| Background and ObjectiveHepatocellular carcinoma (HCC) is one of the most frequently occurring malignant tumors in the world, with an estimation of 1 million new patients per year worldwide. In mainland China, the mortality rate of HCC was 337 for men and 123 for women (per million people) and both ranked top in the world. Early detection and resection is the key to successful treatment for HCC because the mortality rate is high. Screening of high-risk population is therefore very important to decrease the mortality and increase the survival rate.Traditionally epidemiological studies show that infection with HBV and HCV, AFB1 exposure, cigarette smoking, and alcohol drinking are major risk factors. On the other hand, genetic factors are believed to play a key role in cancer susceptibility.Single nucleotide polymorphism (SNP) is one of the most common types of DNA sequence variations, taking the form of substitutions at a single base pair. In addion to being responsible for phenotypic variation, this minor variation among individuals can also promote susceptibility to disease. When a large number of disease carrying patients and unrelated groups of individuals are analyzed for allelicassociations, a particular allele may occur more frequently in patients than the normal control. To clarify the etiological effect of six SNPs on HCC, including p53 Arg72Pro, M6P/IGF2R Asn2020Ser, MTHFR C677T, CCND1 A870G, E-cadherin C-160A and hOGGl Ser326Cys, a large sample size of over 500 cases-controls pairs is included in this study.Materials and methodsFive hundred and twelve cases of HCC and 543 controls were recruited from February 1999 to May 2003 from the Eastern Hepatobiliary Surgery Hospital, Shanghai, China. The genotypes of p53 Arg72Pro, M6P/IGF2R Asn2020Ser, MTHFR C677T, CCND1 A870G, E-cadherin C-160A, and hOGGl Ser326Cys were determined by a PCR based RFLP method.Odds radios (ORs) for HCC and 95% confidence intervals (CIs) from unconditional logistic regression models were used to evaluate relative risks. In the multivariate analyses, potential risk factors were included in the logistic regression models as covariates. A p value of < 0.05 was considered significant. All above analyses were performed using SPSS 10.0 software (SPSS, Chicago, IL). Hardy-Weinberg equilibrium tests, allelotype-specific ORs and Armitage's trend tests were performed using website-based software at http://ihg.gsf.de/ihg/snps.html.1. The Pro allele of p53 Arg72Pro was marginally significantly associated with the presence of HCC and had a 1.19-fold increased risk of HCC (95% CI 1.00-1.41, p = 0.053) compared to the Arg allele. Carriers of the Pro, or the "risk allele", had a 1.33-fold increased risk of HCC compared to Arg-only carriers (p = 0.133). The riskfor Pro/Pro genotype was 1.79 (95% CI 1.06-3.01, p = 0.029) times higher than that for Arg/Arg genotype. This large epidemiological study suggests that Pro/Pro 1homozygote of p53 Arg72Pro is potentially one of the genetic risk factors for HCC in Chinese population.To clarify the etiological effect of p53 Arg72Pro on HCC stratified by HBsAg status, we stratified subjects into four categories, HBsAg-negative HCC cases, HBsAg-negative controls, HBsAg-positive cases, and HBsAg-positive controls, and performed genotype-based case-control analyses.When comparing HBsAg-negative HCC cases and HBsAg-negative controls, the Pro allele was significantly associated with the presence of HCC (p = 0.001) and had a higher risk for HCC (OR = 1.57, 95% CI 1.19-2.06) as compared to the Arg allele. Pro-allele carriers had a higher relative risk of HCC compared to Arg-only carriers (adjusted OR = 1.94, 95% CI 1.14-3.31, p = 0.015). Compared to Arg/Arg genotype, Arg/Pro genotype had a 1.67-fold increased risk (95% CI 0.95-2.92, p = 0.075), whereas Pro/Pro genotype had a 3.02-fold increased risk (95% CI 1.50-6.08, p = 0.002) of HCC after adjusted for potential risk factors (Armitage's trend test, p = 0.001). A significantly higher risk of HCC was observed in those with both family history of HCC...
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