DNA repair and genomic instability in tobacco induced malignancies of the lung and upper aerodigestive tract

Molecular epidemiologic studies using biomarkers (TABLE II) of cancer susceptibility provide a means of identifying genetically susceptible individuals or subpopulations at high risk of developing cancer. Currently, interindividual variation in response to exposure to tobacco carcinogens can be measured with several assays. The genotyping of CYP and GST genes facilitates identification of susceptible individuals who may have higher internal exposure to bioactivated carcinogens such as BPDE from tobacco smoking and therefore higher level of DNA adducts. In addition, DNA adduct levels also reflect inherited cellular DRC, as measured by the host-cell reactivation assays, which controls the rate of adduct removal. The ultrasensitive 32P-postlabeling assay can measure DNA adducts formed both in vivo and in vitro to estimate the removal rate. Unrepaired DNA adducts can cause chromosomal aberrations such as chromatid breaks, which can be measured by the mutagen sensitivity assay, and can cause mutation fixations as observed in the p53 gene (161). A recent receptor indicated that BPDE-DNA adducts occur selectively at the p53 mutation hot-spots (162) commonly found in lung cancer (163,164), providing the first direct link between smoking and lung cancer. As a result, loss of function of tumor suppressor genes such as p53, genomic instability (165-166), and abnormal cell cycles eventually lead to carcinogenesis. The head and neck cancer model has many advantages for teasing out the intricacies of genetic susceptibility. The strong association of head and neck cancer with known carcinogens despite its relatively rarity suggests that genetic susceptibility has significant role in its etiology. The physical accessibility of this system, the defined progression of the disease, and the theoretically hypersusceptible head and neck cancer subpopulations all contribute to not only the ease of study but also the permutations and angles of such work. Secondly, the ease of using peripheral body lymphocytes as the biological material for measuring of genetic susceptibility to lung and upper aerodigestive tract cancer has great potential in cancer risk assessment. Although lymphocytes are not the direct target of tobacco carcinogens, the level of DNA adducts in blood mononuclear cells has been shown to correlate with tobacco carcinogen-induced damage in human lung tissue (167), indicating that lymphocytes are a reasonable surrogate tissue. Biomarkers that measure different endpoints can shed light on the underlying mechanisms of carcinogenesis and provide critical information for risk assessment. However, it is unlikely that one marker alone will accurately predict risk. Using a panel of biomarkers will increase the probability of identifying individuals susceptible to tobacco carcinogens. Such biomarkers for cancer susceptibility, once verified in studies with larger samples, will be valuable for refining risk assessment for tobacco-related cancers.

Duke Scholars

Author Qingyi Wei Population Health Sciences