The association between TP53 Arg72pro polymorphism and non-melanoma skin cancer risk: a meta-analysis including 7,107 subjects.

BACKGROUND: The p53 gene is a critical molecular in the protection of cells from DNA damage due to Ultraviolet (UV) exposure, and TP53 mutation is very common in non-melanoma skin cancer.
OBJECTIVES: To assess the association between the TP53 Arg72Pro polymorphism and non-melanoma skin cancer (NMSC) risk.
METHODS: We performed this meta-analysis with 13 case-control studies involving 3,520 cases and 3,587 controls.
RESULTS: Our meta-analysis showed that TP53 Arg72Pro polymorphism was not associated with non-melanoma skin cancer susceptibility in overall population.(for Arg/Arg vs. Pro/Pro: OR 0.98, 95% CI 0.80-1.19; for Arg/Pro vs. Pro/Pro: OR 0.99, 95% CI 0.84-1.17; for the recessive model Arg/Arg vs. Arg/Pro + Pro/Pro: OR 1.10, 95% CI 0.89-1.35; for the dominant model Arg/Arg + Arg/Pro vs. Pro/Pro: OR 1.00, 95% CI 0.85-1.18). We also detected no effect of this polymorphism on any subtype of non-melanoma skin cancer, such as squamous cell carcinoma (SCC), and basal cell carcinoma (BCC). Furthermore, no significant association in any subgroup was detected in stratified analyses according to ethnicity. However, in the stratified analysis by sample collection resources, Arg/Arg carriers from tumor tissue subgroup had 3.42 times risk of cancer (95% CI, 1.19 to 9.84) as compared with the variant type Pro/Pro in NMSC.
CONCLUSIONS: TP53 Arg72Pro polymorphism may have little involvement in the pathogenesis of NMSC, regardless of type, including SCC, and BCC.

What was known?

1. Polymorphisms of TP53 have previously been reported to be possible risk factors for a variety of tumors.

2. Studies have focused on the association between TP53 Arg72Pro polymorphism and NMSC susceptibility, but the results are inconclusive.

Introduction

Skin cancer is the most frequent cancer in the Western world.[1] Statistics have shown that one in three whites will develop skin cancer in their lifetime.[2] DNA damage that results from excess ultraviolet irradiation contributes to the development of non-melanoma skin cancer, and the response variability to ultraviolet damage between different individuals may alter disease risk.[3] The p53 gene is critical to this DNA damage response, and is a logical node for investigating genetic susceptibility to non-melanoma skin cancer.

As a tumor suppressor, TP53 suppresses tumor growth by inducing cell-cycle arrest or apoptosis, TP53 is also critical in the regulation of cellular response to stress.[4] Polymorphisms of TP53 have previously been reported to be possible risk factors for a variety of tumors.[5-13] The most common polymorphism of TP53 is at the 72nd amino acid residue, resulting in either a praline residue (p53Pro) or an arginine residue (p53Arg) at this position.[14] The two forms of p53 are not functionally equivalent: the abilities of each form to induce apoptosis and suppress transformed cell growth are different, In particular, the Arg72 variant induces apoptosis more efficiently than the Pro72 variant;[15] differences also exist in their transcriptional activities.[16] Due to their functional differences, important implications can be drawn for the management of patients with wild-type p53-containing tumors, depending on their p53 genotype.

In recent years, several studies have focused on the association between TP53 Arg72Pro polymorphism and non-melanoma skin cancer susceptibility,[917-28] but the results are inconclusive. Therefore, we performed a meta-analysis of all eligible studies to derive a more precise estimation of the association to help us better understand its possible influence on non-melanoma skin cancer risk.

Search Strategy

In this meta-analysis, a comprehensive literature research of the US National Library of Medicine's Pub Med database (update to August, 2011) was conducted using the search terms including“p53”,“TP53”,“polymorphism”, “skin cancer”, “non-melanoma”, “squamous cell carcinomas”, “basal cell carcinomas”, and the combined phrases in order to obtain all genetic studies on the relationship of TP53 Arg72Pro polymorphism and non-melanoma skin cancer risk. We also used a hand search of references of original studies or reviewed articles on this topic to identify additional studies. The following criteria was used to select the eligible studies: (1) a case–control study on the association between TP53 Arg72Pro polymorphism and non-melanoma skin cancer, (2) detailed number of different genotypes for estimating an odds ratio (OR) with 95% confidence interval (3) when several publications reported on the same population data, the largest or most complete study was chosen. As a result, 13 eligible case–control studies were included in our meta-analysis.

Data Extraction

Two investigators independently extracted data. For each eligible study, the following information was recorded: The first author's name, the year of publication, country of origin, sources of controls, racial descent of the study population, number of cases and number of controls with different genotypes, and minor allele frequency in controls. Different ethnicities were categorized as Caucasian, Asian and Others.

Statistical analysis

The strength of relationship between TP53 Arg72Pro polymorphism and non-melanoma skin cancer risk was assessed by using Crude OR with 95% CI. The codominant model (Arg/Arg vs. Pro/Pro; Arg/Pro vs. Pro/Pro), the dominant model (Arg/Arg + Arg/Pro vs. Pro/Pro), and the recessive model (Arg/Arg vs. Arg/Pro + Pro/Pro) were used in this study to evaluate the risk. Between-study heterogeneity was evaluated by Q-test. Fixed effects model was used to pool the data when the P value of Q-test ≥ 0.05, otherwise, random-effects model was selected. Both funnel plot and Egger's test were used to assess the publication bias. (P < 0.10 was considered representative of statistical significance). All statistical analyses were performed in Statistical Analysis System software (v. 9.1.3; SAS Institute, Cary, NC) and Review Manage (v. 5; Oxford, England).

Results

Eligible studies

In total, 13 eligible case–control studies involving 3,520 cases and 3,587 controls were selected in this meta-analysis. The main characteristics of these studies are shown in Table 1. These eligible publications including 11 studies of Europeans, 1 of Asians and one other population. Distribution of TP53 Arg72Pro polymorphism genotype frequencies among skin cancer cases and controls of the 13 studies are shown in Table 2. The genotype distributions in the controls of all studies were in agreement with HWE except for three studies.[8913] The minor allele frequency of the Arg72 allele among controls ranged from 0.57 in the Asian population to 0.86 in a European population.

Table 1

Main characteristics of included studies in the meta-analysis

Table 2

Distribution of TP53 Arg 72 Pro genotypes among non-melanoma skin cancer cases and controls included in the meta-analysis

Meta-analysis

The main results of this meta-analysis and the heterogeneity tests are shown in Table 3. Overall, we found no significant association between TP53 Arg72Pro polymorphism and non-melanoma cancer risk in overall population (for Arg/Arg vs. Pro/Pro: OR 0.98, 95% CI 0.80-1.19; for Arg/Pro vs. Pro/Pro: OR 0.99, 95% CI 0.84--1.17; for the recessive model Arg/Arg vs. Arg/Pro + Pro/Pro: OR 1.10, 95% CI 0.89-1.35; for the dominant model Arg/Arg + Arg/Pro vs. Pro/Pro: OR 1.00, 95% CI 0.85–1.18). Next, we investigated the effect of the TP53 Arg72Pro polymorphism on the susceptibility to subtypes of non-melanoma skin cancer. No evidence of association was observed in any genetic model between TP53 genotype and risk of non-melanoma skin cancer, SCC, and BCC. In addition, we did analysis in the subgroup by ethnicity; significant association was also not detected in all genetic models [Table 3]. However, In the stratified analysis by sample collection resources (tumor tissue, blood or normal tissue), in the non-melanoma skin cancer but not BCC and SCC group, Arg/Arg carriers from tumor tissue subgroup had a significantly higher risk compared to those with Pro/Pro genotype (Arg/Arg vs. Pro/Pro: OR3.42, 95% CI 1.19-9.84) [Table 3]. Due to this group contains only two studies and the sample sizes are relatively small, the results should to be interpreted cautiously.

Table 3

Results of meta-analysis for TP53 Arg 72Pro polymorphisms and the risk of subtypes of non-melanoma skin cancers

Publication bias

Both Begg's funnel plot and Egger's test were performed to assess the publication bias of the literature. The shape of the funnel plots did not reveal any evidence of obvious asymmetry for all genetic models in the overall meta-analysis [Figure 1 shows the funnel plot of overall Arg/Pro vs. Pro/Pro]. Then, Egger's test was used to provide statistical evidence of funnel plot symmetry. The results still did not present any obvious evidence of publication bias for any of the genetic models (Arg/Arg vs. Pro/Pro, P = 0.208, Arg/Pro vs. Pro/Pro, P = 0.791, Arg/Arg + Arg/Pro vs. Pro/Pro, P = 0.708, Arg/Arg vs. Arg/Pro + Pro/Pro, P = 0.127). Neither Begg's funnel plot nor Egger's test detected any obvious evidence of publication bias in the subgroup analyses for all genetic models (data not shown).

Figure 1

Funnel plot analysis to detect publication bias (Arg/Pro vs. Pro/ Pro). Each square represents a separate study for the indicated association

Discussion

The main finding of our pooled analysis of 13 published studies encompassing 3,520 cases and 3,587 controls is that no evidence of significant association was found between TP53 genotype and the risk of any type of non-melanoma skin cancer.

Since the TP53 Arg72Pro polymorphism was first identified in 1987.[4] Several studies have reported the effects of TP53Arg72Pro polymorphism on increased risk of cancers such as lung cancer, bladder cancer, hepatocellular carcinoma, ovarian cancer, acute myelogenous leukemia, and breast cancer.[20-28] In a case-control study conducted by Han et al., in 2006, they also found an increased risk of BCC in association with the Arg72 allele of the tp53 gene (OR 1.79; 95% CI 1.01-3.17).[10] Additionally, compared with the immune competent patients, an association between the TP53 polymorphism and both BCC and SCC was found in renal transplant recipients by McGregor et al.,[12] In contrast, a third study found no association of the TP53 polymorphism with either BCC or SCC.[17] In a meta-analysis conducted by De-Ke Jiang et al. No significant association was found for any of the skin cancer in any genetic model.[30] In our study we do not detect any association between the polymorphisms of p53 codon 72 and the risk of non-melanoma skin cancer, however, in the stratified analysis, the wild type Arg/Arg had 3.42 times risk of skin cancer (95% confidence interval, 1.19 to 9.84) as compared with two variant alleles (Pro/Pro) in NMSC. Interestingly, a hospital-based case–control study conducted in southwestern Taiwan shows that the risk of BCC is increased in individuals with the Pro/Pro genotype, compared with the genotype Pro/Arg and the wild type Arg/Arg.[31] Although all these genotypes (Pro/Pro, Arg/Arg, Arg/Pro) do not have a dramatic effect on disease risk, it is possible that they may influence the accumulation of genetic damage and tumor phenotype. In 2002, one study without homozygote Pro/Pro individuals was conducted by McGregor et al., to investigate the relationship between the TP53 polymorphism and mutation, the result shows that the prevalence of mutation among heterozygotes and Arg/Arg cases was 70% and 47% respectively.[20] Additionally, Marin et al., demonstrated that a TP53 mutation on the Arg allele not only has a null p53 phenotype, it confers a dominant-negative phenotype on p73 and p63.[32] More studies are needed to clarify the roles all these phenotypes played in non-melanoma skin cancer development.

In our meta-analysis, Between-study heterogeneity from various factors including diversity in population characteristics, different sample size and genotyping methods. Heterogeneity still existed in subgroup analysis which may be caused by discrepancy in characteristics of studies subjects. As in all research, our study has limitations. First, the controls were not uniformly defined. Second, there is only one study among Asians and the sample size is relatively small, studies involved in different ethnicities especially among Asians and Africans are warranted to estimate the effects of this functional polymorphism on non-melanoma skin cancer risk. Third, due to unavailable original data of the eligible studies. We did not perform the analysis adjusted for some covariates: infection such as the effect of human papillomavirus infection on TP53 Arg72Pro polymorphism, environmental factors such as sun exposure time and so on.

Based on larger sample size, our meta-analysis provided a more precise estimation: TP53 Arg72Pro polymorphism may have little involvement in the pathogenesis of non-melanoma skin cancer, regardless of type, including SCC, and BCC. Nevertheless, well-designed studies are warranted to confirm our findings.

What is new?

TP53 Arg72Pro polymorphism may have little involvement in the pathogenesis of NMSC, regardless of type, including SCC, and BCC.