were determined using the

polymerase chain reaction–restriction fragment length

polymorphism and DNA sequencing methods. The asso-

ciation analysis was evaluated by the unconditional logistic

regression test. Our data suggested that the distributions of

alleles and genotypes were statistically different between

pancreatic cancer patients and healthy controls. The

c.307G[C SNP was associated with the decreased risk of

pancreatic cancer (C vs. G: OR 0.73, 95 % CI 0.59–0.91,

P = 0.006). As for c.828A[G SNP, the significantly

decreased risk of pancreatic cancer was detected (G vs. A:

OR 0.74, 95 % CI 0.59–0.92, P = 0.006). The allele C of

c.307G[C and allele G of c.828A[G SNPs might be

associated with a protection from pancreatic cancer.

Findings from this study indicate that OGG1 SNPs are

associated with pancreatic cancer risk in Chinese Han

population and could be useful molecular biomarkers for

assessing the risk of pancreatic cancer.

Keywords Pancreatic cancer � Cancer susceptibility �OGG1 gene � Single nucleotide polymorphisms �Molecular markers

Introduction

Pancreatic cancer is one of the most common cancer-

related deaths for both men and women worldwide [1–5]. It

causes a constantly rising health burden in the world, with

a 5-year survival rate of less than 5 % [1–3]. It has been

proposed that the possible risk factors for pancreatic cancer

include gender, age, alcohol consumption, smoking status,

body mass index, overweight, diabetes mellitus, genetic

variants and family history of pancreatic cancer [3, 6–9].

Up to date, the exact mechanism of pancreatic cancer still

remains uncertain. Previous studies have shown that the

8-oxoguanine DNA glycosylase gene (OGG1) is an

important candidate gene for influencing the development

of pancreatic cancer [3–5, 10–14]. The OGG1 gene, loca-

ted on chromosome 3p26, is one of the component of DNA

base excision repair (BER) pathway, which play an

important role in repairing damaged DNA [14]. OGG1 is

polygenetic gene, and the OGG1 genetic variants may

affect the expression and function of OGG1 proteins,

which contributing to the risk of pancreatic cancer and

influencing the prognosis of patients. Currently, several

single nucleotide polymorphisms (SNPs), such as proline

(Pro) 90 glutamine (Gln), Serine (Ser) 209Ser, Arginine

(Arg) 299 Glutamine (Gln) and Ser326 Cysteine (Cys),

have been considered to be associated with the risk of

pancreatic cancer [3–5, 11–13]. However, no related

studies have reported the effects of OGG1c.307G[C and

c.828A[G SNPs on influencing the risk of pancreatic

cancer. Therefore, considering the importance of the role of

C. Liu (&) � C. Wang � Y. Kong � H. Zhang � H. Zhang

Department of Hepatobiliary Surgery, The Air Force General

Hospital of People’s Liberation Army, No. 30 Fucheng Road,

Haidian District, Beijing 100142, People’s Republic of China

e-mail: chengli_liu@sina.com

H. Huang

Department of Hepatobiliary Surgery, The 309th Hospital

of Chinese People’s Liberation Army, Beijing 100091,

People’s Republic of China

123

Med Oncol (2014) 31:40

DOI 10.1007/s12032-014-0040-6

OGG1 genetic variants in the development of pancreatic

cancer, the purpose of this study is to evaluate the potential

association between these two SNPs and the risk of pan-

creatic cancer.

Materials and methods

Studied subjects

The study included 370 patients diagnosed and pathologi-

cally confirmed with pancreatic cancer and 395 healthy

unrelated individuals as controls. All subjects were enrol-

led from the Air Force General Hospital of People’s Lib-

eration Army (Beijing, China) between January 2010 and

October 2013. The healthy controls were frequency-mat-

ched to pancreatic cancer patients on gender and age,

excluding those with a history of cancer and other medical

diseases. All individuals were of Chinese Han ethnicity.

Table 1 summarizes the general characteristics of the

pancreatic cancer patients and healthy controls, including

gender, age, alcohol consumption, smoking status, diabetes

mellitus body mass index and family history of pancreatic

cancer. The study was approved by the Ethics Committees

of the Air Force General Hospital of People’s Liberation

Army (Beijing, China). Written informed consent was

obtained from each study individual.

DNA extraction and genotyping

The peripheral venous blood was collected from each

enrolled pancreatic cancer patients and healthy controls.

Genomic DNA was extracted from the peripheral venous

blood using the proteinase K digestion and phenol–chlo-

roform extraction. According to the reference sequences

(GenBank IDs: NG_012106.1 and NM_002542.5) of

human OGG1 gene, the specific polymerase chain reaction

(PCR) primers were designed by Primer Premier 5.0 soft-

ware (Premier Biosoft International, Palo Alto, CA, USA).

The primers sequences, annealing temperature, amplifica-

tion fragment size and region are given in Table 2. The

PCR amplification was carried out in a total volume of

20 lL mixture which containing 50 ng template DNA, 19

buffer (100 mmol Tris–HCl, pH 8.3; 500 mmol KCl),

0.25 lmol primers, 2.0 mmol MgCl2, 0.25 mmol dNTPs

(Bioteke Corporation, Beijing, China) and 0.5 U Taq DNA

polymerase (Promega, Madison, WI, USA). The PCR was

stared at 94 �C for 5 min, followed by 32 cycles at 94 �C

Table 1 Characteristics of the

pancreatic cancer cases and

controls

SD standard deviation

* P values calculated by Chi-

square (v2) test

Characteristics Pancreatic

cancer cases (n)

Controls

(n)

v2 values P values*

Number 370 (%) 395 (%)

Gender (n)

Male 242 (65.41) 253 (64.05) 0.1535 0.6952

Female 128 (34.59) 142 (35.95)

Age (years)

Mean ± SD 57.31 ± 15.45 58.26 ± 16.37 0.0025 0.9598

\55 167 (45.14) 179 (45.32)

C55 203 (54.86) 216 (54.68)

Smoking status 0.9548 0.3285

Never 211 (57.03) 239 (60.51)

Ever 159 (42.97) 156 (39.49)

Alcohol consumption 0.0720 0.7885

Never 226 (61.08) 245 (62.03)

Ever 144 (38.92) 150 (37.97)

Body mass index 0.0060 0.9381

\23 176 (47.57) 189 (47.85)

C23 194 (52.43) 206 (52.15)

Diabetes mellitus (n) 3.1439 0.0762

Yes 107 (28.92) 92 (23.29)

No 263 (71.08) 303 (76.71)

Family history of pancreatic cancer (n) 2.8092 0.0937

Yes 68 (18.38) 55 (13.92)

No 302 (81.62) 340 (86.08)

40 Page 2 of 6 Med Oncol (2014) 31:40

123

for 32 s, at the corresponding temperature (presented in

Table 2) for 32 s, at 72 �C for 32 s, and then an extension

at 72 �C for 5 min. The OGG1 SNPs were genotyped by

the PCR–restriction fragment length polymorphism (PCR–

RFLP) method. According to the manufacturer’s instruc-

tions, each PCR amplified products was digested with 5

units selected restriction enzyme (MBI Fermentas, St.

Leon-Rot, Germany, Table 2) at 37 �C for 10 h and then

verified by agarose gel electrophoresis containing ethidium

bromide and observed under UV light. For quality control,

10 % subjects that present different genotypes were ran-

dom examined using DNA sequencing method (ABI3730xl

DNA Analyzer, Applied Biosystems, Foster City, CA,

USA) to confirm the genotyping results from PCR–RFLP

method.

Statistical analysis

The Hardy–Weinberg equilibrium (HWE) test was per-

formed for the distributions of OGG1 SNPs in the case and

control groups. The Chi-square (v2) test was utilized to

compare the distributions of OGG1 SNPs, and the differ-

ences of general characteristics between pancreatic cancer

patients and healthy controls. To evaluate the potential

associations between the OGG1 SNPs and the susceptibility

to pancreatic cancer, the odds ratios (ORs) with their 95 %

confidence intervals (CIs) were estimated by unconditional

logistic regression analysis. The statistically significant was

settled at P value less than 0.05. All statistical analyses were

analyzed by the STATA 14.0 (Stata Corp., College Station,

TX, USA) and SPSS 15.0 (SPSS Inc., Chicago, IL, USA)

software programs.

Results

Subject characteristics

The subject characteristics are summarized in Table 1. A

total of 765 subjects were enrolled in this case–control study,

which containing 370 pancreatic cancer patients (male: 242,

female: 128, mean age ± standard deviation (SD):

57.31 ± 15.45) and 395 healthy controls (male: 253, female:

142, mean age ± SD: 58.26 ± 16.37). The healthy controls

were comparable with the pancreatic cancer patients in

regard to the distributions of gender, age, alcohol con-

sumption, smoking status, diabetes mellitus, body mass

index and family history of pancreatic cancer (all p values

[0.05, Table 1).

Genotyping and distribution of OGG1 SNPs

Through the PCR–RFLP and DNA sequencing methods, two

novel OGG1 SNPs (c.307G[C and c.828A[G) were

detected in the Chinese Han populations. As for c.307G[C

SNP, sequence analysis indicates that this SNP is a

nonsynonymous mutation. It causes from G to C mutations in

exon2 of human OGG1 gene and leads to aspartic acid (Asp)

to histidine (His) amino acid replacement (p.Asp103His,

reference sequences GenBank IDs: NG_012106.1,

NM_002542.5 and NP_002533.1). The PCR amplified pro-

ducts of this SNP were digested with MaeI restriction

enzyme and divided into three genotypes: GG (170 and

42 bp), GC (212, 170 and 42 bp) and CC (212 bp, Table 2).

As for c.828A[G SNP, sequence analysis reveals that this

SNP is a synonymous mutation. It causes from A to G

mutations in exon5 of human OGG1 gene (p.Gln276Gln).

The MaeII restriction enzyme has been utilized to digest the

PCR amplified products of c.828A[G SNP. All three pos-

sible genotypes have been observed: AA (191 and 25 bp),

AG (216, 191 and 25 bp) and GG (216 bp, Table 2). Table 3

summarizes the genotypic and allelic frequencies of these

two SNPs in cases and controls. As for c.307G[C SNP, the

frequencies of allele G and genotype GG in pancreatic cancer

patients were higher than healthy controls (Table 3). The

allelic frequencies of pancreatic cancer patients (G,

73.78 %; C, 26.22 %) were not consistent with healthy

controls (G, 67.34 %; C, 32.66 %), the differences being

statistically significant (v2 = 7.6180, P = 0.0058, Table 3).

The genotypic frequencies of pancreatic cancer patients

Table 2 The PCR primers and PCR–RFLP method used for investigating OGG1 SNPs

SNPs Primer sequences Annealing

temperature (�C)

Amplification

fragment (bp)

Region Restriction

enzyme

Genotype (bp)

c.307G[C 50-CCACACCAGACGAGCTGGAG-30 61.0 212 Exon2 MaeI GG:170,42

50-TAATCCCCATTTTACAGGTGGC-30 GC:212,170,42

CC:212,

c.828A[G 50-CAACAGTAACCCCAGAGTGAAGG-30 61.7 216 Exon5 MaeII AA:191,25

50-TGGTAGGGTGCCAGCTGTAGTC-30 AG:216,191,25

GG:216

SNPs single nucleotide polymorphisms, PCR polymerase chain reaction, PCR–RFLP PCR–restriction fragment length polymorphism

Med Oncol (2014) 31:40 Page 3 of 6 40

123

(GG, 56.49 %; GC, 34.59 %; CC, 8.92 %) were signifi-

cantly different from those in healthy controls (GG,

46.08 %; GC, 42.53 %; CC, 11.39 %; v2 = 8.3079,

P = 0.0157, Table 3). As for c.828A[G SNP, the allele

frequencies of pancreatic cancer patients were significantly

different from healthy controls (for pancreatic cancer

patients: A, 72.70 %; G, 27.30 %; for healthy controls: A,

66.20 %; G, 33.80 %, v2 = 7.5947, P = 0.0059). The

genotype frequencies of pancreatic cancer patients were not

consistent with healthy controls, the differences being sta-

tistically significant (for pancreatic cancer patients: AA,

54.32 %; AG, 36.76 %; GG, 8.92 %; for healthy controls:

AA, 45.32 %; AG, 41.77 %; GG, 12.91 %, v2 = 7.1155,

P = 0.0285, Table 3). The genotype distribution of these

two SNPs in cases and healthy controls fitted with HWE (all

p values[0.05).

Association of OGG1 SNPs with pancreatic cancer risk

Table 4 shows the potential association of OGG1 SNPs

with pancreatic cancer risk. As for c.307G[C SNP, there

were significantly decreased risk of pancreatic cancer in

the heterozygote comparison (GC versus (vs.) GG: OR

0.66, 95 % CI 0.49–0.90, v2 = 7.02, P = 0.008), domi-

nant model (CC/GC vs. GG: OR 0.66, 95 % CI 0.50–0.88,

v2 = 8.28, P = 0.004) and allele contrast (C vs. G: OR

0.73, 95 % CI 0.59–0.91, v2 = 7.61, P = 0.006). As for

c.828A[G SNP, the significantly decreased risk of pan-

creatic cancer were found in the homozygote comparison

(GG vs. AA: OR 0.58, 95 % CI 0.36–0.93, v2 = 5.09,

P = 0.024), heterozygote comparison (AG vs. AA: OR

0.73, 95 % CI 0.54–0.99, v2 = 3.99, P = 0.046), domi-

nant model (GG/AG vs. AA: OR 0.76, 95 % CI 0.52–0.93,

v2 = 6.19, P = 0.013) and allele contrast (G vs. A: OR

0.74, 95 % CI 0.59–0.92, v2 = 7.59, P = 0.006).

Discussion

Pancreatic cancer is nowadays a common malignancy

worldwide and has a high incidence. It is well known that

the development of pancreatic cancer is a complex and

multifactorial process from environmental and genetic

factors [15–17]. There is no doubt that the genetic factors

play key functions in the pathogenesis of pancreatic cancer

[10, 15–22]. In recent years, OGG1 gene has been selected

as one of the most potentially candidate genes for affecting

pancreatic cancer risk [3–5, 10–14], and these observa-

tions indicated that OGG1 genetic variants might be

associated with the risk of pancreatic cancer [3, 4, 11–13].

Zhang and his colleagues detected a statistically signifi-

cantly increased risk for the variant allele (326Cys) of

OGG1 Ser326Cys genetic variant compared with the wild-Ta

ble

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Gen

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GG

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CC

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AG

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Pan

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tic

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(n=

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209

56.4

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34.5

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73.7

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396

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(n=

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11.3

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32.6

60.4

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0.8

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40 Page 4 of 6 Med Oncol (2014) 31:40

123

type allele (326Ser) (Ser/Cys or Cys/Cys vs. Ser/Ser: OR

1.57, 95 % CI 1.04–2.39). Results from Zhang’s study

suggested that OGG1 genetic variants could influence the

risk of pancreatic cancer [13]. Li et al. indicated that the

homozygous variants of OGG1 G2657A showed a weak

but significant effect on overall survival of patients with

pancreatic cancer. The observations indicated that OGG1

genetic variants significantly influenced the clinical out-

come of pancreatic cancer patients [11]. Chen et al. [5]

observed that that the OGG1 Pro90Gln and Ser209Ser

SNPs were statistically associated with the decreased risk

of pancreatic cancer compared with wild genotype (for

Pro90Gln, AA vs. CC: OR 0.44, 95 % CI 0.27–0.73,

P = 0.001; for Ser209Ser, CC vs. TT: OR 0.57, 95 % CI

0.35–0.94, P = 0.028). Li et al. [4] found that there was a

weak interaction of OGG1 Ser326Cys genetic polymor-

phism CC/CG genotype with diabetes in increased risk of

pancreatic cancer. Nakao et al. [3] found that there was no

significant association with pancreatic cancer risk for the

OGG1 Ser326Cys genetic variant. McWilliams et al. [12]

suggested that no significant differences in the risk of

pancreatic cancer were detected for the OGG1 Arg299Gln

and Ser326Cys SNPs. However, results from these studies

are still inconsistent rather than conclusive. In the current

study, the influencing of OGG1 c.307G[C and c.828A[G

genetic variants on the risk of pancreatic cancer was

determined by association analysis in 370 pancreatic can-

cer patients and 395 healthy controls. We detected that

these two SNPs were statistically associated with pancre-

atic cancer and have significant impact on the risk of

pancreatic cancer in Chinese Han population (Table 4).

Our data suggested that the frequencies of allele and

genotype in pancreatic cancer patients were significantly

different from those of controls for these two SNPs (All

P \ 0.05, Table 3). As for c.307G[C SNP, the GC

genotype and CC/GC carriers were statistically associated

with the decreased susceptibility to pancreatic cancer

compared to wild GG genotype (P = 0.008 and 0.004,

Table 4). As for c.828A[G SNP, the GG genotype, AG

genotype and GG/AG carriers were statistically associated

with the decreased susceptibility to pancreatic cancer

compared with wild AA genotype (P = 0.024, 0.046 and

0.013, Table 4). Results from this study indicated that the

allele C of c.307G[C and allele G of c.828A[G SNPs may

contribute to be associated with a protection from pancre-

atic cancer (P = 0.006, Table 4). The OGG1 genetic

variants could impact on the expression and function of

OGG1 proteins, which influencing the risk of pancreatic

cancer. Our sequences analysis suggested that c.307G[C

genetic variant is a nonsynonymous mutation and causes

Asp to His amino acid replacement (p.Asp103His), and it

might be after the function of OGG1 protein. Although the

c.828A[G genetic variant is a synonymous coding variant

in OGG1 gene (p.Gln276Gln), this genetic variant may

linked to other known nonsynonymous genetic variants,

such as Pro90Gln, Ser209Ser, Arg299Gln and Ser326Cys,

which have been approved to influence the function of

OGG1 proteins and significantly associated with the risk of

pancreatic cancer [4, 11, 13]. To the best of our knowledge,

this is the first investigation regarding the potential influ-

ence of OGG1 c.307G[C and c.828A[G SNPs with the

risk of pancreatic cancer. Our findings indicate that these

two SNPs are significantly associated with the decreased

risk of pancreatic cancer in Chinese Han population and

could be useful molecular biomarkers for evaluating the

risk of pancreatic cancer.

In summary, our data provide evidence for the associ-

ation of OGG1 c.307G[C and c.828A[G SNPs with the

risk of pancreatic cancer. Our finding is suggestive but

need to be confirmed in larger different ethnic populations,

Table 4 The association between OGG1 c.307G[C and c.828A[G SNPs and pancreatic cancer risk

SNPs Comparisons OR (95 % CI) v2 value P values*

c.307G[C CC vs. GG (homozygote comparison) 0.64 (0.39–1.04) 3.23 0.072

GC vs. GG (heterozygote comparison) 0.66 (0.49–0.90) 7.02 0.008

CC/GC vs. GG (dominant model) 0.66 (0.50–0.88) 8.28 0.004

CC vs. GC/GG (recessive model) 0.76 (0.47–1.22) 1.27 0.259

C vs. G (allele contrast) 0.73 (0.59–0.91) 7.61 0.006

c.828A[G GG vs. AA (homozygote comparison) 0.58 (0.36–0.93) 5.09 0.024

AG vs. AA (heterozygote comparison) 0.73 (0.54–0.99) 3.99 0.046

GG/AG vs. AA (dominant model) 0.70 (0.52–0.93) 6.19 0.013

GG vs. AG/AA (recessive model) 0.66 (0.42–1.05) 3.11 0.078

G vs. A (allele contrast) 0.74 (0.59–0.92) 7.59 0.006

SNPs single nucleotide polymorphisms, OR odds ratio, CI confidence interval, vs. versus

* P values calculated by Chi-square (v2) test

Med Oncol (2014) 31:40 Page 5 of 6 40

123

and the underlying molecular mechanisms for pancreatic

cancer carcinogenesis should be fully elucidated.

Acknowledgments None.

Conflict of interest The authors declare no conflict of interests.

References

1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer

statistics, 2007. CA Cancer J Clin. 2007;57:43–66.

2. Tanaka M, Okazaki T, Suzuki H, Abbruzzese JL, Li D. Associ-

ation of multi-drug resistance gene polymorphisms with pancre-

atic cancer outcome. Cancer. 2011;117:744–51.

3. Nakao M, Hosono S, Ito H, Watanabe M, Mizuno N, Sato S,

Yatabe Y, Yamao K, Ueda R, Tajima K, Tanaka H, Matsuo K.

Selected polymorphisms of base excision repair genes and pan-

creatic cancer risk in Japanese. J Epidemiol. 2012;22:477–83.

4. Li D, Suzuki H, Liu B, Morris J, Liu J, Okazaki T, Li Y, Chang P,

Abbruzzese JL. DNA repair gene polymorphisms and risk of

pancreatic cancer. Clin Cancer Res. 2009;15:740–6.

5. Chen H, Zhou B, Lan X, Wei D, Yuan T, Chen P. Association

between single-nucleotide polymorphisms of OGG1 gene and

pancreatic cancer risk in Chinese Han population. Tumour Biol.

2014;35:809–13.

6. Li D, Frazier M, Evans DB, Hess KR, Crane CH, Jiao L,

Abbruzzese JL. Single nucleotide polymorphisms of RecQ1,

RAD54L, and ATM genes are associated with reduced survival

of pancreatic cancer. J Clin Oncol. 2006;24:1720–8.

7. Lowenfels AB, Maisonneuve P. Epidemiology and risk factors

for pancreatic cancer. Best Pract Res Clin Gastroenterol.

2006;20:197–209.

8. Larsson SC, Orsini N, Wolk A. Body mass index and pancreatic

cancer risk: a meta-analysis of prospective studies. Int J Cancer.

2007;120:1993–8.

9. Luo J, Iwasaki M, Inoue M, Sasazuki S, Otani T, Ye W, Tsugane

S. Body mass index, physical activity and the risk of pancreatic

cancer in relation to smoking status and history of diabetes: a

large-scale population-based cohort study in Japan—the JPHC

study. Cancer Causes Control. 2007;18:603–12.

10. Duell EJ, Bracci PM, Moore JH, Burk RD, Kelsey KT, Holly EA.

Detecting pathway-based gene–gene and gene–environment

interactions in pancreatic cancer. Cancer Epidemiol Biomark

Prev. 2008;17:1470–9.

11. Li D, Li Y, Jiao L, Chang DZ, Beinart G, Wolff RA, Evans DB,

Hassan MM, Abbruzzese JL. Effects of base excision repair gene

polymorphisms on pancreatic cancer survival. Int J Cancer.

2007;120:1748–54.

12. McWilliams RR, Bamlet WR, Cunningham JM, Goode EL, de

Andrade M, Boardman LA, Petersen GM. Polymorphisms in

DNA repair genes, smoking, and pancreatic adenocarcinoma risk.

Cancer Res. 2008;68:4928–35.

13. Zhang J, Zhang X, Dhakal IB, Gross MD, Kadlubar FF, Anderson

KE. Sequence variants in antioxidant defense and DNA repair

genes, dietary antioxidants, and pancreatic cancer risk. Int J Mol

Epidemiol Genet. 2011;2:236–44.

14. Yan Y, Chen X, Li T, Li M, Liang H. Association of OGG1

Ser326Cys polymorphism and pancreatic cancer susceptibility:

evidence from a meta-analysis. Tumour Biol. 2013;3:2397–402.

15. Jiang H, Wu D, Ma D, Lin G, Liang J, Jin J. Association between

X-ray repair cross-complementation group 1 rs25487 polymor-

phism and pancreatic cancer risk. Tumour Biol. 2013;6:3417–21.

16. Hansel DE, Kern SE, Hruban RH. Molecular pathogenesis of

pancreatic cancer. Annu Rev Genomics Hum Genet. 2003;4:

237–56.

17. Vaccaro V, Gelibter A, Bria E, Iapicca P, Cappello P, Di Mod-

ugno F, Pino MS, Nuzzo C, Cognetti F, Novelli F, Nistico P,

Milella M. Molecular and genetic bases of pancreatic cancer.

Curr Drug Targets. 2012;13:731–43.

18. Lowenfels AB, Maisonneuve P. Environmental factors and risk

of pancreatic cancer. Pancreatology. 2003;3:1–7.

19. Landi S. Genetic predisposition and environmental risk factors to

pancreatic cancer: a review of the literature. Mutat Res. 2009;

681:299–307.

20. Lin Y, Tamakoshi A, Kawamura T, Inaba Y, Kikuchi S, Mot-

ohashi Y, Kurosawa M, Ohno Y. An epidemiological overview of

environmental and genetic risk factors of pancreatic cancer.

Asian Pac J Cancer Prev. 2001;2:271–80.

21. Chu D, Kohlmann W, Adler DG. Identification and screening of

individuals at increased risk for pancreatic cancer with emphasis

on known environmental and genetic factors and hereditary

syndromes. JOP. 2010;11:203–12.

22. Nitsche C, Simon P, Weiss FU, Fluhr G, Weber E, Gartner S,

Behn CO, Kraft M, Ringel J, Aghdassi A, Mayerle J, Lerch MM.

Environmental risk factors for chronic pancreatitis and pancreatic

cancer. Dig Dis. 2011;29:235–42.

40 Page 6 of 6 Med Oncol (2014) 31:40

123