A cytochrome P4502E1 genetic polymorphism and tobacco smoking in breast cancer

Abstract

Known breast-cancer risk factors account for only part of the variability in breast-cancer incidence. Tobacco smoke is not commonly considered a breast carcinogen, but many of its constituents, such as N-nitrosamines, are carcinogenic in laboratory animal studies. Herein, we assessed a cytochrome P4502E1 (CYP2E1) genetic polymorphism (a Dral restriction enzyme site in intron 6) as a risk factor for breast cancer in both premenopausal and postmenopausal women. Because N-nitrosamines are metabolically activated by CYP2E1, the risk among women smokers was investigated. Caucasian women were enrolled in a case-control study of breast cancer between 1986 and 1991. A subset of the women (219 premenopausal and 387 postmenopausal women) consented to phlebotomy. The allelic frequencies for the premenopausal women (D allele = 0.91 and C allele = 0.09) and postmenopausal women (D allele = 0.93 and C allele = 0.07) were similar to those previously reported. There was no statistically significant association between the CYP2E1 polymorphism and breast-cancer risk for premenopausal or postmenopausal women (adjusted odds ratio (OR) = 1.04, 95% confidence interval (CI) = 0.48, 2.24, and OR = 1.01, 95% CI = 0.55, 1.84, respectively). When the women were categorized as nonsmokers versus smokers (those who smoked more than one cigarette per week for more than 1 yr), premenopausal women with one or two C alleles who had a history of smoking were found to be at increased risk (unadjusted OR = 7.00, 95% CI = 0.75, 14.53, and adjusted OR = 11.09, 95% CI = 1.51, 81.41), although the number of study subjects with those genotypes was small. The small number of study subjects with a C allele precluded meaningful classification by level of smoking, but categorizing the smokers into two groups (above and below the median) also suggested an increased risk. Premenopausal women with the DD genotype and postmenopausal women with any genotype were not at increased risk. Breast-cancer risk was not related to the CYP2E1 genotype in either premenopausal nonsmokers or smokers (adjusted OR = 0.66, 95% CI = 0.20, 2.17, and OR = 2.13, 95% CI = 0.60, 7.59, respectively) or postmenopausal nonsmokers or smokers (OR = 0.90, 95% CI = 0.34, 2.35, and OR = 1.02, 95% CI = 0.46, 2.23, respectively), although the difference in the ORs for premenopausal nonsmokers and smokers suggests an increased risk for smokers. While there are limitations to this study, particularly related to the small number of subjects with the DC and CC genotypes, the study suggests that some women may be susceptible to tobacco smoke because of a CYP2E1 polymorphism. However, these results are preliminary and must be replicated.

Is the Association between Cigarette Smoking and Breast Cancer Modified by Genotype? A Review of Epidemiologic Studies and Meta-analysis

“…In an early case-control study (272 cases and 334 controls, a subset of a larger study with information on genotype), Shields et al (44) showed smoking increased breast cancer risk among premenopausal but not postmenopausal women with 6CYP2E1 variant (a DraI restriction enzyme site in intron 6). Because CYP2E1 enzyme is involved in the metabolic activation of N-nitrosamines, which are contained in tobacco smoke, it is possible that the polymorphism will modify susceptibility to breast cancer due to smoking.…”

Human Cytochrome P450 2E1 Mutations That Alter Mitochondrial Targeting Efficiency and Susceptibility to Ethanol-induced Toxicity in Cellular Models

“…A large volume of literature correlates CYP2E1 polymorphisms with a multitude of diseases, including ALD, diabetes, and several different cancers (31,33,35,36,38,42,43,80,81). A majority of the genetic screens so far have targeted either the 5Ј-promoter region, which regulates CYP2E1 transcription rates (CYP2E1*5B), or the catalytic domain (CYP2E1*6), which alters the catalytic rates of the enzyme (32).…”

“…Vodicka et al (33) showed that polymorphisms in the 5Ј-flanking region and in the DraI site in intron 6 are significantly correlated with single-strand breaks in DNA. The DraI polymorphism is also correlated with increased risk for lung cancer (33)(34)(35)(36)(37), for breast cancer among premenopausal smokers (38), and for renal carcinoma among Caucasian women (39). The RsaI c2 mutated allele in the 5Ј-flanking region was also associated with adenocarcinoma (40), esophageal cancer in a Chinese population (41), nasopharyngeal carcinoma (42), and oral cancer cases (43).…”

Tobacco or Health?

“…A study of cardiovascular risk factors in 166 cigarette smokers revealed lower serum HDL cholesterol (0.76 vs. 0.81 mmole/l) and higher serum triglycerides (1.92 vs. 1.71 mmole/l) in comparison with values measured in 312 nonsmokers [236]. Higher triglyceride and total cholesterol levels have also been reported in other studies of smokers compared with non-smokers and ex-smokers [237][238][239][240][241][242][243][244][245]. A metaanalysis of data obtained in children and adolescents aged 8-19 years revealed associations between smoking (or non-smoking) status, and blood lipids and cholesterol fractions; the findings were analogous to those obtained in adults [228].…”