Polymorphisms in Turkish population

Department of Toxicology, University of Gazi, Pharmacy Faculty, Ankara, Turkey. neslihan@gazi.edu.tr

Increased exposure to environmental carcinogens, including several aromatic and heterocyclic amines (HAs), is suspected to be one factor contributing to incidence of breast cancer. The N-acetyltransferase 2 (NAT2) acetylation polymorphism have been associated with a number of drug-induced toxicities and cancer in various tissues, resulting from decreased capacity to activate/deactivate several aromatic amine, hydrazine drugs, as well as HA carcinogens. Ethnic differences exist in NAT2 genotype frequencies, which maybe a factor in cancer incidence. Our present case-control study in Turkey was performed to explore the association between NAT2 genetic polymorphism and individual susceptibility to breast cancer. The NAT2 genotypes (*4, *12A, *5A, *5B, *5C, *6, *7) were determined using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay in 84 breast cancer patients and 103 healthy controls, and 50% and 56.3%, respectively, were found to be slow acetylator genotypes. There was no significant difference in risk for breast cancer development among patients with rapid and slow acetylators, with adjusted odds ratio 0.78 (95% confidence interval 0.44 to 1.38). Also, risk was not affected by different variables. To our knowledge, this is the first genetic study on the association of NAT2 genotypes with breast cancer in the TUrkish population, and this finding showed that NAT2 polymorphism does not play an important role in breast cancer risk of Turkish women by altering the capacity in deactivation of environmental carcinogens, even though small sample size and wide confidence interval.

Department of Toxicology, University of Gazi, Pharmacy Faculty, Ankara, Turkey. neslihan@gazi.edu.tr

BACKGROUND: Polymorphisms which are inherited alterations in the activity of cytochrome P450 1B1 (CYP1B1), catechol O-methyltransferase (COMT), manganese superoxide dismutase (MnSOD) hold the potential to define differences in estrogen metabolism and, thereby, possibly explain inter-individual differences in cancer susceptibility associated with estrogen-mediated carcinogenesis. METHODS: The CYP1B1 (L432V), COMT (V158M), MnSOD (Ala-9Val) genotypes, to examine estrogen metabolism and the influence of age of menarche/menopause, were determined by using different polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP) based on genotyping assays. RESULTS: Women who carried CYP1B1 *3 and COMT-L alleles had an earlier age at menarche than the women who carried wild alleles (chi2 = 4.57, p = 0.032), whereas I did not observe any correlation in women with all mutant alleles. Also, CYP1B1 *3 and COMT-H genotypes were common among postmenopausal women with a body mass index (BMI) > 27 kg/m2 (Fisher exact test, p = 0.044). CONCLUSIONS: To my knowledge, this is the first genetic study on the association of these genes with susceptibility in Turkish women. Although the small sample size of each combination of estrogen metabolizing, results suggest that the CYP1B1 *3 and COMT-L alleles influence age at menarche in healthy Turkish women.

Department of Toxicology, Pharmacy Faculty, Gazi University, 06330 Hipodrom, Ankara, Turkey. neslihanak@hotmail.com

Epidemiological studies indicate that most risk factors for breast cancer are related to reproductive and hormonal factors. Estrogen has been proposed to trigger breast cancer development via an initiating mechanism involving its metabolite, catechol estrogen (CE). Because of the important role of cytochrome P450 1B1 ( CYP1B1) and catechol O-methyltransferase ( COMT) in mammary estrogen and carcinogen metabolism, we examined the CYP1B1 and COMT genes to determine whether genetic variations could account for inter-individual differences in breast cancer. In this case-control study, we determined CYP1B1 and COMT genotypes in 84 breast cancer patients and 103 healthy unrelated women controls from a Turkish population. In the case of CYP1B1, we genotyped CYP1B1*3 (L432 V) allele. We found that carriers of the CYP1B1*3 allele were more frequent among breast cancer patients with adjusted odds ratio (OR) for age, age at menarche, age at first full-term pregnancy, body mass index (BMI) and smoking status of 2.32 (95% confidence interval 1.26-4.25) associated with the allele. However, this allele appeared to be a significant factor for susceptibility only in patients with a BMI greater than 24 kg/m(2). Menopausal status did not appear to affect susceptibility. In the case of COMT, there was no significant difference in susceptibility for breast cancer development between patients with low activity COMT-L (V158 M) allele and high activity COMT-H allele, and susceptibility was not affected by menopausal status, BMI or CYP1B1 genotype. We conclude that the CYP1B1* 3 allele appears to be a factor for susceptibility to breast cancer in Turkish women especially those with a BMI greater than 24 kg/m(2).