TP53 codon 72 polymorphism and colorectal cancer susceptibility: a meta-analysis
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- Wang, J., Zheng, Y., Sun, L. et al. Mol Biol Rep (2011) 38: 4847. doi:10.1007/s11033-010-0619-8
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Colorectal cancer constitutes a significant proportion of the global burden of cancer morbidity and mortality. A number of studies have been conducted to explore whether TP53 codon 72 polymorphism is associated with colorectal cancer susceptibility. However, controversial results were obtained. In order to derive a more precise estimation of the relationship, we systematically searched Medline, Google scholar, and Ovid database for studies reported before May 2010. A total of 3603 colorectal cancer cases and 5524 controls were included. TP53 codon 72 polymorphism was not associated with colorectal cancer risk in all genetic models (for dominant model: OR = 0.99, 95% CI: 0.86–1.15; for recessive model: OR = 1.00, 95% CI: 0.81–1.23; for Arg/Pro vs. Arg/Arg: OR = 1.00, 95% CI: 0.87–1.15; for Pro/Pro vs. Arg/Arg: OR = 0.97, 95% CI: 0.76–1.25). In the subgroup analyses by ethnic groups and sources of controls, no significant associations were found in all models. Taken together, this meta-analysis suggested that the biologically usefulness of TP53 codon 72 polymorphism as a selection marker in colorectal cancer susceptibility may be very limited.
KeywordsTP53Codon 72Colorectal cancerMeta-analysis
Colorectal (colon and rectum) cancer constitutes a significant proportion of the global burden of cancer morbidity and mortality . Approximately 1 million new cases are diagnosed, and more than half a million people die from colorectal cancer every year . Although numerous epidemiological and biological studies have revealed risk/protective factors for colorectal cancer, present knowledge is still insufficient to elucidate the etiological mechanisms of the disease .
An explosion of information and insights into the molecular pathogenesis of sporadic colorectal cancer can be date back to the late 1980 s, and since then it has served as a paradigm for the investigation of cancer genetics in general . TP53 is one of the most extensively studied genes as a tumor suppressor . It has been thought to plays a pivotal role in modulating cell growth, division, and apoptosis. Mutant TP53 may contribute to increased cell proliferation, loss of ability to undergo apoptosis, and increasing genetic instability . An important TP53 polymorphism is the restriction fragment length polymorphism in codon 72 of exon 4 coding for proline (72Pro: CCC) or arginine (72Arg: CGC) . The both structural forms have been shown to have some different biochemical and biological properties , such as different binding to components of the transcriptional machinery and different activation of transcription .
Recently, the role of TP53 codon 72 polymorphism in the etiology of different types of cancer has drawn more and more attention, including colorectal cancer. A number of studies have been conducted to explore whether TP53 codon 72 polymorphism is associated with colorectal cancer susceptibility [9–31]. However, the results of these studies remain conflicting rather than conclusive. We therefore conducted a meta-analysis to more precisely define the effect of TP53 codon 72 polymorphism on risk for colorectal cancer.
Search strategy and selection criteria
We systematically searched Medline, Google scholar, and Ovid database for studies reported before May 2010, without language restriction, using the search terms: TP53, P53, and colorectal. Non-English articles were translated if necessary. Review articles and bibliographies of relevant literatures were manually scanned to identify eligible studies. Studies were selected according to the following criteria: (a) The study used a case–control study design, (b) the report had available genotype frequency, in the case of the literature without genotype frequency reported, we contact with the author for unavailable genotype frequency, (c) In the case of duplication with multiple articles publishing data on the same population, the most complete data set was included. (d) The gene distributions of control groups were in agreement with Hardy–Weinberg equilibrium (HWE).
Data analysis methods
Pooled ORs and 95% CIs were used to assess the strength of the associations. We calculated pooled ORs and 95% CIs for all studies combined. Furthermore, subgroup analyses were performed by ethnic groups and sources of controls. Ethnic group fewer than three studies and mixed population were grouped together as “Mix” in analyses by ethnicities.
For the assessment of the deviation from HWE in the reported genotype frequencies among controls, the appropriate goodness-of-fit Chi-square test was performed . Statistical heterogeneity among studies was estimated by use of the Q and I2 statistic . P value greater than 0.10 for the Q test indicates a lack of heterogeneity among studies. Dependent on the results of heterogeneity test among individual studies, the fixed effect model (Mantel–Haenszel) or random effect model (DerSimonian and Laird) was selected to summarize the Pooled OR. A sensitivity analysis was performed to illustrate the accuracy and stability of the analytic results. Sensitivity analyses were conducted by deleting a single study each time involved in the meta-analysis . Publication bias was investigated with funnel plots, in which the standard error of log OR of each study was plotted against its OR. An asymmetric plot suggested possible publication bias. The significance of the intercept was determined by the method of the Egger’s linear regression test. Furthermore, Begg’s rank correlation test was performed to check the publication bias. P value < 0.05 was considered representative of statistically significant. Stata version10 (Stata Corp, College Station, Texas, USA) was used for the statistical analysis.
Literature search and meta-analysis databases
Characteristics of eligible studies about TP53 codon 72 polymorphism and colorectal cancer risk included in the meta-analysis
Source of control
Quantitative data synthesis
Results of meta-analysis for dominant, recessive and codominant models for TP53 codon 72 polymorphism and colorectal cancer
(Arg/Pro and Pro/Pro vs. Arg/Arg)
(Pro/Pro vs. Arg/Arg and Arg/Pro)
OR (95% CI)
OR (95% CI)
(Arg/Pro vs. Arg/Arg)
(Pro/Pro vs. Arg/Arg)
OR (95% CI)
OR (95% CI)
A single study involved in the meta-analysis was deleted each time to reflect the influence of the individual data-set to the pooled OR. The corresponding pooled ORs were not materially altered for all genetic models.
The shapes of the funnel plots did not reveal any evidence of obvious asymmetry in dominant model and codominant model (Arg/Pro vs. Arg/Arg). However, obvious asymmetry was observed in recessive model and codominant model (Pro/Pro vs. Arg/Arg). Similarly, the results of Egger’s test did not show any evidence of asymmetry in dominant model (t = −1.17, P = 0.256) and codominant model (for Arg/Pro vs. Arg/Arg: t = −1.04, P = 0.310), whereas evidence of asymmetry was observed in recessive model (t = −3.23, P = 0.005) and codominant model (for Pro/Pro vs. Arg/Arg: t = −3.26, P = 0.004). Furthermore, the results of Begg’s rank correlation test revealed no significant publication bias in dominant (Z = 1.20, P = 0.230), recessive (Z = 1.40, P = 0.163), and codominant model (for Arg/Pro vs. Arg/Arg: Z = 1.01, P = 0.315; for Arg/Arg vs. Pro/Pro: Z = 1.52, P = 0.127).
In the last two decades, and especially in recent years, TP53 is one of the most extensively investigated genes as a tumor suppressor [45–51]. Accordingly, a few meta-analyses have been published on this issue. Hu [ demonstrated TP53 codon72 polymorphism is associated with breast cancer risk within certain populations or regions. Yan  reported that Pro allele might increase the risk of lung cancer under recessive genetic model in adenocarcinoma, Asians, and lung cancer stage I. Recently, pooled analysis  provides evidence that there is no association between TP53 codon 72 polymorphism and cervical cancer when the analysis is restricted to methodologically sound studies. More recently, Zhu  demonstrated that TP53 codon 72 polymorphism is not associated with prostate cancer risk. In the context of colorectal cancer, one meta-analysis has been published . However, the authors didn’t perform on a recessive model.
This meta-analysis includes information on 3603 colorectal cancer cases and 5524 controls indicates TP53 codon 72 polymorphism was not associated with colorectal cancer risk. This finding may point to the validity and the robustness of the results initially presented . More importantly, we revealed that TP53 codon 72 polymorphism is not associated with colorectal cancer in recessive model.
There were differences of genetic backgrounds and the gene-environment interactions in the etiology among different ethnicities. However, no significant association was found in any subgroup of population. Since the hospital-based studies may have some biases because such controls are not representative of the general population, subgroup analyses have also been performed by sources of controls. Similarly, no significant association was found.
Because of the degree of variability among the study characteristics, the results from meta-analyses should be interpreted with an appropriate degree of caution. However, the sensitivity analysis had been performed to confirm the reliability and stability of this meta-analysis. In addition, our inclusion of non-English language reports was important in minimizing a major potential threat to the validity of any meta-analysis-the related threat of a language bias.
Some limitations of this meta-analysis should be discussed. Publication bias is a major problem in performing meta-analysis because the studies with negative results are more likely not to be published. Although we attempted to identify unpublished work in Google scholar, publication biases have been observed in some comparisons. Another potential limitation was that our results were based on unadjusted estimates. More precise analyses can be conducted if individual data was available, which would allow for the adjustment by other covariates including age, sex, and other factors.
Taken together, this meta-analysis suggested that the biologically usefulness of TP53 codon 72 polymorphism as a selection marker in colorectal cancer susceptibility may be very limited. Future studies should focus on gene–gene and gene–environment interactions. The result may be lead to better, comprehensive understanding of the association between the TP53 codon 72 polymorphism and cancer risk.
Conflict of interest