Introduction

Digestive tract cancers are complex, multistep, multifactorial, and highly fatal diseases. Genetic factors, environmental exposures, and gene–environment interactions all contribute to the risk of these cancers’ development. Digestive tract cancers contain alimentary tract and digestive gland cancers. Among them, hepatocellular, colorectal, gastric, and esophagus cancers were common cancers with high incidence and mortality in the world.

Inflammation, smoking, alcohol, and low-nutrition intake were known to be the main exogenous causes to the risk of digestive system cancer. The mechanism includes induce oxidative stress [1–6]. Reactive oxygen species (ROS) is one of the major oxidative pathways, which could increase damage to DNA and modify the structure of genes. When the production of ROS exceeds the antioxidant-defense capacity, the oxidative DNA damage occurs, resulting in mutations that can activate oncogenes or inactivate tumor suppressor genes and eventually lead to cancer [7, 8]. One of the well-studied products of ROS is 8-oxo-7, 8-dihydroguanine (8-oxoGua), a typical biomarker of oxidative stress, which is a strongly mutagenic lesion due to its ability to mispair with adenine during DNA replication, leading to G:C to T:A mutations [9, 10]. DNA repair systems are fundamental to the maintenance of genomic integrity and necessary for the restoration of the mismatched genes. Decreased efficiency of DNA repair accelerates genetic instability and the rate of genetic change, which may play a vital role in carcinogenesis [11]. An important mechanism to protect cell against mutagenic effect of ROS is base excision repair pathway (BER) [12–15]. BER removes modified base by specific glycosylases, which can be assisted by endonucleases. After abasic site priming, gap filling, and ligation, the changed base can be repaired, thus maintaining the stability of DNA. The DNA repair enzyme human oxoguanine glycosylase 1 (hOGG1), a key multifunctional gene involved in BER pathway, plays an important role in preventing carcinogenesis by repairing oxidative damage to DNA [16]. The hOGG1 gene is located at 3p25, a region which is found to be frequently missing in various tumors, which show loss of heterozygosity of markers [17]. Protein hOGG1, the product of hOGG1 gene, is a bifunctional glycosylase that could remove 8-oxoG directly from the oxidatively damaged DNA [18, 19]

Polymorphisms in DNA repair genes are assumed to cause deficit in DNA repair capacity, which may lead to genetic instability and carcinogenesis. Many sequence variants have been detected in hOGG1 gene. Among them, the 1,245 C > G (polymorphism Ser326Cys; rs1052133) is a well-known and well-studied hOGG1 gene polymorphism. This polymorphism is a C to G polymorphism in exon 7 of the hOGG1 gene, resulting in the substitution of cysteine for serine at codon 326. Activity of 8-oxoguanine DNA glycosylase is significantly affected by the Ser326Cys polymorphism in hOGG1. The DNA repair activity of hOGG1-Cys326 was weaker than the hOGG1-Ser326-encoded protein [20].

So far, there were so many reports about the correlation of hOGG1 Ser326Cys polymorphism with the risk of different cancers, including digestive cancers, such as pancreatic [21, 22], gallbladder [23–26], gastric [16, 27–38], colorectal [39–51], esophageal [52–58], oral cancer [59, 60], hepatocellular cancer [14, 61], and so on [13, 26]. Recent meta-analysis has reported the association of hOGG1 Ser326Cys polymorphism and cancers. However, by the limitation of inadequate publications, they did not calculate pooled ORs of digestive system cancers comprehensively, and results from each study have been conflicting and contradictory. To improve the efficiency of analysis on digestive system cancers and reduce the potential heterogeneity between studies which might derive from various cancers in diverse systems, we perform this meta-analysis for the association between hOGG1 Ser326Cys polymorphism and digestive system cancers.

Materials and methods

Identification and eligibility of relevant studies: PubMed, Embase, and other studies in the public domain (until 28 February 2013) search were performed using following search terms: “oxoguanine glycosylase 1, hOGG1 or OGG1,” “polymorphism or variant,” and “cancer, neoplasm or tumor.” Additional studies were identified by a hand search of the references of original studies. In case of the studies with the same or overlapping data, we selected the most recent ones with the largest number of subjects. Studies included in this meta-analysis should meet the following criteria: (a) evaluation of the association of hOGG1 Ser326Cys polymorphism and digestive system cancer risk published in English language; (b) study was designed using the methodology of a case–control study; (c) contains available genotype frequency, and there was sufficient data for the computation of odds ratios and corresponding 95 % confidence intervals (ORs, 95 % CIs).

Data extraction

Two investigators independently extracted the data and reached a consensus on all the items. For each study, the following characteristics were collected: last name of first author, year of publication, country of origin, ethnicity, cancer types, genotyping methods, matching criteria, source of control, and numbers of genotyped cases and controls. Different ethnic descents were categorized as Caucasians, Asians, and Africans. In addition, if only one cancer type was included in a study in the meta-analysis, it was combined into the “others” group. For the study of Hanaoka and colleagues [31], which included subjects of different ethnic groups, data were extracted separately for each ethnic group, and the study of Huang and colleagues [26] contains three cancer types, so we separately extracted the data as three studies.

Statistical analysis

The strength of the association between hOGG1 Ser326Cys polymorphism and digestive system cancer risk was measured by odds ratios (ORs) with 95 % confidence intervals (CIs). We first estimated the risks of the Cys/Cys and Ser/Cys genotypes on risk of cancer compared with the wild-type Ser/Ser as homozygote and heterozygote models, respectively, and then evaluated the risks of “Cys/Cys + Ser/Cys vs. Ser/Ser” and “Cys/Cys vs. Ser/Cys + Ser/Ser” on risk of digestive system cancer, assuming dominant and recessive effects of the variant Cys allele, respectively. Subgroup analysis was also performed based on different ethnicities, cancer types, and source of control.

Heterogeneity was evaluated with a chi-square-based Q test among the studies (P < 0.10 was considered significant) [62, 63]. When the heterogeneity was present, the random effects model was used to calculate the pooled OR [64], whereas the fixed effects model was used in its absence [65]. Sensitivity analysis was performed to assess the stability of the results.

Stratification by cancer types, source of controls, and ethnicity was conducted. All cancers were categorized into different groups based on cancer types: gallbladder cancer, gastric cancer, colorectal cancer, esophageal cancer, oral cancer, hepatocellular cancer, pancreatic cancer, and others. Eligible studies were classified into population-based and hospital-based according to control source. The subjects were classified by ethnicity into Caucasian group and Asian group.

The departure of frequencies of hOGG1 Ser326Cys polymorphism from expectation under Hardy–Weinberg equilibrium (HWE) in control population was judged by the chi-square test. P value less than 0.05 was considered to be a state of disequilibrium. Publication bias was diagnosed with Egger’s linear regression method [66, 67] and funnel plot. The P value less than 0.05 in Egger’s linear regression indicated the presence of potential publication bias. The standard error of logarithm for OR was plotted against its OR in funnel plot. Begg’s funnel plot was also plotted to detect the publication bias and influence of individual study on pooled OR. Log OR was plotted versus standard error of log OR for each included study in Begg’s funnel plot [68], and asymmetric or incomplete funnel-shaped plots demonstrated publication bias also. In the one-way sensitivity analysis, we excluded one single study each time, and the new pooled results could reflect the influence of that deleted study to the overall summary OR. All statistical analysis was implemented with STATA 11.0 (STATA Corp, College Station, TX). All P values were two-sided.

Results

Study characteristics

For digestive system cancer susceptibility, articles were retrieved based on the search criteria. Four hundred forty-one articles were screened. Two hundred forty-five articles were excluded because of no relevant study (e.g., review and meta-analysis). Ninety-one articles were excluded since they have no association with digestive cancer. Forty articles were not case–control studies. Eleven articles were not in English. Nine articles cannot extract useful data. Finally, a total of 48 case–control studies involving 12,073 cancer cases and 19,557 controls were included in the meta-analysis (we separate Hanaoka and colleagues’ study into two studies and Huang and colleagues’ studies into three). The characteristics of included studies were summarized in Table 1. There were 20 studies of Caucasian descendants and 28 studies of Asian descendants. Cancers were confirmed histologically or pathologically in most studies. There were 4 studies of gallbladder cancer, 14 studies of gastric cancer, 14 studies of colorectal cancer, 7 studies of esophageal cancer, 2 studies of oral studies, 2 studies of hepatocellular cancer, 2 studies of pancreatic cancer, and 4 studies of others. There were 23 studies in which the controls come from population-based (PB) source and 25 studies from hospital-based (HB) one. In addition, the distribution of genotypes in the controls was consistent with HWE in all studies, except six studies (P < 0.05).

Table 1 Main characteristics of the selected studies
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Quantitative synthesis

The 326Cys allele frequencies in controls of different ethnicities were calculated. The frequency of the 326Cys allele was 40.70 % (95 % CI = 36.05–45.34 %) among Asian controls, which was significantly higher than that of Caucasian controls (20.95 %; 95 % CI = 19.06–22.84 %, P < 0.001).

We carried out a meta-analysis of the hOGG1 Ser326Cys polymorphism overall and in subgroups according to cancer types, ethnic groups, and source of controls under various genetic models (Table 2). Overall, we found that the hOGG1 Ser326Cys polymorphism was significantly associated with the risk of digestive system cancers (Cys/Cys vs. Ser/Ser: OR = 1.17, 95 % CI = 1.00–1.35, P < 0.001; Cys/Cys vs. Cys/Ser + Ser/Ser: OR = 1.14, 95 % CI = 1.00–1.29, P < 0.001; Table 2, Fig. 1).

Table 2 Stratified analyses of the hOGG1 Ser326Cys polymorphism on digestive system cancer susceptibility
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Fig. 1
figure 1

The forest plot of the homozygote and recessive model. a Cys/Cys vs. Ser/Ser b Cys/Cys vs. Cys/Ser + Ser/Ser. The squares and horizontal lines correspond to the study-specific OR and 95 % CI. The area of the squares reflects the study specific weight (inverse of the variance). The diamond represents the pooled OR and 95 % CI

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In subgroup analyses by cancer types, we found that the hOGG1 Ser326Cys polymorphism was significantly associated with hepatocellular cancer (Cys/Cys vs. Ser/Ser: OR = 1.49, 95 % CI = 1.07–2.09, P < 0.001; Table 2) and others in one model (Cys/Cys vs. Cys/Ser + Ser/Ser: OR = 1.51, 95 % CI = 1.03–2.20, P = 0.35; Table 2), but not with gallbladder, gastric, esophageal, and pancreatic cancer. In addition, we found that the hOGG1 Ser326Cys polymorphism was marginally associated with the risk of colorectal cancer (Cys/Cys + Cys/Ser vs. Ser/Ser: OR = 1.17, 95 % CI = 1.00 (0.999)–1.37, P < 0.001; Table 2). However, we found that hOGG1 Ser326Cys polymorphism could decrease the risk with oral cancer (Cys/Cys vs. Ser/Ser: OR = 0.67, 95 % CI = 0.49–0.91, P = 0.381; Ser/Ser vs. Cys/Cys: OR = 0.72, 95 % CI = 0.55–0.94; Table 2).In subgroup analyses by ethnicities, we did not found that the hOGG1 Ser326Cys polymorphism was associated with overall cancer risk in Asian population and Caucasian population. When stratified in source of control, we found that the hOGG1 Ser326Cys polymorphism was associated with digestive cancer risk in PB controls (Cys/Cys vs. Ser/Ser: OR = 1.25, 95 % CI = 1.02–1.53, P = 0.001; Cys/Cys vs. Cys/Ser + Ser/Ser: OR = 1.18, 95 % CI = 1.00–1.39, P = 0.018; Table 2), but not in HB controls group.

Test of heterogeneity

The heterogeneity was reckoned between each of the studies using the Q test. Overall, the significant heterogeneity was found (Cys/Cys vs. Ser/Ser: pheterogeneity < 0.001; Cys/ Ser vs. Ser/Ser: pheterogeneity < 0.001; Cys/Cys + Cys/Ser vs. Ser/Ser: pheterogeneity < 0.001; Cys/Cys vs. Cys/Ser + Ser/Ser: pheterogeneity < 0.001). In stratified analyses by cancer types, we did not find the significant heterogeneity for esophageal cancer and oral cancer in all models (esophageal cancer: Cys/Cys vs. Ser/Ser: pheterogeneity = 0.128; Cys/ Ser vs. Ser/Ser: pheterogeneity = 0.057; Cys/Cys + Cys/Ser vs. Ser/Ser: pheterogeneity = 0.069; Cys/Cys vs. Cys/ Ser + Ser/Ser: pheterogeneity = 0.058; oral cancer: Cys/Cys vs. Ser/Ser: pheterogeneity = 0.381; Cys/ Ser vs. Ser/Ser: pheterogeneity = 0.925; Cys/Cys + Cys/Ser vs. Ser/Ser: pheterogeneity = 0.650; Cys/Cys vs. Cys/Ser + Ser/Ser: pheterogeneity = 0.427). Then, we assessed the source of heterogeneity for dominant model (Cys/Cys vs. Cys/Ser + Ser/Ser) by cancer type, ethnicity, and source of controls. As a result, cancer type (x 2 = 17.75, df = 7, P = 0.013) and source of controls (x 2 = 5.63, df = 1, P = 0.017), but not ethnicity (x 2 = 0.23, df = 1, P = 0.631) were found to contribute to substantial heterogeneity. However, we did find the source of heterogeneity in meta-regression from the three covariates.

Sensitivity analysis

In the sensitivity analysis, the influence of each study on the pooled OR was examined by repeating the meta-analysis while omitting each study one at a time. This procedure confirmed the stability of the overall result (data not shown). Moreover, when we omitted the six studies that is not consistent with HWE, the final result was almost the same with the former one.

Publication bias

Begg’s funnel plot and Egger’s test were conducted to assess the publication bias of the literatures. The shape of funnel plots did not reveal any evidence of funnel plot asymmetry. Egger’s test further provided statistical evidence of funnel plot symmetry. The Egger’s test also shows that there are no publication bias in all the four models (Cys/Cys + Cys/Ser vs. Ser/Ser: P = 0.545; Fig. 2).

Fig. 2
figure 2

The funnel plot of the homozygote and recessive model. A Cys/Cys vs Ser/Ser B:Cys/Cys + Cys/Ser vs Ser/Ser. Log OR is plotted versus standard error for each of studies in this meta-analysis. Each point represents a separate study for the indicated association of the two models

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Discussion

Digestive system cancer is a kind of severe cancer type, which seriously affected people’s life and health. Among them, colorectal, gastric, liver, esophagus, and oral cavity cancers ranked the first ten cancers of the most estimated new cases in men. In women, colorectal, gastric, and liver cancers were placed in the first ten cancers. In addition, liver, gastric, colorectal, and esophagus cancer were the leading cause of cancer death with 1,539,400 estimated deaths in men. In women, colorectal, gastric, liver, esophagus, and pancreatic cancers ranked ahead in all cancers with 1,037,900 estimated deaths [69].

The presence of 8-oxodG residues, one of the most abundant oxidative products of cellular DNA, leads to GC/TA transversions since it preferentially pairs with adenine instead of cytosine during DNA replication [70–72]. An increase in 8-oxodG in DNA can contribute to the incidence of cancer risk [73]. hOGG1, an important DNA repair enzyme involved in BER pathway, is responsible for repairing 8-OHdG lesions [13, 74]. If hOGG1 could not function effectively, the DNA damage could be left unrepaired, leading to gene mutations or carcinogenesis. Codon 326 polymorphism (Ser326Cys, rs1052133) in hOGG1 gene was the most studied polymorphism. It is located in the 1a-specific exon7 of hOGG1 gene, resulting in an amino acid substitution of serine (Ser) with cysteine (Cys) at codon 326, which has been reported to affect the hOGG1 function [20] and to be associated with cancer susceptibility [75].

The hOGG1 has been studied extensively on its relationship with different cancer types of digestive system, such as pancreatic, gallbladder, gastric, colorectal, esophageal, and so on. Previous conclusions of numerous studies on the association between the hOGG1 Ser326Cys polymorphism and digestive system cancer risk remain conflicting and contradictory. Hence, this meta-analysis was needed to provide a quantitative approach for combining the different results.

The meta-analysis included 12,073 cancer cases and 19,557 controls. In the analysis, we found that hOGG1 Ser326Cys polymorphism was associated with digestive system cancers. This result is consistent with Wang’s meta-analysis of the whole cancers [76]. However, certain publication bias exists in the homozygote and recessive models so that the strength of the association lacks some convincing evidence.

It is well-known that digestive system cancers are intimately associated with inflammation reaction. The hepatitis virus and Helicobacter pylori infection are major causes of hepatocellular cancer and gastric cancer, respectively, and colitis can contribute to the carcinogenesis of colorectal cancer. Inflammation is associated with the release of large amounts of ROS [77], leading to oxidation of nucleic acids, proteins, and lipids [78, 79]. In addition, exposure to smoking, heave alcohol drinking, and unhealthy consumption could be the contributors to the risk of digestive system cancer, which could lead to oxidative stress or weak the antioxidative activity [2, 3, 5]. Exposure to smoking produce major classes of carcinogenic and DNA adducts-productive compounds, polycyclic aromatic hydrocarbons (PAHs), aromatic amines, and heterocyclic amines (HCA), involving ROS generation and oxidative DNA damage [1, 80]. Fresh fruits and vegetables contain micronutrients such as vitamins A, C, and E and β-carotene, which could exert antioxidative activities, scavenge free radicals, and prevent DNA damage, but fat, meat, and alcohol were the ROS-producing food [81–83]. So, the unhealthy diet could induce the micronutrient deficiency, resulting in poor cellular antioxidant status and more ROS generation.

The hOGG1 encodes a DNA glycosylase that is thought to be involved in BER of oxidatively damaged DNA [84], and it could catalyze the cleavage of the glycosylic bond between the modified base and the sugar moiety, leaving an abasic apurinic/apyrimidinic site in DNA. The resulting apurinic/apyrimidinic site is then incised, and the repair is completed by successive actions of a phosphodiesterase, a DNA polymerase, and a DNA ligase [85–87]. Due to the important roles of hOGG1 in DNA repair, it is biologically plausible that hOGG1 Ser326Cys polymorphism may modulate the risk of digestive system cancer, which was confirmed by our data.

In the subgroup analysis by cancer types, we found the hOGG1 Ser326Cys polymorphism has increased the risk of hepatocellular cancer and other cancers, but the results were significant in only one model. In addition, we found marginal significance with colorectal cancer risk. Epidemiology and clinical studies demonstrated that the major risk factors for hepatocellular carcinoma include alcoholism, hepatitis B and C, and liver cirrhosis [88]. Chronic hepatic inflammation caused by hepatitis and exposure to alcohol and tobacco stimulates the generation of ROS causing DNA damage [89–91]. In addition, chronic intestinal inflammation is a known risk factor for developing colorectal cancer [92], and the smoking, alcohol, and low intake of micronutrition could induce DNA damage through oxidative stress [93]. If the hOGG1 could not work properly due to the sequence variants, the DNA damage could silence suppressor genes and active oncogenes, which lead to carcinogenesis. However, the inverse effect existed in oral cancer. There may be some reasons. Firstly, the type of pathology is mainly squamous cancer in oral cancer. While in other digestive cancer type, adenocarcinoma occupied for most of the pathological types. The differentiated biological genesis may lead to the variant results for the hOGG1 polymorphism. Secondly, the number of studies on oral cancer is scary, which may induce some bias for the results. The conclusion should be confirmed further by the larger data. In the stratified analysis by source of controls, we found that hOGG1 Ser326Cys polymorphism could increase the risk of digestive system cancer in PB control group, but we did not find the association in HB control group. This may be because most of the controls in the hospital are somehow unhealthy people, thus affecting the results. When stratifying the ethnicities, we did not find any relationship with the risk of digestive system cancer in both Asian population and Caucasian population.

Unfortunately, the publication bias existed in our analysis. We have searched for or contacted the authors for the unpublished data to ameliorate the effect of publication bias on the results of a meta-analysis. However, these data were not suitable for this meta-analysis. Therefore, the data in our analysis need to be validated by further larger studies.

Several limitations of the meta-analysis should be addressed. First, limited data restricted our evaluation on potential gene–gene interaction. Second, there was not enough data on African population in this meta-analysis. Third, our results exist publication bias, which weak the convincing degree. Forth, some cancer types have limited sample size. In order to provide a more precise estimation, well-designed studies are warranted in the future.

In summary, this meta-analysis indicated that hOGG1 Ser326Cys polymorphism may increase the susceptibility of digestive system cancers, especially in hepatocellular cancer and maybe in colorectal cancer, but the polymorphism can decrease the risk of oral cancer. This SNP may considerably act as a candidate of biomarker for cancer screening, diagnosis, and therapy in the future. Due to the limitations, further well-designed studies with large sample size in diverse ethnic populations, more types of digestive system cancers were warranted to confirm our findings.