DNA adduct burden and tobacco carcinogenesis

Abstract

DNA adducts associated with tobacco smoking could provide a marker of biologically effective dose of tobacco carcinogens and improve individual cancer risk prediction. A significant number of clinical and epidemiologic studies have reported associations of increased DNA adduct levels with the occurrence of the prevalent tobacco related cancers including cancer of the lung, head and neck, and bladder. The inducibility of DNA adducts following in vitro treatments using blood lymphocytes also appears to be a risk factor in the development of lung and head and neck cancer. Corroborative evidence pointing to the importance of DNA adducts in tobacco carcinogenesis include numerous studies showing associations of tobacco smoke exposure with the induction of DNA adducts in humans in vivo. Further effort is necessary, however, to more fully characterize the dose -response relationship between smoking and DNA adducts in exposed target and surrogate tissues. The relationship between gene polymorphisms thought to modify tobacco-related cancer risk and DNA adduct levels is complex. Results of some DNA adduct studies (both in vitro and in vivo) appear inconsistent with the epidemiologic findings. This is evident for polymorphisms involving both carcinogen metabolism (e.g. GSTP1) and DNA repair (e.g. XRCC1). Molecular studies of human tumors suggest associations of p53 mutation with DNA adducts and have revealed correlations of DNA adduct levels with somatic alterations (e.g. 3p21 LOH) that are thought to occur at the very earliest stages of tobacco carcinogenesis. More research is needed to assess the relationship between endogenous sources of DNA adducts and tobacco smoke exposure and the relative oncogenic effects of chemically stable versus unstable DNA adducts. Many potentially fruitful new avenues of cancer research are emerging that integrate DNA adduct analyses with assessments of smoking, genetics, diet and ambient air quality. These investigations aim to understand the multifactorial nature of interindividual variability in response to tobacco carcinogens. As these trends continue a variety of innovative study designs and approaches will become important in human populations.

Residential environmental exposures and other characteristics associated with detectable PAH-DNA adducts in peripheral mononuclear cells in a population-based sample of adult females

“…Some studies have reported that an earlier age at initiation of smoking, during adolescence, for example, may lead to physiological changes that increase the likelihood of adduct formation, such that even after they quit smoking, smokers who started at a younger age still have higher levels of adducts in comparison to those who started smoking in later life (Wiencke et al, 1999;Vineis, 2000;Wiencke, 2002). However, our findings do not support this hypothesis.…”

“…Interindividual differences in DNA adduct formation of persons who are exposed to the same external levels suggest that differences in absorption, activation and detoxification mechanisms, DNA repair, cell turnover, cellcycle control, as well as lifestyle or diet can modify individual response to exposure (Harris et al, 1982;Santella, 1999;Wiencke, 2002). Since the formation of PAH-DNA adducts is a function of exposure and genetic predisposition (Gorlewska-Roberts et al, 2002), it may provide a more objective measure of effective human exposure to environmental carcinogens (Wild and Pisani, 1998).…”

Dose effect of smoking on aberrant methylation in non‐small cell lung cancers

“…Cancers arise following an accumulation of genetic and epigenetic alterations, including point mutations of genes such as p53 1,2 and Ras, chromosomal deletions 3 and methylation of multiple genes; 4,5 and many of these changes occur in tobacco-related lung cancers. In addition, tobacco smoking is associated with a dose-response increase in p53 mutations.…”

“…In addition, tobacco smoking is associated with a dose-response increase in p53 mutations. 3 We previously demonstrated that the aberrant methylation status of p16, RASSF1A, APC, RAR␤ and CDH13 genes in lung cancer is related to smoke exposure and histologic type but not to gender. 6 Here, we report the results of further examination for methylation status in 383 Japanese non-small cell lung cancer (NSCLC) cases.…”

Mass Spectrometric Mapping of the DNA Adductome as a Means to Study Genotoxin Exposure, Metabolism, and Effect

“…smoking, alcohol, certain industrial occupations and living conditions. [20][21][22] The direct measurement of genotoxic chemicals in body tissues and fluids does not take into account important factors such as interindividual differences in exposure, absorption and distribution.…”