Background

Nasopharyngeal carcinoma (NPC) is an illness which related with geographic distribution and distinct ethnic. NPC has a obvious disease burden in Southern China and Southeast Asia, which has an annual about 20 per 100,000 people incidence rate in endemic areas, but is relatively seldom in the Western world (Jeannel and Bouvier, 1999; Parkin et al., 2002). This tumor has been suggested to result from complex interactions of a variety of epidemiological factors. There was evidence which shows that tobacco smoking, alcohol consumption, infection of Epstein-Barr virus (EBV), more exposure of wood dust and a high-salt diet consumption may be risk factors for NPC (Zheng et al., 1994; Cheng et al., 1999; Key et al., 2004; Gullo et al., 2008; Jayaprakash et al., 2008). Only a few exposed persons of exposed people were developed to NPC, which imply that many interactions in some environmental and genetic factors may be the main reason of NPC, and the carcinogenic mechanisms may be contributed by genetic factors, although the risk factors exposed to many persons.

The tumor protein p53 gene, which located on chromosome 17p13, we called TP53, is one of the most likely mutated genes in human tumors and it is probably to be an obviously decisive factor in form of tumor(Tsui et al., 2009). The codon 72 polymorphism, located in exon 4 of TP53 gene, which called rs1042522 involves a leading to a proline (Pro)→arginine (Arg) amino acid substitution CCC→CGC transition at position 72 (Pro72Arg) (Ara et al., 1990). Many publications have showed that the TP53 codon 72 polymorphism could be connected with increased risk to bladder tumor (Zhou et al., 2012), cervical cancer (Xu et al., 2012). Although in some NPC cases the accumulation of P53 protein was reported, as for NPC, TP53 mutation is a rare event, particularly in the juvenile form (10e11). Instead, for NPC possible susceptibility factors would be polymorphisms of TP53.

The relation of the TP53 codon 72 polymorphism and NPC susceptibility have been studied in several previous articles; but the results are not consistent. Zhuo et al. conducted a meta-analysis of five case-control studies and showed that the TP53 codon 72 polymorphism could be a susceptibility factor for nasopharyngeal carcinoma in 2009 (Zhuo et al., 2009). Further, some more articles have been published recently. Best of our knowledge, whether or not NPC susceptibility could have been increased by the TP53 codon 72 polymorphism remains obviously uncertain. To clear the relation could give us better comprehend the possible risk of NPC and further prevent carcinogenesis. For the reason, we do the meta-analysis in order to get precise and latest evaluation of the relation in the TP53 codon 72 polymorphism and NPC risk.

1 Results

1.1 Characteristics of the study

247 studies that met the included criteria were identified by our systematic literature search. Eventually, 9 case-control studies (Golovleva et al., 1997; Yung et al., 1997; Tsai et al., 2002; Tiwawech et al., 2003; Sousa et al., 2006; Hadhri-Guiga et al., 2007; Xiao et al., 2010; Xie et al., 2013; Zhang et al., 2014), which involved 1,588 NPC patients and 1,925 controls were included, after exclusion and deduplication of the obviously irrelevant studies. The study selection process was showed in Figure 1. Table 1 shows the baseline characteristics of the 9 studies.

Figure 1 Flow diagram of study selection

1.2 Meta-analysis results

Figure 2, Figure 3, Figure 4 and Figure 5 review the summary of the meta-analysis results, which shows the relation in the P53 codon 72 polymorphism and NPC. The results exhibited that there was relative association between P53 codon 72 polymorphism and nasopharyngeal carcinoma susceptibility, after we compared ArgArg vs. ProPro, ArgPro vs. ProPro, (ArgPro + ArgArg) vs. ProPro, and ArgArg vs. (ProPro + ArgPro).

Figure 2 Forest plot Note: This represents the NPC risk associated with the TP53 codon 72 polymorphism in Asians for the ArgArg VS. ProPro genetic model

Figure 3 Forest plot Note: This represents the NPC risk associated with the TP53 codon 72 polymorphism in Asians for the ArgProVS. ProProgenetic model

Figure 4 Forest plot Note: This represents the NPC risk associated with the TP53 codon 72 polymorphism in Asians for the ArgPro+ArgArg VS. ProPro genetic model

Figure 5 Forest plot Note: This represents the NPC risk associated with the TP53 codon 72 polymorphism in Asians for the ArgArg VS. ProPro+ ArgProgenetic model

The meta-analysis indicated the persons who carry homozygote Arg/Arg genotype and heterozygote Arg/Pro have a decreased susceptibility of NPC compared with those who carry Pro/Pro genotype [OR 0.59, 95% CI 0.48-0.72; OR 0.66, 95% CI 0.46-0.93]. For Arg allele, the persons who carry an integrated Arg genotype (Arg/Pro + Arg/Arg) have a obviously decreased risk to NPC relative to the ones who with homozygote Pro/Pro genotype [OR 0.62, 95% CI 0.45-0.68]. For Pro allele, the meta-analysis showed that the persons who with an integrated Pro genotype (Arg/Pro + Pro/Pro) have a marked decreased susceptibility of NPC compared with the ones who with Arg/Arg genotype [OR 0.75, 95% CI 0.64-0.87].

1.3 Publication bias

A relatively symmetrical distribution was showed by a based on the four genetic model funnel plot, which enable us to deduce that there was no publication bias.

2 Discussion

The TP53 codon 72 encodeArg and Pro, which are two different functional alleles. And the most informative polymorphism in the TP53 gene is Pro to Arg, which have been found to be associated with the tumors (Ara et al., 1990; Hollstein et al., 1991). Some articles showed an increased risk of disease, among the published publications which explore the relation in the polymorphism and tumors (Xu et al., 2012; Zhou et al., 2012), but some persons could not to find any relation (Matakidou et al., 2003; Sousa et al., 2007; Zhou et al., 2007). The different systematic reviews of the same tumor type could get opposite results, and this is an interesting phenomenon, which is the result from these meta-analyses. Such relation among the people is unclear, although some conclusions were reached by one meta-analyses which studied the relation of the TP53 codon 72 polymorphism and nasopharyngeal carcinoma risk (Zhuo et al., 2009). The systematic review was conducted to further study whether the TP53 codon 72 polymorphism plays an important effect in the form of nasopharyngeal carcinoma, given that NPC has a high incidence in the people.So, the TP53 codon 72 polymorphism is a critical predictive and prognostic marker for the researchers.

Our meta-analysis included a total of 1,588 nasopharyngeal carcinoma patients and 1,925 controls. The meta-analysis indicated the persons who carry homozygote Arg/Arg genotype and heterozygote Arg/Pro have a decreased susceptibility of NPC compared with those who carry Pro/Pro genotype[OR 0.59, 95% CI 0.48-0.72; OR 0.66, 95% CI 0.46-0.93]. For Arg allele, the persons who carry an integrated Arg genotype (Arg/Pro + Arg/Arg) have a obviously decreased risk to NPC relative to the ones who with homozygote Pro/Pro genotype [OR 0.62, 95% CI 0.45-0.68]. For Pro allele, the meta-analysis showed that the persons who with an integrated Pro genotype (Arg/Pro + Pro/Pro) have a marked decreased susceptibility of NPC compared with the ones who with Arg/Arg genotype [OR 0.75, 95% CI 0.64-0.87]. A positive relation of the TP53 codon 72 polymorphism and nasopharyngeal carcinoma was demonstrated by results of the overall population. In the systematic reviews, the current study indicated that the persons who have the homozygote Pro/Pro genotype could have increased NPC susceptibility. In contrast, Arg carriers, particularly the persons who have homozygote Arg/Arg genotype, may have an obvious relation in decreased risk to NPC.

Koushik et al. (2004) indicated susceptibility ofboth squamous cell carcinoma and adenocarcinoma were increased by homozygote Arg/Arg genotype in cervical cancer. A non-association of TP53 codon 72 polymorphisms was showed by previous publication in lung cancer (Matakidou et al., 2003) and gastric carcinoma (Zhou et al., 2007). And Jee et al. (2004) suggested increased susceptibility of cervical adenocarcinoma, but it did not increase squamous cell carcinoma only associates with Arg/Arg genotype. In the present study, TP53 Arg/Arg genotype seemed unlikely to increase NPC risk, but Pro/Pro genotype may act as a risk factor.

The most often studied gene, which is often mutated in some tumors is TP53. This is unclear that the reason underlying TP53 polymorphism increasing NPC risk. However, TP53 gene has reported a few single-nucleotide polymorphisms (Pietsch et al., 2006). TP53 protein is thought to play an important role in apoptotic functions and growth suppression and a proline-rich region was occurred by the polymorphism of TP53 codon 72 (Dumont et al., 2003). Their ability of combining the transcriptional protein, suppressing the transformation and activating transcription of some primary cells were differed by the two polymorphic variants (Chang et al., 2002). Pro variants may induce apoptosis worse than Arg variants do, which may be attributed to the capability of the Arg variant to locate to mitochondria and it controls the release of cytochrome C into cytosol. Thus, at least partly Pro variant seemed to interrelate to apoptosis suppression of cells, which is an important convincing mechanism of tumor form. The distinctive could be the reason that why the Pro allele could increase susceptibility to NPC. In addition, TP53 gene may interact with other genes such as P73 and melanocortin 1 receptor (Nan et al., 2008). Also, it may have a combined effect with some epidemiological factors such as smoking and alcohol consumption, leading to NPC tumorigenesis and progression.

However, there was a number of limitations in the meta-analysis. First, various factors limit the publication, because the publication is a secondary retrospective study, which include the used measurement tools, the original studies quality, and study population differences, like all other meta-analyses. Second, although the publication is very common in systematic reviews of genetic studies, statistical heterogeneity is critical. Therefore, random-effects model analyses were performed by us to think over the factors which could have led to the high level of heterogeneity. Third, this is the reason that the comprehensive genotype information was lacked in our included studies, which induced using unadjusted data analyzed the results of our systematic review. And because the strict inclusion criteria, the studies which been included is small and it is not sufficient to estimate the two relationship. So, based on other adjusted factors, we could not form a more precise analysis. Finally, the number of the systematic review is relatively small and we did not consider the publications for inclusion in languages only including Chinese and English. So, in order to get more precise conclusions between the two, further research should be studied.

3 Materials and Methods

All analyses were based on previous published studies; thus no ethical approvals or patient consents were required. This recommended Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines is adhered to the meta-analysis (Moher et al., 2009).

3.1 Inclusion criteria

Case-control studies which should met the following eligibility criteria were included: (1) polymerase chain reaction (PCR) which include PCR- polymerase chain reaction-single strand conformation polymorphism (SSCP) and PCR-polymerase chain reaction restriction fragment length polymorphism (RFLP) for genotyping were used to genotype; (2) The relation in the TP53 codon 72 polymorphism and NPC susceptibility is evaluated; (3) enabled the genotypes to be computed from the available publications, or the number of the persons genotypes in both the case and control groups were provided; (4) NPC patient who were diagnosed by obviously reported the type or, histologic methods and cancer-free controls or contained healthy were included; (5) the publications should be published in Chinese or English.

3.2 Search strategy

Some databases were searched up to March 2015, which include EMBASE, MEDLINE, AMED, EBM, ACP, Health Technology Assessment, NHS, CNKI and so on. And we searched the following items: [(nasopharyngeal) AND (cancer OR carcinoma) AND (p53 OR TP53) AND polymorphism]. Additionally, we screened for additional studies which included published studies on interrelated topics and the included studies reference lists.

3.3 Data extraction

The following trial data which was extracted from included studies was extracted by two authors independently: the year of publication, the names of the authors, the countries of the publication, the NPC diagnostic method, the method of genotyping, source of control, cases and controls numbers and the genotyping distributions, and the controls Hardy-Weinberg Equilibrium (HWE) (Salanti et al., 2005). If there were disagreements, we should discuss to resolve them.

3.4 Statistical analysis

The Chi-square test (χ2; heterogeneous was p<0.10) and the inconsistency index test (I; indicate higher heterogeneity shows larger I values) evaluated assessment of heterogeneity. Any significant heterogeneity selected to solve the random effects model in the studies. If not, it should use the fixed-effects model (Mantel-Haenszel) (Moher et al., 2009). Publication bias was used to evaluate the Egger regression asymmetry test (Salanti et al., 2005) and Begg’s rank correlation test (Huedo-Medina et al., 2006) and indicative of a lack of publication bias considered a p value of >0.05. We used STATA version 12.0 (StataCorp, Texas, USA) to perform statistical analyses, and it was considered significant, when <0.05.

The fixed-effect analytical model first to pool results of the included studies were employed and statistical heterogeneity was tested by I² statistic (Huedo-Medina et al., 2006). It should be switched to a random-effects model, once I² was more than 40%. In order to quantify in the TP53 codon 72 polymorphism the strength of relation, we used relevant 95% confidence intervals (CIs) and the odds ratios (ORs). And we used four genetic models to assess NPC risk: ArgArg vs. (ProPro + ArgPro), (ArgPro + ArgArg) vs. ProPro, ArgPro vs. ProPro, and ArgArg vs. ProPro. We used examination of funnel plots to detect publication bias. And Review Manager (RevMan) software (version 5.2 for Windows) was used to conduct all statistical analyses.

4Conclusion

In conclusion, this systematic review indicated that TP53 codon 72 polymorphisms are interrelated with NPC risk. Homozygote Pro/Pro genotype could obviously increase risk to NPC, and Arg allele critically decreases NPC risk at the same time.

Authors’ contributions

Zezhang Tao read and approved the final manuscript. ChenggangMao and XiaochunZhou wrote and translated the manuscript. YidaoJiang and LijiaWan collected materials. All authors read and approved the final manuscript.

Acknowledgments

This paper is the outcome of the Jingzhou City project supported by grants from the Science and Technology Program of Jingzhou City (nos. 2017038;2017044).The authors would like to express their great appreciation for the invaluable assistance of Chen Z. and Zhang Z.X.

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