P53 codon 72 polymorphism is associated with susceptibility to hepatocellular carcinoma in the Turkish population: A case-control study

Department of Internal Medicine, Faculty of Medicine, Çukurova University, 01330 Adana, Turkey.
Molecular Biology Reports (Impact Factor: 2.02). 05/2011; 39(2):1639-47. DOI: 10.1007/s11033-011-0903-2
Source: PubMed


The tumor suppressor p53 gene plays a crucial role in preventing carcinogenesis through its ability to induce cell cycle arrest and apoptosis following DNA damage and oncogene activation. A guanine (G)/cytosine (C) common single nucleotide polymorphism (SNP) at second position of codon 72 in exon 4 of p53 gene determines a arginine (Arg) to proline (Pro) (Arg72Pro) aminoacidic substitution within the proline-rich domain of p53 protein. Arg72 and Pro72 allele are different from a biochemical and biological point of view and many reports suggest that they can modulate individual cancer susceptibility. To determine the association of the p53 Arg72Pro polymorphism with the risk of hepatocellular carcinoma (HCC) development in a Turkish population, a hospital-based case-control study was designed consisting of 119 subjects with HCC and 119 cancer-free control subjects matched for age, gender, smoking and alcohol status. The genotype frequency of the p53 Arg72Pro polymorphism was determined by using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Our data shows that the Pro/Pro genotype of the p53 Arg72Pro polymorphism is associated with increased risk of HCC development in this Turkish population (OR = 3.20, 95% CI: 1.24-8.22, P = 0.02). Furthermore, according to stratified analysis, a significant association was observed between the homozygote Pro/Pro genotype and HCC risk in the subgroups of male gender (OR = 3.01, 95% CI: 1.14-7.97, P = 0.03) and patients with hepatitis B virus (HBV)-related HCC (OR = 4.04, 95% CI: 1.46-11.15, P = 0.007). Because our results suggest for the first time that the Pro/Pro homozygote of p53 Arg72Pro polymorphism may be a genetic susceptibility factor for HCC (especially in the male gender and HBV-infected patients) in the Turkish population, further independent studies are required to validate our findings in a larger series, as well as in patients of different ethnic origins.

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    • "The significance of all ORs was not altered after excluding these two studies. For the TP53 R72P polymorphism, a sensitivity analysis was also further performed by omitting those two studies by Sumbul et al. [36] and Yu et al. [38] in which the control populations were deviated from HWE, and the significance of all ORs was also not altered. "
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    ABSTRACT: The association between TP53 R72P and/or MDM2 SNP309 polymorphisms and hepatocellular carcinoma (HCC) risk has been widely reported, but results were inconsistent. To clarify the effects of these polymorphisms on HCC risk, an updated meta-analysis of all available studies was conducted. Eligible articles were identified by search of databases including PubMed, Cochrane Library, EMBASE and Chinese Biomedical Literature database (CBM) for the period up to July 2013. Data were extracted by two independent authors and pooled odds ratio (OR) with 95% confidence interval (CI) was calculated. Metaregression and subgroup analyses were performed to identify the source of heterogeneity. Finally, a total of 10 studies including 2,243 cases and 3,615 controls were available for MDM2 SNP309 polymorphism and 14 studies containing 4,855 cases and 6,630 controls were included for TP53 R72P polymorphism. With respect to MDM2 SNP309 polymorphism, significantly increased HCC risk was found in the overall population. In subgroup analysis by ethnicity and hepatitis virus infection status, significantly increased HCC risk was found in Asians, Caucasians, Africans, and HCV positive patients. With respect to TP53 R72P polymorphism, no significant association with HCC risk was observed in the overall and subgroup analyses. In the MDM2 SNP309-TP53 R72P interaction analysis, we found that subjects with MDM2 309TT and TP53 Pro/Pro genotype, MDM2 309 TG and TP53 Arg/Pro genotype, and MDM2 309 GG and TP53 Pro/Pro genotype were associated with significantly increased risk of developing HCC as compared with the reference MDM2 309TT and TP53 Arg/Arg genotype. We concluded that MDM2 SNP309 polymorphism may play an important role in the carcinogenesis of HCC. In addition, our findings further suggest that the combination of MDM2 SNP 309 and TP53 Arg72Pro genotypes confers higher risk to develop HCC. Further large and well-designed studies are needed to confirm this association.
    PLoS ONE 12/2013; 8(12):e82773. DOI:10.1371/journal.pone.0082773 · 3.23 Impact Factor
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    • "In recent years, a lot of studies were conducted to investigate the association between p53 codon 72 polymorphism and HCC susceptibility in humans, but these studies reported conflicting results (Son et al., 2013; Mohana et al., 2013; Ezzikouri et al., 2007; Sumbul et al., 2012; Xu et al., 2011; Yoon et al., 2008; Zhu et al., 2005; Anzola et al., 2003; Yu et al., 1999; Leveri et al., 2004; Di Vuolo et al., 2011; Mah et al., 2011; Yang et al., 2013; Peng et al., 2004; Zhang et al., 2012). Meta-analysis has the advantage of reducing errors by pooling large amount of available data and providing a more precise estimate on cancer susceptibility. "
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    ABSTRACT: Background: Emerging evidence has shown that p53gene participates in human carcinogenesis as tumor suppressors. Polymorphism of p53 gene codon 72 Arg/Pro (rs1042522) may influence the function of p53 protein and then affect the processing of carcinogenesis. It has been suggested that p53 codon 72 Arg/Pro polymorphism is associated with susceptibility to hepatocellular carcinoma (HCC). However, published results are inconsistent and inconclusive. To examine the validity of the association between the polymorphism and HCC risk, we performed this meta-analysis. Methodology/principal findings: We have conducted a search of case-control studies on the associations of p53 codon 72 polymorphism with susceptibility to HCC in PubMed, ScienceDirect, Bio-Med central, Springer-link, EBSCO, Wanfang databases and Chinese National Knowledge Infrastructure (CNKI) databases. A total of 15 studies were identified with 3704 cases and 4559 controls for codon 72 Arg/Pro polymorphism. The result did support a significant genetic association between Pro allele and susceptibility to HCC in all the genetic models. Similarly, subgroup analysis showed significant associations between the Arg/Pro polymorphism and susceptibility to HCC when stratifying by race, gender, source of controls and hepatitis virus infection status. Conclusions/significance: This meta-analysis suggests that p53 codon 72 Arg/Pro polymorphism may be associated with the risk of HCC, especially in subgroup analysis of Asian and Caucasian population, hospital-based population, the female, and the individuals infected with hepatitis virus. However, well-designed studies based on different ethnic groups with larger sample size and more detailed data are needed to confirm these conclusions.
    Tumor Biology 12/2013; 1(4). DOI:10.1007/s13277-013-1483-7 · 3.61 Impact Factor
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    • "M2 SNP309 and codon72 together , the OR was 20 . 78 , suggesting the existence of synergistic effect . A newly published study in Turkish population also observed the positive association between this mutation and cancer risk with an OR of 3 . 20 , moreover , the significant risk can be detected in male group and HBV group in stratified analysis ( Sümbül et al . , 2012 ) . According to the result of the latest analysis which pooled data from eleven individual case - control studies , this polymorphism is associated with excessive risk of liver cancer , and the association is greater among Caucasians than other races ( Lv et al . , 2013 ) . Growing evidence reveals that IL - 6 may play an important rol"
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    ABSTRACT: Primary liver cancer is one of the most common cancers at the global level, accounting for half of all cancers in some undeveloped countries. This disease tends to occur in livers damaged through alcohol abuse, or chronic infection with hepatitis B and C, on a background of cirrhosis. Various cancer-causing substances are associated with primary liver cancer, including certain pesticides and such chemicals as vinyl chloride and arsenic. The strong association between HBV infection and liver cancer is well documented in epidemiological studies. It is generally acknowledged that the virus is involved through long term chronic infection, frequently associated with cirrhosis, suggesting a nonspecific mechanism triggered by the immune response. Chronic inflammation of liver, continuous cell death, abnormal cell growth, would increase the occurrence rate of genetic alterations and risk of disease. However, the statistics indicated that only about one fifth of HBV carries would develop HCC in lifetime, suggesting that individual variation in genome would also influence the susceptibility of HCC. The goal of this review is to highlight present level of knowledge on the role of viral infection and genetic variation in the development of liver cancer.
    Asian Pacific journal of cancer prevention: APJCP 09/2013; 14(9):4953-60. DOI:10.7314/APJCP.2013.14.9.4953 · 2.51 Impact Factor
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