MDM2 SNP309 polymorphism as risk factor for susceptibility and poor prognosis in renal cell carcinoma.
OBJECTIVE
MDM2 is a major negative regulator of p53, and a single nucleotide polymorphism in the MDM2 promoter region SNP309 (rs2279744) has been shown to increase the affinity of the transcriptional activator Sp1, resulting in elevated MDM2 transcription and expression in some cancers. There is currently no information about the role of MDM2 polymorphism in renal cell carcinoma (RCC). We investigated polymorphisms in p53-related genes, including MDM2, and their interactions in renal cancer.


METHODS
We genotyped three single nucleotide polymorphisms of three genes (p53 Arg(72)Pro, p21 Ser(31)Arg, and MDM2 SNP309) in 200 patients with renal cancer and 200 age- and gender-matched healthy subjects. Genotyping was confirmed by direct DNA sequencing. Samples that showed significant polymorphic variants were analyzed for MDM2 expression by immunohistochemistry. Association of polymorphic variants on survival of RCC patients was analyzed by Kaplan-Meier curves.


RESULTS
A significant increase in the GG genotype of the MDM2 SNP309 was observed in RCC patients compared with healthy controls (odds ratio, 1.80; 95% confidence interval, 1.14-2.84). To investigate the effect of the MDM2 SNP309 polymorphism on MDM2 expression, immunohistochemistry was done in genotyped RCC tissues. Positive staining for MDM2 was detected in 2 of 15 (13%) TT genotype, 4 of 15 (26%) TG genotype, and 5 of 10 (50%) GG genotype carriers. The frequency of MDM2 expression in GG genotype carriers was significantly higher than that in TT genotype carriers. Polymorphisms of p53 Arg(72)Pro and p21 Ser(31)Arg did not show significant association with RCC. In univariate and multivariate analysis, MDM2 SNP309 GG genotype was independently associated with poor prognosis. Kaplan-Meier curve analysis showed that survival of patients with GG carriers was significantly worse than that of carriers with TG + TT genotypes.


CONCLUSIONS
This is the first report to show a significant association between functional polymorphisms in MDM2 and increased risk of developing renal cancer. In addition, the MDM2 polymorphism was shown to be an independent adverse prognostic factor for RCC. Patients with MDM2 309GG genotype showed worse prognosis and low survival.
Hirata
Hiroshi
H
Department of Urology, San Francisco Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, California 94121, USA.
Hinoda
Yuji
Y
Kikuno
Nobuyuki
N
Kawamoto
Ken
K
Suehiro
Yutaka
Y
Tanaka
Yuichiro
Y
Dahiya
Rajvir
R
D000368:Aged; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D012307:Risk Factors; D016019:Survival Analysis; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2