Lymph Node Metastasis of Gastric Cancer Is Associated with the Interaction Between Poly (ADP-Ribose) Polymerase 1 and Matrix Metallopeptidase 2

Abstract

Poly (ADP-ribose) polymerase 1 (PARP1), which plays a critical role in the base excision DNA repair mechanism, and matrix metallopeptidase 2 (MMP2), a member of the matrix metalloprotease family, are involved in tumor formation and metastasis, respectively. In the present study, the possible association of single nucleotide polymorphisms (SNPs) and gene-gene interaction between PARP1 and MMP2 with the increased incidence of gastric cancer (GC) development and lymph node metastasis (LNM) was investigated in a Korean population. Samples were obtained from 326 patients with chronic gastritis and 153 patients with GC and genotyped using the GoldenGate^® method. The PARP1 rs1136410 genotype showed a significant association with the frequency of LNM of GC (odds ratio [OR] = 2.19, p = 0.02), LNM stage (p = 0.035), and tumor invasion (p = 0.035). The allele frequency of MMP2 rs243865 was not associated with the development of GC or with the development of LNM of GC. Epistasis between the PARP1 SNP and the MMP2 SNP was associated with the development of LNM of GC. The combination of the MMP2 rs243865 CC genotype and the PARP1 rs1136410 CC or CC+CT genotypes showed a high risk of LNM of GC (OR = 2.47, p = 0.01; OR = 2.28, p = 0.01, respectively). In summary, PARP1 is associated with the risk of LNM of GC and the stage of LNM and tumor invasion. Epistasis between PARP1 rs1136410 and MMP2 rs243865 increased the risk of LNM of GC.

Introduction

G astric cancer (GC) is the second leading cause of cancer death worldwide (Crew and Neugut, 2006). GC ranks first among all cancers in Korea based on mortality (Lee et al., 2002). GC development and progression is affected not only by genetic factors such as the variation of genes involved in DNA repair and metastasis but also by environmental factors such as Helicobacter pylori infection (Herrera and Parsonnet, 2009). Among these factors, H. pylori infection is associated with GC development in the Korean population (Chang et al., 2001). H. pylori infection induces an increased production of reactive oxygen species (ROS), which result in oxidative DNA damage (Obst et al., 2000) and the proliferation (Xia and Talley, 2001) of gastric epithelial cells. Errors that occur during the replication of genomic DNA or through the effect of ROS are corrected by DNA repair mechanisms. The base excision repair (BER) pathway is important in the maintenance of the integrity of genomic DNA and in the repair of errors induced by ROS (Maynard et al., 2009). Poly (ADP-ribose) polymerase 1 (PARP1) plays a critical role in the BER pathway. PARP1 binds to DNA single-strand breaks and recruits repair proteins such as X-ray repair, thus complementing defective repair in Chinese hamster cells 1 (XRCC1) and the DNA ligase III-α complex (Miwa and Masutani, 2007). The PARP1 single nucleotide T to C polymorphism rs1136410 causes an amino acid change from Val to Ala and results in lower enzymatic activity (Wang et al., 2007).

The development of lymph node metastasis (LNM) in GC is a critical factor in the determination of the prognosis and survival after treatment (Coburn, 2009). The most important step in metastasis and invasion is the break down and penetration of the basement membrane (Schwartz, 1996). The matrix metallopeptidase (MMP) family plays a critical role in cancer invasion and metastasis through the degradation of extracellular matrix or basement membrane barriers (Curran and Murray, 1999; Stamenkovic, 2000). Among the MMP family, MMP2 hydrolyzes type IV collagen (Stamenkovic, 2000) and its expression is associated with LNM stage in GC (Monig, 2001; Wu et al., 2006). In particular, the frequency of the MMP2 rs243865 genotype is associated with the incidence of nasopharyngeal cancer (Zhou et al., 2007), GC (Miao et al., 2003), and LNM from GC (Wu et al., 2007). The MMP2 rs243865 single nucleotide polymorphism (SNP) is located in the promoter region, and the C to T transition is associated with reduced MMP2 gene expression levels (Price et al., 2001).

Considering interaction of polymorphisms in more than two genes is important to explain the inheritance of polygenic diseases. Recent studies revealed that gene-gene interactions show a stronger association with increased cancer risk than individual SNPs (Zhang et al., 2005; Chen et al., 2009). The present study investigated the potential association of PARP1, which is involved in the BER pathway, and MMP2, which is involved in metastasis, with GC development and metastasis. In addition, the interactions between these two proteins and their association with GC and LNM were assessed through a case-control study.

Materials and Methods

Subjects for the case-control study and sample preparation

A total of 326 patients with chronic gastritis (CG) and 153 patients with GC were recruited from the division of gastroenterology of the Ajou University hospital. The patients with CG were diagnosed by endoscopic examination between January 2002 and December 2006; and only patients with H. pylori-positive CG participated in this study. Patients with GC who were all operative cases for the eradication of a gastric tumor after being diagnosed by endoscopic examination and biopsy between January 2001 and December 2008 and who were H. pylori-positive were included in the study. H. pylori infection was detected using the Campylobacter-like organism test and the ¹³C-urea breath test.

TNM stage of patients with GC was determined using isolated tumor mass and lymph nodes according to the 6th edition of the GC staging system, which was devised by an American Joint Committee on Cancer (AJCC) (Greene et al., 2002). The TNM classification by AJCC sixth was decided by a surgeon in the division of gastroenterology of the Ajou University Hospital where patients with GC were treated.

Genomic DNA (gDNA) was extracted from blood samples using G-DEX^™ blood gDNA purification kits (Intron Biotechnology, Seungnam, Korea). Purified DNA was quantified by using the picogreen dsDNA quantification reagent according to a standard protocol (Molecular Probes, Eugene, OR). The gDNA was then stored at −20°C until genotypic analysis was performed. Genotypic analysis was performed by using the GoldenGate^® Assay Kit (Illumina, San Diego, CA). Oligos was amplified by allele-specific primer extension. After hybridization to a sentrix array matrix, signal intensities were read by BeadArray Reader (Illumina). BeadStudio III software (Illumina) was used for the clustering of genotype data.

Statistical analysis

The associations between genotype and risk of GC were estimated by odds ratio (OR), and the 95% confidence interval was calculated by logistic regression adjusting for age and sex. Genotype distributions were compared between the CG and LNM of GC groups using the same statistical analysis. The genetic models were divided into additive (AA vs. AB vs. BB), dominant (AA vs. AB plus BB), and recessive (AA plus AB vs. BB). Associations between the PARP1 rs1136410 genotype and clinicopathological features were evaluated by using Fisher's exact test. Logistic regression and Fisher's exact test were performed by using the SAS (SAS Institute, Cary, NC; version 9.1.3). Epistasis analyses were performed by logistic regression adjusting for age and gender using the PLINK program. (http://pngu.mgh.harvard.edu/∼purcell/plink/, version 1.07). Power calculation was performed by using the Power and Precision V4 software (www.power-analysis.com/).

Results

The characteristics of the 326 CG and 153 GC patients are summarized in Table 1. The age and sex distribution among patients with GC and CG was statistically different. The mean ages of the patients with GC and CG were 57.8 years and 55.2 years, respectively. Among the patients with GC, 61.4%, 20.9%, 14.4%, and 3.3% were classified as N0, N1, N2, and N3, respectively, based on LNM stage; and 45.1%, 24.2%, 28.8%, and 2.0% were classified as T1, T2, T3, and T4, respectively, based on tumor invasion stage.

Table 1.

Clinicopathological Characteristics of Patients with Chronic Gastritis and Gastric Cancer

	Chronic gastritis		Gastric cancer
Characteristic	n	%	n	%	p-Value ^a
Patients (n)	326	100	153	100
Age (mean)	55.2	—	57.8	—
≤50	103	31.60	46	30.07	<0.0001
51–60	129	39.57	40	26.14
60–70	93	28.53	46	30.07
≥71	1	0.31	21	13.73
Gender
Male	160	49.1	101	66.0	0.0005
Female	166	50.9	52	34
Helicobacter pylori infection
Positive	326	100	153	100
Negative	—		—
LNM^b
N0	—		94	61.4
N1	—		32	20.9
N2	—		22	14.4
N3	—		5	3.3
Tumor invasion^b
T1	—		69	45.1
T2	—		37	24.2
T3	—		44	28.8
T4	—		3	2.0

The p-value was calculated by Chi-square test.

LNM and tumor invasion were determined according to the sixth edition of the gastric cancer staging system, which was devised by an American joint committee on cancer.

LNM, lymph node metastasis.

To study the association of PARP1 and MMP2 with the risk of GC, the genotype distribution of well-characterized SNPs (PARP1 rs1136410 and MMP2 rs243865) from both genes was determined (Table 2). The distribution of genotypes satisfied the Hardy-Weinberg equilibrium (p > 0.05) by χ ² test (data not shown). The frequencies of the PARP1 rs1136410 TT, TC, and CC genotypes were 31.9%, 50.3%, and 17.8% among patients with CG, and 27.8%, 46.4%, and 25.8% among patients with GC, respectively. The frequencies of the MMP2 rs243865 CC, CT, and TT genotypes were 83.1%, 16.6%, and 0.3%, respectively, among patients with CG, and 78.4%, 20.9%, and 0.7% in patients with GC, respectively. The distribution of the rs1136410 and rs243865 SNPs was not significantly associated with the risk of GC development.

Table 2.

Genotype Distribution of Poly (ADP-Ribose) Polymerase 1 and Matrix Metallopeptidase 2 Polymorphisms and Their Impact on Gastric Cancer Risk

	Chronic gastritis		Gastric cancer
	n	%	n	%	Model	OR	95% CI	p-Value ^a	Power ^b
PARP1
TT	102	31.9	42	27.8	Allele	1.28	0.97–1.68	0.08	0.407
TC	161	50.3	70	46.4	Additive	1.26	0.95–1.67	0.11	—
CC	57	17.8	39	25.8	Dominant	1.24	0.80–1.92	0.34	0.199
					Recessive	1.52	0.95–2.44	0.08	0.498
MMP2
CC	271	83.1	120	78.4	Allele	1.33	0.85–2.09	0.21	0.161
CT	54	16.6	32	20.9	Additive	1.3	0.81–2.10	0.28	—
TT	1	0.3	1	0.7	Dominant	1.31	0.80–2.14	0.29	0.251
					Recessive	1.86	0.11–31.48	0.67	0.05

Six patients with chronic gastritis and two patients with gastric cancer were excluded from the analysis, because the PARP1 genotype could not be defined.

The p-value was calculated by logistic regression.

Power was calculated by Power and Precision V4 software.

OR, odds ratio; CI, confidence interval; PARP1, poly (ADP-ribose) polymerase 1; MMP2, matrix metallopeptidase.

The 153 patients with GC were subdivided into 59 patients with LNM and 94 patients without LNM. The genotype distribution of the two polymorphisms (PARP1 rs1136410 and MMP2 rs243865) was compared between patients with CG and LNM of patients with GC to assess for the risk of the development of LNM (Table 3). The frequencies of the PARP1 rs1136410 TT, TC, and CC genotypes were 28.8%, 39.0%, and 32.2% in patients with LNM GC. The PARP1 rs1136410 CC genotype was significantly associated with an increased risk of LNM in patients with GC (OR = 2.19, p = 0.02). The frequencies of the MMP2 rs243865 CC, CT, and TT genotypes were 83.1%, 15.3%, and 1.7% in patients with LNM of GC. For the MMP2 rs243865 SNP, no significant deviation was observed in the genotype distribution of the polymorphism between CG and LNM of GC.

Table 3.

Genotype Distribution of Poly (ADP-ribose) Polymerase 1 and Matrix Metallopeptidase 2 Polymorphisms and Their Impact on Lymph Node Metastasis Risk

	Chronic gastritis		LNM of gastric cancer
	n	%	n	%	Model	OR	95% CI	p-value ^a	Power ^b
PARP1
TT	102	31.9	17	28.8	Allele	1.42	0.95–2.11	0.08	0.436
TC	161	50.3	23	39	Additive	1.43	0.95–2.14	0.09	—
CC	57	17.8	19	32.2	Dominant	1.18	0.62–2.24	0.62	0.074
					Recessive	2.19	1.15–4.15	0.02	0.63
MMP2
CC	271	83.1	49	83.1	Allele	1.09	0.56–2.16	0.79	0.05
CT	54	16.6	9	15.3	Additive	0.94	0.46–1.92	0.86	—
TT	1	1	1	1.7	Dominant	0.85	0.39–1.84	0.68	0.05
					Recessive	4.21	0.24–73.24	0.32	0.0889

The p-value was calculated by logistic regression.

Power was calculated by Power and Precision V4 software.

Bold face indicates significant p-value (p<0.05).

The association between the clinicopathological features of GC and the distribution of the PARP1 rs1136410 polymorphism was assessed (Table 4). A significant correlation between the PARP1 rs1136410 genotype and tumor invasion stage (p = 0.035) and LNM stage (p = 0.035) was found in the GC patient group. The risk allele CC genotype frequency was significantly higher in the T3 and T4 subgroups and in the N1 and N3 subgroups.

Table 4.

Association Between the rs1136410 Poly (ADP-Ribose) Polymerase 1 Polymorphism and the Clinicopathological Features of Gastric Cancer

	CC		CT+TT
Genotype	n	%	n	%	p-Value ^a
LNM
N0	20	51.28	72	64.29	0.035
N1	14	35.9	18	16.07
N2	3	7.69	19	16.96
N3	2	5.13	3	2.68
Tumor invasion
T1	16	41.03	51	45.54	0.035
T2	7	17.95	30	26.79
T3	13	33.33	31	27.68
T4	3	7.69	0	0

The p-value was calculated by Fisher's exact test.

Bold face indicates significant p-value (p<0.05).

Gene-gene interactions between PARP1 and MMP2 were also investigated (Table 5). A significant association between LNM GC risk and the combined effects of the rs243865 and rs1136410 SNPs was found. The MMP2 rs243865 CC and PARP1 rs1136410 CC polymorphism combination contributed to an increased risk of LNM among patients with GC (OR = 2.47, p = 0.010). The combination variant rs243865 CC+CT and rs1136410 CC exhibited a 2.28-fold increase in the risk for LNM development (OR = 2.28, p = 0.012). The p-value after correction by Bonferroni's multiple testing showed a significant association between gene-gene interaction and LNM of GC (p-value <0.0167). Power values of the interaction in a dominant manner and in a recessive manner were 0.76 and 0.68, respectively.

Table 5.

Age–Sex Adjusted Odds Ratios for the Combination of Poly (Adp-Ribose) Polymerase 1 and Matrix Metallopeptidase 2 Polymorphisms

rs243865			rs1136410
Model	Type	Group	TT+CT	CC	OR (95% CI)	p-Value ^a	Power ^b
Dominant	CC	LNM of GC	32	17	2.47 (1.24–5.00)	0.01	0.76
		CG	221	47
	CT+TT	LNM of GC	8	2	0.11 (0.01–1.12)	0.79	0.052
		CG	42	10
Recessive	CC+CT	LNM of GC	39	19	2.28 (1.20–4.34)	0.01	0.68
		CG	263	56
	TT	LNM of GC	1	0	—	—	—
		CG	0	1

The p-value less than 0.0167 was considered significant after Bonferroni correction.

Power was calculated by Power and Precision V4 software.

GC, gastric cancer; CG, chronic gastritis.

Bold face indicates significant p-value (p<0.05).

Discussion

The present study investigated the interaction between PARP1 rs1136410 and MMP2 rs243865 and the association between these two SNPs and the incidence of GC and LNM of GC using logistic regression analyses adjusted for age and gender. The PARP1 rs1136410 genotype was significantly associated with the development of LNM of GC, LNM stage, and tumor invasion, but not with GC development. The MMP2 rs243865 polymorphism was not associated with GC susceptibility or LNM of GC. Interestingly, the interaction between these two SNPs was found to increase the risk of LNM of GC more than each SNP alone.

H. pylori infection is one of the most important environmental factors involved in the pathogenesis of GC. Patients with H. pylori-infected CG and GC were included in the present study to rule out the effect of H. pylori infection and to emphasize the effect of genetic factors. Uemura et al. (2001) reported an association between H. pylori infection and the incidence of GC. H. pylori induces cell proliferation, ROS formation, and causes DNA damage in gastric epithelial cells (Obst et al., 2000); and infection with H. pylori results in the down-regulation of the BER pathway in vitro and in vivo (Machado et al., 2009).

The BER pathway is involved in the repair of DNA damaged by ROS generated by H. pylori infection, ionizing radiation, or alkylating agents (Hoeijmakers, 2001). Various genes such as APEX nuclease (multifunctional DNA repair enzyme) 1, polymerase (DNA directed) beta, XRCC1, NEIL1, and PARP1 are involved in the BER pathway. These genes play a role in tumor suppression mechanisms (Sweasy et al., 2006). Polymorphisms of genes that are part of the BER pathway have frequently been associated with various cancers (Mitra et al., 2008; Sliwinski et al., 2009; Goto, 2010). In particular, PARP1 plays a critical role in the BER pathway by forming a functional complex involved in DNA repair. PARP1 is located on chromosome 1 and consists of a DNA-binding domain, an automodification domain, and a catalytic domain. PARP1 enzymatic activity is affected by the T to C substitution in the rs1136410 polymorphism, which results in an amino acid change from Val to Ala. The V to A substitution increases the Km, which results in a decrease in enzyme activity (Mitra et al., 2008). PARP1 rs1136410 CC type was found to significantly decrease enzyme activity in prostate cancer in an allele dosage-dependent manner (Lockett et al., 2004). Zhang et al. (2005, 2009) reported an association between PARP1 rs1136410 and GC risk and lung cancer risk in the Chinese population.

In the present study, PARP1 rs1136410 was significantly associated with patients with CG and LNM of patients with GC (Table 2, OR = 2.19, p = 0.02). The PARP1 rs1136410 CC genotype was significantly associated with the LNM stage (p = 0.035) and tumor invasion stage (p = 0.035) in the GC patient group by Fisher's exact test, which is appropriate for small sample sizes (Table 4). The PARP1 rs1136410 CC genotype correlated with the development of LNM of GC and cancer progression, but did not influence GC development.

In addition, the PARP1 rs1136410 SNP showed almost perfect linkage disequilibrium (LD) with rs1805415 (r² = 0.998), as revealed by Korean LD data obtained from the Korea association resource dataset (Cho et al., 2009) merged with imputed data by using the IMPUTE program (Marchini et al., 2007). Cao et al. (2007) reported a perfect LD between two SNPs (rs1136410 and rs1805415) in a French population. The minor A allele of PARP1 rs1805415 is associated with increased interleukin-6 (IL-6) levels (Walston et al., 2009), and high IL-6 levels were associated with LNM stage (Kim et al., 2009). Among the two SNPs (rs1136410 and rs1805415) that have the two haplotypes (Hts) TG and CA, the CA Ht has a lower DNA repair capacity and higher IL-6 level than the TG Ht. Therefore, the PARP1 rs1136410 and rs1805415 CA Ht might be associated with the development of LNM of GC.

MMP2 is a critical protein for cancer progression due to its role in metastasis and invasion. The MMP2 rs243865 SNP is located on the promoter sequence, and its C to T transition disrupts the SP1-type promoter site (CCACC box), resulting in lower promoter activity (Price et al., 2001). The MMP2 rs243865 polymorphism is associated with various diseases, including nasopharyngeal carcinoma (Zhou et al., 2007), esophageal cancer (Yu et al., 2004), lung cancer (Yu et al., 2002), oral carcinoma (Lin et al., 2004), GC (Miao et al., 2003), and lymphatic invasion of GC (Wu et al., 2007). The MMP2 rs243865 polymorphism is also associated with stroke in the Portuguese population (Manso et al., 2010) and rheumatoid arthritis among the Spanish population (Rodriguez-Lopez et al., 2006). However, certain studies reported that the MMP2 rs243865 polymorphism is not associated with intestinal metaplasia (Zhu et al., 2009), breast cancer, (Beeghly-Fadiel et al., 2009), or melanoma (Cotignola et al., 2007).

In the present study, MMP2 rs243865 genotype frequency was not significantly associated with GC development among patients with CG and GC, and it was not associated with LNM in patients with GC. The MMP2 rs243865 T minor allele was found at a frequency of 9% in CG, 11% of GC according to the present data. MMP2 polymorphisms might not be associated with the development of GC or LNM of GC in the Korean population. Further studies, including a larger number of samples, are necessary to clarify the involvement of MMP2 polymorphisms in the development of GC and LNM in GC. Additionally, a more detailed LNM staging system such as lymphatic invasion designation might be useful.

Gene-gene interactions are important in polygenic diseases such as cancers. The interaction between the PARP1 and XRCC1 genes, which are involved in the BER pathway, is associated with an increased risk of lung cancer (Zhang et al., 2005) and LNM in thyroid carcinoma (Chiang et al., 2008). Interaction between the MMP9 and TIMP3 genes, which play important roles in metastasis, is associated with breast cancer risk (Lei et al., 2007). However, there are no studies investigating the interactions between two different but functionally related pathways such as the BER pathway and the LNM process. In the present study, the interaction between PARP1 rs1136410 and MMP2 rs243865 was significantly associated with LNM of GC. In the MMP2 rs243865 CC group, the PARP1 CC genotype was significantly associated with an increase in the risk of LNM from GC. In the MMP2 rs243865 CC+CT group, the PARP1 CC genotype significantly increased the risk of LNM from GC. Notably, the combination of polymorphisms from two different genes affected the incidence of GC formation and metastasis of GC. The statistical powers of this interaction in a dominant and recessive manner were 0.76 and 0.68, respectively (Table 5). Recent association reports based on similar sample sizes to that of this study were found to have similar or lower power than that in this study (Supplementary Table S1; Supplementary Data are available online at www.liebertonline.com/dna). Further studies, including a larger number of samples, are necessary to confirm the involvement of interaction between PARP1 and MMP2 polymorphisms in the LNM of GC.

Although functional validation of PARP1 gene and MMP2 gene interaction will require a bigger sample size, speculation on the functional role of SNPs in the genes involved in BER and metastasis pathways might be helpful to design future experiments. The PARP1 rs1136410 CC genotype might be characterized by reduced DNA repair capacity and enhanced oncogenic capacity. The PARP1 rs1805415 A allele, which is associated with elevated levels of IL-6, might promote the LNM of GC. The MMP2 rs243865 C allele, which could enhance the activity of the promoter resulting in increased MMP2 gene expression, could result in an elevated level of extracellular matrix degradation. Koreans who have been infected with H. pylori and have the PARP1 rs1136410 CC genotype and the rs1805415 A and MMP2 rs243865 C alleles might have an elevated risk of LNM of GC. Therefore, the interaction between PARP1 and MMP2 may be a valuable cancer prognosis marker.

Conclusion

In conclusion, the present case-control study of H. pylori infection-associated GC showed a significantly increased risk of LNM of GC, LNM stage, and tumor invasion stage in patients with PARP1 CC type SNPs. In addition, the present results indicated that the risk of LNM of GC was associated with gene-gene interactions between MMP2 rs243865 CC+CT type and PARP1 CC type SNPs in the Korean population.

Footnotes

Acknowledgments

We are thankful to every individual who gave us informed consent for this study. Informed consent was acquired from each patient, and the sampling protocols and informed consent forms used were approved by the IRB of Ajou University. Protocols for handling the human genomic materials and all the experimental procedures used were approved by the IRB of CHA University. This work was funded by grants from the Ministry of Health and Welfare, Republic of Korea (A010383, A080734).

Disclosure Statement

No competing financial interests exist.

References

Beeghly-Fadiel

, Lu

, Long

J.R.

, Shu

X.O.

, Zheng

, Cai

, Gao

Y.T.

, Zheng

2009. Matrix metalloproteinase-2 polymorphisms and breast cancer susceptibility. Cancer Epidemiol Biomarkers Prev, 18:1770–1776.

Cao

W.H.

, Wang

, Frappart

, Rigal

, Wang

Z.Q.

, Shen

, Tong

W.M.

2007. Analysis of genetic variants of the poly(ADP-ribose) polymerase-1 gene in breast cancer in French patients. Mutat Res, 632:20–28.

Chang

W.K.

, Kim

H.Y.

, Kim

D.J.

, Lee

, Park

C.K.

, Yoo

J.Y.

, Kim

H.J.

, Kim

M.K.

, Chol

B.Y.

, Choi

H.S.

, Park

K.N.

2001. Association between Helicobacter pylori infection and the risk of gastric cancer in the Korean population: prospective case-controlled study. J Gastroenterol, 36:816–822.

Chen

, Han

, Wang

, Zhou

, Zhang

, Dong

, Shi

, Qian

, Wang

, Wei

, Shen

, Hu

2009. Interactions of IL-12A and IL-12B polymorphisms on the risk of cervical cancer in Chinese women. Clin Cancer Res, 15:400–405.

Chiang

F.Y.

, Wu

C.W.

, Hsiao

P.J.

, Kuo

W.R.

, Lee

K.W.

, Lin

J.C.

, Liao

Y.C.

, Hank Juo

S.H.

2008. Association between polymorphisms in DNA base excision repair genes XRCC1, APE1, and ADPRT and differentiated thyroid carcinoma. Clin Cancer Res, 14:5919–5924.

Cho

Y.S.

, Go

M.J.

, Kim

Y.J.

, Heo

J.Y.

, Oh

J.H.

, Ban

H.J.

, Yoon

, Lee

M.H.

, Kim

D.J.

, Park

, Cha

S.H.

, Kim

J.W.

, Han

B.G.

, Min

, Ahn

, Park

M.S.

, Han

H.R.

, Jang

H.Y.

, Cho

E.Y.

, Lee

J.E.

, Cho

N.H.

, Shin

, Park

, Lee

J.K.

, Cardon

, Clarke

, McCarthy

M.I.

, Lee

J.Y.

, Lee

J.K.

, Oh

, Kim

H.Y.

2009. A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits. Nat Genet, 41:527–534.

Coburn

N.G.

2009. Lymph nodes and gastric cancer. J Surg Oncol, 99:199–206.

Cotignola

, Roy

, Patel

, Ishill

, Shah

, Houghton

, Coit

, Halpern

, Busam

, Berwick

, Orlow

2007. Functional polymorphisms in the promoter regions of MMP2 and MMP3 are not associated with melanoma progression. J Negat Results Biomed, 6:9–16.

Crew

K.D.

, Neugut

A.I.

2006. Epidemiology of gastric cancer. World J Gastroenterol, 12:354–362.

10.

Curran

, Murray

G.I.

1999. Matrix metalloproteinases in tumour invasion and metastasis. J Pathol, 189:300–308.

11.

Herrera

, Parsonnet

2009. Helicobacter pylori and gastric adenocarcinoma. Clin Microbiol Infect, 15:971–976.

12.

Hoeijmakers

J.H.

2001. Genome maintenance mechanisms for preventing cancer. Nature, 411:366–374.

13.

Goto

, Shinmura

, Tao

, Tsugane

, Sugimura

2010. Three novel NEIL1 promoter polymorphisms in gastric cancer patients. World J Gastrointest Oncol, 15:117–120.

14.

Greene

F.L.

, Page

, Fleming

I.D.

, Fritz

A.G.

, Balch

C.M.

, Haller

D.G.

, Morrow

2002. American Joint Committee Classification Cancer Staging Manual, sixth. Springer: Chicago, ILChapter 10101.

15.

Kim

D.K.

, Oh

S.Y.

, Kwon

H.C.

, Lee

, Kwon

K.A.

, Kim

B.G.

, Kim

S.G.

, Kim

S.H.

, Jang

J.S.

, Kim

M.C.

, Kim

K.H.

, Han

J.Y.

, Kim

H.J.

2009. Clinical significances of preoperative serum interleukin-6 and C-reactive protein level in operable gastric cancer. BMC Cancer, 9:155–163.

16.

Lee

H.J.

, Yang

H.K.

, Ahn

Y.O.

2002. Gastric cancer in Korea. Gastric Cancer, 5:177–182.

17.

Lei

, Hemminki

, Altieri

, Johansson

, Enquist

, Hallmans

, Lenner

, Forsti

2007. Promoter polymorphisms in matrix metalloproteinases and their inhibitors: few associations with breast cancer susceptibility and progression. Breast Cancer Res Treat, 103:61–69.

18.

Lin

S.C.

, Lo

S.S.

, Liu

C.J.

, Chung

M.Y.

, Huang

J.W.

, Chang

K.W.

2004. Functional genotype in matrix metalloproteinases-2 promoter is a risk factor for oral carcinogenesis. J Oral Pathol Med, 33:405–409.

19.

Lockett

K.L.

, Hall

M.C.

, Xu

, Zheng

S.L.

, Berwick

, Chuang

S.C.

, Clark

P.E.

, Cramer

S.D.

, Lohman

, Hu

J.J.

2004. The ADPRT V762A genetic variant contributes to prostate cancer susceptibility and deficient enzyme function. Cancer Res, 64:6344–6348.

20.

Machado

A.M.

, Figueiredo

, Touati

, Maximo

, Sousa

, Michel

, Carneiro

, Nielsen

F.C.

, Seruca

, Rasmussen

L.J.

2009. Helicobacter pylori infection induces genetic instability of nuclear and mitochondrial DNA in gastric cells. Clin Cancer Res, 15:2995–3002.

21.

Manso

, Krug

, Sobral

, Albergaria

, Gaspar

, Ferro

JM.

, Oliveria

S.A.

, Vicente

A.M.

2010. Variants of the matrix metalloproteinase-2 but not the matrix metalloproteinase-9 genes significantly influence functional outcome after stroke. BMC Med Genet, 11:40–48.

22.

Marchini

, Howie

, Myers

, McVean

, Donnelly

2007. A new multipoint method for genome-wide association studies by imputation of genotypes. Nat Genet, 39:906–913.

23.

Maynard

, Schurman

S.H.

, Harboe

, de Souza-Pinto

N.C.

, Bohr

V.A.

2009. Base excision repair of oxidative DNA damage and association with cancer and aging. Carcinogenesis, 30:2–10.

24.

Miao

, Yu

, Tan

, Xiong

, Liang

, Lu

, Lin

2003. A functional polymorphism in the matrix metalloproteinase-2 gene promoter (-1306C/T) is associated with risk of development but not metastasis of gastric cardia adenocarcinoma. Cancer Res, 63:3987–3990.

25.

Mitra

A.K.

, Singh

, Garg

V.K.

, Agarwal

, Sharma

, Chaturvedi

, Rath

S.K.

2008. Association of polymorphisms in base excision repair genes with the risk of breast cancer: a case-control study in North Indian women. Oncol Res, 17:127–135.

26.

Miwa

, Masutani

2007. PolyADP-ribosylation and cancer. Cancer Sci, 98:1528–1535.

27.

Monig

S.P.

, Baldus

S.E.

, Hennecken

J.K.

, Spiecker

D.B.

, Grass

, Schneider

P.M.

, Thiele

, Dienes

H.P.

, Holscher

A.H.

2001. Expression of MMP-2 is associated with progression and lymph node metastasis of gastric carcinoma. Histopathology, 39:597–602.

28.

Obst

, Wagner

, Sewing

K.F.

, Beil

2000. Helicobacter pylori causes DNA damage in gastric epithelial cells. Carcinogenesis, 21:1111–1115.

29.

Price

S.J.

, Greaves

D.R.

, Watkins

2001. Identification of novel, functional genetic variants in the human matrix metalloproteinase-2 gene: role of Sp1 in allele-specific transcriptional regulation. J Biol Chem, 276:7549–7558.

30.

Rodriguez-Lopez

, Perez-Pampin

, Gomez-Reino

J.J.

, Gonzalez

2006. Regulatory polymorphisms in extracellular matrix protease genes and susceptibility to rheumatoid arthritis: a case-control study. Arthritis Res Ther, 8:R1–R7.

31.

Schwartz

G.K.

1996. Invasion and metastases in gastric cancer: in vitro and in vivo models with clinical correlations. Semin Oncol, 23:316–324.

32.

Sliwinski

, Markiewicz

, Rusin

, Pietruszewska

, Olszewski

, Morawiec-Sztandera

, Mynarski

, Majsterek

2009. Polymorphisms of the DNA base excision repair gene MUTYH in head and neck cancer. Exp Oncol, 31:57–59.

33.

Stamenkovic

2000. Matrix metalloproteinases in tumor invasion and metastasis. Semin Cancer Biol, 10:415–433.

34.

Sweasy

J.B.

, Lang

, DiMaio

2006. Is base excision repair a tumor suppressor mechanism? Cell Cycle, 5:250–259.

35.

Uemura

, Okamoto

, Yamamoto

, Matsumura

, Yamaguchi

, Yamakido

, Taniyama

, Sasaki

, Schlemper

R.J.

2001. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med, 345:784–789.

36.

Walston

J.D.

, Matteini

A.M.

, Nievergelt

, Lange

L.A.

, Fallin

D.M.

, Barzilai

, Ziv

, Pawlikowska

, Kwork

, Cummings

S.R.

, Kooperberg

, LaCroix

, Tracy

R.P.

, Atzmon

, Lange

E.M.

, Reiner

A.P.

2009. Inflammation and stress-related candidate genes, plasma interleukin-6 levels, and longevity in older adults. Exp Gerontol, 44:350–355.

37.

Wang

X.G.

, Wang

Z.Q.

, Tong

W.M.

, Shen

2007. PARP1 Val762Ala polymorphism reduces enzymatic activity. Biochem Biophys Res Commun, 354:122–126.

38.

C.Y.

, Wu

M.S.

, Chen

Y.J.

, Chen

C.J.

, Chen

H.P.

, Shun

C.T.

, Chen

G.H.

, Huang

S.P.

, Lin

J.T.

2007. Clinicopathological significance of MMP-2 and TIMP-2 genotypes in gastric cancer. Eur J Cancer, 43:799–808.

39.

Z.Y.

, Li

J.H.

, Zhan

W.H.

, He

Y.L.

2006. Lymph node micrometastasis and its correlation with MMP-2 expression in gastric carcinoma. World J Gastroenterol, 12:2941–2944.

40.

Xia

H.H.

, Talley

N.J.

2001. Apoptosis in gastric epithelium induced by Helicobacter pylori infection: implications in gastric carcinogenesis. Am J Gastroenterol, 96:16–26.

41.

, Pan

, Xing

, Liang

, Tan

, Zhang

, Lin

2002. Correlation between a single nucleotide polymorphism in the matrix metalloproteinase-2 promoter and risk of lung cancer. Cancer Res, 62:6430–6433.

42.

, Zhou

, Miao

, Xiong

, Tan

, Lin

2004. Functional haplotypes in the promoter of matrix metalloproteinase-2 predict risk of the occurrence and metastasis of esophageal cancer. Cancer Res, 64:7622–7628.

43.

Zhang

, Li

, Zhou

, Shi

, Chen

, Yuan

2009. PARP-1 Val762Ala polymorphism, CagA+ H. pylori infection and risk for gastric cancer in Han Chinese population. Mol Biol Rep, 36:1461–1467.

44.

Zhang

, Miao

, Liang

, Hao

, Wang

, Tan

, Li

, Guo

, He

, Wei

, Lin

2005. Polymorphisms in DNA base excision repair genes ADPRT and XRCC1 and risk of lung cancer. Cancer Res, 65:722–726.

45.

Zhou

, Zhai

, Cui

, Qiu

, Yang

, Zhang

, Dong

, He

, Yao

, Zhang

, Peng

, Yuan

, Zhi

, Zhang

, He

2007. Functional polymorphisms and haplotypes in the promoter of the MMP2 gene are associated with risk of nasopharyngeal carcinoma. Hum Mutat, 28:1091–1097.

46.

Zhu

, Loh

, Hill

, Lee

, Koh

K.X.

, Lai

K.W.

, Salto-Tellez

, Iacopetta

, Yeoh

K.G.

, Soong

Singapore Gastric Cancer Consortium. 2009. Genetic factors associated with intestinal metaplasia in a high risk Singapore-Chinese population: a cohort study. BMC Gastroenterol, 9:76–84.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.03 MB