Genetic factors that may alter the repair of damaged gastric and colonic epithelial cell DNA, resulting in their transformation into cancer cells remain poorly understood. Accumulation of permanently generated reactive oxygen species during cellular metabolism and extracellular processes may lead to carcinogenesis caused by oxidative DNA damage. p53, a tumor suppressor protein encoded in humans by the p53 gene, regulates the cell cycle and preserves the stability of the human genome to prevent cancer initiation (1,2). Gastric cancer (GC) is the fourth most common malignancy and the second primary cause of cancer mortality, resulting in >800,000 mortalities worldwide annually (3,4). In addition to environmental factors, genetic variants are significant. As a crucial tumor suppressor gene, p53 is critical in cell-cycle regulation, DNA repair, cellular differentiation and apoptosis in various types of cancer. Furthermore, variants of p53 gene exert an important effect on tumor development and cancer risk (5–7).

Recently, numerous studies have evaluated the interaction between p53 and its regulators in carcinogenesis. Of these regulators, the murine double minute clone 2 (MDM2) proto-oncogene, an important negative regulator of the p53 gene, has become a point of interest (8). MDM2 is a major regulator of p53 function. p53 and MDM2 act in a feedback cycle whereby p53 activates MDM2 at the transcriptional level, while MDM2 binds, obstructs and degrades the p53 protein through E3 ligase activity (9–11). The human MDM2 gene is located on chromosome 12q13-14 (genomic size, 34 kb) and contains two promoters, the constituent promoter and the p53-responsive intronic promoter (12). The inherently occurring sequence variation in the MDM2 promoter results in a changed MDM2 protein expression leading to the alteration in p53 mediated tumor suppression activity. A single nucleotide polymorphism (SNP; T309G) located in the first intron of the core promoter region of the MDM2 gene influences binding of the transcription factor, Sp1. Sp1 binds with higher affinity to the G allele than to the T allele, which results in increased transcription of the MDM2 gene and higher expression levels of MDM2 protein, thereby obstructing the tumor suppressor function of p53. This SNP leads to increased MDM2 mRNA and protein expression levels and, as a result, p53 inhibition. Additionally, there is a disposition, which demonstrated earlier cancer inception in certain groups of patients harboring the GG or TG genotype for MDM2 T309G (13). The MDM2 T309G polymorphism has been reported to be associated with certain tumors, such as colon, gastric and hepatocellular cancer (14–16).

In the present study, the aim was to investigate the association between genetic polymorphisms of the MDM2 gene, a major regulator of p53 function, and primary GC risk in a Turkish population.

In the present study, the association between the MDM2 polymorphism and GC was investigated in a Turkish population. The polymorphism in the MDM2 gene, T309G has been determined in 65 patients with GC and in 67 healthy control subjects using the PCR-RFLP method.

The demographic characteristics of the study population are presented in Table I. The mean age of the GC patients and control subjects were 62.25±10.95 years (males, 62.32±10.55; females, 61.92±13.08) and 62.34±10.54 years (males, 62.58±9.86; females, 61.43±13.19), respectively. The percentage of males and females in the cases were 81.5 and 18.5%, respectively (Table I). No statistically significant differences were identified between the cases and control subjects by age and sex (P>0.05). Nor were there statistically significant associations between the cases and control subjects for smoking history (OR=0.99; 95% CI, 0.50–1.97; P=0.989; Table II). Furthermore, no statistically significant differences were identified regarding alcohol consumption among the cases and control subjects (OR=2.35; 95% CI, 0.88–6.27; P=0.082) (Table II). Comparison between GC cases and control subjects indicated statistically significant differences in family history of cancer (OR=0.17; 95% CI, 0.05–0.56; P=0.01; Table II). Individuals with the GG genotype were associated with a higher risk for GC and the GG polymorphism was significantly associated with this disease (OR=4.58; 95% CI, 1.18–17.79; P=0.022; Table III). Analysis of the MDM2 gene T309G polymorphisms is presented in Fig. 1.

GC is the fourth most common cancer and the second leading cause of cancer-associated mortality worldwide (4). GC is a complex trait caused by genetic and environmental factors (19). Genetic polymorphisms in the carcinogen detoxification, antioxidant protection, DNA repair and cell proliferation processes are also crucial in the development of GC (20).

In the current study, of 65 GC cases and 67 control subjects, the crude OR of GC patients for family history of cancer was 0.17, indicating an association between GC incidence and family history of cancer (P=0.01; Table II). To the best of our knowledge, GC and family history of cancer association has not been proposed in previous studies. In addition, GC patients and control subjects were evaluated by logistic regression analysis for smoking habits. No statistically significant difference was identified between GC patients and smoking habits in the Turkish population investigated in the current study (P=0.989; Table II).

The MDM2 T309G polymorphism in GC patients has been investigated in various different regions of the world; however, to the best of our knowledge, no research has been performed in Turkey. This study was the first study to evaluate the polymorphic variants of MDM2 T309G polymorphism and risk of GC. The MDM2 protein negatively regulates p53 function via multiple independent mechanisms, such as by binding to transcription activation domains, inhibiting acetylation, promoting nuclear export and, most importantly, promoting proteasomal degradation via ubiquitination (9,11,21,22). The MDM2 T309G polymorphism is a single nucleotide T to G polymorphism located at the 309th nucleotide in the MDM2 gene promoter. Over the last two decades, it has been confirmed that the MDM2 T309G polymorphism is capable of significantly altering the expression levels of MDM2, thereby suppressing the p53 signaling pathway. Furthermore, a number of epidemiological studies have investigated the association between the MDM2 T309G polymorphism and the risk of various types of cancer (23–26), including renal, hepatocellular, endometrial, bladder and stomach cancers. However, the results of previous studies regarding the association between the MDM2 T309G polymorphism and GC risk were different or even contradictory (27,28). Recently, numerous studies demonstrated that significant associations between the MDM2 T309G polymorphism and GC risk were identified for the G and T alleles, and the GG and TT genotypes. The G allele was revealed to act as a key factor for increasing the risk of GC, which is consistent with the study by Pan et al (29). In addition, in a meta-analysis, Chen et al (30) proposed that the G allele of the MDM2 T309G polymorphism is a high risk factor for developing GC. In the present study, a statistically significant difference was identified in the GG genotype distribution between GC patients and control subjects in the investigated Turkish population (OR=4.58; 95% CI, 1.18–17.79; P=0.022; Table III). MDM2 T309G GG genotype was associated with an increased risk of gastric carcinoma when compared with the TT genotype or T carriers (P<0.01), and a joint effect between MDM2 T309G GG and the Helicobacter pylori infection was observed to intensify the GC risk (31). Tian et al (32) proposed that the GG genotype is associated with a significantly increased risk of GC (OR=1.43; 95% CI, 1.08–1.91; P=0.013). Consistent with these studies, the current study identified that the overall GC risk for T309G GG was significantly increased when it was compared with T carriers (OR=4.58; 95% CI, 1.18–17.79; P=0.022), as presented in Table III. The distribution of MDM2 genotypes in different populations is provided in Table IV. While the genotype distribution of the control group of the present study was similar to those of the other studies (15,26–29,31,33) the case groups differed.

In conclusion, the present results indicate a significant association between the MDM2 GG genotype and GC; although, it is not possible to conclude that a single polymorphism determines an individual's susceptibility to GC development. Furthermore, the MDM2 GG genotype may be defined as an independent marker for GC.