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Gastric Cancer

, Volume 14, Issue 3, pp 242–247 | Cite as

p53 codon 72 polymorphism in patients with gastric and colorectal cancer in a Korean population

  • Hye-Rim Song
  • Sun-Seog Kweon
  • Hee Nam Kim
  • Jin-Mei Piao
  • Woo-Jun Yun
  • Jin-Su Choi
  • Jun-Eul Hwang
  • Ju-Young Yoon
  • Hyeong-Rok Kim
  • Young-Kyu Park
  • Soo-Hyun Kim
  • Yoo-Duk Choi
  • Min-Ho Shin
Original Article

Abstract

Background

The common p53 codon 72 polymorphism has been investigated as a risk factor for cancer in different populations; however, the results have been inconsistent. This study investigated the risk of developing gastric or colorectal cancer associated with the p53 codon 72 polymorphism in a Korean population.

Methods

We conducted a large-scale case–control study that included 2,213 gastric cancer patients; 1,829 colorectal cancer patients; and 1,700 healthy controls. Genotyping was performed with real-time polymerase chain reaction (PCR), using a TaqMan single-nucleotide polymorphism (SNP) genotyping assay.

Results

The frequencies of Arg/Arg, Arg/Pro, and Pro/Pro genotypes of the p53 codon 72 polymorphism were 43.3, 42.0, and 13.0% in the gastric cancer patients; 40.5, 45.0, and 14.0% in the colorectal cancer patients; and 43.2, 45.6, and 11.2% in the controls, respectively. The Pro/Pro genotype was associated with an increased risk of gastric [age- and sex-adjusted odds ratio (OR) = 1.25, 95% confidence interval (CI) = 1.01–1.56, P = 0.04] and colorectal cancer (OR = 1.36, 95% CI = 1.07–1.72, P = 0.01). There were no significant interactions between the p53 codon 72 polymorphism and smoking or drinking.

Conclusions

Our results suggest that the Pro/Pro genotype is associated with modest increases in the risks of gastric cancer and colorectal cancer in a Korean population.

Keywords

p53 codon 72 polymorphism Gastric cancer Colorectal cancer 

Introduction

Gastric and colorectal cancers are the most common cancers in the world. Although the incidence and mortality of gastric cancer have fallen dramatically worldwide, the current mortality is 43/100,000 in Korea and the age-adjusted incidence is as high as 70/100,000 in Korean males [1, 2]. Colorectal cancer is thought to be less common among Asians compared with Caucasians; however, recent studies in Korea and Japan have shown not only high incidence rates, but also an increasing trend in the population [3]. Gastric and colorectal cancer are described by a multistep genetic model, in which mutations within several genes, including that encoding p53, accumulate during the progression from a normal epithelium to adenoma to invasive cancer [4, 5, 6].

TP53, which encodes p53, is a tumor suppressor gene and key player in the stress responses that preserve genomic stability, responding to a variety of insults, including DNA damage, hypoxia, metabolic stress, and oncogene activation [7, 8]. Mutations in p53 occur in at least 50% of all cancers, and more than 90% of these eliminate the ability of p53 to bind its DNA targets, underscoring the importance of this protein in tumorigenesis [9]. Recently, several common polymorphisms in TP53 have been described, including a codon 72 polymorphism (rs1042522), which involves the substitution of arginine (CGC) by proline (CCC) in exon 4. The area around exon 4 in TP53 encodes amino acids that lie close to the central hydrophobic area, which determines the conformation of the protein and, consequently, DNA-specific binding [10]. Changes in its amino acid sequence can alter the ability of p53 to bind to response elements in target genes, alter recognition motifs for post-translational modifications, or alter p53 stability and interactions with other proteins [11, 12, 13, 14]. Such changes may contribute to tumor progression and a poor prognosis [15].

The p53 codon 72 polymorphism is associated with an increased risk of a number of cancers, including gastric and colorectal cancers [16, 17, 18, 19]. In addition, several studies have linked environmental factors such as cigarette smoking, heavy alcohol consumption, micronutrient deficiency, and dietary carcinogen exposure to these cancers [19, 20]. However, the results have been inconsistent. Therefore, we designed a large-scale case–control study to evaluate the potential role of the p53 codon 72 polymorphism in gastric and colorectal cancer risk in Korea. We also assessed interactions between the p53 codon 72 polymorphism and such environmental factors as age, cigarette smoking, and alcohol consumption; additionally, we determined the risk based on TNM stage, anatomical tumor site, and histological type.

Methods

Subjects

The study population consisted of 2,213 patients with newly diagnosed gastric cancer, 1,829 patients with newly diagnosed colorectal cancer, and 1,700 population-based controls. In all enrolled patients (cases) the disease was pathologically confirmed by Chonnam National University Hwasun Hospital between April 2004 and June 2008. Patients with secondary or recurrent tumors were excluded. The tumor stages were classified according to the TNM classification, including clinical or pathological TNM stages. Gastric cancer was classified by anatomical site as cardia (C16.0) or non-cardia (C16.1–16.8) and by histological type, as intestinal, diffuse, or mixed type. Colorectal cancer was classified by anatomical site as right (C18.0–18.4), left (C18.5–18.7), or rectum (C20.9).

The control group (n = 1,700) consisted of participants in the Thyroid Disease Prevalence Study conducted from July 2004 to January 2006 in Yeonggwang and Muan Counties of Jeollanam-do Province and in Namwon City of Jeollabuk-do, Korea. A total of 4,018 subjects, aged 50.6 ± 14.6 years (range 20–74 years), were randomly selected by 5-year age strata and sex. Of the total number, 3,486 were eligible subjects. Of those eligible, 1,700 (48.8% of the eligible subjects; 821 men and 879 women), aged 52.2 ± 14.3 years, underwent clinical examinations. At the time of their peripheral blood collections, all case and control subjects provided their informed consent to participate in this study. This study was approved by the Institutional Review Board of the Chonnam National University Hwasun Hospital in Hwasun, Korea.

Genotyping

Genomic DNA was extracted from peripheral blood using a QIAamp DNA Blood Mini Kit (Qiagen, Valencia, CA, USA), according to the manufacturer’s protocol. Genotyping was performed with real-time polymerase chain reaction (PCR), using a TaqMan (Sigma-Proligo, The Woodlands, TX, USA) single-nucleotide polymorphism (SNP) genotyping assay. PCR primers and probes were designed and synthesized by Sigma-Aldrich (Singapore). PCR primers producing a 122-bp amplicon were as follows: forward primer, 5′-TCCAGATGAAGCTCCCAGAATG-3′ and reverse primer, 5′-GGGAAGGGACAGAAGATGACAG-3′. Dual-labeled probes were 5′-FAM-CTGCTCCCCCCGTGGCCCC-3′ for the C allele and 5′-HEX-CTGCTCCCCGCGTGGCCCC-3′ for the G allele. Real-time PCR was performed using a Rotor-Gene 3000 multiplex system (Corbett Research, Sydney, Australia) in a 10-μL reaction volume containing 200 nM PCR primer, 10-10 nM each probe, 0.5 U f-taq polymerase (Solgent, Daejeon, Korea), and 40 ng of genomic DNA.

Statistical analysis

A t- test was used to evaluate differences in continuous variables and the χ2 test was used for categorical variables in the demographic characteristics of the subjects. Adjusted odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated using logistic regression models, adjusted for age and sex, to estimate the association between genotype and gastric cancer and colorectal cancer. Subjects with the wild-type genotype (p53 codon 72 Arg/Arg) were considered to have a baseline risk. The expected frequency of control genotypes was checked by the Hardy–Weinberg equilibrium test. Interactions of genotype with age, smoking, and alcohol consumption were estimated using a logistic regression model, which included an interaction term, as well as variables for exposure (smoking and alcohol drinking), genotypes, and potential confounders (sex and age). The subjects for whom there were missing data for smoking, drinking, TNM stage, anatomical site, and histological type were excluded in the interaction analysis related to these variables. All tests were conducted at the P = 0.05 level of significance, and were done using SPSS for Windows version 16.0 (SPSS, Chicago, IL, USA).

Results

The demographic and tumor characteristics of the subjects are summarized in Table 1. Because one of the colorectal cancers could not be genotyped, our ultimate sample pool included 2,213 gastric cancers; 1,828 colorectal cancers; and 1,700 controls. Compared with the controls, both cancer groups were older, included fewer females, and had fewer drinkers. The proportion of smokers in the gastric cancer group was higher than that in the controls, while the proportion among the colorectal cancer cases was lower than that in the controls.
Table 1

General characteristics of subjects

Characteristics

Controls

Gastric cancer

Colorectal cancer

No.

1,700

2,213

1,828

Age, years (range)

52.2 (20–74)

60.2 (21–87)*

61.9 (22–88)**

 ≤65 Years

1,321 (77.7)

1,314 (59.4)

984 (53.9)

 >65 Years

379 (22.3)

899 (40.6)*

844 (46.1)**

Sex

 Male

821 (48.3)

1,510 (68.2)

1,148 (62.8)

 Female

879 (51.7)

703 (31.8)*

680 (37.2)**

Smoking habit

 Never

1,000 (58.8)

1,127 (50.9)

1,137 (62.2)

 Ever

655 (38.5)

997 (45.1)*

581 (31.8)**

 Missing data

45 (2.6)

89 (4.0)

110 (6.0)

Drinking habit

 Never

825 (48.5)

1,198 (54.1)

1,084 (59.3)

 Current

833 (49.0)

921 (41.6)*

622 (34.1)**

 Missing data

42 (2.5)

94 (4.3)

122 (6.7)

TNM stage

 I

 

1,138 (51.4)

291 (15.9)

 II

 

305 (13.8)

546 (29.9)

 III

 

290 (13.1)

614 (33.6)

 IV

 

386 (17.4)

230 (12.6)

 Unspecified stage

 

94 (4.2)

147 (8.0)

Tumor site

 Gastric cancer

  Cardia

 

106 (4.8)

 

  Non-cardia

 

2,093 (94.6)

 

  Unspecified site

 

14 (0.6)

 

 Colorectal cancer

  Right colon

  

377 (20.6)

  Left colon

  

450 (24.6)

  Rectum

  

996 (54.5)

  Multiple sites

  

5 (0.2)

 Histological type

  Intestinal

 

1,286 (58.1)

 

  Diffuse

 

561 (25.4)

 

  Mixed

 

240 (10.8)

 

  Unspecified type

 

126 (5.7)

 

* P < 0.05 Gastric cancer compared with control; ** P < 0.05 colorectal cancer compared with control

Right colon: cecum, ascending colon, hepatic flexure, transverse colon

Left colon: descending and sigmoid colon, splenic flexure

Multiple sites: overlapping lesion of colon

Table 2 shows the genotype distributions for the p53 codon 72 polymorphism in gastric and colorectal cancer. The observed genotype frequencies among the controls were in Hardy–Weinberg equilibrium (P = 0.516). Compared with Arg/Arg, the Pro/Pro genotype was significantly associated with increased risks of gastric [odds ratio (OR) = 1.276; 95% confidence interval (CI) = 1.026–1.587] and colorectal cancer (OR = 1.343; 95% CI = 1.056–1.693).
Table 2

p53 codon 72 polymorphisms and adjusted odds ratios for gastric and colorectal cancers

p53 Arg72Pro

Controls

Gastric cancer

Colorectal cancer

Gastric cancer

Colorectal cancer

OR (95% CI)

P value

OR (95% CI)

P value

Arg/Arg

734 (43.2)

939 (42.4)

740 (40.5)

1

 

1

 

Arg/Pro

776 (45.6)

977 (44.1)

844 (46.1)

0.99 (0.86–1.14)

0.88

1.08 (0.93–1.26)

0.33

Pro/Pro

190 (11.2)

297 (13.4)

244 (13.3)

1.28 (1.03–1.59)

0.03

1.34 (1.06–1.69)

0.01

Arg

2,244 (66.0)

2,855 (64.5)

2,324 (63.6)

1

 

1

 

Pro

1,156 (34.0)

1,571 (35.5)

1,332 (36.4)

1.09 (0.98–1.20)

0.10

1.13 (0.98–1.31)

0.10

OR odds ratio adjusted for age and sex, CI confidence interval

As shown in Table 3, the OR of the Pro/Pro genotype was higher in gastric cardia cancer (OR = 2.476; 95% CI = 1.339–4.580) than in gastric non-cardia cancer (OR = 1.249; 95% CI = 1.001–1.558). Interestingly, in contrast to previous studies, stratification analyses by the histological type of gastric cancer indicated that the Pro/Pro genotype was associated with an increased risk of only the intestinal type (OR = 1.401; 95% CI = 1.076–1.823), but not of the diffuse (OR = 1.17; 95% CI = 0.86–1.60) and mixed types (OR = 1.08; 95% CI = 0.68–1.71). We did not find any significant associations between the p53 codon 72 polymorphism and other subgroups. Age, smoking, and drinking did not modify the association between the p53 codon 72 genotypes and the risk of gastric or colorectal cancer (Table 4).
Table 3

Association between p53 codon 72 polymorphisms and clinicopathological characteristics

 

Arg/Pro versus Arg/Arg

Pro/Pro versus Arg/Arg

OR (95% CI)

OR (95% CI)

Gastric cancer

 TNM stage

  I + II

1.00 (0.85–1.17)

1.34 (1.05–1.71)

  III + IV

0.97 (0.80–1.19)

1.23 (0.91–1.67)

 Tumor site

  Cardia

1.53 (0.97–2.42)

2.48 (1.34–4.58)

  Non-cardia

0.97 (0.84–1.12)

1.25 (1.00–1.56)

 Histological type

  Intestinal

1.04 (0.87–1.23)

1.40 (1.08–1.82)

  Diffuse

0.96 (0.78–1.18)

1.17 (0.86–1.60)

  Mixed

0.95 (0.71–1.29)

1.08 (0.68–1.71)

Colorectal cancer

 TNM stage

  I + II

1.15 (0.95–1.39)

1.38 (1.03–1.85)

  III + IV

1.03 (0.86–1.25)

1.43 (1.08–1.88)

 Tumor site

  Right colon

0.95 (0.74–1.22)

1.40 (0.97–2.01)

  Left colon

0.99 (0.79–1.26)

1.27 (0.89–1.80)

  Rectum

1.20 (1.00–1.44)

1.39 (1.06–1.82)

Multiple site cancers are not included in this analysis by tumor site

OR odds ratio adjusted for age and sex, CI confidence interval

Right colon: cecum, ascending colon, hepatic flexure, transverse colon

Left colon: descending and sigmoid colon, splenic flexure

Multiple sites: overlapping lesion of colon

Table 4

Interaction between p53 polymorphisms and smoking and drinking habit and age for gastric and colorectal cancer risk

 

Arg/Pro versus Arg/Arg

Pro/Pro versus Arg/Arg

P for interactiona

OR (95% CI)

OR (95% CI)

Gastric cancer

 Smoking habit

  Never

0.93 (0.76–1.13)

1.38 (1.03–1.85)

 

  Ever

1.16 (0.93–1.44)

1.21 (0.86–1.69)

0.18

 Drinking habit

  Never

0.99 (0.80–1.23)

1.31 (0.96–1.80)

 

  Current

1.05 (0.85–1.29)

1.23 (0.89–1.69)

0.86

 Age

  ≤65 Years

0.97 (0.82–1.16)

1.26 (0.97–1.63)

 

  >65 Years

1.02 (0.79–1.33)

1.36 (0.90–2.05)

0.90

Colorectal cancer

 Smoking habit

  Never

1.07 (0.87–1.32)

1.49 (1.09–2.02)

 

  Ever

1.13 (0.88–1.93)

1.32 (0.91–1.93)

0.99

 Drinking habit

  Never

1.09 (0.87–1.36)

1.30 (0.93–1.81)

 

  Current

1.08 (0.86–1.36)

1.46 (0.03–2.07)

0.99

 Age

  ≤65 Years

0.99 (0.82–1.19)

1.34 (1.02–1.77)

 

  >65 Years

1.30 (0.96–1.69)

1.31 (0.86–2.00)

0.61

OR adjusted for age and sex

aP value for heterogeneity

Discussion

In this case-control study, we investigated the association between the p53 codon 72 polymorphism and susceptibility to gastric and colorectal cancers in a Korean population. We found that the genotype distribution differed significantly between the patients with gastric and colorectal cancer and the controls. Subgroup analyses in gastric cancer showed that the OR of the Pro/Pro genotype was higher in cardia cancer than in non-cardia cancer and was higher in the intestinal type than in the diffuse and mixed types.

Several case–control studies have examined the association between the p53 codon 72 polymorphism and the risk of gastric cancer. In a Chinese study of 206 gastric cancer patients and 415 healthy controls, Mu et al. [21] showed that patients carrying the Pro/Pro genotype had a borderline increased risk of developing gastric cancer. Yi et al. [17] analyzed 291 cases and 216 controls in a Korean population and found that the p53 codon 72 Pro/Pro genotype was associated with a 3.9-fold increased risk of gastric cancer. These results are consistent with our, larger, study. By contrast, two studies reported that the Arg/Arg genotype was associated with an increased risk of gastric cancer [16, 22], while other studies found no association [20, 23, 24, 25, 26, 27]. Although the reason for these inconsistencies is unclear, they may be explained by differences in ethnicity, small numbers of patients, and substantial interindividual variation in the susceptibility to genetic events and tumor development.

We also found a possible increased risk of colorectal cancer associated with the Pro/Pro genotype. An earlier colorectal cancer study of a Chinese population reported that the p53 codon 72 Pro/Pro genotype had a significant dose-dependent effect on colorectal cancer risk (OR = 1.6; 95% CI = 1.17–2.18 vs. OR = 2.37; 95% CI = 1.61–3.47 for Arg/Pro vs. Pro/Pro) [19]. Although we did not find a dose-dependent effect, our results are in line with those of Zhu et al. [19]. Conversely, three Caucasian studies with small sample sizes (from n = 53 to n = 93) found a significant association between the Arg/Arg genotype and an increased risk of colorectal cancer [28, 29, 30], while two larger studies, one with 442 cases and 904 controls in the United States [18] and one with 352 cases and 316 controls in Spain [31], found no association between the p53 codon 72 polymorphism and the risk of colorectal cancer.

In the present study, subgroup analysis in gastric cancer demonstrated that the effect size of the Pro/Pro genotype was larger in cardia cancer than in non-cardia cancer and larger in the intestinal type than in the diffuse and mixed types. It has been postulated that gastric cardia cancer and gastric non-cardia cancer differ in their epidemiological characteristics, etiology, pathogenesis, and clinical behavior [2]. Like the differences in epidemiology and pathogenesis according to tumor location, histological research has suggested that the intestinal and diffuse types of gastric cancer also have distinct characteristics. The intestinal type predominates in high-risk geographic areas such as East Asia, and is related to the prevalence of Helicobacter pylori infection among the elderly, whereas the diffuse type is found more uniformly worldwide and is apparently unrelated to H. pylori prevalence [2]. The exact biological mechanism underlying these differences is unclear; thus, a well-designed study is needed to elucidate the role of p53 codon 72 polymorphism in gastric tumorigenesis.

We found no interaction between the p53 codon 72 polymorphism and age, smoking, or drinking in gastric and colorectal cancer. Previously, Sul et al. [20] reported no interaction between the p53 codon 72 polymorphism and smoking or alcohol for gastric cancer. Zhu et al. [19] indicated that there was no interaction between alcohol consumption and the p53 codon 72 genotype in relation to colorectal cancer [19]. These findings are consistent with our results.

There are certain limitations to our study. First, we cannot rule out the possibility that differential misclassification bias occurred in our study, because we gathered information about smoking and drinking retrospectively from electronic medical records in both case groups, while we gathered information about these factors from cross-sectional surveys in the controls. Second, we did not consider other genetic polymorphisms.

The major strength of our study is its large sample size. Studies with small sample sizes may have insufficient statistical power to detect a slight effect or may generate a fluctuating risk estimate. As our study was based on a relatively large number of cases and controls, we were able to examine the potential effect modification of risk factors for gastric and colorectal cancers and to conduct analyses separately by tumor characteristics in gastric and colorectal cancers.

In conclusion, our results suggest that the p53 codon 72 Pro/Pro genotype is associated with a modest increased risk of gastric and colorectal cancer among Koreans, and that age, smoking, and drinking do not modify the association between the p53 codon 72 polymorphism and gastric and colorectal cancers.

Notes

Acknowledgments

This work was supported by research grants from the National R&D Program for Cancer Control, Ministry for Health and Welfare, Republic of Korea.

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Copyright information

© The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2011

Authors and Affiliations

  • Hye-Rim Song
    • 1
  • Sun-Seog Kweon
    • 1
    • 2
  • Hee Nam Kim
    • 3
  • Jin-Mei Piao
    • 1
    • 8
  • Woo-Jun Yun
    • 1
  • Jin-Su Choi
    • 1
  • Jun-Eul Hwang
    • 4
  • Ju-Young Yoon
    • 4
  • Hyeong-Rok Kim
    • 5
  • Young-Kyu Park
    • 5
  • Soo-Hyun Kim
    • 6
  • Yoo-Duk Choi
    • 7
  • Min-Ho Shin
    • 1
  1. 1.Department of Preventive MedicineChonnam National University Medical SchoolGwangjuSouth Korea
  2. 2.Jeonnam Regional Cancer CenterChonnam National University Hwasun HospitalHwasunKorea
  3. 3.Genome Research Center for Hematopoietic DiseasesChonnam National University Hwasun HospitalHwasunKorea
  4. 4.Department of Hemato-OncologyChonnam National University Medical SchoolKwangjuKorea
  5. 5.Department of SurgeryChonnam National University Hwasun HospitalHwasunKorea
  6. 6.Department of Laboratory MedicineChonnam National University Medical SchoolGwangjuKorea
  7. 7.Department of PathologyChonnam National University Medical SchoolGwangjuKorea
  8. 8.Yanbian University College of MedicineYanjiChina

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