Association Of Genetic Polymorphisms In MDM2,PTEN And P53with Risk Of Esophageal Squamous Cell Carcinoma

BackgroundEsophageal squamous cell carcinoma (ESCC) is the sixth leading cause of cancer death worldwide. This disease shows a considerable geographic variation globally, with an exceptionally high incidence in certain areas of China and some other countries. There are many factors involved in esophagus carcinogenesis, with genetic variations mostly studied in recent years. Oncogene MDM2is a crucial negative regulator of P53. Besides directly inhibiting the transcriptional activity of P53, MDM2also stimulates its nuclear export and degradation as an E3ubiquitin ligase. PTEN tumour-suppressor gene has a high mutation frequency in human cancers. It controls cellular growth mainly by inhibiting PI3K activation, and this restricts MDM2to the cytoplasm, thus protecting P53from degradation. MDM2, PTEN and P53tumor suppressor-oncogene regulate cell growth and viability. Genetic variations in these genes might lead to the disturbance of cell cycle and foster cancer development.ObjectiveTo investigate the associations between polymorphisms and haplotypes in MDM2, PTEN and P53genes and ESCC susceptibility in Anyang area.MethodsMDM2T309G, DEL1518, PTEN rs701848, rs2735343and P53Arg72Pro polymorphisms were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in226ESCC patients and226cancer-free controls. Demographic variables between the study groups were compared by conditional univariate logistic regression. Hardy-Weinberg equilibrium was evaluated by Chi-square test. Odds ratios (ORs) and95%confidence intervals (CIs) were calculated by conditional multivariate logistic regression as a measure of association with ESCC, adjusted for age, smoking and drinking status. Haplotype frequencies were estimated by Phase2.1.ResultsGenotype distributions in these polymorphisms were all in Hardy-Weinberg equilibrium in controls. The risk of ESCC was elevated in individuals with any of the variant genotypes of PTEN rs2735343(CG and GG) and P53Arg72Pro (Arg/Pro and Pro/Pro) polymorphisms (P=0.001,OR=2.76,95%CI2.58-4.82; P<0.001, OR=4.30,95%CI2.27-8.13;P=0.032,OR=l.74,95%CI1.05-2.89;P=0.012,OR=2.06,95%CI1.17-3.62, respectively), but not any genotype of MDM2or PTEN rs701848. Moreover, multiplicative interactions were observed between PTEN rs2735343and P53Arg72Pro or smoking status on risk of ESCC. Haplotype analyses of PTEN showed that--/GC was a risk factor for ESCC (P<0.001, OR=2.44,95%CI1.52-3.91), while CT/CT was a protective one (P<0.001, OR=0.21,95%CI0.11-0.42). None of the MDM2haplotypes was associated with ESCC susceptibility (P>0.1).ConclusionPTEN rs2735343and P53Arg72Pro might be susceptibility factors in ESCC development in this area. The results of this study provided important markers for screening the high-risk population for ESCC and genetic therapy.