The Role ofP53andMDM2Polymorphisms in the Risk of Esophageal Squamous Cell Carcinoma

Abstract

The tumor suppressor P53 pathway plays a crucial role in preventing carcinogenesis and genetic variations of this pathway may be associated with cancer susceptibility. We tested this hypothesis by examining the contribution of functional polymorphisms in P53 and MDM2 to risk of esophageal squamous cell carcinoma (ESCC). DNA from 758 ESCC patients and 1,420 controls were genotyped for P53 codon 72Arg>Pro and MDM2 309T>G polymorphisms. Odds ratios (OR) and 95% confidence intervals (CI) of ESCC were estimated by logistic regression. We observed an increased risk of ESCC associated with the P53 Pro/Pro (OR, 1.83; 95% CI, 1.43-2.35; P < 0.001) or MDM2 GG (OR, 1.49; 95% CI, 1.16-1.91; P = 0.002) genotype, compared with the P53 Arg/Arg or MDM2 TT genotype, respectively. Interaction between these P53 and MDM2 polymorphisms increased risk of ESCC in a multiplicative manner, with the OR being 3.10 (95% CI, 2.07-4.69) for subjects carrying both P53 Pro/Pro and MDM2 GG genotypes. Significant interactions were observed between these polymorphisms and smoking, with risk being the highest (OR, 5.29; 95% CI, 2.91-9.61) in smokers having both P53 Pro/ Pro and MDM2 GG genotypes. The MDM2 GG genotype was also associated with risk of developing poorly differentiated and advanced ESCC compared with the GT or TT genotype (OR for high-grade and stages III-IV versus low-grade and stages I-II = 1.60; 95% CI, 1.00-2.64; P = 0.049). The P53 and MDM2 polymorphisms may be genetic determinants for the development of ESCC. (Cancer Res 2005; 65(20): 9582-7)

Association of genetic polymorphisms in MDM2, PTEN and P53 with risk of esophageal squamous cell carcinoma

“…20,21 In spite of the above discrepancy, we observed a similar association between P53 Arg72Pro and ESCC risk compared with Hong's and other previous studies (OR B2 for Pro/Pro genotype compared with Arg/Arg genotype, adjusted for age, sex, smoking or drinking status), though sample size, matching mode and study population were quite different from each other. [13][14][15][16] We confirm that P53 Arg72Pro polymorphism is a common susceptibility factor for ESCC in Chinese populations.…”

“…Thus, all the participants were relatively homogeneous with regard to genetic background and environmental risk factors. Previous studies conducted in various tumour types in China showed that the GG genotype frequency ranged from 18 to 30% in controls, 16,[20][21][22][23][24] which indicated that genotype frequency varied in different populations even in the same country. Two of these studies also included MDM2 Del1518 and no association was observed between this polymorphism and cancer risk.…”

“…A recent report conducted by Hong et al 16 demonstrated that the GG genotype of MDM2 T309G led to a 1.5-fold increased risk of ESCC compared with the TT genotype. The GG genotype frequency was 26.7% and 20.5% in cases and controls, respectively.…”

“…11,12 Till now, the P53 Arg72Pro polymorphism has been well studied in ESCC in Chinese populations. [13][14][15][16] But little is known about the association between MDM2 or PTEN polymorphisms and ESCC susceptibility. 16,17 Here we genotyped MDM2 T309G, Del1518 (rs150550023), PTEN rs701848 and rs2735343 and investigated the associations between these polymorphisms and ESCC risk in a case-control study conducted in a high-risk population of China.…”

Polymorphic variants in the p53 pathway

“…Several groups report that the G allele is associated with attenuation of the p53 pathway and enhanced early onset of, and increased risk for, tumorigenesis. [33][34][35][36] In contrast, several other groups have found no association between SNP309 and cancer risk or age of onset. [37][38][39][40] It is possible that the impact of this polymorphism may differ for different tumor types, or may depend upon the initiating molecular event that drives tumor cell development.…”