Wiencke John K
Laboratory for Molecular Epidemiology, Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, CA 94143-0560, USA.
Oncogene. 2002 Oct 21;21(48):7376-91. doi: 10.1038/sj.onc.1205799.
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.
与吸烟相关的DNA加合物可作为烟草致癌物生物有效剂量的标志物，并改善个体癌症风险预测。大量临床和流行病学研究报告称，DNA加合物水平升高与包括肺癌、头颈癌和膀胱癌在内的常见烟草相关癌症的发生有关。使用血液淋巴细胞进行体外处理后DNA加合物的诱导性似乎也是肺癌和头颈癌发生的一个风险因素。指向DNA加合物在烟草致癌过程中重要性的佐证包括众多研究表明，烟草烟雾暴露与人体体内DNA加合物的诱导之间存在关联。然而，有必要进一步努力，以更全面地表征暴露的靶组织和替代组织中吸烟与DNA加合物之间的剂量反应关系。被认为会改变烟草相关癌症风险的基因多态性与DNA加合物水平之间的关系很复杂。一些DNA加合物研究（包括体外和体内研究）的结果似乎与流行病学研究结果不一致。这在涉及致癌物代谢（如GSTP1）和DNA修复（如XRCC1）的多态性中很明显。对人类肿瘤的分子研究表明p53突变与DNA加合物有关，并揭示了DNA加合物水平与体细胞改变（如3p21杂合性缺失）之间的相关性，这些改变被认为发生在烟草致癌的最早阶段。需要更多研究来评估内源性DNA加合物来源与烟草烟雾暴露之间的关系，以及化学稳定与不稳定DNA加合物的相对致癌作用。许多潜在富有成果的癌症研究新途径正在出现，这些途径将DNA加合物分析与吸烟、遗传学、饮食和环境空气质量评估相结合。这些研究旨在了解个体对烟草致癌物反应中个体差异的多因素性质。随着这些趋势的持续，各种创新的研究设计和方法在人群中将变得很重要。
