XPG Gene Polymorphisms and the Risk of Gastric Cardia Adenocarcinoma

Abstract

Background: Polymorphisms in DNA repair genes can alter an individual's DNA repair capability and contribute to the risk of various cancers. Aims: This study was designed to evaluate the association of single-nucleotide polymorphisms (SNPs) in the XPG gene with the risk of gastric cardia adenocarcinoma (GCA) in a high-incidence population in northern China. Methods: Two SNPs from 431 GCA patients and 432 healthy controls were genotyped using the polymerase chain reaction/ligase detection reaction (PCR-LDR) method. Results: The rs751402 C/T SNP T allele and the T/T genotype were associated with an increased risk of GCA in younger individuals (≤61 years) (odds ratio [OR] = 1.33 and 1.77, 95% confidence interval [CI] = 1.00-1.76 and 1.12-3.30, respectively). The rs873601 G/A SNP was not associated with susceptibility to GCA. Conclusions: Our findings indicate that the rs751402 C/T SNP has potential as a predictive marker for the risk of GCA and that carriers of the T/T genotype should receive periodic upper gastrointestinal fiber tests to facilitate the early detection and early treatment of GCA.

Introduction

Gastric cardia adenocarcinoma (GCA) is an adenocarcinoma with an epicenter at the gastroesophageal junction, that is, 1 cm above to 2 cm below the junction between the end of the tubular esophagus and the beginning of the saccular stomach (Siewert and Stein, 1998). Compared with cancer of the pyloric antrum, tumors situated within the gastric cardia are associated with increased operative mortality, a lower 5-year survival rate, and a poorer prognosis (Fielding et al., 1989).

Ci County of Hebei province is one of the high-incidence regions for GCA in China. One study indicated that the incidence of GCA in Ci County drastically increased between 1988 and 2007 (Chen et al., 2011). The most recent data indicated that the incidence of GCA in Ci County was 33.16 per 10⁵ people in 2011. Therefore, GCA remains a major cancer-associated healthcare burden in Ci County. It is well established that the interplay of multiple environmental and genetic factors over time mediates the development of complex diseases such as GCA. A growing body of evidence suggests that helicobacter pylori infection, low socioeconomic status, low intake of fruits and vegetables, nutritional deficiencies, smoking, and alcohol intake are risk factors for GCA (Tran et al., 2005; Kamangar et al., 2009). However, the precise genetic factors associated with the predisposition to GCA are not well defined.

The human genome is constantly being damaged by endogenous (oxidants, methylating agents, byproducts of normal cellular metabolism, etc.) and exogenous carcinogens (UV radiation, tobacco, etc.) (Li, 2012; Lindahl, 2013). The DNA repair system plays a vital role in maintaining genomic integrity and stability and in protecting the genome from carcinogen-induced DNA damage.

The XPG gene, also known as ERCC5, plays an important role in the excision of an ∼24-32 bp DNA segment containing the bulky adduct during nucleotide excision repair (NER). XPG is a structure-specific endonuclease that cleaves the 3′ terminus of a damaged DNA strand through the catalytic activity of amino acids located in its N-terminus (Scherly et al., 1993; Clarkson, 2003). In addition, XPG participates in the incision of the damaged DNA strand at the 5′ terminus through a nonenzymatic mechanism (Wakasugi et al., 1997) and stimulates base excision repair of DNA damaged by oxidative stress to facilitate efficient transcription by RNA polymerase II (Bessho, 1999; Klungland et al., 1999). In summary, XPG plays an indispensable role in the DNA repair process.

Defects in DNA repair mechanisms are associated with an increased risk of various cancers (Wei et al., 1996; Cheng et al., 1998), and genetic variants of XPG have been implicated in interindividual variations in DNA repair efficiency (Lalle et al., 2002). Accumulating data suggest that XPG polymorphisms are associated with the susceptibility to a wide variety of cancers and with the efficacy of some chemotherapies (Chen et al., 2009; Duan et al., 2012; He et al., 2012; Hu et al., 2014), and this correlation might be caused by interindividual variations in DNA repair efficiency resulting from XPG genetic variations.

Deng et al. (2014) evaluated XPG protein expression in 176 gastric cancer (GC), 131 adjacent nontumorous, 53 atrophic gastritis (AG), and 49 superficial gastritis (SG) tissue samples using immunohistochemical staining and observed a significantly greater XPG expression in GC tissues compared with adjacent nontumorous tissues. Furthermore, XPG expression was significantly elevated in AG and GC tissues compared with SG tissues, indicating that XPG expression levels were directly correlated with disease severity according to the sequence of disease progression (SG→AG→GC). Thus, XPG plays a crucial role in the development of GCA.

The XPG gene rs751402 C/T single-nucleotide polymorphism (SNP) is located within the cis-acting site for the E2F1/YY1 transcription factor (Cartharius et al., 2005), indicating that this SNP is likely to affect gene expression by altering the DNA binding activity of this transcription factor. The rs873601 G/A SNP, located in a microRNA binding site of the XPG gene, might modulate the interaction of a microRNA with XPG mRNA, thereby influencing the expression of the XPG gene at the mRNA or protein level (He et al., 2012). Therefore, these two SNPs might influence the risk of developing disease by regulating XPG gene expression. Given the importance of XPG in gastric carcinogenesis and the unclear genetic basis of susceptibility to GCA, we conducted a population-based case-control study to assess the association of the XPG gene rs751402 C/T and rs873601 G/A SNPs with the risk of GCA in a high-incidence population from a region of northern China.

Materials and Methods

Study subjects

The study included 431 GCA patients and 432 healthy controls. All of the study subjects were from the ethnically homogeneous Han nationality and were permanent residents of Ci County. All the GCA patients and healthy controls were recruited during an endoscopic screening campaign between 2008 and 2013. The GCA cases were histologically confirmed, and the self-reported cancer-free subjects who did not have upper gastrointestinal cancer (UGIC), as demonstrated by endoscopy, were selected as the healthy controls. Information regarding age, sex, smoking habit, and family history of UGIC was obtained from the cancer patients and healthy controls by two professional interviewers immediately after samples were obtained. Ultimately, 431 GCA patients and 432 age-, sex-, and smoking status-matched healthy controls were enrolled in the study. Smokers were defined as former or current smokers if they smoked five or more cigarettes per day for at least 2 years. Individuals who had at least one first-degree relative or at least two second-degree relatives who had been diagnosed with esophageal/cardia/GC were defined as having a family history of UGIC. The study was approved by the Ethics Committee of Hebei Provincial Cancer Institute and consent forms were obtained from all the recruited subjects.

DNA extraction

Five milliliters of venous blood from each subject was drawn into Vacutainer tubes containing ethylenediaminetetraacetic acid, and the samples were stored at 4°C. Genomic DNA was extracted within 1 week of sampling using Proteinase K (Merck) digestion followed by a salting-out procedure according to the method published by Miller et al. (1998).

Polymorphism genotyping

The genotypes of the XPG gene rs751402 C/T and rs873601 G/A SNPs were determined by the Shanghai Generay Biotech Co., Ltd. (www.generay.com.cn) using the polymerase chain reaction/ligase detection reaction (PCR-LDR) method. The primers used for amplification were 5′-acagccagaagatgtccctgc-3′ and 5′-taaccaccaaggcatcaccac-3′ for the rs751402 C/T SNP, and 5′-tatcctctataattagttatg-3′ and 5′-aaacaaatgtcagatttagac-3′ for the rs873601 G/A SNP. PCRs were carried out in a total volume of 15 μL containing 50 ng genomic DNA, 1.5 μL of 10× PCR buffer, 1.5 μL of 25 mM MgCl₂, 0.3 μL of 10 mM dNTPs, 0.25 μL of 10 pmol/μL of each primer, and 2.5 U of Taq DNA-polymerase (TaKaRa). The cycling parameters were as follows: 94°C for 2 min, 35 cycles at 94°C for 15 s and 55°C for 15 s, 72°C for 25 s, and a final extension step at 72°C for 3 min. Two specific probes and one common probe for LDR were synthesized for each SNP locus. The two specific probes used to discriminate the specific nucleotides at the SNP loci were 5′-ttcgctggtgggtccgcaaacccac-3′ and 5′-tttttcgctggtgggtccgcaaacccat-3′ for the rs751402 C/T SNP, and 5′-ttttaaagacgtaataaaattaactggta-3′ and 5′-tttttttaaagacgtaataaaattaactggtg-3′ for the rs873601 G/A SNP. The common probe was phosphorylated at the 5′ end and labeled at the 3′ end with 6-carboxy-fluorescein (FAM). The common probes for the rs751402 C/T and rs873601 G/A SNPs were 5′-P-gaaaaatgggcccgctcggtttccg-FAM-3′ and 5′-P-gcacggtctttgtatttagtgtgtggtt-FAM-3′, respectively. LDRs were performed in a 10 μL reaction volume containing 3 μL of PCR product, 1 μL of 10× Taq DNA ligase buffer, 0.01 μL of 10 pmol/μL of each probe, and 5 U of Taq DNA ligase (New England Biolabs). The LDR parameters were as follows: 25 cycles of 94°C for 30 s and 56°C for 1 min. After the LDR, 1 μL of the LDR product was mixed with 10 μL of loading buffer containing a marker. The mixture was then denatured at 95°C for 3 min, immediately chilled in ice water, and analyzed using an ABI 3730XL DNA sequencer. In addition, the DNA of representative PCR products was directly sequenced to confirm the accuracy of the LDR method, and the results were 100% concordant.

Statistical analyses

Statistical analyses were performed using the SPSS version 11.5 software package (SPSS). p < 0.05 was considered significant for all statistical analyses. Hardy-Weinberg analysis was performed by comparing the observed and the expected genotype frequencies in the control group using the χ²-test. Comparison of genotype distribution in the patients and healthy controls was performed by calculating the means of two-sided contingency tables using the χ²-test. The odds ratio (OR) and 95% confidence interval (CI) for genotypic-specific risk were calculated using an unconditional logistic regression model and the values were adjusted for age, sex, smoking status, and family history of UGIC accordingly.

Results

Subject characteristics

The mean age of the GCA patients and the healthy controls were 61.1 ± 7.87 and 61.2 ± 7.78 years, respectively. The proportion of male subjects in GCA patients was 76.8%, similar to the proportion observed in the control group. The proportion of smokers in the GCA group was slightly greater than that of the control group, but the difference was not statistically significant. No statistically significant difference was observed in the distribution of age, sex, and smoking status between the GCA patients and the healthy controls (p = 0.92, 0.81, and 0.18, respectively), suggesting that the frequency matching was adequate. Although the frequency of a positive family history of UGIC was greater in GCA patients (44.3%) than in the healthy controls (39.4%), the difference was not statistically significant (Table 1). However, a significantly greater proportion of younger patients (≤61 years) had a positive family history of UGIC compared with their healthy controls (p = 0.04) (Table 2).

Table 1.

Distribution of Selected Characteristics in GCA Patients and Healthy Controls

Group	Control, n (%)	GCA, n (%)	χ²	p
Sex
Male	333 (77.1)	331 (76.8)
Female	99 (22.9)	100 (23.2)	0.01	0.92
Age (years)
≤61	216 (50.0)	212 (49.2)
>61	216 (50.0)	219 (50.8)	0.06	0.81
Smoking status
Smoker	209 (48.4)	228 (52.9)
Nonsmoker	223 (51.6)	203 (47.1)	1.76	0.18
Family history of UGIC
Positive	170 (39.4)	191 (44.3)
Negative	262 (60.6)	240 (55.7)	2.19	0.14

GCA, gastric cardia adenocarcinoma; UGIC, upper gastrointestinal cancer.

Table 2.

The Family History of UGIC of GCA Patients and Healthy Controls in Different Age Groups

Group	Negative, n (%)	Positive, n (%)	p	OR (95% CI) ^a
Age ≤61
Control	129 (59.7)	87 (40.3)		1.00
GCA	105 (49.5)	107 (50.5)	0.04	1.50 (1.03-2.21)
Age >61
Control	133 (61.6)	83 (38.4)		1.00
GCA	135 (61.6)	84 (38.4)	0.99	1.00 (0.68-1.47)

Adjusted for age, sex, and smoking status.

CI, confidence interval; OR, odds ratio.

Association of the XPG gene rs751402 C/T and rs873601 G/A SNPs with the risk of GCA

The genotype distributions of the XPG gene rs751402 C/T and rs873601 G/A SNPs in the healthy controls were consistent with the Hardy-Weinberg equilibrium (χ² = 0.05 and 2.06, p = 0.83 and 0.15, respectively). The frequencies of the C/C, C/T, and T/T genotype in the XPG gene rs751402 C/T SNP in healthy controls were 44.7%, 44.7%, and 10.6%, respectively. The genotype frequency of the XPG gene rs751402 C/T SNP in the GCA patients was not significantly different from that of healthy controls (χ² = 3.11, p = 0.21). The frequency of the T variant allele in GCA patients and the healthy controls was 0.37 and 0.33, respectively (Table 3). Overall, there was no significant association between the rs751402 C/T SNP and GCA risk in all the genetic models. Analyses of subgroups stratified by sex, age, smoking status, and family history of UGIC revealed that the rs751402 C/T SNP T allele and the T/T genotype enhanced the risk of GCA in subjects 61 years of age or younger (OR = 1.33 and 1.77, 95% CI = 1.00-1.76 and 1.12-3.30, respectively) (Table 4).

Table 3.

Correlation of rs751402 C/T and rs873601 G/A SNPs to Susceptibility of GCA

Group	Control, n (%)	GCA, n (%)	p	OR (95% CI) ^a
rs751402 C/T SNP
C/C	193 (44.7)	174 (40.4)		1.00
C/T	193 (44.7)	196 (45.5)	0.48	1.11 (0.83-1.48)
T/T	46 (10.6)	61 (14.1)	0.10	1.44 (0.93-2.23)
C/T+T/T	239 (55.3)	257 (59.6)	0.25	1.17 (0.89-1.54)
C/C+C/T	386 (89.4)	370 (85.9)		1.00
T/T	46 (10.6)	61 (14.1)	0.14	1.37 (0.91-2.06)
C allele	579 (67.0)	544 (63.1)		1.00
T allele	285 (33.0)	318 (36.9)	0.09	1.19 (0.97-1.45)
rs873601 G/A SNP
G/G	132 (30.6)	115 (26.7)		1.00
G/A	200 (46.3)	215 (49.9)	0.24	1.21 (0.88-1.66)
A/A	100 (23.1)	101 (23.4)	0.52	1.13 (0.78-1.65)
G/A+A/A	300 (69.4)	316 (73.3)	0.28	1.18 (0.88-1.59)
G/G+G/A	332 (76.9)	330 (76.6)		1.00
A/A	100 (23.1)	101 (23.4)	0.96	1.01 (0.74-1.39)
G allele	464 (53.7)	445 (51.6)		1.00
A allele	400 (46.3)	417 (48.4)	0.39	1.09 (0.90-1.31)

Adjusted for age, sex, smoking status, and UGIC family history except allele frequency comparison.

SNP, single-nucleotide polymorphism.

Table 4.

Stratification Analysis for Association Between rs751402 C/T SNP and Susceptibility to GCA

Group	No. of control/GCA	OR (T vs. C)	OR (C/T vs. C/C) ^*	OR (T/T vs. C/C) ^*	Dominant model OR (C/T+T/T vs. C/C) ^a	Recessive model OR (T/T vs. C/C+C/T) ^a
Sex
Male	333/331	1.24 (0.98-1.55)	1.16 (0.84-1.60)	1.60 (0.95-2.70)	1.23 (0.91-1.68)	1.48 (0.90-2.43)
Female	99/100	1.05 (0.70-1.57)	0.99 (0.53-1.85)	1.13 (0.50-2.56)	1.01 (0.57-1.81)	1.14 (0.54-2.41)
Age (years)
≤61	216/212	1.33 (1.00-1.76)	1.21 (0.80-1.83)	1.77 (1.12-3.30)	1.32 (0.89-1.95)	1.61 (0.89-2.88)
>61	216/219	1.06 (0.80-1.41)	1.03 (0.69-1.53)	1.13 (0.61-2.11)	1.06 (0.72-1.55)	1.14 (0.63-2.05)
Smoking status
Smoker	209/228	1.26 (0.95-1.66)	1.54 (0.77-1.73)	1.68 (0.90-3.12)	1.24 (0.85-1.82)	1.54 (0.86-2.76)
Nonsmoker	223/203	1.12 (0.84-1.49)	1.06 (0.70-1.60)	1.23 (0.66-2.30)	1.09 (0.74-1.61)	1.19 (0.66-2.15)
Family history of UGIC
Positive	170/191	1.31 (0.97-1.78)	1.48 (0.94-2.31)	1.60 (0.80-3.21)	1.49 (0.97-2.29)	1.29 (0.68-2.46)
Negative	262/240	1.09 (0.84-1.42)	0.90 (0.62-1.32)	1.26 (0.71-2.24)	0.98 (0.69-1.40)	1.39 (0.81-2.39)

Adjusted for age, sex, smoking status, and UGIC family history except allele frequency comparison (T vs. C).

The frequency of the G/G, G/A, and A/A genotype in the XPG gene rs873601 G/A SNP in the healthy controls was 30.6%, 46.3%, and 23.1%, respectively. There was no significant difference in the genotype frequency of the XPG gene rs873601 G/A SNP between the GCA patients and the controls (χ² = 1.72, p = 0.42). The frequency of the A variant allele in GCA patients was similar to that of the healthy controls (0.48 vs. 0.46, respectively) (Table 3). The XPG gene rs873601 G/A SNP was not associated with the risk of GCA according to the analysis of the GCA and control groups as a whole or in any of the subgroup analyses (data not shown).

Discussion

In this molecular epidemiological study, we investigated whether the XPG gene rs751402 C/T and rs873601 G/A SNPs were associated with the risk of GCA in a high-incidence population from northern China. We observed that GCA patients 61 years of age or younger demonstrated a significantly greater frequency of a family history of UGIC compared with their healthy controls, implying that genetic factors play a crucial role in the development of GCA. In fact, Wen et al. (2010) also reported that GCA patients with a family history of UGIC were younger at the age of disease onset compared with patients who did not have a family history of UGIC. In the overall study population, the XPG gene rs751402 C/T and rs873601 G/A SNPs exhibited no impact on the susceptibility to GCA. However, stratification analyses according to sex, age, smoking status, and UGIC family history demonstrated that the rs751402 C/T SNP T allele and the T/T genotype were associated with an increased risk of GCA in the subjects 61 years of age or younger.

The XPG gene rs751402 C/T SNP might modulate XPG gene expression by affecting the DNA binding capability of the E2F1/YY1 transcription factor. For instance, the rs751402 A variant allele (which is equivalent to the T allele in our study) reduced promoter activity and transcription levels of XPG gene in colorectal cancer cells (Chen, 2009). In addition, the rs751402 C/T SNP might be involved in the regulation of XPG expression by CEBPG transcription factor in human bronchial epithelial cells (Crawford et al., 2007). Therefore, the rs751402 C/T SNP might represent a functionally significant SNP. It is biologically plausible that this SNP contributes to disease susceptibility. Similar to the results of a study investigating GC (Duan et al., 2012), our study evaluating GCA specifically found that the T allele and the T/T genotype were associated with an increased risk of GCA in younger individuals. Carriers of the T allele or the T/T genotype might have defects in DNA repair mechanisms due to reduced XPG gene expression (Chen, 2009).

Cancer is a complex and multifactorial disease, and the combination of environmental and genetic factors over time can promote carcinogenesis. It is reasonable to hypothesize that the risk of GCA gradually increases with age as a result of the accumulation of DNA damage induced by exogenous and endogenous mutagens over time. In older subjects, the impact of genetic variants might be surpassed by the effect of environmental carcinogens. Genetic risk factors render individuals more prone to developing cancer when they have been exposed to a low level of carcinogens (Wang et al., 2012). Therefore, the elevated risk of GCA associated with the T allele and the T/T genotype in younger subjects highlights the potentially critical role of genetic factors in the development of cancer. These results suggest that individuals with the T/T genotype would benefit from periodic upper gastrointestinal fiber tests to facilitate the early detection and early treatment of GCA.

Except for the association with GC risk, rs751402 C/T SNP C/C genotype was linked to reduced risks of oral squamous cell carcinoma and hepatocellular carcinoma (Yoon et al., 2011; Zavras et al., 2012), which was in agreement with our finding. However, a case-control study of 133 patients with salivary gland tumors and 142 healthy controls demonstrated that the T/T genotype was associated with a decreased risk of salivary gland tumors (Meng et al., 2013). This discrepancy might be due to the differences in sample size among different studies or to diversities in the pathogenesis of various cancers.

The rs873601 G/A SNP might regulate the expression of the XPG gene by modulating the interaction of microRNA with XPG mRNA. He et al. (2012) reported that lower mRNA expression levels in both adjacent normal gastric tissues of GC patients and lymphoblastoid cell lines from normal peripheral blood lymphocytes were consistently associated with XPG rs873061 G/A SNP A variant genotype in a recessive manner. Furthermore, the A variant genotype increased the risk of gastric adenocarcinoma specifically in patients with NGCA but not in patients with GCA. In this study, which examined a relatively larger sample size compared with the study on GC (431 vs. 305), we also found that the rs873601 G/A SNP did not affect the susceptibility to GCA in the overall study population or in subgroups stratified by various parameters, suggesting that the rs873601 G/A SNP is not likely to be a useful molecular biomarker for the risk of GCA. However, it is also possible that the sample size evaluated in our study was not large enough to detect a weak association between the rs873601 G/A SNP and a predisposition to GCA. Similarly, this SNP did not influence the risk of either esophageal squamous cell carcinoma or squamous cell carcinoma of the head and neck (Ma et al., 2012; Zhu et al., 2012).

DNA repair systems not only affect the predisposition to multiple types of cancers but also influence the therapeutic efficacy of anticancer platinum compounds. The DNA repair system may be a two-edged sword such as a deficient NER activity associated with the higher disease susceptibility but with a well clinical outcome. The rs873601 G/A SNP was not associated with the prognosis of acute myeloid leukemia patients or melanoma patients (Xu et al., 2012; Li et al., 2013). Although the G/G genotype was correlated with a higher expression of the XPG gene possibly, nonsmall-cell lung cancer patients with G/G genotype had a favorable outcome for progression-free survival and overall survival (Hu et al., 2014). In fact, despite the reported consistent association between the sequence variants in the region of chromosome 5p15.33 and 8q24 and the risk of various types of cancer, most studies have indicated that the same SNP might be cancer specific (Gudmundsson et al., 2007; Haiman et al., 2007; Tomlinson et al., 2007; Yeager et al., 2007; Kiemeney et al., 2008).

The present study had multiple strengths worth noting. This study was a population-based molecular epidemiological study that avoided potential selection bias, and the frequency of various genotypes observed in healthy controls might represent the actual frequency in the general population. It is well known that smoking is one of the major environmental factors involved in the development of GCA (Tran et al., 2005). In the present study, the patient and the control groups were matched according to sex, age, and smoking status, thereby minimizing the effect of these potentially confounding factors. In addition, using the information regarding UGIC family history, we confirmed the significant role of genetic background in the development of GCA.

In our future studies, detailed information regarding additional risk factors for GCA, such as H. pylori infection, should be collected. Furthermore, additional functional SNPs in the XPG gene or other NER genes should be included in our analyses to evaluate the effect of gene-gene interactions and gene-environment interactions on the development of GCA, as cancer is a complex and multifactorial disease. Furthermore, it is necessary to validate our findings in additional studies with larger sample sizes as our partial results were based on stratification analyses with a relatively small sample size and to further dissect the mechanism by which the SNPs influence the development of GCA.

In conclusion, this was the first study to evaluate the association between two potentially functional SNPs in the XPG gene and the risk of GCA in a population from the high-incidence region of Ci County. Our results indicated that the rs751402 C/T SNP T allele and T/T genotype were associated with an increased risk of GCA in patients 61 years of age or younger. These results suggested that carriers of the T/T genotype should receive periodic upper gastrointestinal fiber tests to facilitate the early detection and early treatment of GCA.

Footnotes

Acknowledgment

This study was supported by the Hebei Province Medical Scientific Research Key Project (No. 20110146).

Author Disclosure Statement

No competing financial interests exist.

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