Mdm2 Snp309 G allele displays high frequency and inverse correlation with somatic P53 mutations in hepatocellular carcinoma

Abstract

a b s t r a c tLoss of function of the p53 protein, which may occur through a range of molecular events, is critical in hepatocellular carcinoma (HCC) evolution. MDM2, an oncogene, acts as a major regulator of the p53 protein. A polymorphism in the MDM2 promoter, SNP309 (T/G), has been shown to alter protein expression and may thus play a role in carcinogenesis. MDM2 SNP309 is also associated with HCC. However, the role of SNP309 in hepatocarcinogenesis with respect to TP53 mutations is unknown. In this study, we investigated the distribution of the MDM2 SNP309 genotype and somatic TP53 (the p53 tumor suppressor gene) mutations in 99 human HCC samples from Africa, Europe, China and Japan. Samples exhibited striking geographical differences in their distribution of SNP309 genotypes. The frequency and spectrum of p53 mutations also varied geographically; TP53 mutations were frequent in Africa, where the SNP309 T/T genotype predominated but were rare in Europe and Japan, where the SNP309 G allele was present more frequently.TP53 mutations were detected in 18% (4/22) of SNP309 T/G and G/G and 82% (18/22) of SNP309 T/T genotype holders; this difference was statistically highly significant (P-value = 0.0006).Our results indicated that the presence of the SNP309 G allele is inversely associated with the presence of somatic TP53 mutations because they only coincided in 4% of HCC cases. This finding suggests that the SNP309 G allele may functionally replace p53 mutations, and in addition to known etiological factors, may be partly responsible for differential HCC prevalence.

Association of the MDM2 SNP285 and SNP309 Genetic Variants with the Risk, Age at Onset and Prognosis of Breast Cancer in Central European Women: A Hospital-Based Case-Control Study

“…Since associations of SNP309 with the age at onset, estrogen receptor (ER) status and p53 status have been reported [14,17,33,34,35], odds ratios in relevant breast cancer subpopulations were determined. In this exploratory analysis, no significant associations of SNP309 with breast cancer risk were observed in any subpopulation under a dominant inheritance model (Table S3.…”

Autoantibody Response to Murine Double Minute 2 Protein in Immunodiagnosis of Hepatocellular Carcinoma

“…The findings from different areas support that MDM2 is significantly associated with increased risk of hepatocellular carcinoma [32–35]. MDM2 SNP309 G allele is a susceptibility gene for the development of viral hepatitis-related hepatocellular carcinoma [36–38]. The combination of MDM2 SNP 309 and TP53 Arg72Pro genotypes confers higher risk to develop HCC [39–41].…”

Association between transforming growth factor‐β1 polymorphisms and hepatocellular cancer risk: A meta‐analysis

“…HEPATOCARCINOGENESIS IS A complex process associated with accumulation of genetic and epigenetic changes that occur during initiation, promotion, and progression of diseases. Genetic polymorphisms in candidate genes for HCC have been reported as potential risk factors for HCC 20 . TGF‐β1 is a critical regulator of normal and transformed epithelial cell phenotype, functioning as both a tumor suppressor and promoter of tumor progression.…”

“…Genetic polymorphisms in candidate genes for HCC have been reported as potential risk factors for HCC. 20 TGF-b1 is a critical regulator of normal and transformed epithelial cell phenotype, functioning as both a tumor suppressor and promoter of tumor progression. For most normal cell types, TGF-b1 acts in vitro as a potent inhibitor of proliferation and migration and promotes apoptosis and properties associated with tumor suppression.…”