p53 and p21 genetic polymorphisms and susceptibility to endometrial cancer

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Abstract

Objective. Recently, there has been considerable interest in the association of specific cancers with single nucleotide polymorphisms (SNPs). In this regard, genetic polymorphism at codon 72 (CCC/proline to CGC/arginine [Pro72Arg]) of the p53 gene is one of the most frequently studied subjects. An association between endometrial cancer and the polymorphism at codon 31 (AGC/serine to AGA/arginine [Ser31Arg]) of the p21 gene, which is known to be a downstream mediator of p53, has also been reported.

Methods. The authors designed a hospital-based case-control study of 95 endometrial cancer patients and 285 non-cancer controls. For the determination of p53 and p21 polymorphism, allele-specific polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism assay was applied, respectively.

Results. We found statistically significant differences in the frequency of the p53 and p21 genotypes between these two groups (P < 0.001), respectively. The p53 genotypes containing the Pro allele were significantly associated with endometrial cancer with an odds ratio (OR) of 3.56 (95% confidence interval [CI] 2.10–6.04). Also, homozygous carriers of the p21 Ser allele showed a substantially increased risk of developing endometrial cancer (OR 2.68, 95% CI 1.59–4.51) as compared to homozygous and heterozygous carriers of the Arg allele. In addition, the combination of the pro allele containing genotypes of p53 and the Ser homozygous genotype of p21 posed a remarkably increased risk (OR 9.55, 95% CI 4.30–21.24) of endometrial cancer development. These significant differences were maintained throughout the groups after they were stratified by menopausal status.

Conclusions. These data suggest that there is a significant association between the genetic polymorphisms of p53, p21, and specific combinations of the at-risk genotypes of these genes and the risk of developing endometrial cancer in Korean women.

Introduction

Endometrial cancer is the most common female tract malignancy in many developed countries [1], and its prevalence has also been increasing in Korea during the last decade [2]. The major risk factor for endometrial cancer can be traced to reproductive events, which influence the lifetime levels of estrogen. A large proportion of endometrial cancer cases cannot, however, be explained purely by the hormonal risk factors. The identification of susceptibility factors, that is, genetic factors that predispose individuals to endometrial cancer would provide further insight into the etiology of this malignancy. Recently, there has been a great deal of interest in the association of specific diseases with single nucleotide polymorphisms (SNPs), which might explain the individual differences of susceptibility to specific malignant neoplasms. Because of their higher frequencies in the general population, SNPs may represent a greater overall risk factor as compared with mutations [3]. Candidate SNPs are involved in carcinogen metabolism, DNA damage repair, steroid metabolism, and steroid receptor activation pathways. Polymorphisms in p53 and p21, which constitute a major downstream component of the p53 tumor suppressor pathway, are considered to be candidate risk factors, because of the crucial role played by these genes in the maintenance of genomic integrity following genotoxic insult [4], [5]. The reported data which indicate that mutations in the p53 gene, whose incidence ranges from 4.8% to 20%, are relatively infrequent in endometrial cancer compared to other malignancies, supports the possible association of these polymorphisms with endometrial cancer [6], [7], [8].

Codon 72 of exon 4 was the first polymorphism detected in p53 and it was suggested that the two alleles of codon 72 might have different oncogenic properties [9]. In the field of breast cancer, the studies reported so far on the polymorphism of p53 codon 72 have provided discrepant results [10], [11], [12]. Although no association between the genetic polymorphisms in codon 72 of the p53 gene and the risk of endometrial cancer has been found in previous studies [13], [14], the significance of SNPs associated with an increased cancer risk could be dramatically different between ethnic groups [15]. Allelic differences of p53 polymorphisms were observed in various ethnic groups [16]. We have already published the data that the allele frequencies of codon 72 of the p53 gene differ between Caucasian and Korean women [17]. We found that p53 polymorphism was associated with the development of adenocarcinoma of cervix (unpublished data), although the association was not found in squamous cell carcinoma of cervix [17]. The authors considered the possibility that p53 polymorphism might be associated with the risk of endometrial cancer, another adenocarcinoma of female genital tract.

p21, which is a downstream mediator of p53, functions as a universal inhibitor of cyclin-dependent kinases, also known as WAF1 or CIP1. Genetic changes in p21 are potentially important in human malignancies because they could have an impact on the control of the cell cycle [18]. A polymorphism at codon 31 of p21 resulting in a change from serine to arginine has been reported [19]. Until now, only a few reports have been published on the association between p21 polymorphism and the risk of developing gynecologic cancers, such as endometrial, cervical, and ovarian cancers [20], [21], [22]. We have already found that the codon 31 Serine homozygous of p21 gene could be a risk factor for the development of cervical adenocarcinoma but not for squamous cell carcinoma of cervix [21]. The authors hypothesized that this polymorphism could be associated with the risk of adenocarcinoma of uterine corpus adjacent to the uterine cervix.

Although endometrial cancer is a common female malignancy and the prevalence has been increased rapidly in Korea, relatively little attention has been given to the genetic susceptibility factors associated with this disease, as was mentioned above. In this article, we attempted to identify p53 and p21 alleles associated with endometrial cancer risk in Korean women.

Section snippets

Study population

Between March 1993 and April 2001, 95 consecutive patients with a new diagnosis of endometrial cancer, who were managed at the Department of Obstetrics and Gynecology in Seoul National University Hospital, were recruited in this study. Clinicopathologic parameters such as age, age at menarche, age at the first pregnancy, body mass index, a history of diabetes mellitus and/or hypertension, International Federation of Gynecology and Obstetrics (FIGO) stage, histologic grade, the presence of lymph

Results

The values of the putative risk factors for endometrial cancer in the cases and controls are shown in Table 1. Education, obesity (BMI > 25 kg/m2), a family history of endometrial cancer, and a history of diabetes showed significant differences between the cases and the controls. The results of this case-control study on the association between p53 and p21 genetic polymorphisms and endometrial cancer are presented in Table 2. In both groups, the distribution of genotypes fits the Hardy–Weinberg

Discussion

Two forms of polymorphism can occur in exon 4 of the wild-type p53 gene due to a 1-bp change, which involves coding for Arginine (Arg) or Proline (Pro) residues at codon 72. Although it was suggested that the two alleles of codon 72 might have different oncogenic properties, inconsistent results have been reported in various type of cancers [24], [25], [26]. In the case of breast cancer, one of the hormone-related cancers and which has similar epidemiologic-risk factors compared with

Acknowledgements

We thank Professor Daehee Kang (Faculty of Preventive Medicine, Seoul National University) for his assistance with the data analysis. This work was supported in part by grants from the Cancer Research Institute Research Fund (2003-CRI-4), Seoul National University, and in part by the Seoul National University Hospital Research Fund (05-2003-002-0).

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