MDM2 Promoter SNP309 Is Associated with the Risk of Hepatocellular Carcinoma in Patients with Chronic Hepatitis C

Abstract

Purpose: A single nucleotide polymorphism (SNP) in the promoter region of MDM2 gene, SNP309, has recently been shown to be associated with accelerated tumor formation in both hereditary and sporadic cancers in humans. However, the association of SNP309 with hepatocellular carcinoma is unknown. We evaluated the association of SNP309 with the risk of hepatocellular carcinoma development among Japanese patients with chronic hepatitis C virus infection. Experimental Design: We genotyped the SNP309 at the MDM2 promoter in 435 Japanese patients with chronic hepatitis C virus infection, including 187 patients with hepatocellular carcinoma and 48 healthy subjects, using a fluorogenic PCR. Presence of SNP was also confirmed by direct sequencing of the MDM2 promoter region. Results: The proportion of G/G genotype of the SNP309 in patients with hepatocellular carcinoma (33%) was significantly higher than that in patients without hepatocellular carcinoma (23%), with an odds ratio (95% confidence interval) of 2.28 (1.30-3.98). A multivariate analysis revealed that MDM2 SNP309 (G/G versus T/T), age >60 years, male gender, presence of cirrhosis, serum a-fetoprotein >20 Ag/L, and serum albumin <3.2 g/dL were independently associated with the hepatocellular carcinoma development at odds ratio of 2.27, 2.46, 3.08, 4.15, 4.87, and 6.33, respectively. Conclusions: The MDM2 promoter SNP309 is associated with the presence of hepatocellular carcinoma in Japanese patients with chronic hepatitis C.

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

“…Because of lack of healthy control samples in corresponding ethnic groups or countries, we were not able to test this hypothesis with a case-control study. However, in a recent study, Dharel et al reported that SNP309 is associated with the presence of hepatocellular carcinoma in Japanese patients with chronic hepatitis C [22]. In concordance with the study by Dharel et al, two recent studies indicated an association between the G genotype and risk for hepatocellular carcinoma in Moroccan and Korean patients with chronic hepatitis B infections [23,24].…”

A single nucleotide polymorphism in the p53 pathway interacts with gender, environmental stresses and tumor genetics to influence cancer in humans

“…This hypothesis has been supported by the work on MDM2 SNP309. As the initial publication (Bond et al, 2004), multiple studies have shown that the G-allele of MDM2 SNP309 is associated with the attenuation of the p53 pathway and an enhanced early onset of and increased risk for, tumorigenesis (Bougeard et al, 2006;Hong et al, 2005;Swinney et al, 2005;Allazzouzi et al, 2006;Bond et al, 2006a, b;Dharel et al, 2006;Lind et al, 2006;Menin et al, 2006;Ohmiya et al, 2006;Park et al, 2006;Ruijs et al, 2007;Zhang et al, 2006). Because modest changes in levels of other central nodes of the p53 pathway (e.g.…”

“…As previously proposed, it is likely that individuals with inherently different levels of p53 function will respond differently to such environmental stresses and have different levels of risk for developing the associated cancers (Bond et al, 2005a). Three recent studies have provided evidence that this could be the case (Hong et al, 2005;Zhang et al, 2006;Dharel et al, 2006). DNA damage is just one form of genotoxic stress that cells undergo when exposed to smoke (DeMarini, 2004).…”

“…In a recent study, evidence was provided that the MDM2 SNP309 locus alters the risk of developing liver cancer associated with chronic HCV infection (Dharel et al, 2006). Specifically, in 435 Japanese patients with chronic HCV infection, a significant enrichment of individuals G/G in genotype at the SNP309 locus was found in those patients with hepatocellular carcinoma compared to cancer-free chronically infected patients.…”

Combined effects of p53 and MDM2 polymorphisms on susceptibility and surgical prognosis in hepatitis B virus-related hepatocellular carcinoma

“…In the cell model, the MDM2 SNP309G/G genotype shows elevated MDM2 transcription and expression, resulting in attenuation of the p53 pathway and accelerating tumor formation (Bond et al, 2004). It has been reported that the association of MDM2 SNP309 with various cancers and the correlation between MDM2 expression with poor prognosis (Hirata et al, 2007;Cescon et al, 2009;Toffoli et al, 2009); however, the association of MDM2 SNP309 with HCC is inconsistent between studies (Dharel et al, 2006;Yoon et al, 2008;Leu et al, 2009).…”