Genetic cancer susceptibility and DNA adducts: Studies in smokers, tobaccochewers, and coke oven workers

Preventive strategies require identification of cancer-susceptible individu als resulting from combinations of carcinogen exposure, cancer-predisposing genes, and lack of protective factors. To this aim, related to tobacco smo king and chewing (betel quid), we measured PAH-DNA adducts as exposure and susceptibility markers together with genetic polymorphism in drug-metaboliz ing enzymes related to CYP1A1, GSTM1, and GSTT1 genes in case-control studi es. (+)-anti-Benzo(a)pyrene diol-epoxide (BPDE)-DNA adduct levels were quan titated in white blood cells (WBCs) and lung tissue DNA. CYP1A1 polymorphis m and GSTM1 or GSTT1 gene deletion was analyzed in genomic DNA from hmg par enchyma, 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 combina tions with BPDE-DNA adduct levels. Smokers with homozygous CYP1A1 variant a nd 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 GST M1 null and GSTT1 null genotypes was significantly higher, as compared to h ealthy controls. The combined GST null genotypes prevailed in 60% of the ca ses with none detected in controls. Based on this short review we conclude that (i) BPDE-DNA adduct levels resulting from "at risk" genotype combinati ons may serve as markers to identify most susceptible individuals; (ii) in Indian betel quid/tobacco chewers, the null genotypes of GSTM1 and GSTT1 gr eatly increased the risk for developing oral leukoplakia.