Mutagenesis vol. 18 no. 4 pp. 377-385,
July 2003
© 2003 UK Environmental Mutagen Society/Oxford University Press
TP53 polymorphisms and lung cancer risk: a systematic review and meta-analysis
1Section of Cancer Genetics, Institute of Cancer Research, Sutton SM2 5NG, UK and 2Cancer Research Unit, Section of Medicine, Royal Marsden Hospital, Downs Road, Sutton, UK
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Abstract |
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To examine the risk of lung cancer associated with the codon 72, intron 6 and intron 3 TP53 polymorphisms a meta-analysis of published case–control studies was undertaken. The principle outcome measure was the odds ratio (OR) for the risk of lung cancer using homozygosity of the ‘wild-type allele’ as the reference group. Data from 13 studies detailing the relationship between lung cancer and the codon 72 polymorphism of TP53 and three studies examining the intron 3 and 6 polymorphisms of TP53 were analysed. The ORs of lung cancer associated with the Pro-Pro and Pro-carrier genotypes of codon 72 were 1.18 [95% confidence interval (CI) 0.99–1.41] and 1.02 (95% CI 0.86–1.20), respectively. The ORs of lung cancer associated with homozygous and variant allele carrier genotypes of the intron 6 (MspI RFLP) polymorphism were 1.13 (95% CI 0.55–2.27) and 1.30 (95% CI 0.75–2.26) and of the intron 3 (16 bp duplication) polymorphism were 1.50 (95% CI 0.76–2.97) and 1.11 (95% CI 0.53–2.35), respectively. Although polymorphic variations in TP53 represent attractive candidate susceptibility alleles for lung cancer the results from this analysis provide little support for this hypothesis. Additional well-designed studies based on sample sizes commensurate with the detection of small genotypic risks may allow a more definitive conclusion.
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Introduction |
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Lung cancer accounts for
19% of all cancers and 29% of all cancer deaths (Flehinger et al., 1993
). It is the commonest cause of cancer death in men and is second only to breast cancer in women (Flehinger et al., 1993; Strauss, 1997). Tobacco smoking is undoubtedly the most important aetiological risk factor in the development of this cancer, the risk being at least 10 times higher in long-term smokers compared with non-smokers (Peto, 2001). Hence, it is frequently cited as an example of a malignancy solely attributed to environmental factors (exposure to carcinogens). There is, however, a growing appreciation that the development of most cancers results from a complex interaction between both environmental and genetic factors. Epidemiological studies have shown that relatives of lung cancer cases are at a 2-fold increased risk of developing the disease (Houlston and Peto, 1996), and although part of this is likely to be attributable to familial non-genetic factors, there is some support for an inherited predisposition. It is possible that part of an inherited susceptibility to lung cancer may be determined by inter-individual variation in genes encoding DNA repair proteins, cell cycle control proteins and metabolic enzymes responsible for the bioactivation and detoxification of carcinogens.
TP53 occupies a central role in mediating cellular responses to genotoxic insults through its effects on gene transcription, DNA synthesis and repair, genomic plasticity and programmed cell death (Vogelstein and Kinzler, 1992).
Germline mutation in TP53 as a determinant of cancer risk has been the subject of considerable research over the last 10 years, especially in the context of Li–Fraumeni syndrome (reviewed in Evans and Lozano, 1997). Somatic mutations in TP53 can be detected in over half of all human cancers (Hollstein et al., 1991), including lung cancer (Takahashi et al., 1989). Loss of TP53 function is an early event of lung tumorigenesis and TP53 mutations have been observed in preneoplastic lesions, such as bronchial epithelial dysplasia (Bennett et al., 1993). Furthermore, mutations have been detected in non-tumorous peripheral lung tissue from lung cancer patients (Hussain et al., 2001).
TP53 is polymorphic, and 13 different variants have been described to date (Table I). It has recently been shown that certain polymorphic variants of TP53 differentially affect the properties of the mutant p53 proteins (Thomas et al., 1999), raising the possibility that TP53 polymorphic variation may directly influence individual susceptibility to lung cancer. The codon 72 polymorphism in exon 4, which is carried by 20–40% of the population, leads to an arginine to proline substitution. Weston et al. (1992a) first reported an association between this polymorphism and lung cancer. Since the publication of this report, over 14 studies have appeared in the literature either supporting or refuting an association. Similarly, studies of the 16 bp duplication in intron 3 and the MspI restriction fragment length polymorphism (RFLP) in intron 6 have yielded conflicting results. To date, one study evaluating the intron 2 polymorphism and lung cancer risk has been reported. Most of the studies published are based on the analysis of small numbers of cases and controls. To clarify the effect of variation within TP53 defined by these four polymorphisms on the risk of lung cancer, we have undertaken a systematic review and meta-analysis.
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Materials and methods |
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Identification of studies
A search of the literature was made using the electronic database PUBMED (www.ncbi.nml.nih.gov/pubmed) for the years 1992–2002 to identify articles which have determined germline TP53 status defined by codon 72, intron 6, intron 3 and intron 2 polymorphisms in lung cancer cases and controls. Additional articles were ascertained through references cited in these publications. Articles included for analyses were primary references and of case–control design. Care was taken to include only primary data or data which superseded earlier work. Characteristics of the studies were extracted from published articles and summarized in a consistent manner to aid comparison.
Statistical analysis
The odds ratio (OR) of lung cancer associated with the variant allele carrier and homozygous genotype for each TP53 polymorphism were based on homozygosity of the ‘wild-type allele’ as the reference group. Where adjusted ORs were provided, these were used in the analysis. Otherwise unadjusted ORs were computed from the data presented (sufficient data to allow calculation of adjusted ORs was not available).
Pooled estimates of the OR were obtained by calculating a weighted average of the logarithm of ORs (Breslow and Day, 1987). A P value of 0.05 was considered statistically significant. Studies were analysed jointly using both a fixed effects and a random effects model (if significant heterogeneity between studies was present a random effects model was utilized) (DerSimonian and Day, 1986). A random effects model assumes that the studies in question are a random sample of a hypothetical population of studies taking into account variability within and between studies. Specific analyses considering confounding factors were not possible because the raw data were not available.
The presence of publication bias was examined by plotting ORs in order according to the variance of the logOR estimate. Estimates from small studies that have less precision in estimating the underlying OR will scatter widely at the base of the graph, with a narrowing among larger studies. In the absence of publication bias the plot resembles a symmetrical inverted funnel (Egger et al., 1997). Conversely, if there is bias, the funnel plot will be asymmetrical. Statistical manipulations were undertaken using the program STATA version 7.0 (Stata Corp., Texas, TX) utilizing the META (Sharpe and Sterne, 1998a,b) module.
In order to test for evidence of population stratification, the distribution of genotypes in controls was tested for a departure from Hardy–Weinberg equilibrium (HWE) by means of the 
2 test.
The power of each study was computed as the probability of detecting an association between TP53 carrier status for each polymorphism and lung cancer at the 0.05 level of significance, assuming a genotypic risk of 1.5 and 2.0. Estimates of power were performed using the method published by Fleiss et al. (1980), implemented in the statistical program POWER (Version 1.30; Epicenter Software; http://icarus2.hsc.usc.edu/epicenter).
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Results |
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Codon 72 polymorphism
Table II details the studies examining the possible association between TP53 codon 72 polymorphism and lung cancer risk that were suitable for analysis. Reports were excluded if the same data were available in more than one study (Murata et al., 1996
; Fan et al., 2000; Biros et al., 2001b; Miller et al., 2002), in which case the most recent publication or the publication with the largest study population were included, or if no information on genotype OR was presented (Weston et al., 1992b). The study reported by Murata et al. in 1996 has been superseded by the study published by the same authors in 1998, hence the latter (Murata et al., 1998) was used to estimate the overall risk. The 1996 study did, however, provide information on TP53 polymorphic status by histology, which was used in the sub-analysis. The study by Miller et al. (2002) provided additional data to the study of Liu et al. (2001) and was used to estimate risk by ethnic group.
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Data on smoking exposure in cases and controls has not been universally collected. Hospital disease controls were used exclusively in three studies (Table II). ORs adjusted for age, gender and ethnicity were provided in some but not all studies (Weston et al., 1994
; Pierce et al., 2000; Liu et al., 2001; Wu et al., 2002). Some studies have analysed the relationship between TP53 status and cancer risk in a stratified manner or by logistic regression, taking into account other covariates, such as histology or other polymorphisms. Table II shows the power of each study to demonstrate an association between the TP53 carrier status and lung cancer risk. Power >80% was attained by 10 of the 16 studies (63%) if the genotypic risk is ≥2.0 (data not shown). However, if the genotypic risk is 1.5, only four of 16 (25%) of the studies have 80% power.
The distribution of genotypes among controls are in HWE in most studies. However, the control groups in Weston et al. (1994), Wu et al. (2002), Miller et al. (2002), Papadakis et al. (2002) and Jin et al. (1995) show departure from HWE, which suggests possible population stratification.
Figures 1 and 2 show plots of ORs and associated 95% confidence intervals (CI) for the risk of developing lung cancer in Pro-Pro homozygotes and Pro-carriers for the 13 studies. There was evidence of heterogeneity between the studies in the Pro-carrier genotype analysis (P = 0.005). The pooled ORs for the Pro-Pro homozygotes and Pro-carriers are 1.18 (95% CI 0.99–1.41) and 1.02 (95% CI 0.86–1.20), respectively. There was no obvious evidence of publication bias based on the constructed funnel plots of the ORs.
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These analyses are based on pooling data from studies of all ethnic groups. Restricting the analyses to the eight studies of Caucasians (Weston et al., 1994
; Birgander et al., 1995; To-Figueras et al., 1996; Pierce et al., 2000; Biros et al., 2001a; Miller et al., 2002; Papadakis et al., 2002; Wu et al., 2002), the pooled ORs associated with the Pro-Pro and the Pro-carrier genotypes are 1.12 (95% CI 0.74–1.71) and 0.98 (95% CI 0.75–1.29), respectively. There was some evidence of study heterogeneity in both analyses (P < 0.05). The respective ORs calculated for the Asian population (Kawajiri et al., 1993; Murata et al., 1998; Wang et al., 1999; Pierce et al., 2000) are 1.23 (95% CI 0.93–1.64) and 1.02 (95% CI 0.85–1.23). Two studies provided data on the African-American population (Weston et al., 1994; Jin et al., 1995), and the pooled OR(s) are 0.89 (95% CI 0.35–2.27) and 0.59 (95% CI 0.27–1.27) for the homozygous and Pro allele carrier genotypes. There was no evidence of heterogeneity between the studies. Jin et al. (1995) studied Mexican-Americans and reported the respective ORs to be 2.20 (95% CI 0.22–22.3) and 1.33 (95% CI 0.56–3.18). One study of native Hawaiians (Pierce et al., 2000) did not ascertain a significant association between the TP53 codon 72 polymorphism and lung cancer risk; OR 1.30 (95% CI 0.52–3.27) for Pro-Pro homozygotes and 1.30 (95% CI 0.66–2.53) for the Pro-carriers. It is conceivable that this polymorphism may be associated with a specific histological form of lung cancer. Of the 16 studies that examined a relationship between genotype and lung cancer risk 10 contain information on histology in a form suitable for a pooled analysis (Table II). The pooled ORs for the homozygous Pro-Pro and the Pro-carrier genotypes are 1.14 (95% CI 0.90–1.45, no heterogeneity) and 0.87 (95% CI 0.67–1.13, evidence of heterogeneity, P = 0.005) for adenocarcinoma and 0.88 (95% CI 0.65–1.18, no heterogeneity) and 0.95 (95% CI 0.81–1.11, no heterogeneity), respectively, for squamous cell carcinoma. Insufficient data precluded this analysis for other histological types.
Intron 6 (MspI RFLP) polymorphism
Three studies have examined the association of the intron 6 polymorphism with lung cancer risk (Table III). All the controls were in HWE. Pooling data, absence of the MspI restriction site is associated with an OR of 1.13 (95% CI 0.55–2.27, no heterogeneity) for the homozygous genotype and 1.30 (95% CI 0.75–2.26, evidence of heterogeneity, P = 0.01) for the carrier genotype.
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Intron 3 (16 bp duplication) polymorphism
Two studies have examined the association between the intron 3 polymorphism and lung cancer risk (Table III). Birgander et al. (1995
) did not detect a significant association between this polymorphism and lung cancer risk; OR 1.24 (95% CI 0.37–4.20) for variant allele homozygotes and 0.74 (95% CI 0.46–1.18) for carriers. Wu et al. (2002) reported an increased risk of lung cancer associated with homozygous (adjusted OR 2.37, 95% CI 0.76–7.39) and variant allele carrier genotypes (1.77, 95% CI 1.24–2.52) in Caucasians and Mexican-Americans (data not presented). For African-Americans there was no significant association reported (data not presented). The pooled ORs for the variant allele homozygous and carrier genotypes in the Caucasian population were 1.50 (95% CI 0.76–2.97) and 1.11 (95% CI 0.53–2.35), respectively.
Intron 2 polymorphism
Only one study of the association of intron 2 polymorphism and lung cancer risk has been published to date. Ge et al. (1996) studied 61 lung cancer patients, 27 healthy individuals, and 30 bronchiectasis patients of Chinese origin. The frequency of the A2 (G at position 38) homozygous genotype was 22% in the healthy population, 30% in bronchiectasis patients, 29.4% in non-small cell lung cancer patients and 29.6% in patients with small cell lung cancer. The ORs associated with the A2 homozygous and A2 allele carrier genotypes were 2.35 (95% CI 1.04–5.35) and 1.97 (95% CI 1.01–3.82), respectively. The distribution of genotypes in the control group shows a deviation from HWE.
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Discussion |
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The hypothesis that variation in the function of genes responsible for DNA repair mechanisms and cell cycle control in the presence of carcinogen-mediated cell damage is an attractive mechanism for explaining any inter-individual variation in lung cancer susceptibility. As the TP53 tumour suppressor gene is an important mediator against genotoxic insults it therefore represents a suitable candidate for a lung cancer susceptibility locus.
Although no attempt was made in this meta-analysis to quality score reports (Sacks et al., 1987; Dickersin and Berlin, 1992) for inclusion, it is clear that the design of some studies is not optimal. Population stratification is an area of concern, and can lead to spurious evidence for or against an association between the marker and disease. The frequency of TP53 polymorphisms varies between ethnic groups and therefore a failure to match cases and controls represents the most serious source of bias. Testing the distribution of genotypes in controls for a deviation from HWE provides a simple method of assessing this, although deviation can also indicate genotyping errors. To address possible population stratification in future studies requires the identification of sub-populations defined in terms of factors which can influence disease and marker allele frequencies.
Smoking is the major risk factor for lung cancer and tobacco carcinogens have been shown to exert a direct mutagenic action on DNA of cancer-related genes and TP53 in particular (Rodin and Rodin, 2000). The majority of the studies used in this analysis reported information on smoking habits of cases and controls. Unfortunately, most of the studies did not provide ORs adjusted for smoking history or the raw data to enable direct calculation of the relative risks, and hence a sub-analysis of the effect of TP53 polymorphisms on lung cancer risk in relation to tobacco exposure was not possible.
A number of the studies were based on a comparison of cases and non-lung cancer disease controls. The use of a healthy population is preferable since it is conceivable that the TP53 gene might confer susceptibility to both other cancer and non-cancer diseases. This is, however, unlikely to represent a major source of confounding.
Prime candidate genes for involvement in lung cancer development are those thought to be involved in the aetiology of the disease and variation of which affects protein structure or expression. The codon 72 polymorphism of TP53 is a single base pair substitution resulting in the replacement of an arginine by a proline in the amino acid sequence of the encoded protein. There is some evidence suggesting that the two variants confer different properties to the TP53 protein. Thomas et al. (1999) reported that the Pro variant of TP53 is less efficient in suppressing cell transformation and slower in inducing apoptosis than the Arg variant. Paradoxically, cells harbouring the Arg variant appear to be more susceptible to the degradation induced by human papillomavirus E6 protein (Storey et al., 1998). Marin et al. (2000) have suggested that the codon 72 polymorphism influences the ability of TP53 mutants to form stable complexes with p73 (a homologue of p53), correlating with a loss of p73 DNA-binding capability, and ability to induce apoptosis. They observed that the Arg allele was preferentially mutated and retained in squamous cell tumours arising in Arg-Pro germline heterozygotes and concluded that the codon 72 polymorphic residue within TP53 affects mutant protein behaviour. If the intronic TP53 polymorphisms confer an increase in lung cancer risk the effect has to be mediated through linkage disequilibrium with a functional variant or changes in gene expression.
Lohmueller et al. (2003) recently performed a meta-analysis of a number of genetic association studies (cancer and non-cancer) and reported that up to 25% of published associations are probably real associations but that the inconsistency of findings is accounted for by underpowered studies.
Most of the studies reviewed in our meta-analysis of TP53 polymorphisms and lung cancer risk had insufficient power to detect an association between the TP53 polymorphisms and lung cancer risk, if the true increase in risk is less than 2.
The studies used in this meta-analysis provide data on over 3000 cases and controls. Based on this analysis there is limited evidence to support the hypothesis that polymorphic variation in TP53 defined by the codon 72, intron 2, intron 3 and intron 6 polymorphisms represent risk factors for lung cancer. We cannot, however, preclude each being associated with a small increase in risk (1.2). Moreover, it does not preclude other TP53 variants acting as susceptibility alleles for lung cancer. Further studies of TP53 polymorphisms should be based on sample sizes commensurate with the detection of small genotypic risks.
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Acknowledgement |
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A.Matakidou was in receipt of a clinical research fellowship from the Allan J. Lerner Fund.
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Notes |
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3To whom correspondence should be addressed at Section of Cancer Genetics, Institute of Cancer Research, Sutton SM2 5NG, UK. Tel: +44 208 643 8901; Fax: +44 208 643 0257; Email: athenam{at}icr.ac.uk
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Received on January 6, 2003; accepted on April 8, 2003.
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