Ap53genetic polymorphism as a modulator of hepatocellular carcinoma risk in relation to chronic liver disease, familial tendency, and cigarette smoking in hepatitis B carriers

Abstract

This study evaluated whether the codon 72 p53 polymorphism was related to hepatocellular carcinoma (HCC). Genotypes of p53 were determined in 80 incident cases of HCC and 328 controls nested in a cohort study of 4,841 male chronic hepatitis B carriers. No overall increase in HCC risk with the Pro variant allele of the p53 polymorphism was apparent. However, there were synergistic effects on HCC development for the Pro allele with chronic liver disease and family history of HCC in first-degree relatives. Compared with subjects without the Pro allele and chronic liver disease, the increase in HCC risk associated with chronic liver disease among those without the Pro allele was only threefold. Subjects with both chronic liver disease and the Pro allele were at an increased risk of 7.60 (95% CI ‫؍‬ 2.28-25.31). When subjects without family history of HCC and the Pro allele were considered as the reference group, there was no apparent increased risk of HCC for those without the Pro allele who had family history of HCC. Among those with both factors, there was a significantly increased risk of 3.29 (95% CI ‫؍‬ 1.10-9.85). Both cigarette smoking and glutathione S-transferase M1 genotype modified the risk of HCC associated with the p53 polymorphism. Significantly increased risk associated with the p53 genotype was observed only among smokers who were glutathione S-transferase-null (Pro/Pro vs. Arg/Arg: odds ratio ‫؍‬ 6.46; 95% CI ‫؍‬ 1.55-26.94). The p53 polymorphism also interacted with the cytochrome P450 1A1 and carotenoid levels in smoking-related hepatocarcinogenesis. (HEPATOLOGY 1999;29:697-702.) Chronic infection with hepatitis B virus (HBV) is the major cause of at least 80% of hepatocellular carcinoma (HCC) throughout the world. 1 However, only about one fifth of chronic HBV carriers develop HCC in their lifetime, 2 suggesting that there is interindividual variation in susceptibility to hepatocarcinogenesis.Both viral and chemical carcinogens are involved in the multistage process of human hepatocarcinogenesis.

p53 polymorphisms associated with mutations in and loss of heterozygosity of the p53 gene in male oral squamous cell carcinomas in Taiwan

“…Among the more than 10 DNA sequence polymorphisms identified, the codon 72 polymorphism (Arg/Pro) has been explored in depth for a potential association with cancer. Although this polymorphism has been implied to be associated with certain cancer types (Yu et al, 1999;Fan et al, 2000;Shepherd et al, 2000), Sun et al (1999) reviewed 31 epidemiological case -control studies and suggested that codon 72 allelism did not have an impact on human cancer risk. The present study found that there was no significant difference in the frequency of codon 72 genotype between patients and referent controls (P ¼ 0.27).…”

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

“…On the other hand, familial clustering and early onset of HCCs in some populations suggest an inherited genetic predisposition to liver cancer [2]. Germline polymorphisms of several genes have been studied as potential risk factors for HCCs [3][4][5]. However, the pathogenesis of human HCC is a multistage process with the involvement of a series of genes, including oncogenes and tumor suppressor genes; germline polymorphisms of these genes may also determine individual susceptibility to HCC.…”

“P53 Codon 72 Single Base Substitution in Viral Hepatitis C and Hepatocarcinoma Incidences”

“…The P53 gene displays common polymorphisms in the general population, one of which, characterized by an Arg to Pro substitution at codon 72 in the transactivation domain of exon 4, has been investigated as risk modifier in several cancer models [17,18]. The variant Pro allele has been shown to be less efficient to suppress cell transformation and to induce apoptosis and to be less sensitive to degradation by viral oncogenic proteins [19].…”

“…Intriguingly, Yu et al [17] found that P53 gene polymorphism involved in hepatocarcinogenesis may determine individual susceptibility to HCC. The P53 wild-type is polymorphic at residue 72 in exon 4, where a single-base change causes a substitution of Pro for Arg (CCC/CGC) in the transactivation domain [14].…”