title: An aflatoxin-associated mutational hotspot at codon 249 in the p53 tumor suppressor gene occurs in hepatocellular carcinomas from Mexico.
abstract: The p53 tumor suppressor gene is commonly mutated in human hepatocellular carcinoma (HCC). The most frequent mutation in HCC in populations exposed to a high dietary intake of aflatoxin B1 (AFB1) is an AGGarg-->AGTser missense mutation in codon 249 of the p53 gene. We analyzed HCCs from Monterrey, Mexico, for the codon 249ser 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 population. Moreover, the presence of hepatitis B and/or C viral infection (HBV or HCV) was analyzed serologically in the patients. Tumor cells were microdissected from tissue sections and exon 7 p53 sequences were amplified by polymerase chain reaction from genomic DNA and sequenced directly. The serological tests for anti-p53 antibodies, HBV or HCV were done by ELISA. Immunohistochemical analysis of p53 protein was done using a polyclonal rabbit antiserum (CM-1). Eight of 21 cases were positive by p53 immunohistochemistry. Of the 16 cases sequenced for exon 7 of p53 three codon 249 AGGarg-->AGTser mutations were found. Serum 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. The serum AFB1-albumin adduct levels in this population ranged from 0.54 to 4.64 pmol aflatoxin/mg albumin. These results indicate that dietary AFB1 and hepatitis viruses are etiological agents in the molecular pathogenesis of HCC in this geographic region of Mexico.
authors.affiliation: Laboratory of Human Carcinogenesis, National Cancer Institute, NIH, Bethesda, MD 20892-4255, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Soini
authors.forename: S C
authors.initials: SC
authors.lastname: Chia
authors.forename: W P
authors.initials: WP
authors.lastname: Bennett
authors.forename: J D
authors.initials: JD
authors.lastname: Groopman
authors.forename: J S
authors.initials: JS
authors.lastname: Wang
authors.forename: V M
authors.initials: VM
authors.lastname: DeBenedetti
authors.forename: H
authors.initials: H
authors.lastname: Cawley
authors.forename: J A
authors.initials: JA
authors.lastname: Welsh
authors.forename: C
authors.initials: C
authors.lastname: Hansen
authors.forename: N V
authors.initials: NV
authors.lastname: Bergasa
authors.forename: E A
authors.initials: EA
authors.lastname: Jones
authors.forename: A M
authors.initials: AM
authors.lastname: DiBisceglie
authors.forename: G E
authors.initials: GE
authors.lastname: Trivers
authors.forename: C A
authors.initials: CA
authors.lastname: Sandoval
authors.forename: I E
authors.initials: IE
authors.lastname: Calderon
authors.forename: L E
authors.initials: LE
authors.lastname: Munoz Espinosa
authors.forename: C C
authors.initials: CC
authors.lastname: Harris
mesh_terms: D000328:Adult; D016604:Aflatoxin B1 / Q000378:metabolism / Q000633:toxicity*; D000368:Aged; D000818:Animals; D001483:Base Sequence; D002273:Carcinogens / Q000633:toxicity*; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000235:genetics; D003062:Codon; D005260:Female; D016158:Genes, p53; D006509:Hepatitis B / Q000150:complications; D006526:Hepatitis C / Q000150:complications; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D011817:Rabbits; D012709:Serum Albumin / Q000378:metabolism
chemical_list: D002273:Carcinogens; D003062:Codon; D012709:Serum Albumin; D016604:Aflatoxin B1