Combined effect of CYP1B1 codon 432 polymorphism and N-acetyltransferase 2 slow acetylator phenotypes in relation to breast cancer in the Turkish population.

BACKGROUND: Breast cancer (BC), is more prevalent in subjects who have had prolonged exposure to heterocyclic amines, aromatic amines and high levels of oestradiol. Cytochrome P450 1B1 (CYP1B1) and N-acetyltransferase2 (NAT2) have complementary role in metabolism of xenobiotics such as arylamines and heterocyclic amines, CYP1B1 also hyroxylates 17-beta oestradiol. CYP1B1*3 polymorphism and seven missense and four silent polymorphisms of NAT2 were investigated. PATIENTS AND METHODS: Sixty Turkish female BC patients and 103 healthy controls were phenotyped by polymerase chain reaction (PCR) based restriction fragment length polymorphism (RFLP). RESULTS AND CONCLUSION: The distribution of NAT2 activity in the healthy control group was found to be correlated with that of healthy caucasians. Patients had slow acetylator phenotypes of NAT2, 1.8 times higher than controls but no statistical differences were found (p=0.07). In addition, the NAT2*5 alelle was more statistically correlated with breast cancer patients rather than the controls (p=0.02). Moreover, NAT2*5B was the most frequent haplotype of the NAT2*5 family (p=0.000). Breast cancer patients were detected to posses more CYP1B1*3 mutant alleles than the controls (p=0.043). The combined effect of CYP1B1*3 polymorphism and NAT2 slow acetylator genotype contributed to an increased risk for breast cancer in patients in this study (p=0.004).

CYP17 (T-34C) and CYP19 (Trp39Arg) polymorphisms and their cooperative effects on breast cancer susceptibility.

BACKGROUND: Breast cancer is the commonest cancer among women in industrialized countries. Most sporadic breast carcinomas are likely to be caused by low-penetrance genes. Genes encoding enzymes involved in estrogen and carcinogen metabolism are among these low-penetrance genes. In this study, for the first time the T/C (A1/A2) polymorphism at the 5' untranslated region (UTR) of CYP17 and the Arg/Trp (T/C) polymorphism at codon 39 of CYP19 among genes regulating endogenous estrogen levels was studied. PATIENTS AND METHODS: Fifty-five female breast cancer patients and ninety-one controls took part in the study. DNA was extracted from paraffin-embedded tissues for the patients and from blood cells for the controls. The distribution of genotypes was determined using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) techniques. RESULTS: The frequency of the TC genotype of CYP19 was significantly higher in the patient group (p<0.001, kappa(2): 12.31, OR: 7.30, 95% CI: 2.29-25.64). CYP17 frequencies were similar to those in Caucasian populations. In combined analysis, when the high risk alleles were evaluated together, the results reached significance (p=0.006, kappa(2)=7.01, OR: 2.53, %95 CI: 1.26-5.07) for the A2 allele of CYP17 and the C allele of CYP19, being more frequent in the patient group compared to the control. The risk possesed by the TC varient of CYP19 was reduced when evaluated with A1, the protective allele of CYP17 (p=0.082). The cumulative protective effects of both A1 allele and the TT genotype were ascertained to occur significantly less frequently in the patient group (p=0.001, kappa(2): 10.53, OR: 8.47, %95 CI: 1.9-37.04). CONCLUSION: The results were consistent with the individual studies of CYP17 and CYP19 in the literature, however, in combined analysis of the alleles of the two genes, the frequency of high risk alleles was higher and the frequencies of low risk alleles were lower in the patient group. The CYP17 A1 + CYP19 TT haplotype may be protective for breast cancer.

192R allele of paraoxanase 1 (PON1) gene as a new marker for susceptibility to bladder cancer.

BACKGROUND: The human body has a number of endogenous free-radical scavenging systems. Paraoxonase1 (PON1) is one of the enzymes involved in such systems. The purpose of this study was to investigate the relationship between bladder cancer and the polymorphism of PON1 which results in Q/R substitution at codon 192. This is the first report of this polymorphism in bladder cancer. PATIENTS AND METHODS: Seventy-six bladder cancer patients and 135 healthy controls took part in the study. DNA from paraffin-embedded tissues for patients and from blood cells for controls was extracted. The distribution of PON1(192) polymorphism was determined by Polymerase Chain Reaction (PCR) and Restriction Fragment Length Polymorphism (RFLP) techniques. RESULTS: There was significant difference in PON1 genotype frequencies (patients/controls QQ: 8/37, QR: 53/84, RR: 15/14, p=0.007) between the control and bladder cancer patients. Moreover, in patients there was significant association of the RR genotype of PON1 with invasive growth pattern (p=0.027), perineural invasion (p=0.016), distant metastasis (p<0.001), radical cystectomy (p=0.016) and death (p=0.005). CONCLUSION: In patients, the QQ genotype was statistically less frequent, while the RR genotype frequency was somewhat less than in controls. QQ type PON1 enzyme activity might be protective for bladder carcinogenesis. These findings support that genotypical differences of PON1 might contribute to prognosis and pathogenesis of bladder cancer. Arylamines are well-known bladder carcinogens, especially after a sulfate or an acetate esterification and PON1 has arylesterase activity. We hypothesize that arylesterase activity of PON1 would help the formation of free-radical type arylamine derivates on the bladder epithelial surface, so that secondary metabolites of paraoxon or related chemicals and biotransformed intermediates of arylamines might be involved in formation of bladder carcinoma.