MDM 2 Promoter SNP 309 Is Associated with the Risk of Hepatocellular Carcinoma in Patients with Chronic Hepatitis C

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 inJapanese patients with chronic hepatitis C. It has been estimated that hepatitis C virus (HCV) infects at least 170 million people worldwide, which often leads to the dreadful sequels of cirrhosis, end-stage liver disease, and hepatocellular carcinoma (1–4). The risk of hepatocellular carcinoma development increases with the severity of inflammation and liver fibrosis (5–7). Several factors, such as alcohol intake, older age at time of infection, male gender, and coinfection with the hepatitis B virus or HIV, are known to accelerate disease progression in HCV infection (5, 7, 8). In addition, host genetic factors have been reported to affect the outcome of HCV infection (9–15). Recently, we reported that genetic polymorphisms in interleukin-1b and UDP glucuronosyltransferase 1A7 genes were associated with the development of hepatocellular carcinoma in Japanese patients with chronic HCV infection (13, 14), which was followed by similar reports by other groups as well (16). We further did a large-scale search of gene polymorphisms associated with the hepatocellular carcinoma development in a much larger population of HCV patients and found that three single nucleotide polymorphisms (SNP) in three genes (SCYB14, GFRA1 , and CRHR2) were significantly associated with hepatocellular carcinoma development in Japanese patients with chronic HCV infection (15). The association of both the germ-line and somatic inactivating mutations of the p53 gene with increased tumor development is well known (17–20). Gene polymorphisms at critical nodes of the p53 pathways have also been reported to be associated with development of cancers (21–23). Recently, a SNP (SNP309, rs2279744) in the promoter region of MDM2 , a negative regulator of p53, has been shown to be associated with accelerated tumor formation in both hereditary and sporadic cancers in humans (24). However, it is not known whether the SNP309 is associated with the development of hepatocellular carcinoma as well. In the present study, we investigated the association of the MDM2 promoter SNP309 with development of hepatocellular carcinoma among Japanese patients with chronic HCV