Mechanisms underlying aflatoxin-associated mutagenesis - Implications in carcinogenesis

Area of Science:

• Hepatocellular carcinoma (HCC) research
• Molecular carcinogenesis
• DNA repair mechanisms

Background:

• Chronic aflatoxin B1 (AFB1) exposure and hepatitis B virus (HBV) infection are major risk factors for liver cancer (HCC) in endemic regions.
• Dietary aflatoxins are a significant global environmental risk factor for cancer development, yet molecular mechanisms remain under investigation.

Purpose of the Study:

• To review key discoveries linking chronic inflammation (HBV) and aflatoxin exposure to increased HCC risk.
• To highlight recent findings on AFB1-induced mutagenic signatures, DNA repair, specific DNA polymerases, and genetic susceptibility factors.

Main Methods:

• Review of recent scientific literature on aflatoxin B1 (AFB1) and hepatocellular carcinoma (HCC).
• Analysis of in vitro and in vivo studies detailing mutagenic signatures and DNA repair pathways.
• Investigation of DNA polymerase involvement and human genetic variants in AFB1 carcinogenesis.

Main Results:

• Aflatoxin-induced mutagenesis shows specific sequence context dependencies, consistent across in vitro and in vivo models.
• DNA polymerase zeta (Pol ζ) is identified as the primary enzyme responsible for the characteristic G to T transversion mutation.
• NEIL1-initiated base excision repair is more critical than nucleotide excision repair (NER) for removing the mutagenic AFB1-Fapy-dG adduct.

Conclusions:

• Specific genetic sequence contexts influence susceptibility to aflatoxin-induced mutagenesis.
• DNA polymerase zeta plays a key role in AFB1-induced G to T transversions.
• Inactivating NEIL1 variants may increase HCC risk in populations exposed to aflatoxins, underscoring the importance of base excision repair.