AN AFLATOXIN-ASSOCIATED MUTATIONAL HOTSPOT AT CODON-249 IN THE P53 TUMOR-SUPPRESSOR GENE OCCURS IN HEPATOCELLULAR CARCINOMAS FROM MEXICO

The p53 tumor suppressor gene is commonly mutated in human hepatocellu lar carcinoma (HCC), The most frequent mutation in HCC in populations exposed to a high dietary intake of aflatoxin B1 (AFB1) is an AGG(arg) -->AGT(ser) missense mutation in codon 249 of the p53 gene, We analyze d HCCs from Monterrey, Mexico, for the codon 249(ser) hotspot mutation , We also analyzed the serum AFB1-albumin adduct levels of the donors and family members to measure the current AFB1 exposure in this popula tion, Moreover, the presence of hepatitis B and/or C viral infection ( HBV or HCV) was analyzed serologically in the patients. Tumor cells we re microdissected from tissue sections and exon 7 p53 sequences were a mplified by polymerase chain reaction from genomic DNA and sequenced d irectly, The serological tests for anti-p53 antibodies, HBV or HCV wer e done by ELISA, Immunohistochemical analysis of p53 protein was done using a polyclonal rabbit antiserum (CM-1). Eight of 21 cases were pos itive by p53 immunohistochemistry. Of the 16 cases sequenced for exon 7 of p53 three codon 249 AGG(arg)-->AGT(ser) mutations were found, Ser um antibodies recognizing p53 protein were found in one of 18 patients , Positive serology for HBV and/or HCV was found in 12 of 20 cases, Th e serum AFB1-albumin adduct levels in this population ranged from 0.54 to 4.64 pmol aflatoxin/mg albumin, These results indicate that dietar y AFB1 and hepatitis viruses are etiological agents in the molecular p athogenesis of HCC in this geographic region of Mexico.