The Association of Ala133Ser Polymorphism and Methylation in Ras Association Domain Family 1A Gene With Unfavorable Prognosis of Hepatocellular Carcinoma

The functional and prognostic significance of Ras association domain family 1A gene (RASSF1A) on hepatocellular carcinoma (HCC) has not been well characterized. This study aimed to investigate the association between Ala133Ser polymorphism or promoter methylation in RASSF1A and the prognosis of HCC in Nantong City, one of the areas with the highest incidence of cancer in China. Using peripheral blood plasma, the incidence rate of RASSF1A Ala133Ser in 235 controls and subjects with 260 HCC was analyzed by the polymerase chain reaction and sequencing. We further investigated the RASSF1A methylation status in HCC and corresponding peri-tumorous normal tissues using the methylation-specific polymerase chain reaction approach. It was found that the frequency of the RASSF1A Ala133Ser T allele (Ala/Ser and Ser/Ser) genotype in HCC cases was observably higher than that of normal subjects (P < 0.001). In comparison to the Ala/Ala genotype, the T allele genotype improved the susceptibility to HCC. The study also found that RASSF1A methylation improves the risk of HCC. Furthermore, in contrast with the corresponding peri-tumorous normal tissues, we observed that the RASSF1A methylation status was markedly higher in HCC tissues (P < 0.001). The Kaplan-Meier and multivariate analyses suggested that the poor survival of HCC patients was closely connected with hepatocirrhosis, Barcelona Clinic Liver Cancer stage, Edmondson division, RASSF1A methylation and Ala133Ser polymorphism (P < 0.001). The polymorphism and promoter methylation of RASSF1A may be a significant factor in HCC, and can be an indicator for poor prognosis in patients with HCC.