| Summary: | 碩士 === 中山醫學大學 === 牙醫學系碩士班 === 102 === Both genetic and environmental factors contribute to the development of oral cancers. Approximately 90% of oral cancers are squamous cell carcinomas. Major risk factors include the use of tobacco products, betel nut chewing, and alcohol consumption.1–3 Tobacco smoke components include polycyclic aromatic hydrocarbons (PAHs), aromatic amines, and N-nitrosamines, all of which are potent carcinogens.4
It has been shown that the increased level of tobacco-related carcinogen DNA adducts is a risk factor for smoking related oral cancer development.5–7 Benzo[a]pyrene (BaP) is an important carcinogen in cigarette smoke. BaP is made up of polycyclic aromatic hydrocarbons (PAHs) and has been found to cause p53 mutations and then tumorigenesis. BaP 7,8-diol 9,10-epoxide (BPDE) is an ultimate metabolite of BaP, which attacks deoxyguanosine to form a BPDE-N2–dG adduct which results in p53 mutations. The mutation hotspots of p53 in human lung tumours (codons 154, 157, 158, 245, 248, and 273) are caused by the BPDE-N2–dG adduct.8 Thus, an evaluation of DNA adducts induced by BaP and other PAHs is a suitable marker for cancer risk. BaP is oxidized by a series of well-characterized enzymes such as cytochrome p450 1A1, 2C9, and 3A4.9,10 A thymine/cytosine point mutation in the MspI restriction site of CYP1A1 has been reported to result in increased enzyme activity.11 The CYP1A1 MspI polymorphism has been linked to susceptibility for smoking-related cancers, such as oral, colon, breast, and lung cancers.12–14 Not only cytochrome P450 but other enzymes, such as glutathione s-transferase M1 (GSTM1) have been shown to be involved in BaP metabolism.15–17 GSTM1 has also been shown to be polymorphic. A deletion is responsible for the existence of a null allele associated with the lack of expression of a functional protein.18,19 The polymorphic GSTM1 null genotype has been found in 20–50% of populations of various ethnic origins, and this genotype has been correlated with the risk for various tobacco-related cancers.20–23 Therefore, the genetic polymorphisms of the CYP1A1 and GSTM1 genes may contribute to BPDE-like DNA adduct formation in oral cancer.
In this study, we examined the BPDE–DNA adduct levels in oral tissue from oral cancer patients and non-cancer controls using ELISA and immunohistochemistry. This study was done to understand the role of BPDE–DNA adducts in oral cancer and to determine whether BaP is the major contributor in DNA damage from cigarette exposure. The CYP1A1 and GSTM1 polymorphisms were also analysed to verify the effects of the genotype of both genes on the formation of DNA adducts in oral tissue.
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