Analysis of Novel DNA Adducts Derived from Acetaldehyde

Alcohol consumption is a known risk factor for esophageal and liver cancers. Recently, it was reported that mutation signatures characterized by T:A to C:G mutations (SBS16), which are suggested to be associated with alcohol intake, are frequently detected in esophageal, liver, and stomach cancers among the Japanese population. However, the scientific evidence linking alcohol consumption to SBS16 remains lacking. Acetaldehyde (AA), a carcinogenic metabolite of alcohol, is considered a key contributor to alcohol-related cancer development. Although the guanine adducts associated with alcohol exposure have been reported as part of its carcinogenic mechanism, an adenine adduct, <i>N</i>⁶-ethyl-deoxyadenosine (<i>N</i>⁶-ethyl-dA), a potential contributor to the SBS16 mutation pattern, was recently identified using a mass spectrometry-based DNA adductome approach. However, the mutagenicity assessment of <i>N</i>⁶-ethyl-dA using primer extension assays and the <i>supF</i> gene mutation test showed that this adenine adduct is not mutagenic. To identify another candidate as a driver adduct for SBS16, a DNA adductome approach was conducted, leading to the identification of a novel adenine adduct, 3-(2'-deoxyribos-1'-yl)-7,9-dimethyl-3,9-dihydro-7<i>H</i>-[1,3,5]oxadiazino[4,3-<i>i</i>]purine (<i>N</i>¹-oxydiethylidene-dA), in which two AA molecules are bound to an adenine base. Moreover, <i>N</i>¹-oxydiethylidene-dA was detected in mouse livers, and its levels increased following ethanol administration, suggesting that alcohol may contribute to SBS16 induction via the formation of <i>N</i>¹-oxydiethylidene-dA.