Abstract：
Reactive aldehydes, for instance, formaldehyde and acetaldehyde, are important endogenous or environmental mutagens by virtue of their abilities to produce a DNA lesion called interstrand crosslink (ICL). Aldehyde-metabolizing enzymes such as aldehyde dehydrogenases (ALDHs) and the Fanconi anemia (FA) pathway constitute the main defense lines against aldehyde-induced genotoxicity. Biallelic mutations of genes in any one of the FA complementation groups can impair the ICL repair mechanism and cause FA, a heterogeneous disorder manifested by bone marrow failure (BMF), congenital abnormality and a strong predisposition to cancer. The defective ALDH2 polymorphism rs671 (ALDH2*2) is a known risk and prognostic factor for alcohol drinking-associated cancers. Recent studies suggest that it also promotes BMF and cancer development in FA, and its combination with alcohol dehydrogenase 5 (ADH5) mutations causes aldehyde degradation deficiency syndrome (ADDS), also known by its symptoms as aplastic anemia, mental retardation, and dwarfism syndrome. ALDH2*2 and another pathogenic variant in the alcohol-metabolizing pathway, ADH1B1*1, is prevalent among East Asians. Also, other ALDH2 genotypes with disease-modifying potentials have lately been identified in different populations. Therefore, it would be appropriate to summarize current knowledge of genotoxic aldehydes and defense mechanisms against them to shed new light on the pathogenic effects of ALDH2 variants together with other genetic and environmental modifiers on cancer and inherited BMF syndromes. Lastly, we also presented potential treatment strategies for FA, ADDS and cancer based on the manipulation of aldehyde-induced genotoxicity.
摘要：
反应性醛，例如,甲醛和乙醛，是重要的内源性或环境诱变剂，因为它们能够产生称为链间交联（ICL）的DNA损伤。醛代谢酶如醛脱氢酶(ALDHs)和范可尼贫血(FA)途径构成对抗醛诱导的遗传毒性的主要防御线。任何一个FA互补组中基因的双等位基因突变都会损害ICL修复机制并导致FA,表现为骨髓衰竭（BMF）的异质性疾病，先天性异常和强烈的癌症倾向。缺陷型ALDH2多态性rs671（ALDH2*2）是饮酒相关癌症的已知风险和预后因素。最近的研究表明，它还可以促进FA中的BMF和癌症的发展，其与乙醇脱氢酶5（ADH5）突变的组合导致醛降解缺乏症（ADDS），其症状也被称为再生障碍性贫血，智力迟钝,和侏儒症.ALDH2*2和酒精代谢途径中的另一种致病变体，ADH1B1*1，在东亚人中普遍存在。此外，最近在不同人群中发现了其他具有疾病改善潜能的ALDH2基因型。因此,总结目前有关基因毒性醛及其防御机制的知识是适当的，以阐明ALDH2变体以及其他遗传和环境调节剂对癌症和遗传性BMF综合征的致病作用。最后,我们还提出了FA的潜在治疗策略，基于醛诱导的遗传毒性操纵的ADDS和癌症。
