P53 codon 72 polymorphism and gastric cancer: A meta-analysis

of the literature

Yong Zhou1, Ni Li2, Wen Zhuang1, Guan-Jian Liu3, Tai-Xiang Wu3, Xun Yao3, Liang Du3, Mao-Ling Wei3

and Xiao-Ting Wu1*

1Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China2Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China3Chinese Evidence-Based Medicine/Cochrane Center, Chengdu, China

Studies investigating the association between p53 codon 72 poly-morphism and gastric cancer risk report conflicting results. Theobjective of this study was to quantitatively summarize the evi-dence for such a relationship. Two investigators independentlysearched the Medline and Embase databases. This meta-analysisincluded 12 case-control studies, which included 1,665 gastric can-cer cases and 2,358 controls. The combined results based on allstudies showed that there was no significant difference in genotypedistribution [Arg/Arg odds ratio (OR) 5 0.96, 95% confidenceinterval (CI) 5 0.79, 1.16; Pro/Pro (OR 5 1.21, 95% CI 5 0.92,1.58); Pro/Arg (OR 5 0.95, 95% CI 5 0.79, 1.14)] between gastriccancer and noncancer patients. When stratifying for race, resultswere similar except that patients with gastric cancer had a signifi-cantly lower frequency of Arg/Arg (OR 5 0.84, 95% CI 5 0.72,0.99) than noncancer patients among Asians. Stratified the variousstudies by the location, stage, Lauren’s classification, and histolog-ical differentiation of gastric cancer, we found that (i) patientswith cardia gastric cancer had a significantly higher frequency ofPro/Pro (OR 5 3.20, 95% CI 5 1.46,7.01) than those with noncar-dia gastric cancer among Asians; (ii) patients with advanced (stageIII/IV) gastric cancer had a significantly higher frequency of Arg/Arg (OR 5 1.48, 95% CI 5 1.01, 2.16) than those with early (stageI/II) gastric cancer among Asians; (iii) patients with poor differen-tiation had a significantly lower frequency of Pro/Pro (OR 5 0.13,95% CI 5 0.03, 0.64) than those with well differentiation amongCaucasians. This meta-analysis suggests that the p53 codon 72polymorphism may be associated with gastric cancer amongAsians, and that difference in genotype distribution may be associ-ated with the location, stage, and histological differentiation ofgastric cancer.' 2007 Wiley-Liss, Inc.

Key words: gastric cancer; p53 codon 72; gene polymorphism;meta-analysis

Gastric cancer, the second leading cause of death from cancerthroughout the world, is an important health problem. A 2005analysis of the worldwide incidence of and mortality from cancershowed that 934,000 cases of gastric cancer occurred in 2002 andthat 700,000 patients die annually of this disease.1 Despite theoverall decline in gastric cancer rates in most of the WesternWorld, gastric cancer remains a serious fatal disease throughoutmuch of the rest of the world. Thirty-eight percent of worldwidecases occur in China, where it remains the most common cancerin both sexes as it is elsewhere in Eastern Asia.2 Conversely, theincidence rates of adenocarcinomas of the proximal stomach anddistal esophagus have been increasing, particularly in the WesternWorld.3 Gastric carcinogenesis is a complex, multistep and multi-factorial process, in which many factors are implicated. The ma-jority of gastric cancers are thought to be caused by environmentalfactors that result in damage to the mucosa and that inhibit its abil-ity to repair itself. This response is regulated, in part, by inhibitoryand stimulatory factors that are products of proto-oncogenes andtumor suppressor genes.4

The p53 tumor suppressor gene, located on chromosome 17p13,is one of the most commonly mutated genes in all types of humancancer.5 It contains 11 exons, and encodes a 53 kDa phosphopro-tein that is a transcription factor for genes that induce cell cyclearrest or apoptosis. The p53 acts as a tumor suppressor gene,

negatively regulates the cell cycle and requires loss of functionmutations for tumor formation.6 Although p53 contains severalpolymorphic sites, only those in exon 4 have been examined ingastric cancer. Exon 4 contains 2 polymorphic sites, 1 at codon 36and another at codon 72. Of these, the codon 72 polymorphism isby far more common. The polymorphism consists of a single basepair change of either arginine or proline which creates 3 distinctgenotypes: homozygous for arginine (Arg/Arg), homozygous forproline (Pro/Pro) and a heterozygote (Pro/Arg).7 P53 codon 72polymorphisms have been reported to be associated with cancersof the lung,8 esophagus,9 colorectum,10 breast,11 bladder12 andcervix.13

Over the last two decades, a number of case–control studieswere conducted to investigate the association between p53 codon72 polymorphism and gastric cancer risk in humans. But thesestudies reported conflicting results. No quantitative summary ofthe evidence has ever been performed. The purpose of this meta-analysis was to quantitatively summarize the evidence for such arelationship.

Material and methods

Literature search strategy

Search was applied to the following electronic databases: theCochrane Library (third quarter, 2006), MEDLINE (1966 to Janu-ary 2007), EMBASE (1980 to January 2007) and Chinese Bio-medicine Database (1979 to January 2007). The following keywords were used: �p53� or �codon 72�, �gastric� or �stomach,� �carci-noma� or �cancer� or �tumor.� The search was without restriction onlanguage, conducted on human subject. The reference lists ofreviews and retrieved articles were hand searched at the sametime. We did not consider abstracts or unpublished reports. Ifmore than 1 article was published by the same author using thesame case series, we selected the study where the most individualswere investigated.

Inclusion and exclusion criteria

We reviewed abstracts of all citations and retrieved studies. Forinclusion in the meta-analysis, the identified articles have to pro-vide information on: (i) the number of gastric cancer cases andcontrols studied; (ii) the number of individuals homozygous for ar-ginine (Arg/Arg), proline (Pro/Pro) and heterozygote (Pro/Arg) incases and controls. Major reasons for exclusion of studies were(i) no control; (ii) duplicate; (iii) no usable data reported.

Grant sponsor: Chinese Medical Board Grant on Evidence-based Medi-cine; Grant number: 98-680.*Correspondence to: Department of Gastrointestinal Surgery, West

China Hospital, Sichuan University, 37 Guo Xue Rd., Chengdu 610041,Sichuan Province, China. E-mail: nutritioner@hotmail.comReceived 21 February 2007; Accepted after revision 11 April 2007DOI 10.1002/ijc.22833Published online 1 June 2007 in Wiley InterScience (www.interscience.

wiley.com).

Int. J. Cancer: 121, 1481–1486 (2007)' 2007 Wiley-Liss, Inc.

Publication of the International Union Against Cancer

Data extraction

All data were extracted independently by 2 reviewers (Zhou Yand Li N) according to the prespecified selection criteria. Dis-agreement was resolved by discussion. The following data wereextracted: study design and period, statistical methods, population,number of gastric cancer cases and controls studied and results ofstudies.

Statistical analysis

The statistical analysis was conducted using STATA 8.2 (Stata-Corp, College Station, Tex), p < 0.05 was considered statisticallysignificant. Dichotomous data were presented as odds ratio (OR)with 95% confidence interval (CI). Statistical heterogeneity wasmeasured using the Q statistic (p < 0.10 was considered represen-tative of significant statistical heterogeneity).14 Heterogeneity wasalso assessed through visual examination of L’Abbe plots. Fixedeffects model was used when there was no heterogeneity of theresults of the trials. Otherwise, the random effects model wasused. For dichotomous outcomes, patients with incomplete ormissing data were included in sensitivity analyses by countingthem as treatment failures. To establish the effect of clinical heter-ogeneity between studies on meta-analysis’ conclusions, subgroupanalysis was conducted on the basis of race and the location,stage, Lauren’s classification, histological differentiation of gastriccancer.

Several methods were used to assess the potential for publica-tion bias. Visual inspection of asymmetry in funnel plots was con-ducted. The Begg rank correlation method and the Egger weightedregression method were also used to statistically assess publicationbias (p < 0.05 was considered representative of statistically signif-icant publication bias).

Results

Study characteristics

There were 1,254 papers relevant to the searching words(Fig. 1). Through the step of screening the title, 1,079 of thesearticles were excluded (246 were not English or Chinese Lan-guages, 98 were not case–control studies, 735 were not conductedin humans). Abstracts from 175 articles were reviewed and anadditional 158 trials were excluded (55 were not case-control stud-ies, 103 were not conducted in humans), leaving 17 studies for fullpublication review. Of these, 5 were excluded [2 were not case–control studies,7,15 2 did not report usable data,16,17 1 was dupli-cate18]; thus, 12 papers,19–30 which included 1,665 gastric cancercases and 2,358 controls, were found to conform to our inclusioncriteria. Twelve studies, including 4 population-based case-controlstudies and 8 hospital-based case–control studies were included inthis meta-analysis. Studies were carried out in Japan, UK, China,Mexico, USA, Korea and Russia. Characteristics of studiesincluded in this meta-analysis are presented in Table I.

Quantitative data synthesis

The combined results based on all studies showed that therewas no significant difference in genotype distribution [Arg/Arg(OR 5 0.96, 95% CI 5 0.79, 1.16); Pro/Pro (OR 5 1.21, 95% CI5 0.92, 1.58); Pro/Arg (OR 5 0.95, 95% CI 5 0.79, 1.14)]between gastric cancer and noncancer patients. When stratifyingfor race, results were similar except that patients with gastric can-cer had a significantly lower frequency of Arg/Arg (OR 5 0.84,95% CI 5 0.72, 0.99) than noncancer patients among Asians(Figs. 2–4).

When we stratified the various studies by the location of gastriccancer, no statistically significant results was observed for all anal-ysis except that patients with cardia gastric cancer had a signifi-cantly higher frequency of Pro/Pro (OR 5 3.20, 95% CI 5 1.46,7.01) than those with noncardia gastric cancer among Asians.When we stratified the various studies by the stage of gastric can-cer, no statistically significant results was observed for all analysis

except that patients with advanced (stage III/IV) gastric cancerhad a significantly higher frequency of Arg/Arg (OR 5 1.48, 95%CI 5 1.01, 2.16) than those with early (stage I/II) gastric canceramong Asians. When we stratified the various studies by the histo-logical differentiation of gastric cancer, no statistically significantresults was observed for all analysis except that patients with poordifferentiation had a significantly lower frequency of Pro/Pro (OR5 0.13, 95% CI 5 0.03, 0.64) than those with well differentiationamong Caucasians. When we stratified the various studies by theLauren’s classification of gastric cancer, no statistically significantresults was observed for all analysis (Table II).

Statistically significant heterogeneity was observed between tri-als for all analysis with the Q statistic (Arg/Arg p 5 0.04; Pro/Prop 5 0.01; Pro/Arg p 5 0.06). In addition, L’Abbe plots did showevidence of heterogeneity (Fig. 5). Review of funnel plots couldnot rule out the potential for publication bias for all analysis. Pub-lication bias was not evident when the Begg rank correlationmethod (Arg/Arg p 5 0.73; Pro/Pro p 5 0.94; Pro/Arg p 5 0.30)and the Egger weighted regression method (Arg/Arg p 5 0.70;Pro/Pro p 5 0.94; Pro/Arg p 5 0.07) were used (Figs. 6 and 7).

Discussion

A genetic predisposition to gastric cancer has been suggestedby both epidemiological studies and case reports of gastric cancerfamilies.31 Recent studies suggest that single nucleotide polymor-phisms may be related to the tumorigenesis of gastric cancer.32

Individual genetic susceptibility may be critical in a variety ofprocesses relevant to gastric cancer tumorigenesis, such as (i) mu-cosal protection in the face of Helicobacter pylori infection andother carcinogens, (ii) the inflammatory response, which condi-tions the maintenance, severity and outcome of the Helicobacterpylori infection, (iii) the functioning of carcinogen detoxificationand antioxidant protection, (iv) cell proliferation ability, (v) theintrinsic variability of DNA repair processes; and (vi) the cellapoptotic pathway.26,33 The mechanism of human gastric tumori-genesis is still relatively unknown, and single nucleotide polymor-phisms can be used as a tool in searching for genetic variations ofthe disease gene and susceptibility, and to increase understandingof the disease mechanism.34

FIGURE 1 – Studies identification, inclusion, and exclusion.

1482 ZHOU ET AL.

A number of studies have reported the role of p53 codon 72polymorphisms in gastric cancer. The genotype frequency in theinitial study was as follows: Arg/Arg (54%); Pro/Arg (33%); andPro/Pro (14%). The genotype differed significantly with race (p 50.0001): 64% of whites had the Arg/Arg genotype compared with24% of African Americans. There was no statistical significancefor tumor location or histological tumor type.7 Another study

indicated that codon 72 Arg p53 might be associated with a pro-longed survival for patients who had had gastric adenocarcinoma,especially non-cardia adenocarcinoma.21 The summary OR fromour meta-analyses revealed that patients with gastric cancer had asignificantly lower frequency of Arg/Arg (OR 5 0.84, 95% CI 50.72, 0.99) than noncancer patients among Asians. Stratified thevarious studies by the location, stage, Lauren’s classification, andhistological differentiation of gastric cancer, we found that (i)patients with cardia gastric cancer had a significantly higher fre-quency of Pro/Pro (OR 5 3.20, 95% CI 5 1.46, 7.01) than thosewith noncardia gastric cancer among Asians; (ii) patients withadvanced (stage III/IV) gastric cancer had a significantly higherfrequency of Arg/Arg (OR 5 1.48, 95% CI 5 1.01, 2.16) thanthose with early (stage I/II) gastric cancer among Asians;(iii) patients with poor differentiation had a significantly lower fre-quency of Pro/Pro (OR 5 0.13, 95% CI 5 0.03, 0.64) than thosewith well differentiation among Caucasians.

A number of studies have shown significant differences in thebiochemical properties of the p53 protein, depending on the par-ticular polymorphic form. There is little information, however,on their respective biologic activities. In Pim’s study, they haveused an inducible switch system for expressing both polymor-phic forms of p53 within Saos-2 cells. Cell cycle analysis post-induction of p53 function reveals striking differences in how the2 forms of p53 bring about a cessation of cell growth. Thus, theArg72 form of p53 is significantly more efficient than the Pro72form at inducing apoptosis. In contrast, the Pro72 form appearsto induce a higher level of G1 arrest than the Arg72 form. Theseresults demonstrate significant differences in how the codon 72

TABLE I – CHARACTERISTICS OF STUDIES INCLUDED IN THE META-ANALYSIS

Study (reference) Design Study period Population No. ofcases

No. ofcontrols

Arg/Argof cases

Pro/Argof cases

Pro/Proof cases

Arg/Argof controls

Pro/Argof controls

Pro/Proof controls

Hiyama19 HCC 1996–2000 Asians (Japan) 117 116 49 52 16 50 52 14Hamajima20 HCC 1999–2000 Asians (Japan) 144 241 54 64 26 85 117 39Zhang21 HCC 1992–2000 Caucasians (UK) 120 277 64 50 6 125 129 23Wu22 HCC 2000–2002 Asians (China) 89 192 11 53 25 40 95 57Shen23 PCC 1997–1999 Asians (China) 324 317 96 180 48 94 160 63Perez24 PCC DNR Caucasians (Mexico) 65 182 35 21 9 68 88 26Mu25 PCC 2000 Asians (China) 194 390 42 88 64 118 178 94Lai26 PCC 2000–2001 Asians (China) 51 59 18 22 11 25 26 8Sul27 HCC 1992–1994 Caucasians (USA) 155 134 51 73 31 51 61 22Chung28 HCC 2002–2003 Asians (Korea) 84 109 30 42 12 41 50 18Belyavskaya29 HCC 1997–1998 Caucasians (Russia) 30 125 18 1 11 60 46 19Yi30 HCC 2001–2005 Asians (Korea) 292 216 101 126 65 89 103 24

HCC, hospital-based case–control; PCC, population-based case–control; DNR, data not reported.

FIGURE 2 – Meta-analysis of p53 codon 72 Arg/Arg and gastriccancer risk.

FIGURE 3 – Meta-analysis of p53 codon 72 Pro/Pro and gastric can-cer risk.

FIGURE 4 – Meta-analysis of p53 codon 72 Pro/Arg and gastric can-cer risk.

1483P53 CODON 72 POLYMORPHISM AND GASTRIC CANCER

polymorphism affects the biological activity of p53.35 Dumontet al. also found that in cell lines containing inducible versionsof alleles encoding the Pro72 and Arg72 variants, and in cellswith endogenous p53, the Arg72 variant induces apoptosismarkedly better than does the Pro72 variant. Their data indicatethat at least one source of this enhanced apoptotic potential is

the greater ability of the Arg72 variant to localize to themitochondria; this localization is accompanied by release ofcytochrome c into the cytosol. These data indicate that the twopolymorphic variants of p53 are functionally distinct, and thesedifferences may influence cancer risk or treatment.36 From ourmeta-analyses, we found that patients with gastric cancer had asignificantly lower frequency of Arg/Arg than noncancerpatients among Asians (p 5 0.04). But patients with advanced(stage III/IV) gastric cancer had a significantly higher frequencyof Arg/Arg than those with early (stage I/II) gastric canceramong Asians (p 5 0.04). We also found that the study by Yiand Lee30 may be the reason why although those with Arg/Arghad the low risk of gastric cancer, they were susceptible toadvanced gastric cancer, because only this study had the statisti-cal significance (OR 5 1.95, 95% CI 5 1.15, 3.32) and weighted45.8% in these 4 included studies.

P53 codon 72 polymorphisms also have been extensively stud-ied for many other cancers. Individuals with the p53 Pro/Pro geno-type have been shown to be more likely to develop lung cancer(especially in smokers), and to have slightly worse outcomes.37–40

The Pro allele has also been found in increased frequency in breastcancer patients.41–43 Conversely, recent studies with HPV-inducedcervical cancer show that more cases have the homozygous Argallele.44,45 These studies suggest that p53 codon 72 polymor-phisms may serve as risk factors for many different types ofcancers, and may play a role in the modulations of certain environ-mental risk factors.

TABLE II – META-ANALYSIS OF P53 CODON 72 POLYMORPHISM AND GASTRIC CANCER

Stratification of gastric cancer No. of studies(reference)

OR (95% CI) ofArg/Arg

p forheterogeneity

OR (95%CI) of Pro/Pro

p forheterogeneity

OR (95% CI)of Pro/Arg

p forheterogeneity

Location: Cardia versusNoncardia

6(19,21,23,26–28) 0.91(0.53,1.55) 0.03 2.07(0.95,4.50) 0.01 0.81(0.61,1.09) 0.49

Asians 4(19,23,26,28) 0.70(0.47,1.04) 0.37 3.20(1.46,7.01) 0.09 0.85(0.60,1.20) 0.54Caucasians 2(21,27) 1.78(0.73,4.32) 0.10 0.72(0.34,1.55) 0.35 0.75(0.45,1.25) 0.15

Stage: Advanced (III, IV)versus Early (I/II)

4(19,26,28,30) 1.48(1.01,2.16) 0.35 0.65(0.41,1.03) 0.87 0.84(0.58,1.20) 0.69

Asians 4(19,26,28,30) 1.48(1.01,2.16) 0.35 0.65(0.41,1.03) 0.87 0.84(0.58,1.20) 0.69Caucasians 0

Lauren’s classification: Diffuseversus Intestinal

6(19,21,24,28–30) 0.91(0.53,1.55) 0.04 1.22(0.80,1.84) 0.45 1.05(0.77,1.44) 0.26

Asians 3(19,28,30) 0.96(0.35,2.61) 0.006 1.25(0.79,1.99) 0.19 1.00(0.69,1.44) 0.10Caucasians 3(21,24,29) 0.82(0.47,1.43) 0.56 1.08(0.43,2.75) 0.52 1.22(0.67,2.21) 0.51

Histological differentiation:Poor versus Well

3(21,26,28) 2.25(0.21,23.84) 0.002 0.36(0.05,2.73) 0.05 0.76(0.20,2.95) 0.06

Asians 2(26,28) 1.64(0.04,74.92) 0.002 0.68(0.05,9.71) 0.13 0.69(0.06,8.50) 0.02Caucasians 1(21) 4.7(0.95,23.16) 0.13(0.03,0.64) 0.83(0.24,2.85)

OR, odds ratio; CI, confidence interval.

FIGURE 5 – L’Abbe plots of p53 codon 72 polymorphism and gas-tric cancer risk.

FIGURE 6 – Begg’s funnel plot of p53 codon 72 polymorphism andgastric cancer risk.

FIGURE 7 – Egger’s publication bias plot of p53 codon 72 polymor-phism and gastric cancer risk.

1484 ZHOU ET AL.

Statistically significant heterogeneity was observed between trialsfor all analysis with the Q statistic (Arg/Arg p 5 0.04; Pro/Pro p 50.01; Pro/Arg p 5 0.06). The most important factor that contributedto the heterogeneity was whether or not the genotype frequencieswere in Hardy-Weinberg equilibrium, because the equilibrium maynot hold among a case group if the genotype is truly associated withdisease. Observed departures from equilibrium therefore suggestpossible issues with the control group, or the study population ingeneral, that might have generated less than ideal circumstances forthe investigation of the p53 polymorphism and gastric cancer.46 Adeparture from Hardy-Weinberg equilibrium can also imply possibleethnic admixture in the population, if the polymorphic site varies ingenotype by race.47,48 In fact, race-specific variation in the distribu-tion of genotypes in the p53 codon 72 polymorphism has been dem-onstrated.7,49 Because race may be related to disease, either throughcommon risk factors or other genes in linkage disequilibrium withp53, confounding by race, or population stratification, may have bi-ased results in studies conducted on ethnically diverse populationsthat did not account for possible confounding.50 In this meta-analy-sis, subgroup analysis was conducted on the basis of race. In fact, 8studies were conducted among Asians, and 4 studies were conductedamong Caucasians. When stratifying for race, patients with gastriccancer had a significantly lower frequency of Arg/Arg (OR 5 0.84,95% CI5 0.72, 0.99) than noncancer patients among Asians.

There are some limitations to this meta-analysis. First, onlypublished studies were included in the meta-analysis; therefore,

publication bias may have occurred, even though the use of a sta-tistical test did not show it. Second, we could not obtain informa-tion from most studies on the presence or absence of a history ofinfection with Helicobacter pylori, a strong risk factor for gastriccancer. Third, as in most meta-analyses, these results should beinterpreted with caution because the population from 7 countriesand controls were not uniform. Fourth, our meta-analysis is basedon unadjusted estimates, while a more precise analysis could beperformed if individual data were available, which would allowfor an adjustment estimate (by age and sex). To be made, how-ever, this approach requires the authors of all of the publishedstudies to share their data. Finally, meta-analysis remains retro-spective research that is subject to the methodological deficienciesof the included studies. We minimized the likelihood of bias bydeveloping a detailed protocol before initiating the study, by per-forming a meticulous search for published studies, and by usingexplicit methods for study selection, data extraction, and dataanalysis.

In conclusion, this meta-analysis suggests that the p53 codon 72polymorphism may be associated with gastric cancer amongAsians, and that difference in genotype distribution may be associ-ated with the location, stage, and histological differentiation ofgastric cancer. Since more than half of the included studies werebased on a limited number of cases (<150), it is critical that largerand well-designed multicentric studies based on the same ethnicgroup confirm our results.

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