Abstract
Dietary exposure to aflatoxin B(1) (AFB(1)) is associated with an increased incidence of hepatocellular carcinoma (HCC), especially in populations in which exposure to hepatitis B virus (HBV) is a common occurrence. Most HCC samples from people living where HBV is prevalent have one striking mutational hotspot: a GC-->TA transversion at the third position of codon 249 of the p53 gene. In this review, the chemical reaction of an electrophilic derivative of aflatoxin with specific DNA sequences is examined, along with the types of mutations caused by AFB(1) and the sequence context dependence of those mutations. An attempt is made to assign the source of these mutations to specific chemical forms of AFB(1)-DNA damage. In addition, epidemiological and experimental data are examined regarding the synergistic effects of AFB(1) and HBV on HCC formation and the predominance of one hotspot GC-->TA transversion in the p53 gene of affected individuals.
Highlights
Aflatoxin B1 (AFB1) is a fungal metabolite that contaminates the food supply in certain areas of the world [1]
Despite the structurally varied population of DNA adducts that forms in cells treated with the toxin, the mutational spectrum of the toxin is dominated by one genetic change: the GC→TA
This study demonstrates that AFB1 reacts with 20% of the bases in exons 5–8 of the p53 gene, ~85% of which are guanines that are in several different sequence contexts
Summary
Dietary exposure to aflatoxin B1 (AFB1) is associated with an increased incidence of hepatocellular carcinoma (HCC), especially in populations in which exposure to hepatitis B virus (HBV) is a common occurrence. Most HCC samples from people living where HBV is prevalent have one striking mutational hotspot: a GC→TA transversion at the third position of codon 249 of the p53 gene. The chemical reaction of an electrophilic derivative of aflatoxin with specific DNA sequences is examined, along with the types of mutations caused by AFB1 and the sequence context dependence of those mutations. An attempt is made to assign the source of these mutations to specific chemical forms of AFB1-DNA damage. Epidemiological and experimental data are examined regarding the synergistic effects of AFB1 and HBV on HCC formation and the predominance of one hotspot GC→TA transversion in the p53 gene of affected individuals
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