© 2007 Foundation for Promotion of Cancer Research
Association of the TP53 Codon 72 Polymorphism with Colorectal Cancer in a Chinese Population
1 Department of Pathology, No. 113 Hospital of People's Liberation Army, Ningbo
2 Department of Pathology, Lihuili Hospital, Ningbo, China
3 Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
4 Shanghai GeneCore Biotechnologies Co. Ltd, Shanghai, China
For reprints and all correspondence: Zhong-Zheng Zhu, Department of Pathology, No. 113 Hospital of People's Liberation Army, No. 377 East Zhongshan Road, 315040 Ningbo, Zhejiang Province, China. E-mail: zzzhu1170{at}yahoo.com
Received October 15, 2006; accepted December 17, 2006
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Abstract |
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 TOP Abstract INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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A TP53 gene polymorphism, resulting in an arginine (R) to proline (P) at codon 72 (TP53 R72P), has been associated with the susceptibility to various cancers. To better understand the role of this polymorphism in colorectal cancer etiology, we examined the association between TP53 R72P and colorectal cancer risk in 345 patients with colorectal cancer and 670 controls in a Chinese population. We observed that subjects with RP and PP genotypes had a 1.60-fold and a 2.37-fold increased risk for colorectal cancer, respectively. The 72P allele conferred a more pronounced increase in colorectal cancer risk among alcohol consumers (heterozygotes: OR = 3.01; homozygotes: OR = 4.71). The TP53 R72P polymorphism was not linked to tumor location, histologic grade, lymph node metastases, Dukes stage, p53 positivity, or age at diagnosis, but to tumor size. We conclude that the TP53 R72P polymorphism may contribute to the etiology of colorectal cancer in the Chinese population, particularly among alcohol consumers.
Key Words: TP53 • colorectal cancer • single nucleotide polymorphism
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INTRODUCTION |
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TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Colorectal cancer is the third most common cancer worldwide (1) and its incidence has been significantly increasing in China in the last two decades (2). The risk of developing colorectal cancer is influenced by a number of factors, including sex, age, diet and a variety of genetic factors (3,4). Among the genetic factors, the TP53 tumor suppressor gene is a suitable candidate for modulating colorectal cancer risk, as it is involved in many important cellular processes (5). TP53 is frequently over-expressed (6), deleted (7,8), or mutated (9) in colorectal tumor, and is required for the response of colorectal cancer to 5-fluorouracil-based chemotherapy (10–12). The gene has a common single nucleotide polymorphism (SNP) that results in either arginine or proline at codon 72 (TP53 R72P, rs1042522). The polymorphism occurs in the proline-rich domain of p53 protein, which is necessary for the protein to fully induce apoptosis (13). It has been reported that the 72P variant allele is associated with an increased risk for various cancers (14–22). In colorectal cancer, several studies found no association with the 72P genotype (23–27), while other two studies indicated a positive association (28,29), whereas another reported an inverse association (30).
Thus the results reported so far were not consistent with respect to the association of codon 72 polymorphism with colorectal cancer susceptibility. In addition, a previous study has shown that the codon 72 polymorphism varies greatly in different ethnic populations (31) and this ethnic difference might have a significant effect on cancer risk in different ethnic populations. However, the role of the polymorphism in relation to colorectal cancer risk in the Chinese population has not been reported. In the present study, we investigated the genotypic frequency at codon 72 in a case-control study of 345 patients with colorectal cancer and 670 controls frequency matched to the cases by sex, age, cigarette smoking and alcohol consumption in a Chinese population.
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SUBJECTS AND METHODS |
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Subjects
This study included 345 newly diagnosed patients with primary colorectal adenocarcinoma and 670 cancer-free controls. All subjects were unrelated Han Chinese. Patients were recruited between January 2003 and December 2005 at the No. 113 hospital of People's Liberation Army and Lihuili hospital in Ningbo, China. Patients with familial adenomatous polyposis or hereditary nonpolyposis colorectal cancer were excluded from the study. The average age of the patients was 59 years (range, 25–85 years). Final diagnoses of cases were confirmed by routine histopathological examination. Control subjects were cancer-free individuals randomly selected from a cancer screening program for early detection of cancer conducted in the same regions during the same period when the case patients were recruited. The selection criteria for the controls included no individual history of cancer and frequency matched to case patients based on sex, age (±3 years), cigarette smoking and alcohol consumption.
Each subject was personally interviewed by trained personnel using a questionnaire to determine demographic and lifestyle characteristics such as age at diagnosis, sex, habits of cigarette smoking and alcohol consumption, body mass index (BMI, kg/m2) and first-degree family history of colorectal cancer used for the present study. Cigarette smokers were defined as regular consumption of more than 10 cigarettes a day for at least 6 months, alcohol consumers as consumption of alcoholic beverage more than once a week for more than 6 months. Tumor characteristics such as tumor location, tumor size, histologic grade, presence of lymph node metastases, Dukes stage and p53 positivity, were made on the basis of pathology reports of the specimens obtained by surgery. Each subject provided written consent to participate in the study and to donate a 5 ml blood sample for genetic testing. The research protocol was approved by the Institutional Review Board of the two hospitals.
Genotyping of TP53 Gene Codon 72 Polymorphisms
Genomic DNA was extracted from peripheral blood lymphocytes by proteinase K digestion and phenol/chloroform extraction. The TP53 R72P genotype was determined using polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) as described previously by Zhu et al. (17).
Statistical Methods
Differences in sex, age, cigarette smoking, alcohol consumption, BMI and first-degree family history of colorectal cancer between colorectal cancer cases and controls were evaluated using the 
2-test. The associations between the TP53 codon 72 polymorphism and colorectal cancer risk were estimated by computing the ORs and their 95% CIs from multivariate logistic regression analyses with adjustment for sex, age, cigarette smoking, alcohol consumption, BMI and first-degree family history of colorectal cancer. The regression coefficient corresponding to the integer score provides an overall measure of strength of association and is reported as the trend statistic. The statistical significance of a multiplicative interaction term between alcohol consumption and TP53 genotype was tested using the likelihood ratio test, comparing logistic regression models with and without the appropriate interaction term. Hardy–Weinberg equilibrium was tested using the asymptotic Pearson's 2-test. One-way ANOVA was used to compare the group means of age among cases. A P value of < 0.05 was considered statistically significant. All statistical analyses were conducted using the Stata 9.0 (Stata Corporation, College Station, TX) statistical package.
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RESULTS |
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TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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The general characteristics of the cases and controls are shown in Table 1. Distributions of age, sex, cigarette smoking, alcohol consumption and BMI were similar in cases and controls. Cases were found to have more frequency of family history of colorectal cancer than the controls. Crude RRs due to smoking and alcohol consumption were 1.11 (95% CI = 0.84–1.47) and 0.92 (95% CI = 0.68–1.24), respectively.
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Genetic data are summarized in Table 2. The distribution of the genotypes among the controls was in Hardy–Weinberg equilibrium (P = 0.973). The TP53 72P allele was found more often in patients than in controls (P < 0.001) and carriers of the 72P allele had a significantly increased risk of colorectal cancer. This effect was observed for both heterozygote individuals with an OR of 1.60 (95% CI = 1.17–2.18, P = 0.003) and for homozygotes carriers, with an OR of 2.37 (95% CI = 1.61–3.47, P < 0.001). The P value of the trend test was < 0.001. A similar magnitude of the ORs was observed when the subjects were stratified by sex, age, cigarette smoking, BMI, and first-degree family history of colorectal cancer (data not shown). However, the TP53 polymorphism was associated with a stronger increase in colorectal cancer risk among alcohol consumers, with OR of 3.01 (95% CI = 1.48–6.12) for heterozygotes carriers and 4.71 (95% CI = 1.90–11.68) for homozygotes carriers (Table 3). The interaction between alcohol consumption and TP53 genotype in relation to colorectal cancer risk was not statistically significant (P = 0.213, Table 3).
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The potential associations of the TP53 genotype with tumor characteristics are presented in Table 4. No correlation was found between TP53 genotype and tumor location, histologic grade, presence of lymph node metastases, Dukes stage, p53 positivity, or age at diagnosis. The PP genotype was more frequently found in patients with a larger size tumor (>4 cm) (P = 0.031).
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DISCUSSION |
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TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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We found that the 72P variant allele had a significant effect on colorectal cancer risk, with a dose-dependent effect demonstrated by increasing ORs with the number of 72P alleles (1.60 versus 2.37 for RP versus PP) in the genotypes of TP53 R72P SNP, and this risk effect was more pronounced among alcohol consumers. This study of 345 cases and 670 controls is somewhat larger than previous studies of colorectal cancer and TP53 R72P polymorphism (23–30). Kawajiri et al. (28) and Gemignani et al. (29) indicated that the 72P is a risk allele for colorectal cancer, which is consistent with our results. In contrast, Perez et al. (30) reported a protective effect of the same genetic variant against colorectal cancer. This discrepancy seems to be ascribable to their choice of genotyping materials. Although a preferential loss of the 72P arising in RP germline heterozygotes was reported in colorectal (27) and other (32–36) cancers, tumor tissue DNA was chosen as genotyping materials in their study. Another five studies did not show a significant association of the polymorphism with colorectal cancer risk (23–27). The lack of consistent association of the TP53 R72P polymorphism with colorectal cancer risk in different studies may be due to differences of allele frequencies between ethnic groups, genetic heterogeneity in the pathogenesis of colorectal cancer, different environmental factors, and/or sample size limitations. It is also possible that this TP53 R72P polymorphism could be in linkage disequilibrium with other putative etiological variants (25) which would likely differ across different ethnic populations.
Alcohol intake is a well-known risk factor for colorectal cancer (37). In the present study, we found that the TP53 72P allele had a stronger effect on colorectal cancer risk among alcohol consumers. To the best of our knowledge, the association between the TP53 codon 72 polymorphism and colorectal cancer risk concerning alcohol consumption was not previously studied. The dose–response relationship between alcohol consumption and the TP53 polymorphism could not be further evaluated in this study because we did not have detailed dietary quantitative data on these subjects. Our study is in agreement with Cai et al.'s study (38), which found that elevation of esophageal squamous cell carcinoma risk was most pronounced among alcohol consumers with the TP53 PP genotype who consumed a low level of dietary selenium. The mechanism(s) responsible for these findings remains unclear. In a study of oral squamous cell carcinomas in Taiwan, Hsieh et al. (36) reported alcohol intake could increase the frequency of 72R allele loss arising in RP germline heterozygotes among cigarette smokers and areca quid chewers. Thus, the RP heterozygotes have more chance to develop cancer in consumers, because the 72P risk allele is retained. In line with this hypothesis, our data demonstrated that RP heterozygotes were more frequent in colorectal cancer patients who consume alcohol than in those who did not consume (61.0% versus 48.3%). However, this finding is preliminary and needs to be confirmed in larger molecular epidemiological studies.
The TP53 R72P polymorphism was not linked to tumor location, histologic grade, presence of lymph node metastases, Dukes stage, p53 positivity, or age at diagnosis, but, interestingly, was linked to tumor size. These observations suggest that the tumor characteristics-associated effect of the TP53 polymorphism was limited even though the p53 protein may have certain effect on tumor characteristics in general. Nevertheless, it must be emphasized that these post-hoc analyses in the present study were not performed to test previously defined hypotheses. In addition, the TP53 codon 72 polymorphism has been reported to be associated with colorectal tumor malignant potential (27,30), age of onset (39), and survival (40). Further studies, therefore, should be performed to analyze this potential role of the TP53 polymorphism for colorectal tumor characteristics.
In conclusion, our study provides evidence that the TP53 R72P SNP may contribute to the etiology of colorectal cancer in the Chinese population, particularly among alcohol consumers. Further studies should be performed to analyze the potential role of the TP53 polymorphism for colorectal tumor characteristics.
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Conflict of interest statement |
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TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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None declared.
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Acknowledgments |
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This work was supported by a grant (No. 06MA27) from Medical Science and Technology Research Foundation for the 11th 5-Year Program of PLA, Nanjing branch, P.R. China.
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References |
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TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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