Genetic cancer susceptibility and DNA adducts: studies in smokers, tobacco chewers, and coke oven workers.
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 lung parenchyma, WBCs, or oral biopsies (leukoplakia patients from India) and from oral exfoliated cells (healthy controls). Results from lung cancer patients and PAH-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.
Bartsch
H
H
Division of Toxicology and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany. h.bartsch@dkfz-heidelberg.de
Rojas
M
M
Nair
U
U
Nair
J
J
Alexandrov
K
K
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000378:metabolism; D014408:Biomarkers, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000235:genetics; D018736:DNA Adducts / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005982:Glutathione Transferase / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D007971:Leukoplakia / Q000235:genetics*; D008175:Lung Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D008297:Male; D016273:Occupational Exposure / Q000009:adverse effects*; D010947:Plants, Toxic; D011084:Polycyclic Aromatic Hydrocarbons / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012189:Retrospective Studies; D012907:Smoking / Q000009:adverse effects*; D014030:Tobacco, Smokeless / Q000009:adverse effects*
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D014408:Biomarkers, Tumor; D019363:Cytochrome P-450 CYP1A1; D018736:DNA Adducts; D004273:DNA, Neoplasm; D005982:Glutathione Transferase; D011084:Polycyclic Aromatic Hydrocarbons; C095911:polycyclic aromatic hydrocarbons-DNA adduct; C413545:glutathione S-transferase T1