p53 and p21 genetic polymorphisms and susceptibility to endometrial cancer☆
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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Cited by (64)
DR-GAS: A database of functional genetic variants and their phosphorylation states in human DNA repair systems
2014, DNA RepairCitation Excerpt :The phosphorylation takes place at serine (S), threonine (T) or tyrosine (Y) residues [29] in the proteins which not only influences the structure but also affects the function, stability, sub-cellular localizations and interaction with other proteins [30,31]. Few cases of key DNA repair proteins, where nsSNPs such as S31R (CDKN1A), S326C (OGG1) and T241M (XRCC3) have already been associated with risks for endometrial [32], esophageal [33,34], lung [35] and breast cancers [36] due to change in their phosphorylation states. The change may be from phosphorylated to dephosphorylated residue or vice-versa affecting the activity of the repair proteins.
Lack of association between p53 codon 72 polymorphism and endometrial cancer: A meta-analysis
2012, Cancer EpidemiologyCitation Excerpt :Studies have reported that the codon 72 polymorphism may be a risk factor for the development of cancer [16]. A number of studies have been conducted to investigate the potential association between p53 codon 72 polymorphism and endometrial cancer in humans [8,17–24]. However, the results have been inconsistent.
Evaluation of the frequency of TP53 gene codon 72 polymorphisms in Iranian patients with endometrial cancer
2010, Cancer Genetics and CytogeneticsCitation Excerpt :Few reported case–control studies have addressed the association of polymorphism of TP53 codon 72 with endometrial cancer (EC). There was a significant association between TP53 gene polymorphism and EC in some studies [20–25], and a relation between TP53 gene polymorphism and the type of EC has been suggested [26,27]. In other studies, however, no association of these SNPs was found with EC [28].
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Presented as a poster at the 33rd Annual Meeting of the Society of Gynecologic Oncologists in Miami, FL.