Is there a relation between Murine double minute 2 T309G polymorphism and lung cancer risk in the Turkish population?

Introduction

Lung cancer (LC) is the most common and lethal cancer worldwide. LC account for approximately 13% of all new cancer cases and about 19.4% of all cancer related death in America and worldwide [1]. According to data obtained from Turkey’s Lung Cancer Map Project, the number of annual expected new cases in Turkey is about 30,000 [2].

The molecular mechanism of lung tumorigenesis has not been clearly understood, yet. However, it has been known that, multiple signal pathways and key regulator genes in the pathways such as p53 and Murine double minute 2 (MDM2) play role in development of LC and often interconnected with cross-talk between pathways involved in carcinogenesis. The detailed examination of these pathways and regulators in LC pathogenesis will provide opportunities for detecting of target molecules and developing of new treatment strategies [3].

p53 is a tumor suppressor gene localized on short arm of chromosome 17. During DNA damage response, p53 is a key protein for preventing of cell proliferation via some mechanisms including apoptosis and cell cycle arrest. However, excessively expression of p53 in absence of stress causes to destroy of normal cells. Therefore, several genes play role for attenuation of the negative mechanism of p53, as a means to maintain homeostasis. MDM2 is principal regulator of p53 and an oncogene located on the long arm of chromosome 12. Both proteins are intricately dependent on each other for normal cell proliferation and growth [4]. Overexpression of MDM2 inhibits the function of p53. Thus, it enables damaged cells to escape the cell cycle checkpoint and become carcinogenic in a variety of human cancers. Recently, two SNPs altering the MDM2 expression in MDM2 promoter region have been identified. One of them is MDM2 (rs2279744). The SNP at nucleotide 309 characterized as a change of thymine (T) to guanine (G). T-to-G SNP in the promoter region of MDM2 (rs2279744) leads to increased MDM2 expression by binding of the transcriptional activator to promoter of MDM2. [5], [6]. This polymorphism has been associated with several cancers such as gastric, bladder, breast and lung cancer [5], [6], [7], [8]. The majority of previous studies explaining the association between LC risk and the rs2279744 polymorphism have shown discrepant results. Until now, there is not any study regarding to LC risk and MDM2 T309G polymorphism in Turkish population from Central Anatolia. In brief, effect of this polymorphism on LC risk for Turkish population is unknown. Therefore, in this study, we aimed to investigate whether there is a relationship between the rs2279744 polymorphism and LC in a Turkish population.

Materials and methods

Results

Demographic features of the study group were shown on Table 1. Frequencies of characteristics including mean age, gender, alcohol consumption, familial history of cancer were not different in patient and control groups. We observed that subjects with smoking habit as an independent risk factor for LC had 8.27 fold higher risk of cancer than non-smokers (p=0.0001) in this population (Table 1). Besides, the frequencies of smokers were significantly higher in the patients compared to the controls. In addition, smoking habit was more frequently in patients with squamous carcinoma than patients with adenocarcinoma (χ²=6.19, p>0.04), when smoker ratio was evaluated according to LC subtypes. Other than this, there was no difference between frequencies of characteristics and histological types of LC consisting of small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), yet.

In this study, genotype frequencies of both groups were not deviate from Hardy-Weinberg equilibrium. In addition, there was no difference between both groups for genotype distributions (χ²=3.50, p>0.17) (Table 2). Besides, genotype distributions of the rs2279744 polymorphism did not different among individuals with SCLC-NSCLC and adenocarcinoma-squamous carcinoma-others (χ²=0.09, p>0.95; χ²=2.89, p>0.57, respectively) (Table 2).

When demographic features, clinicopathological findings and genotype frequencies of this polymorphism together were evaluated, we did not find any association with risk of LC except smoking habit (Table 3).

Discussion

In this study, we did not observe any positive or negative effects of MDM2 T309G polymorphism on LC risk for our population. As consistent with our study, the similar result for LC risk has been found in Han Chinese of southeast China [10], African-Americans and Caucasians [11]. On the contrary, significant association between this polymorphism and LC risk was detected in Han Chinese of north Chine [12], Korean [13], Norwegian [14], and non-Hispanic white populations [15]. It is considerable that there was were discrepancies into among themselves of the studies. Namely, G allele was related to significantly increased risk for LC in three studies [12], [13], [14], even though the allele has a significantly decreased risk for LC in another study [15]. It has been suggested that reason of the discrepancy might be ethnic group differences.

However, different results from each other have been found in two meta-analyses investigated same Asian, European and African populations [16], [17]. In subgroup analysis based on ethnicity, the results under three models including dominant, recessive and co-dominant models have been shown that G allele of MDM2 SNP309 has been evaluated as a low-penetrant risk factor for developing of LC in Asians in spite of this result was found neither in Europeans nor in Africans [16]. In another meta-analysis, results under the recessive model as the most suitable genetic model have been investigated and, statistically significant risk has not been defined in both Asians and Europeans [16]. It has been reported that the principal difference among these two studies was the genetic model selection [18]. The other difference was that smoking status and histological type of LC has been analysed in subgroup analysis in addition to ethnicities. Bai et al. obtained a stronger relationship between a higher risk of LC (particularly for NSCLC) and GG genotype in never smokers [17]. The high risk for NSCLC in never smoker has also been found by Liu et al. [19]. On the contrary, the increased risk for NSCLC inclusive adenocarcinoma-AC and/or squamous cell carcinoma-SCC has been found in ever smokers in several studies [11], [14], [15], [19], [20]. In our study, we found no significant association between this polymorphism and LC or subtypes of LC, when the each of the three genetic models and similar subgroup analysis were used.

After these inconsistent results, we think that effects of the other risk factors on LC development such as age and gender should be also evaluated. We did not obtain any correlation among GG genotype and the two factors (age and gender) for LC risk in present study. As consistent with findings of our study, some researchers did not find any association among the rs2279744 polymorphism and age [12], [16], [21] and gender [10], [19], [22] for LC risk. In contrast to this data, it has been reported that age [12], [13], [14] or gender [18], [23] together with the MDM2 polymorphism may an effect on the LC risk. However, there were also remarkable discrepancies among these studies. At LC diagnosis, although, risk factor accompanied with GG genotype, was older age in a study [18], but was younger age in another study [13], [14], [17]. Conversely, younger age in smoker man compared to women has been shown protective effect for LC risk in non-Hispanic Whites [15]. On the other hand, in two meta-analyses, women with GG genotype for MDM2 SNP309 had increased LC susceptibility [18], [21]. The reason of this discrepancy may be estrogen-signaling pathway that Bond et al. shown that there was a gender-specific association with MDM2 SNP309 GG genotype and an active estrogen-signalling pathway, either directly or indirectly, allows for the G-allele of SNP309 to accelerate tumor formation in women [24]. Furthermore, increased LC risk has been detected in never-smoker Chinese females and in non-Hispanic White males for MDM2 SNP309. The risk factor in these studies was TT genotype instead of GG genotype [15], [21]. In addition, Chien et al. [22] and Dong et al. [25] found an association between TT genotype and increased death risk in NSCLC survival. According to the experimental study; the higher risk of cancer is predicted from G allele compared to T allele. It has been declared by Liu et al. [19] that the data about function of the G allele may be achieved with experimental researches; however epidemiologic studies may resolve more complicated interactions among all variants in MDM2 gene or other candidate genes regarding to carcinogenesis. Therefore, it might not be possible to make a clear inference in human from the in vivo allele function based on experimental data, was suggested by Li and colleagues [15]. As different from these findings, when effect of SNP309 TT genotype on LC risk was analysed, any association was not found in our study (the data not shown).

All conflict results show us that different genetic background of cases and various risk factors may effect to the relationship between MDM2 T309G polymorphism and LC risk in different populations. Besides, same factors consisting of limited sample size, non-random sampling and the pitfalls arising from unknown confounders also need to be considered.

Conclusion

We did not find any association between MDM2 polymorphism and LC risk in our Turkish population. In addition, we did not detect that any effect of the polymorphism on clinicohistopathological parameters of LC. We suggested that MDM2 T309G polymorphism may not be a suitable indicator of LC for the Turkish population from Central Anatolia. It is first study performed with Turkish population despite some limitation factors. In addition, it is a considerable study due to it will be a baseline study for other Turkish population studies. Besides, our results will offer an opportunity to compare to results of other studies which will be made in future.