Abstract
Simple SummaryAlcohol consumption is linked to 26.4% of all lip and oral cavity cancer cases worldwide. Despite this clear causal relationship, the exact molecular mechanisms by which ethanol damages cells are still under investigation. It is well-established that the metabolism of ethanol plays an important role. Ethanol metabolism yields reactive metabolites that can directly damage the DNA. If the damage is repaired incorrectly, mutations can be fixed in the DNA sequence. Whenever mutations affect key regulatory genes, for instance cell cycle regulating genes, uncontrolled cell growth can be the consequence. Recently, global patterns of mutations have been identified. These so-called mutational signatures represent a fingerprint of the different mutational processes over time. Interestingly, there were ethanol-related signatures discovered that did not associate with ethanol metabolism. This finding highlights there might be other molecular effects of ethanol that are yet to be discovered.Alcohol consumption is an underestimated risk factor for the development of precancerous lesions in the oral cavity. Although alcohol is a well-accepted recreational drug, 26.4% of all lip and oral cavity cancers worldwide are related to heavy drinking. Molecular mechanisms underlying this carcinogenic effect of ethanol are still under investigation. An important damaging effect comes from the first metabolite of ethanol, being acetaldehyde. Concentrations of acetaldehyde detected in the oral cavity are relatively high due to the metabolization of ethanol by oral microbes. Acetaldehyde can directly damage the DNA by the formation of mutagenic DNA adducts and interstrand crosslinks. Additionally, ethanol is known to affect epigenetic methylation and acetylation patterns, which are important regulators of gene expression. Ethanol-induced hypomethylation can activate the expression of oncogenes which subsequently can result in malignant transformation. The recent identification of ethanol-related mutational signatures emphasizes the role of acetaldehyde in alcohol-associated carcinogenesis. However, not all signatures associated with alcohol intake also relate to acetaldehyde. This finding highlights that there might be other effects of ethanol yet to be discovered.
Highlights
Heavy alcohol consumption negatively impacts human health
In 2016, the World Health Organization (WHO) estimated that 3 million deaths worldwide were attributable to alcohol consumption [7,8]
It should be noted that this association is dependent on geographical location, as not all studies conducted in Europa and North-America found a significant association between smokeless tobacco and increased risk of oral tumors [27,28]
Summary
Oral cancers are a defined subset of head and neck cancers These include cancers of the tongue, the floor of the mouth, cheeks, palate, lips, or gums but exclude cancers of the pharynx and larynx, corresponding to the International Classification of Diseases, 10th revision codes C00-C06 [14]. Established risk factors for developing oral malignancies include tobacco smoking or chewing, heavy alcohol drinking, and human papillomavirus (HPV) infection [18]. Tobacco is an undeniable risk factor for several cancer types, including oral cancers. Epidemiological studies associate both smoked and smokeless tobacco with the formation of tumors in the oral cavity [24,25,26,27,28]. HPV positivity is associated with a better prognosis [39,41]
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