Frequent Detection of Abasic Sites and O6-Methyl-2′-Deoxyguanosine and Absence of Substituted Aromatic DNA Adducts in Colorectal Tissue of Smokers and Meat-Eaters with Colorectal Cancer

Colorectal cancer (CRC) is a leading cause of cancer mortality worldwide. Epidemiological studies have linked the consumption of processed and cooked red meat, as well as tobacco smoking, to increased CRC risk. Processed meats cured with nitrite contain genotoxic N-nitroso compounds (NOCs), and the consumption of both processed and unprocessed red meats can lead to endogenous NOC formation. High-temperature cooking of processed and unprocessed red meats produces genotoxic heterocyclic aromatic amines (HAAs) and polycyclic aromatic hydrocarbons (PAHs), many of which also arise in tobacco smoke. These chemicals form pro-mutagenic DNA adducts, some of which destabilize glycosidic bonds, leading to apurinic/apyrimidinic (AP) abasic sites that are potentially mutagenic and cytotoxic if unrepaired. These DNA lesions may contribute to CRC development; however, the chemicals responsible for the damage and the DNA adduct structures that lead to mutations in the colorectum remain uncertain. We applied nanoflow liquid chromatography-Orbitrap mass spectrometry to profile DNA adducts in nontumorous colorectal tissue of CRC patients. AP sites and the NOC-related DNA adduct O⁶-methyl-2′-deoxyguanosine (O⁶-MedG) were frequently detected. AP sites, but not O⁶-MedG, were significantly elevated in current smokers compared to former and never smokers. In contrast, the NOC related O⁶-carboxymethyl-2′-deoxyguanosine (O⁶-CMedG) adduct, and DNA adducts associated with high-temperature meat cooking, including several common HAAs and benzo[a]pyrene, were not detected in colorectal tissue of current, former, or never smokers, nor among meat-eaters. The frequent detection of AP sites and their co-occurrence with O⁶-MedG demonstrates that alkylating agents contribute to colorectal DNA damage and may play an important role in CRC risk.