The aflatoxin B1‐induced imidazole ring‐opened guanine adduct: High mutagenic potential that is minimally affected by sequence context

Abstract

AbstractDietary exposure to aflatoxin B1 (AFB1) is a recognized risk factor for developing hepatocellular carcinoma. The mutational signature of AFB1 is characterized by high‐frequency base substitutions, predominantly G>T transversions, in a limited subset of trinucleotide sequences. The 8,9‐dihydro‐8‐(2,6‐diamino‐4‐oxo‐3,4‐dihydropyrimid‐5‐yl‐formamido)‐9‐hydroxyaflatoxin B1 (AFB1‐FapyGua) has been implicated as the primary DNA lesion responsible for AFB1‐induced mutations. This study evaluated the mutagenic potential of AFB1‐FapyGua in four sequence contexts, including hot‐ and cold‐spot sequences as apparent in the mutational signature. Vectors containing site‐specific AFB1‐FapyGua lesions were replicated in primate cells and the products of replication were isolated and sequenced. Consistent with the role of AFB1‐FapyGua in AFB1‐induced mutagenesis, AFB1‐FapyGua was highly mutagenic in all four sequence contexts, causing G>T transversions and other base substitutions at frequencies of ~80%–90%. These data suggest that the unique mutational signature of AFB1 is not explained by sequence‐dependent fidelity of replication past AFB1‐FapyGua lesions.