Etiological Dissection, Genetic Marker Demonstration And Its Clinical Implications In Hepatocellular Carcinoma Of High Incidence Area

Background: Hepatitis B and C viruses (HBV and HCV) and aflatoxins are known risk factors for hepatocellular carcinoma (HCC). We assessed the absolute importance of each factor and their combined effect in causing HCC in area of prevalence, analyzed the causal association of the 249 codon mutated p53 (249ser-p53) with aflatoxin and HBV co-exposure, as well as explored the functional change of the mutated p53 gene in immuno-therapeutic perspective.Methods: A consecutive series of 181 pathologically diagnosed HCC cases in Qidong were studied for the presence of viral markers: HBsAg, anti-HBc, HBV X gene sequence, and anti-HCV by using updated techniques as well as for the presence of pathological features of chronic hepatitis. The 249 codon arg/ser mutation of p53 gene (249ser-p53) was detected by Haelll digestion profile following PCR of HCC DNA, and confirmed by sequencing. The 249ser-p53 mutation was also analyzed in 7 HCC cases incurring in a cohort of 78 men with chronic HBV hepatitis and detectable aflatoxin exposure. They were matched in 6 to 1 ratio with 42 Beijing counterparts from a pool of 190 male HCC for statistical comparison. Serological data of 287 Qidong men and 181 male factory workers in Beijing were also used. The age specific incidence data were obtained from published reports.The function of 249ser-p53 was assessed by transduction of 249ser-p53 constructed in pRetro-on vector into p53 functionally null Hep3B cell line using wild type p53 as control. The loss of apoptotic function and its mechanistic aspects were assessed following induction with doxycycline. The immuno-therapeutic potential of the 249arg/ser mutated p53 was explored in human...