Gender difference in DNA adduct levels among nonsmoking lung cancer patients

Abstract

Lung cancer is the leading cause of cancer mortality in Taiwanese women. Cigarette smoking cannot explain the high lung cancer mortality in this population because less than 10% of women in Taiwan are smokers. Therefore, environmental factors other than smoking may play an important role in lung cancer development in female nonsmokers. The purpose of this study was to elucidate the role of environmental carcinogen exposure in lung cancer development in Taiwanese female nonsmokers, based on DNA adduct formation. We collected nontumorous lung tissues resected from 62 nonsmoking lung cancer patients and 20 noncancer controls to investigate whether differences in susceptibility to DNA adduct formation exist between men and women. (32)P-postlabeling and ELISA (enzyme-linked immunosorbent assay) with polyclonal antibody against BPDE (7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene)-DNA adduct were used to evaluate DNA adduct levels in lung tissues of study subjects. Our data showed that the DNA adduct levels of lung cancer patients determined by both assays were significantly higher than those of noncancer controls (P = 0.0001 for (32)P-postlabeling; P = 0.01 for ELISA). Moreover, DNA adduct levels in females were markedly greater than those in males (P = 0.014 for (32)P-postlabeling; P = 0.001 for ELISA). The difference in DNA adduct levels could not be explained by genetic polymorphisms of cytochrome P-4501A1 (CYP1A1) or glutathione S-transferase (GSTM1), as determined by polymerase chain reaction and restriction fragment length polymorphism. These results demonstrate that lung cancer patients have a higher susceptibility to DNA damage than that of noncancer controls. In addition, differences in susceptibility to DNA damage derived from environmental carcinogen exposure were observed between male and female nonsmokers. In conclusion, high susceptibility to DNA damage in females may partially explain the high mortality rate of lung cancer in nonsmoking Taiwanese women.

The Impact of Sex and Smoking Status on the Mutational Spectrum of Epidermal Growth Factor Receptor Gene in Non–small Cell Lung Cancer

“…We divided our cases into four groups based on sex and smoking status: 420 female never-smoker cases, 140 female ever-smoker cases, 130 male never-smoker cases, and 788 male ever-smoker cases. In females, never smokers had 119 mutations in exon 19, 100 in exon 21,8 The EGFR mutation spectrum of the total group, East Asia, and the United States and Australia cases stratified by histologic subtypes are shown in Table 2 and Supplementary Material 1.…”

“…Previous molecular data indicate that cancers arising in women smokers harbored significantly more tobacco-related p53 mutations, G:C to T:A transversions, than those in male smokers (20). Furthermore, DNA adduct levels of benzo(a)pyrene diol epoxide (a tobacco carcinogen) in females with lung cancer were markedly greater than those arising in males, suggesting sex differences in susceptibility to DNA damage derived from environmental carcinogen exposure (21). Of note, there was no specific association between smoking status and the type of point mutation (transversion and transition) in EGFR mainly because that majority of point mutation is G to T transversion at the second letter of codon 858.…”

EGFR exon 19 in‐frame deletion and polymorphisms of DNA repair genes in never‐smoking female lung adenocarcinoma patients

“…Furthermore, it has been shown that females are more susceptible to environmental carcinogens because DNA mutations were more frequently found in never-smoking female than never-smoking male lung cancer patients. 22 Moreover, it has been shown that females have a lower capacity of DNA repair than males, which is suggested to be the result of epigenetic and genetic effects of genes related to metabolic detoxification and DNA repair pathways. 23 Thus, sex-related difference in mutagenesis may be explained by the interplay between genes and the environment.…”

DNA adduct burden and tobacco carcinogenesis

“…Studies of DNA adducts in lung cancer patients have indicated higher adduct levels in lung tissue of cancer cases (Cheng et al, 2000b(Cheng et al, , 2001) and in their peripheral white blood cells (Vulimiri et al, 2000;Perera et al, 1989) compared with controls. Higher adduct levels were reported in lung tissue from women compared with men (Cheng et al, 2001).…”

“…Higher adduct levels were reported in lung tissue from women compared with men (Cheng et al, 2001). In a prospective study, researchers reported that increased adduct levels in white blood cells were associated with lung cancer risk among those who were current smokers at the time of blood sampling (Tang et al, 2001).…”