Dietary exposure to aflatoxin B1 (AFB1) is a risk factor for the development of hepatocellular carcinomas. Following metabolic activation, AFB1 reacts with guanines to form covalent DNA adducts, which induce high-frequency G > T transversions. The molecular signature associated with these mutational events aligns with the single-base substitution signature 24 (SBS24) in the Catalog of Somatic Mutations in Cancer database. Deficiencies in either base excision repair due to the absence of Nei-like DNA glycosylase 1 (NEIL1) or nucleotide excision repair due to the absence of xeroderma complementation group A protein (XPA) contribute to hepatocellular carcinomas in murine models. In the current study, ultra-low error duplex sequencing was used to characterize mutational profiles in liver DNAs of NEIL1-deficient, XPA-deficient, and DNA repair-proficient mice following neonatal injection of 1 mg/kg AFB1. Analyses of AFB1-induced mutations showed high cosine similarity to SBS24 regardless of repair proficiency status. The absence of NEIL1 resulted in an approximately 30% increase in the frequency of mutations, with the distribution suggesting preferential NEIL1-dependent repair of AFB1 lesions in open chromatin regions. A trend of increased mutagenesis was also observed in the absence of XPA. Consistent with the role of XPA in transcription-coupled repair, mutational profiles in XPA-deficient mice showed disruption of the transcriptional bias in mutations associated with SBS24. Implications: Our findings define the roles of DNA repair pathways in AFB1-induced mutagenesis and carcinogenesis in murine models, with these findings having implications in human health for those with base excision repair and nucleotide excision repair deficiencies.
©2024 American Association for Cancer Research.