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

Abstract

Dietary 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.

Keywords: COSMIC signature SBS24; base substitution; hepatocellular carcinoma; replication bypass.