Genetic cancer susceptibility and DNA adducts: Studies in smokers, tobacco chewers, and coke oven workers
Genetic cancer susceptibility and DNA adducts: Studies in smokers, tobacco chewers, and coke oven workers
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DOI：
10.1046/j.1525-1500.1999.99055.x
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发表时间：
1999-01-01
影响因子：
--
通讯作者：
Alexandrov, K
中科院分区：
文献类型：
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作者：
Bartsch, H;Rojas, M;Alexandrov, K
预防策略需要识别致癌物暴露，癌症易感基因和缺乏保护因素的组合导致的癌症易感个体。为了这个目的，与吸烟和咀嚼（槟榔），我们测量多环芳烃-DNA加合物作为暴露和易感性标志物连同遗传多态性的药物代谢酶相关的CYP 1A 1，GSTM 1和GSTT 1基因的病例对照研究。定量测定了白色血细胞（WBC）和肺组织DNA中的（+）-抗苯并（a）芘二醇-环氧化物（BPDE）-DNA加合物水平。在来自hmg实质、WBC或口腔活检（来自印度的白斑病患者）和口腔脱落细胞（健康对照）的基因组DNA中分析CYP 1A 1多态性和GSTM 1或GSTT 1基因缺失。肺癌患者和接触PAM的焦炉工人的结果将CYP 1A 1-GSTM 1基因型组合与BPDE-DNA加合物水平相关。吸烟者与纯合子CYP 1A 1变异体和GSTM 1无效有最高的加合物水平，并在日本吸烟者中显示，最容易患肺癌。与健康对照组相比，咀嚼槟榔/烟草相关的口腔癌前白斑病例中，GSTM 1缺失和GSTT 1缺失基因型的患病率显著较高。合并GST空基因型占60%的情况下，没有检测到对照组。基于这一简短的审查，我们得出结论：（一）BPDE-DNA加合物水平导致的“风险”基因型组合可能作为标记，以确定最易感的个人;（二）在印度槟榔/烟草咀嚼，GSTM 1和GSTT 1的无效基因型大大增加了发展口腔白斑的风险。
Preventive strategies require identification of cancer-susceptible individuals resulting from combinations of carcinogen exposure, cancer-predisposing genes, and lack of protective factors. To this aim, related to tobacco smoking and chewing (betel quid), we measured PAH-DNA adducts as exposure and susceptibility markers together with genetic polymorphism in drug-metabolizing enzymes related to CYP1A1, GSTM1, and GSTT1 genes in case-control studies. (+)-anti-Benzo(a)pyrene diol-epoxide (BPDE)-DNA adduct levels were quantitated in white blood cells (WBCs) and lung tissue DNA. CYP1A1 polymorphism and GSTM1 or GSTT1 gene deletion was analyzed in genomic DNA from hmg parenchyma, WBCs, or oral biopsies (leukoplakia patients from India) and from oral exfoliated cells (healthy controls). Results from lung cancer patients and PAM-exposed coke oven workers correlated CYP1A1-GSTM1 genotype combinations with BPDE-DNA adduct levels. Smokers with homozygous CYP1A1 variant and GSTM1 null had the highest adduct levels and were, as shown in Japanese smokers, most susceptible to lung cancer. In oral premalignant leukoplakia cases associated with betel quid/tobacco chewing, the prevalence of the GSTM1 null and GSTT1 null genotypes was significantly higher, as compared to healthy controls. The combined GST null genotypes prevailed in 60% of the cases with none detected in controls. Based on this short review we conclude that (i) BPDE-DNA adduct levels resulting from "at risk" genotype combinations may serve as markers to identify most susceptible individuals; (ii) in Indian betel quid/tobacco chewers, the null genotypes of GSTM1 and GSTT1 greatly increased the risk for developing oral leukoplakia.