Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR 97239, United States; Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, United States.
Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR 97239, United States; Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, United States; Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, OR 97239, United States.
DNA Repair (Amst). 2019 May;77:76-86. doi: 10.1016/j.dnarep.2019.03.004. Epub 2019 Mar 7.
Chronic dietary exposure to aflatoxin B (AFB), concomitant with hepatitis B infection is associated with a significant increased risk for hepatocellular carcinomas (HCCs) in people living in Southeast Asia and sub-Saharan Africa. Human exposures to AFB occur through the consumption of foods that are contaminated with pervasive molds, including Aspergillus flavus. Even though dietary exposures to aflatoxins constitute the second largest global environmental risk factor for cancer development, there are still significant questions concerning the molecular mechanisms driving carcinogenesis and what factors may modulate an individual's risk for HCC. The objective of this review is to summarize key discoveries that established the association of chronic inflammation (most commonly associated with hepatitis B viral (HBV) infection) and environmental exposures to aflatoxin with increased HCC risk. Special emphasis will be given to recent investigations that have: 1) refined the aflatoxin-associated mutagenic signature, 2) expanded the DNA repair mechanisms that limit mutagenesis via adduct removal prior to replication-induced mutagenesis, 3) implicated a specific DNA polymerase in the error-prone bypass and resulting mutagenesis, and 4) identified human polymorphic variants that may modulate individual susceptibility to aflatoxin-induced cancers. Collectively, these investigations revealed that specific sequence contexts are differentially resistant against, or prone to, aflatoxin-induced mutagenesis and that these associations are remarkably similar between in vitro and in vivo analyses. These recent investigations also established DNA polymerase ζ as the major polymerase that confers the G to T transversion signature. Additionally, although the nucleotide excision repair (NER) pathway has been previously shown to repair aflatoxin-induced DNA adducts, recent murine data demonstrated that NEIL1-initiated base excision repair was significantly more important than NER relative to the removal of the highly mutagenic AFB-Fapy-dG adducts. These data suggest that inactivating polymorphic variants of NEIL1 could be a potential driver of HCCs in aflatoxin-exposed populations.
慢性饮食暴露于黄曲霉毒素 B（AFB），同时合并乙型肝炎病毒（HBV）感染，与生活在东南亚和撒哈拉以南非洲的人群罹患肝细胞癌（HCC）的风险显著增加相关。人类通过食用受普遍存在的霉菌（包括黄曲霉）污染的食物而接触 AFB。尽管饮食中接触黄曲霉毒素是癌症发展的全球第二大环境风险因素，但仍有许多关于驱动致癌作用的分子机制以及哪些因素可能调节个体 HCC 风险的重大问题。本综述的目的是总结确定慢性炎症（最常与乙型肝炎病毒感染相关）和环境暴露于黄曲霉毒素与 HCC 风险增加相关的关键发现。特别强调最近的研究进展，这些研究：1）完善了与黄曲霉毒素相关的致突变特征；2）扩展了 DNA 修复机制，通过在复制诱导的致突变之前去除加合物来限制致突变；3）表明特定的 DNA 聚合酶在易错旁路和由此产生的致突变中起作用；4）鉴定了可能调节个体对黄曲霉毒素诱导的癌症易感性的人类多态性变体。总的来说，这些研究表明，特定的序列上下文对黄曲霉毒素诱导的突变具有不同的抗性或易感性，并且这些关联在体外和体内分析中非常相似。这些最近的研究还确定了 DNA 聚合酶 ζ 是赋予 G 到 T 颠换特征的主要聚合酶。此外，尽管核苷酸切除修复（NER）途径已被证明可修复黄曲霉毒素诱导的 DNA 加合物，但最近的鼠类数据表明，相对于 NER 而言，NEIL1 起始的碱基切除修复在去除高度致突变的 AFB-Fapy-dG 加合物方面更为重要。这些数据表明，失活 NEIL1 的多态性变体可能是黄曲霉毒素暴露人群中 HCC 的潜在驱动因素。
