P53 IS NOT MUTATED IN HEPATOCELLULAR CARCINOMAS FROM ALASKA NATIVES

Hepatocellular carcinoma is common among Alaska Natives. The known ris k factor in this population is hepatitis B viral infection; fungal tox ins, including aflatoxin B1, have not been detected in foodstuffs. In this series of 14 patients (including 4 siblings and 2 second cousins) , 3 patients were less than 12 years old at diagnosis of hepatocellula r carcinoma, 8 patients were 13-24 years old, and 3 patients were more than 60 years old. Since p53 mutations occur in 29% of hepatocellular carcinomas worldwide, we tested the tumors for p53 mutations and seru m samples for anti-p53 antibodies. Serum samples from these 14 patient s did not contain detectable levels of anti-p53 antibodies. Loss of he terozygosity within the p53 locus was not detected in any of 9 informa tive cases. Immunohistochemical analysis for p53 protein accumulation was negative in all of 11 tumors. DNA sequence analysis of 12 tumor sa mples showed no evidence of p53 mutation in the highly conserved regio ns included in exons 5-8. These data, combined with one case from a pr evious report, indicate a mutation frequency of 0 of 13, which differs significantly from the worldwide frequency of 29% (CHI2 3.9; P = 0.04 8). These results indicate that liver carcinogenesis among Alaska Nati ves occurs independently of a traditional p53 pathway. The familial cl ustering and early onset in this population strongly suggest an inheri ted genetic predisposition to develop liver cancer. Germline mutations in a tumor suppressor or a cancer susceptibility gene are likely. Fut ure studies of these samples should include investigations of candidat e suppressor or susceptibility genes which map to chromosomal regions commonly deleted in liver cancers.