Duplex sequencing of spontaneous and aflatoxin B1-induced mutations in livers of NEIL1-deficient, XPA-deficient and repair proficient mice

Dietary exposure to aflatoxin B1 (AFB1) is a major risk factor for the development of hepatocellular carcinomas (HCCs). AFB1, following metabolic activation in the liver, reacts with guanines to form covalent DNA adducts which induce high frequency G > T transversions and are associated with single base substitution signature 24 (SBS24) in the Catalog of Somatic Mutations in Cancer (COSMIC) database. AFB1 DNA adducts can be repaired through base excision repair (BER) or nucleotide excision repair (NER). Deficiencies in BER due to the absence of Nei-like DNA glycosylase 1 (NEIL1) or NER due to absence of Xeroderma Complementation group A protein (XPA) have been shown to promote induction of HCCs in murine models. The presence of BER and NER deficiencies in populations with known exposure to AFB1-contaminated foods underscore the need to understand the role of these pathways on AFB1-induced mutagenesis and carcinogenesis. In the current study, ultra-low error duplex sequencing was used to characterize mutational profiles in liver DNA of NEIL1-deficient, XPA-deficient and DNA repair proficient 2.5 month old mice following a single neonatal injection of 1 mg/kg AFB1 or with no treatment.