Association between a functional single nucleotide polymorphism in the MDM2 gene and sporadic endometrial cancer risk
Introduction
Endometrial cancer is the most common gynecologic malignancy among women in the United States. As with all solid tumors, it is a heterogeneous disease with complex genetic and environmental influences. Genetic alterations that result in the functional inactivation of DNA mismatch repair genes, such as MLH1, MSH2, and MSH6, can cause a hereditary form of endometrial cancer [1], [2], [3]. These high-penetrance, inherited genetic mutations occur rarely in the population and are responsible for the development of only 5–10% of all endometrial cancers [4]. The vast majority of endometrial cancers occur sporadically. More commonly occurring, lower-penetrance, variant genetic alleles may influence susceptibility to sporadic carcinogenesis through subtle effects on protein expression or function [5]. Polymorphisms that affect the function of pathways known to influence the neoplastic process may be particularly relevant.
Among the most critical of these pathways is that involving the p53 tumor suppressor protein. Under conditions of genotoxic stress, p53 is activated to turn on a number of downstream effectors that halt progression through the cell cycle, allowing for DNA repair or programmed cell death to occur, and preventing the transmission and propagation of genetic errors [6], [7]. The importance of p53 activity in preventing either the formation or progression of cancer is underscored by the fact that inactivating mutations of the TP53 gene are found in over half of all human cancers [8], [9], [10]. Functional inactivation of normal p53 protein can also occur through binding to a viral oncoprotein, such as the human papillomavirus E6 protein, or to a cellular regulatory partner, such as murine double minute 2, or MDM2 [11], [12].
MDM2 is an E3 ubiquitin ligase that suppresses the activity of p53 through ubiquitinization, as well as, through direct protein binding [12], [13], [14]. Overexpression of the MDM2 protein has an oncogenic effect through the reduction of p53 levels [15], [16], which allows damaged cells to progress unchecked through the cell cycle. Amplification and/or overexpression of MDM2 are states found in a number of human cancers [17], [18], [19], [20]. Recently, a naturally occurring single nucleotide polymorphism (SNP) located in the promoter region of the MDM2 gene, named SNP309, was found to have the functional effect of increasing MDM2 protein levels and impairing p53 tumor suppressor activity [21]. The SNP309 T to G base substitution occurs at a relatively high frequency in the general population (40% heterozygous T/G, 10% homozygous G/G) and has been associated with accelerated tumorigenesis in hereditary Li-Fraumeni associated cancers as well as in sporadic soft tissue sarcomas [21]. Because of its functional effect of reducing p53 activity, MDM2 SNP309 is a genetic polymorphism that could predispose to sporadic cancer risk.
We sought to examine the association between SNP309 and sporadic endometrial cancer risk. We also examined the association between SNP309 and prognostic histopathologic features in endometrial cancer.
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Materials and methods
Investigations were performed under institutional review board approval at Cedars-Sinai Medical Center in Los Angeles, CA. Genotyping was performed using PCR amplification followed by restriction fragment length polymorphism (RFLP) analysis. Genomic DNA was isolated using standard methods from the peripheral blood lymphocytes of 73 patients with endometrial cancer and 79 healthy, female controls. For each sample, the MDM2 gene promoter region was amplified by a polymerase chain reaction (PCR)
Results
The ethnic/racial breakdown was similar between endometrial cancer cases and controls with the majority of patients being Caucasian. Among 73 endometrial cancer patients, 58 (80%) were Caucasian, 4 (5%) were African American, 2 (3%) were Hispanic, 7 (9%) were Asian, and 2 (3%) were unknown. Among 79 control patients, 67 (85%) were Caucasian, 6 (7%) were African American, 3 (4%) were Hispanic, and 3 (4%) were Asian.
Genotyping was successfully performed for all samples in the study. The MDM2
Discussion
We have found the MDM2 SNP309 homozygous G/G genotype to be a genetic variant that may influence sporadic endometrial cancer susceptibility. In this study, women carrying the G/G genotype had a 2.76-fold increased risk of developing endometrial cancer compared to those with either the T/T or T/G genotype in an age-adjusted analysis. Compared to the more prevalent T allele, the variant G allele has been found to increase cellular levels of MDM2 and thereby attenuate the p53 response [21]. The
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