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Keywords:

  • gastric cancer;
  • p53;
  • codon 72;
  • polymorphism;
  • Helicobacter pylori;
  • chronic gastritis

Abstract

  1. Top of page
  2. Abstract
  3. MATERIAL AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

p53 codon 72, which produces variant proteins with an arginine (Arg) or proline (Pro), has been reported to be associated with cancers of the lung, esophagus and cervix. However, there have been no reports on the p53 codon 72 polymorphism in gastric cancer susceptibility in patients with Helicobacter pylori-associated chronic gastritis (H. pylori-CG). We, therefore, examined the polymorphism in 117 gastric cancer patients (72 intestinal type and 45 diffuse type) with H. pylori-CG and 116 H. pylori-CG patients without gastric cancer as controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was performed to analyze the p53 codon 72 polymorphism. The crude genotypic frequencies in the gastric cancer patients were similar to those of the controls. However, when gastric cancers were classified by histologic subtype, the Pro/Pro was more frequent in the patients with diffuse type gastric cancer than in the controls (22.2% of cases vs. 12.1% of controls). The Pro/Pro genotype was associated with a 2.98-fold higher risk of diffuse-type cancer compared to the Arg/Arg genotype (95% confidence interval [CI] 1.07–8.32, p = 0.038). These results suggest that the Pro/Pro genotype at p53 codon 72 contributes to susceptibility for diffuse-type gastric cancer in patients with H. pylori-CG. The p53 codon 72 polymorphism may serve as the genetic marker for the risk assessment of the diffuse-type gastric cancer development in patients with H. pylori-CG. © 2002 Wiley-Liss, Inc.

The p53 tumor suppressor gene, located on chromosome 17p13, is one of the most commonly mutated genes in all types of human cancer.1, 2 Recent studies of the function of the wild-type p53 demonstrated that its antiproliferative effect is mediated by stimulation of a 21 kDa protein (p21/cip1/waf1) that inhibits cyclin-dependent kinase activity and, thereby, cell division.3 This negative cell cycle controller effect may explain why the wild-type p53 can suppress the transformation of cells by activated oncogenes, thereby inhibiting the growth of malignant cells.4 Analysis of somatic tissue from many human cancers has shown that the wild-type p53 allele is frequently lost and a mutant allele retained, providing a growth advantage for malignant cells.1, 5 The p53 mutation can damage its DNA-binding properties and transcription factor function, inhibiting its normal function in cell cycle control and in cell proliferation.6 Recently, several polymorphisms in the wild-type p53 have been described. The codon 72 polymorphism on exon 4 of the p53, which produces variant proteins with an arginine (Arg) or proline (Pro), has been reported to be associated with cancers of the lung, esophagus and cervix.7, 8, 9, 10, 11, 12 The Pro/Pro homozygotes were found more frequently in those cancers.9, 10, 11 Some researchers, however, reported different results, that the Arg allele alone was frequently associated with those cancers.12

Gastric cancer is the second most frequent malignant tumor in the world and contributes to significant cancer mortality, particularly in Asia.13 Gastric cancer is often preceded by sequential steps including Helicobacter pylori-associated chronic gastritis (H. pylori-CG) with or without intestinal metaplasia.14, 15, 16 Shepherd et al.17 reported that p53 codon 72 polymorphism in gastric cancer patients differs significantly with race. However, there have been no other reports on the polymorphism in gastric cancer patients. To assess the risk of gastric cancer by the difference of the p53 codon 72, we examined the polymorphism in gastric cancer susceptibility in patients with H. pylori-CG.

MATERIAL AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIAL AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patients

One hundred-seventeen gastric cancer patients with H. pylori-CG were randomly selected at the Hiroshima University Hospital from 1996–2000. For controls, we chose 116 H. pylori-CG patients without gastric cancer who were matched with gastric cancer patients by age and sex. H. pylori infection was examined by both histologic examination and rapid urease test.

Histologic Examination

Four-micrometer sections were prepared from formalin-fixed and paraffin-embedded gastric biopsy or surgically resected specimens. The sections were stained with hematoxylin-eosin (HE) for histologic examination and with Giemsa stain for H. pylori identification. Gastric cancers were classified into intestinal (differentiated) type and diffuse (undifferentiated) type as defined by Lauren.18 Tumor stage was determined according to the General Rules for Gastric Cancer Studies as outlined by the Japanese Research Society for Gastric Cancer.19 To analyze the relationship between the p53 codon 72 polymorphism and tumor location, the stomach was divided into 2 parts: the upper and the lower parts. When a tumor was located on the border, the tumor location was determined as the part where the tumor occupied dominantly. In H. pylori-CG, density of H. pylori, polymorphonuclear neutrophil activity, chronic inflammation, glandular atrophy and intestinal metaplasia were scored according to the Updated Sydney System.20

DNA Extraction

Ten-micrometer-thick tissue sections were placed on a glass slide and stained with HE. Then the tissue sections were dehydrated in graded ethanol solutions and dried without a cover glass. The noncancerous tissues on the slides were scraped off with sterile razors. DNA was extracted from the tissues with 20–200 μl of extraction buffer (100 mM Tris-HCl; 2 mM ethlenediamine tetraacetic acid (EDTA), pH 8.0; 400 μl/ml of proteinase K) at 55°C overnight. The tubes were boiled for 7 min to inactivate the proteinase K, and then 2 μl of these extracts were used for polymerase chain reaction (PCR) amplification.

p53Codon 72 Polymorphism

PCR-restriction fragment length polymorphism (RFLP) analysis of codon 72 of the p53 originally described by Ara et al.21 was used to identify the p53 BstUI genotypes. The two primers were 5′-TTGCCGTCCCAAGCAATGGATGA-3′ and 5′-TCTGGGAAGGGACAGAAGATGAC-3′. Each PCR reaction mixture (50 μl) contained 10 pmol of each primer, 2.0 mM MgCl2, 200 mM each dNTP, 1 unit of AmpliTaq Gold (Perkin-Elmer, Branchburg, NJ) and genomic DNA. The reaction mixtures were preincubated for 10 min at 94°C. The PCR conditions were 94°C for 30 sec and 55°C for 1 min, followed by 72°C for 1 min for 40 rounds. After confirmation of an amplified fragment of the expected size, 199 bp, on an agarose gel, the PCR products were digested with 2 units of restriction enzyme BstUI (New England Biolabs, Beverly, MA) at 60°C for 16 hr. The DNA fragments were electrophoresed through a 2% agarose gel and stained with ethidium bromide. The Pro allele is not cleaved by BstUI at codon 72 and has a single band with a fragment length of 199 bp. The Arg allele is cleaved by BstUI and yields 2 small fragments, 113 bp and 86 bp. The heterozygote has 3 bands, 199, 113 and 86 bp.

Statistical Analysis

Differences of the histologic limit in H. pylori-CG between gastric cancer patients and controls were evaluated by the Mann-Whitney U-test. The demographic characteristics as well as the p53 genotypes in gastric cancer patients and controls were compared and tested using the χ2 test and the Fisher's exact probability test. Multivariate logistic regression was used to evaluate the effect of p53 genotypes, after adjusting for other potential confounders. A value of p < 0.05 was regarded as significant.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIAL AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The mean ± standard deviation of age was 61.2 ± 11.7 years for gastric cancer patients and 58.4 ± 10.6 years for the controls. The male/female ratios were 71/46 for gastric cancer patients and 71/45 for the controls. Seventy-two (61.5%) patients had the intestinal-type cancer and 45 (38.5%) patients had the diffuse-type cancer. No patients had the unclassified-type cancer.

Histologic parameters in the antrum and the corpus scored according to the Updated Sydney System in H. pylori-CG are shown in Tables I and II, respectively. Grades of glandular atrophy and intestinal metaplasia were significantly higher in gastric cancer patients than in the controls.

Table I. Histologic Parameters in the Antrum Graded according to the Updated Sydney system in H. Pylori-associated Chronic Gastritis Patients with and without Gastric Cancer
 Density of H. pyloriPolymorphonuclear neutrophil activityChronic inflammationGlandular atrophyIntestinal metaplasia
  • Mean ± standard error (SE).

  • 1

    p < 0.0001 compared to H. pylori-CG patients without gastric cancer by the Mann-Whitney U-test.

  • 2

    p = 0.0004 compared to H. pylori-CG patients without gastric cancer by the Mann-Whitney U-test.

Gastric cancer patients1.31 ± 0.071.42 ± 0.071.48 ± 0.061.69 ± 0.1011.52 ± 0.112
H. pylori-CG patients without gastric cancer1.38 ± 0.081.40 ± 0.091.57 ± 0.081.11 ± 0.111.04 ± 0.12
Table II. Histologic Parameters in the Corpus Graded according to the Updated Sydney system in H. Pylori-associated Chronic Gastritis Patients with and without Gastric Cancer
 Density of H. pyloriPolymorphonuclear neutrophil activityChronic inflammationGlandular atrophyIntestinal metaplasia
  • Mean ± standard error (SE).

  • 1

    p = 0.038 compared to H. pylori-CG patients without gastric cancer by the Mann-Whitney U-test.

  • 2

    p < 0.0001 compared to H. pylori-CG patients without gastric cancer by the Mann-Whitney U-test.

  • 3

    p = 0.002 compared to H. pylori-CG patients without gastric cancer by the Mann-Whitney U-test.

Gastric cancer patients1.40 ± 0.071.52 ± 0.0811.75 ± 0.181.67 ± 0.1221.33 ± 0.133
H. pylori-CG patients without gastric cancer1.45 ± 0.071.26 ± 0.081.59 ± 0.090.91 ± 0.110.62 ± 0.10

We examined the distribution of the p53 codon 72 genotypes among the controls and gastric cancer patients by histologic subtype (Table III, Fig. 1). The frequencies of the 3 genotypes, Arg/Arg, Arg/Pro and Pro/Pro, were 43.1, 44.8 and 12.1%, respectively, in the controls. The crude genotypic frequencies in the gastric cancer patients were similar to those of the controls: the frequencies of the Arg/Arg, Arg/Pro and Pro/Pro genotypes were 41.9%, 44.4% and 13.7%, respectively. When gastric cancers were classified by histologic subtype, the distribution of the 3 genotypes in the patients with diffuse-type gastric cancer differed from the controls: Arg/Arg, Arg/Pro and Pro/Pro genotypes were 26.7, 51.1 and 22.2%, respectively. The Pro/Pro genotype was more frequent in the patients with diffuse-type gastric cancer than in the controls. Odds ratios (ORs) increased with number of the Pro alleles. Using the Arg/Arg genotype as the referent, the ORs of the Arg/Pro and Pro/Pro genotypes were 1.84 (95% confidence interval [CI] 0.83–4.10, p = 0.13) and 2.98 (95% CI 1.07–8.31, p = 0.038), respectively. There were no significant differences in the prevalence of the p53 polymorphism between the patients with intestinal-type gastric cancer and the controls: Arg/Arg, Arg/Pro and Pro/Pro genotypes in patients with intestinal-type cancer were 51.4, 40.3 and 8.3%, respectively.

Table III. Frequency of p53 Codon 72 Genotypes among H. Pylori-associated Chronic Gastritis Patients with and without Gastric Cancer
 No.Arg/Arg no. (%)Arg/Pro no. (%)Pro/Pro no. (%)
  • 1

    H. pylori-CG, H. pylori-associated chronic gastritis.

H. pylori-CG patients without gastric cancer111650 (43.1%)52 (44.8%)14 (12.1%)
Gastric cancer patients11749 (41.9%)52 (44.4%)16 (13.7%)
 Intestinal type7237 (51.4%)29 (40.3%)6 (8.3%)
 Diffuse type4512 (26.7%)23 (51.1%)10 (22.2%)
thumbnail image

Figure 1. Detection of p53 codon 72 polymorphism by BstUI digestion. The Pro allele is not cleaved by BstUI at codon 72 and has a single band with a fragment length of 199 bp. The Arg allele is cleaved by BstUI and yields 2 small fragments, 113 and 86 bp. The heterozygote has 3 bands, 199, 113 and 86 bp.

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In the gastric cancer patients, the differences in genotype by sex, age, tumor location, stage and histologic subtype were examined (Table IV). The Pro/Pro genotype was significantly associated with those patients whose age was more than 60 compared to those patients whose age was 60 or less (20.0% vs. 4.3%, p = 0.012). The Pro/Pro genotype was also significantly associated with female patients (23.9% for female vs. 7.0% for male, p = 0.011), and patients with tumor of the upper stomach (26.3% for the upper stomach vs. 8.2% for the lower stomach, p = 0.012). The Pro/Pro genotype tended to be associated with patients with diffuse-type gastric cancer (22.2% for the patients with diffuse-type cancer vs. 8.3% for the patients with intestinal-type cancer, p = 0.065). In the female gastric cancer patients over age 60, the Pro/Pro genotype was more frequent in patients with the diffuse-type cancer than patients with the intestinal type (7/15 [46.7%] vs. 2/12 [16.7%]).

Table IV. p53 Codon 72 Genotypes and Clinicopathologic Findings in all Gastric Cancer Patients
CharacteristicsFrequency of genotypep value in frequencies of Pro/Pro genotype1
Arg/ArgArg/ProPro/Pro
  • 1

    Evaluated by the Fisher's exact probability test.

  • 2

    Classified according to the General Rules for Gastric Cancer Studies as outlined by the Japanese Research Society for Gastric Cancer (1995).

Age (yr)   0.012
 ≤6017 (36.2%)28 (59.5%)2 (4.3%) 
 >6032 (45.7%)24 (34.3%)14 (20.0%) 
Sex   0.011
 Male34 (47.9%)32 (45.1%)5 (7.0%) 
 Female15 (32.6%)20 (43.5%)11 (23.9%) 
Tumor location   0.012
 Upper14 (36.8%)14 (36.8%)10 (26.3%) 
 Lower33 (45.2%)34 (46.6%)6 (8.2%) 
 Unknown2 (33.3%)4 (66.7%)0 (0%) 
Stage2   0.205
 I, II37 (41.3%)38 (42.7%)14 (15.7%) 
 III, IV12 (42.9%)14 (50.0%)2 (7.1%) 
Histologic subtype   0.065
 Intestinal type37 (51.4%)29 (40.3%)6 (8.3%) 
 Diffuse type12 (26.7%)23 (51.1%)10 (22.2%) 

We then examined the association of the p53 genotype with diffuse-type gastric cancer, using the multivariate logistic regression model. Female gender, the Pro/Pro and the Arg/Pro genotypes of the p53 codon 72 were significant risks for diffuse-type gastric cancer (Table V). Female H. pylori-CG patients had a 2.63-fold increased risk compared to male patients (95% CI 1.27–5.46, p= 0.009). Patients with the Pro/Pro and Arg/Pro genotypes had 2.42- and 1.97-fold increased risks (95% CIs 0.83–7.02 and 0.86–4.50), respectively. None of these factors were significant risks for intestinal-type gastric cancer.

Table V. Multivariate Analysis of Significant Risk Factors for Diffuse-Type Gastric Cancer
VariablesOR (95% CI)p-value
  • 1

    Using the male gender as the referent.

  • 2

    Using the Arg/Arg genotype as the referent.

Female12.63 (1.27–5.46)0.009
p53 (Pro/Pro)22.42 (0.83–7.02)0.104
p53 (Arg/Pro)21.97 (0.86–4.50)0.108

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIAL AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

This is the first study showing that the p53 codon 72 polymorphism is associated with gastric cancer development in patients with H. pylori-CG. Recently, the association of H. pylori infection with gastric cancer has been reported.22 Concurrent or previous H. pylori infection is associated with a 2.7–12-fold risk of gastric cancer. Therefore, H. pylori has been defined as a class I gastric carcinogen.23 Gastric cancers are divided into 2 major histologic subtypes, intestinal type and diffuse type. Although these 2 histologic subtypes may be caused by distinct genetical backgrounds,24H. pylori infection has been reported to play an important role in gastric cancer development of both histologic subtypes.25

However, not all patients with H. pylori-CG will develop gastric cancer. In Japan, it has been reported that each year, gastric cancer develops in 300,000 (0.5%) of the 60 million people who are H. pylori-positive, which means that gastric cancer develops in 5% of H. pylori-positive persons over 10 years.26 Uemura et al.26 reported that gastric cancers developed in 2.9% of H. pylori-positive Japanese patients and none of H. pylori-negative subjects during a mean follow-up period of 7.8 years. Which patients with H. pylori-CG will develop gastric cancer? It could be said that the differences in H. pylori virulence are associated with gastric cancer development. Two genes, the vacuolating cytotoxin gene (vacA) and the cytotoxin-associated gene (cagA), have been identified as virulence determinants.27 The vacA encodes a toxin that induces vacuolation in mammalian cell lines, and gastric epithelial cell damage and mucosal ulceration on intragastric administration to mice. The cagA encodes a 120–140 kDa protein, the role of which is unknown. The expression of cagA closely correlated with in vitro cytotoxin production and gastroduodenal pathology. In Western countries, the vacA is secreted by about 50% of H. pylori isolates, and the cagA is secreted by about 60% of the isolates.28 In contrast, most H. pylori isolates in Japan are positive for the vacA and the cagA.29 Thus, these virulence factors cannot be used as markers to discern the risk of gastric cancer development in Japan.

Therefore, host factors, such as the differences in tumor suppressor function(s) of individuals, may be important. There is an expanding body of literature suggesting that host factors, including genetic polymorphisms, may explain some of the individual differences in cancer occurrence.7, 8, 9, 10, 11, 12 The tumor suppressor gene, p53, exists in 2 principal polymorphic forms that have either Arg or Pro at codon 72. This polymorphism is balanced, although the selective pressure maintaining this is not known. The difference in the allele causes changes in the primary structure of the protein resulting in a difference in migration during sodium dodecyl sulfate-polyacrylamide gel electrophoresis.30 Thomas et al.31 reported that there are a number of differences between the p53 variants in their ability to bind components of the transcriptional machinery, activate transcription, induce apoptosis and repress the transformation of primary cells. Some researchers have shown that the codon 72 polymorphism of the p53 contributes to susceptibility to various cancers, including the lung, esophagus, breast, uterus, and vulva.7–12, 32–34 Patients with the Pro/Pro genotype are more likely to develop lung cancer than those with other genotypes, especially in patients who are smokers.10, 32 In contrast, nonsmokers with lung cancer have an increased frequency of the homozygous Arg genotype.33 An increased frequency of the Pro/Pro genotypes is also found in patients with breast cancer.34 Our data suggest that the Pro/Pro genotype at p53 codon 72 contributes to the susceptibility of diffuse-type gastric cancer in patients with H. pylori-CG. It has been reported that the codon 72 genotype varied significantly with race: the Pro/Pro genotype was detected in 37% of blacks, in 22% of Asians and in 7% of whites.17 Blacks and Asians have a higher incidence of gastric cancer than whites.35, 36 Although the higher prevalence of H. pylori infection is thought to be one of the causes of frequent gastric cancer occurrence in blacks and Asians, not only H. pylori infection but also the frequent Pro/Pro genotype at p53 codon 72 may be associated with a higher incidence of gastric cancer in these populations. The p53 codon 72 polymorphism may serve as a risk factor for human cancers and may play a role in modulating environmental risk factors for cancer.

Recent studies have shown that patients with corpus-dominant gastritis along with intestinal metaplasia are at high risk for intestinal-type gastric cancer.26, 37 On the other hand, many of the patients with diffuse-type gastric cancer have pangastritis.26 We therefore stratified our data by corpus-dominant gastritis, pangastritis and antrum-dominant gastritis. However, there were no significant relationships between the genotypes of the p53 codon 72 and the types of gastritis (data not shown). The genotype of p53 codon 72 and type of gastritis seem to be independent factors, and diffuse-type gastric cancer may develop predominantly in patients with pangastritis and p53 Pro/Pro genotype. The factors associated with gastritis type are still unknown. Further investigations are necessary to clarify the factors and the mechanism(s).

In addition to showing a potential risk of gastric cancer development, the p53 codon 72 genotypes may affect patient prognosis. Wang et al.38 found that Taiwanese lung cancer patients with the Pro/Pro allele had a significantly worse prognosis than those with the Arg/Pro genotype. The prognosis of the patients with diffuse-type gastric cancer is worse than the patients with intestinal-type gastric cancer.39 In our study, the Pro/Pro allele was significantly frequent in patients with diffuse-type gastric cancer. The p53 Arg/Arg genotype induces apoptosis with faster kinetics and suppresses transformation more efficiently than the Pro/Pro variant.31 The p53 Arg/Arg genotype is a better inducer of transcription because of its stronger affinity for the TAFII32 and TAFII70 transcription factors.37 One might expect that the Pro/Pro genotype would be more associated with therapeutic resistance when compared to the Arg/Arg genotype. We are not yet in a position to determine whether this is true because the patient follow-up is not yet complete in these patients. This question will be addressed at a future time.

Gastric cancers are associated with not only H. pylori infection but also other factors such as smoking, alcohol and dietary habits. Smoking has been reported to play the most harmful role in the initial development of gastric cancer, and drinking alcohol may promote the process.40 It has also been reported that gastric cancer risk increased with increasing intake of protein, nitrite, and sodium.41 In contrast, laboratory experiments and case-control studies have suggested that consumption of green tea provides protection against gastric cancer.42 Although we could not verify the smoking, drinking and dietary habits of our patients, such factors may contribute to the development of gastric cancer. Further investigations are necessary to clarify the role of the p53 polymorphism and affecting factors, such as smoking, drinking and dietary habits.

Histologically, intestinal-type cancers were dominant in our gastric cancer patients. This histologic distribution is typical in Japan, different from Western countries.36 The prevalence of H. pylori infection is higher in Japanese populations than in the populations in Western countries.16 Although H. pylori infection has been reported to play an important role in the gastric cancer development in both histologic subtypes, the infection is more closely associated with intestinal-type gastric cancers than diffuse-type gastric cancers.25 This may be one of the reasons for the different histologic distribution of gastric cancer between Japanese populations and the populations in Western countries.

In conclusion, our results suggest that the Pro/Pro genotype at p53 codon 72 contributes to susceptibility of diffuse-type gastric cancer in patients with H. pylori-CG. The p53 codon 72 polymorphism may serve as a genetic marker for the risk assessment of diffuse-type gastric cancer development in patients with H. pylori-CG.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIAL AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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