P53 codon 72 Arg/Pro polymorphism and lung cancer risk in Asians: an updated meta-analysis

The p53 codon 72 Arg/Pro variant, the most informative polymorphism of p53 gene, has been found to be significantly associated with an increased risk of lung cancer in a previous meta-analysis [35]. However, not all publications included into the meta-analysis agreed with HWE, and only eight individual studies were conducted in the Asian population. Moreover, they did not assess the role of p53 codon 72 Arg/Pro polymorphism in lung cancer risk concerning the histological types of lung cancer and smoking status among Asians. In the present meta-analysis, a significant relationship of the p53 codon 72 Arg/Pro variant with lung cancer risk was identified under the dominant genetic model in overall (OR_{Arg/Pro + Pro/Pro vs. Arg/Arg} = 1.14) and the subgroup analyses of population-based studies (OR_{Arg/Pro + Pro/Pro vs. Arg/Arg} = 1.17) in Asians. A slightly but not statistically significant association was found in the allelic, homozygous, additive, and recessive contrast models. Additionally, no statistically significant correlation was observed under all genetic contrast models in subgroup analyses according to the histological types of lung cancer and smoking status.

Lung cancer risk increases with cigarette smoking and other environmental exposures. Zhou et al. found that smoking could modify the effects of X-ray cross-complementing group 1 and excision repair cross-complementing group 2 polymorphisms on the risk for lung cancer, indicating a gene–environmental interaction in the lung carcinogenesis [36]. It has been well-established that there is a range of genetic susceptibility to lung cancer risk, such as microsomal epoxide hydrolase 1, matrix metalloproteinase-1, and glutathione S-transferase P1 [37‐39]. In addition, the polymorphism of p53 codon 72 Arg/Pro also has been demonstrated to modify the risk for lung cancer among Asians in many previous case–control studies [21‐34]. Murata et al. initially reported that the Arg/Arg homozygote seemed to be susceptible to smoking-unrelated lung cancer, while the Pro/Pro homozygote did not exert effects on the risk of this deadly disease [21]. A recent study by Liu et al. revealed that the frequencies of Pro/Pro genotype and Pro allele were lower in lung cancer patients and might modify the risk for smoking-related lung cancer in a Chinese population [30]. Reversely, our meta-analysis of all included studies showed that the Pro/Pro genotype and Pro allele were predominant in Asians with lung cancer, although there is lack of statistical significance. Interestingly, the mutant Pro/Pro genotype and Pro allele of p53 codon 72 played a protective but not statistically significant role in lung cancer risk in subgroup analysis of hospital-based studies. Nevertheless, there were only four individual hospital-based studies involving 699 cases and 819 controls included in this meta-analysis. Studies with small sample size were insufficient enough in statistical power to determine a true association. When stratifying by the histological types of lung cancer, patients with SC had lower frequencies of Pro/Pro genotype and Pro allele compared with patients with AC, although there was no statistical significance. When considering the stratified analysis based on the smoking status, the frequencies of Pro/Pro genotype and Pro allele were lower but not statistically significant in smoking-related lung cancer patients, similar to the finding by Liu et al. [30].

The frequencies of p53 codon 72 alleles and haplotypes differ across ethnicities [40], which may be the leading cause for different effects of the p53 codon 72 Arg/Pro polymorphism on lung cancer risk in different ethnicities. Significantly increased risks for lung cancer were found among Asians, but not Africans for both the homozygote Pro/Pro and the Pro allele carriers in a previous meta-analysis by Li et al. [41]. Similarly, the present meta-analysis with more available data suggests that the p53 codon 72 Arg/Pro variant is a risk factor for lung cancer in Asians. The inconsistent findings among ethnicities may be attributed to different genetic backgrounds and environments. Furthermore, the effect of p53 codon 72 Arg/Pro polymorphism on lung cancer risk differs in Asians. Jung et al. demonstrated that the p53 codon 72 Arg/Pro polymorphism was not significantly associated with lung cancer susceptibility in a Korean population [27]. On the contrary, the p53 codon 72 polymorphism was confirmed to be related to an elevated risk of lung cancer in another Korean population [29]. Different study design, sample size, genotyping method, and source of controls may be responsible for the conflicting findings among individual studies.

To the best of our knowledge, tobacco smoking is a major risk factor for lung cancer. It can affect carcinogenesis by interacting with the genetic polymorphisms. Tobacco carcinogens have been shown to exert a direct mutagenic action on DNA, particularly on p53 [42]. The study by Liu et al. suggested that the p53 codon 72 polymorphism modified the smoking-related lung cancer risk, indicating the smoking–gene interplay in lung carcinogenesis [30]. Nevertheless, we found that the p53 codon 72 Arg/Pro polymorphism was not significantly associated with the risk of lung cancer no matter among smokers or nonsmokers. Future studies with high quality and large sample size may further explore the potential role of gene–environment interactions in lung cancer risk.

Some limitations should be acknowledged when elucidating the results of our meta-analysis. Firstly, the genotype distribution of p53 codon 72 among controls was not all in agreement with HWE among total included studies. Secondly, as above mentioned, the appreciable association of smoking–gene interplay with lung cancer risk needs further confirmation in more future studies with high quality. Last but not the least, the p53 codon 72 Arg/Pro polymorphism may modify the risk for lung cancer among Asians in combination with other genetic polymorphisms, such as cytochrome P-450 1A1 [43] and p21 Ser31Arg [44]. Thus, the possible effect of gene–gene interactions on lung cancer risk is recommended to be further investigated.

In summary, our meta-analysis shows a significant association between the p53 codon 72 Arg/Pro polymorphism and lung cancer risk in the Asian population. However, we failed to identify this association regarding the smoking status and histological types of lung cancer patients. In addition, the potential effect of gene–gene and gene–environment interactions on lung cancer development needs further investigation in future studies.