Role of xenobiotic metabolizing gene polymorphisms in breast cancer susceptibility and treatment outcome

Metabolic activation and inactivation of potential genotoxic agents occur by Phase I and Phase II enzymes in multiple interactions. An expanding body of literature demonstrates that ethnic differences in breast cancer incidence may be partly caused by host genetic factors particularly genetic polymorphisms of these carcinogen-metabolizing enzymes. The present case-control study aimed at identification of such low penetrance breast cancer susceptibility genes in 224 Indian women and to investigate the potential effects of their polymorphisms on sporadic breast cancer risk. The main objective of the study was to evaluate the effects of genetic polymorphisms of the xenobiotic metabolizing genes CYP1A1, GSTM1 and GSTT1 on breast cancer risk by PCR-RFLP and DNA sequencing. Our results showed a significant association between CYP1A1 m1, m2 polymorphisms and breast cancer risk; however there was a lack of association between GSTM1 null deletion and breast cancer. The associations of CYP1A1, GSTM1 and GSTT1 genotypes with breast cancer risk were more pronounced among the pre-menopausal patients. Combined genotype analysis revealed the CYP1A1 m2 ValVal-GSTM1 homozygous null deletion genotype combinations to be associated with the highest risk of breast cancer (OR=10.3, 95% CI=1.2-86.1). Correlations with clinicopathological factors and treatment outcome were also analyzed for predicting disease free survival by univariate and multivariate analysis. Significant differences in disease free survival between the wild and polymorphic genotypes were observed only for CYP1A1 m2, GSTT1 genotypes. Our results based on the analysis of functionally relevant polymorphisms in these low penetrance genes may provide a better model that would exhibit additive effects on individual susceptibility to breast cancer. Such genotype analysis resulting in a high-risk profile holds considerable promise for individualizing screening and therapeutic intervention in breast cancer. Hence, the present study may provide strong supportive evidence for genetic interactions in the etiology of breast cancer.     

Role of epoxide hydrolase, NAD(P)H:quinone oxidoreductase, cytochrome P450 2E1 or alcohol dehydrogenase genotypes in susceptibility to colorectal cancer

Colorectal cancer (CRC) is one of the most common forms of cancer in Western countries. CRC has been associated with genetic and lifestyle factors. Individual susceptibility to CRC may be due partly to variations in detoxification capacity in the gastrointestinal tract. Genetic polymorphisms in detoxification enzymes may result in variations in detoxification activities, which subsequently might influence the levels of toxic/carcinogenic compounds, and this may influence the risk for CRC. Therefore, we determined whether polymorphisms in the genes coding for microsomal epoxide hydrolase (EPHX1), NAD(P)H:quinone oxidoreductase (NQO1), cytochrome P450 2E1 (CYP2E1) and alcohol dehydrogenase (ADH3) predispose to the development of CRC. DNA samples were obtained from 371 patients with sporadic CRC and 415 healthy controls. Patients and controls were all of Caucasian origin. All genetic polymorphisms were determined by polymerase chain reaction, eventually followed by restriction-fragment-length-polymorphism analyses, except for the EPHX1 codon 113 polymorphism, which was genotyped by an allele-specific discrimination assay. Calculation of crude Odds Ratios (ORs) revealed an increased risk for CRC associated with variant NQO1 (OR 1.5, 95% CI 1.1-2.0) and CYP2E1 intron 6 genotypes (OR 2.2, 95% CI 1.3-3.8). However, after adjustment for age and gender, logistic regression analyses only showed a statistically significant risk for CRC associated with variant NQO1 genotypes (OR 1.6, 95% CI 1.03-2.4). No associations were found between CRC and the other polymorphic genes as mentioned above. In conclusion, these data suggest that the presence of variant NQO1 genotypes, with expected reduced enzyme activities might enhance susceptibility to CRC.     

Combined effect of GSTM1, GSTT1 and GSTP1 polymorphisms on histological subtypes of lung cancer

Genetic polymorphisms are natural genetic variations in the gene sequence that occur at a frequency of >1% in the population. This genetic variability (polymorphisms) can be a factor in cancer risk. The functional polymorphisms in GST genes play an important role in susceptibility to lung cancer. In our previous study, we reported that the combination of certain genotypes of GSTM1, GSTT1 and CYP1A1 is associated with lung cancer. The study has been extended to investigate the potential role of polymorphism in GSTP1 alone or in combination with the status of GSTM1 and GSTT1 genes in the likelihood of development of lung cancer. A total of 302 subjects (151 cases and 151 controls) were evaluated. Using a case-control design, individuals were genotyped for GSTs using multiplex polymerase chain reaction and restriction fragment length polymorphism techniques. The data obtained were analyzed using multiple logistic regression. The combined 'at risk' genotypes of GSTM1 null and GSTT1 null in comparison with 'wild-type' genotypes seems to be associated with a greater risk of lung cancer, but the results are not significant (odds ratio (OR) 2.0, 95% confidence interval (CI) 0.68-5.96) and for squamous cell carcinoma (SqCC) it was 1.6-fold (OR 1.6, 95% CI 0.49-5.68). In summary, our case-control study of lung cancer revealed that the effect of these polymorphisms is not very marked for different genotypic combinations of GSTP1, GSTM1 and GSTT1 in the context of developing lung cancer in a north Indian population. However, the increased risk was limited to SqCC, and was not found for other histological subtypes. Further analyses on this topic are needed.     

南京汉族群体肺癌易感性相关基因的研究

为了探讨南京汉族群体肺癌易感性相关基因,我们采用1:1病例对照研究方法,以PCR—RFLP技术检测了152对肺癌和健康对照的CYP1A1、CYP2E1、GSTM1、GSTT1、GSTP1、mEH和NQO1基因的基因型并分析其与肺癌的相关性。结果发现携带CYP1A1突变基因型（wt/mt和mt/mt）的个体明显增加患肺鳞癌的风险(OR=2.31,95%CI=1.23-4.36);GSTT1（-）基因型可使肺癌发生的风险增加2.06倍（95%CI=1.30-3.24）;具有NQO1wt/mt与mt/mt基因型者发生肺癌的风险也有所增高（OR=1.66,95CI%=1.01-2.74）; CYP1A1突变基因型与GSTT1缺失基因型、CYP1A1突变基因型与NQO1突变基因型对肺癌的发生存在协同作用,同时具有两种易感基因型的个体更容易发生肺癌。研究结果表明,CYP1A1、GSTT1、NQO1基因可能与南京汉族群体肺癌遗传易感性有关,基因型之间的联合检测更有助于高危人群的筛选。Abstract: To investigate the genes related to lung cancer susceptibility in Nanjing Han population, China, a 1:1 matched case-control study was performed in which 152 hospital controls were matched to the 152 original lung cancer cases. The polymorphisms of CYP1A1, CYP2E1, GSTM1, GSTT1, GSTP1, mEH and NQO1 genes were analyzed by PCR—RFLP assay. The results showed that the heterozygote and mutation homozygote genotypes of CYP1A1 were related to the risk of squamous cell carcinoma (OR=2.31, 95%CI=1.23-4.36). The risk of suffering from lung cancer was increased 2.06-fold in the individuals with GSTT1（-） genotype (95%CI= 1.30-3.24). The genotype of NQO1 wt/mt and mt/mt was found also to be associated with the risk of lung cancer (OR=1.66,95%CI=1.01-2.74). It was shown that there was no difference in the genotype distribution of CYP2E1, GSTM1, GSTP1 or mEH between cases and controls. Furthermore, stratified analysis suggested that the combination of genotypes of both CYP1A1 and GSTT1 enzymes had a synergistic action in risk of lung cancer (OR=3.41, 95%CI =1.77-6.55). Similarly, there was a cooperation between CYP1A1 mutation genotype and NQO1 mutation genotype (OR=2.45, 95%CI=1.13-5.31). This study suggested that CYP1A1, GSTT1 and gene NQO1 polymorphisms might be associated with the susceptibility to lung cancer in Nanjing Han population. Analysis of gene-gene interactions was helpful to identification of susceptible individuals and screening high-risk population to lung cancer.     

CYP1A1 gene polymorphisms and smoking status as modifier factors for lung cancer risk

Objective

Lung cancer remains the most prevalent malignancy worldwide. Susceptibility to lung cancer has been shown to be modulated by inheritance of polymorphic genes. Several metabolic enzymes are currently under investigation for their possible role in lung cancer susceptibility, including members of the cytochrome P450 (CYP) superfamily. The aim of this work was to identify the correlation between CYP1A1 m1 and m2 polymorphisms and lung cancer risk and figure its interactions with smoking as genetic modifiers in the etiology of lung cancer in the Egyptian population.

Materials and methods

One hundred and ten patients with lung cancer and one hundred and ten controls were enrolled in the study. CYP1A1 m1 and m2 polymorphisms were determined using polymerase chain reaction restriction fragment length polymorphism.

Results

Subjects carrying TC and CC genotypes of CYP1A1 m1 and AG and GG genotypes of CYP1A1 m2 were significantly more likely to develop lung cancer especially squamous cell carcinoma. The proportion of lung cancer attributable to the interaction of smoking and CYP1A1 m1 and CYP1A1 m2 polymorphisms was 32% and 52% respectively.

Conclusion

Our results revealed that CYP1A1 m1 and m2 polymorphisms contribute to smoking related lung cancer risk in the Egyptian population.     

Combined effect of GSTM1, GSTT1 and GSTP1 polymorphisms on histological subtypes of lung cancer

Genetic polymorphisms are natural genetic variations in the gene sequence that occur at a frequency of >1% in the population. This genetic variability (polymorphisms) can be a factor in cancer risk. The functional polymorphisms in GST genes play an important role in susceptibility to lung cancer. In our previous study, we reported that the combination of certain genotypes of GSTM1, GSTT1 and CYP1A1 is associated with lung cancer. The study has been extended to investigate the potential role of polymorphism in GSTP1 alone or in combination with the status of GSTM1 and GSTT1 genes in the likelihood of development of lung cancer. A total of 302 subjects (151 cases and 151 controls) were evaluated. Using a case–control design, individuals were genotyped for GSTs using multiplex polymerase chain reaction and restriction fragment length polymorphism techniques. The data obtained were analyzed using multiple logistic regression. The combined ‘at risk’ genotypes of GSTM1 null and GSTT1 null in comparison with ‘wild-type’ genotypes seems to be associated with a greater risk of lung cancer, but the results are not significant (odds ratio (OR) 2.0, 95% confidence interval (CI) 0.68–5.96) and for squamous cell carcinoma (SqCC) it was 1.6-fold (OR 1.6, 95% CI 0.49–5.68). In summary, our case–control study of lung cancer revealed that the effect of these polymorphisms is not very marked for different genotypic combinations of GSTP1, GSTM1 and GSTT1 in the context of developing lung cancer in a north Indian population. However, the increased risk was limited to SqCC, and was not found for other histological subtypes. Further analyses on this topic are needed.     

Meta-analysis of the association of CYP1A1 polymorphisms with gastric cancer susceptibility and interaction with tobacco smoking

The association of two cytochrome P4501A1 (CYP1A1) polymorphisms, m1 (T6235C transition) and m2 (A4889G transition), with gastric cancer risk is inconclusive. We conducted a meta-analysis of all available studies to evaluate the potential role of the polymorphisms and their interactions with tobacco smoking in gastric cancer susceptibility. Published literature from PubMed was retrieved by two investigators independently. Fourteen case-control studies with 2,032 gastric cancer cases and 5,099 controls were selected. A fixed effects model or a random-effects model was used to estimate the odds ratio (OR) for the CYP1A1 polymorphisms and the occurrence of gastric cancer. Significant associations between CYP1A1 m1 and m2 polymorphisms and gastric cancer susceptibility were not observed in all genetic models in the overall analyses. Subgroup analyses by ethnicity and source of controls did not reveal significant associations with gastric cancer risk. Stratification analysis by smoking status found that carriers of the heterozygous and homozygous m1 genotypes decreased the susceptibility of gastric cancer among ever-smokers (pooled OR = 0.56, 95 % CI 0.36-0.89, fixed effects). In contrast, the m2 genotypes (G/G and A/G) did not show any relevance to gastric cancer risk among the smoking population (pooled OR = 1.30, 95 % CI 0.84-2.00, fixed effects). Overall, we found that the CYP1A1 polymorphism itself, either m1 or m2, did not represent an independent genetic risk factor influencing gastric cancer. However, subgroup analyses suggest that carriers of the heterozygous and homozygous m1 genotype who are exposed to tobacco smoke have a significantly lower risk of developing gastric cancer. To explain the observed reduction of gastric cancer risk, we proposed a novel hypothesis of "observation bias". This hypothesis is also applicable to explain the combined effects of other genetic polymorphisms and environmental factors on the risk of developing cancers, and the rationality of the hypothesis needs to be further investigated.     

Phase I Metabolic Genes and Risk of Lung Cancer: Multiple Polymorphisms and mRNA Expression

Polymorphisms in genes coding for enzymes that activate tobacco lung carcinogens may generate inter-individual differences in lung cancer risk. Previous studies had limited sample sizes, poor exposure characterization, and a few single nucleotide polymorphisms (SNPs) tested in candidate genes. We analyzed 25 SNPs (some previously untested) in 2101 primary lung cancer cases and 2120 population controls from the Environment And Genetics in Lung cancer Etiology (EAGLE) study from six phase I metabolic genes, including cytochrome P450s, microsomal epoxide hydrolase, and myeloperoxidase. We evaluated the main genotype effects and genotype-smoking interactions in lung cancer risk overall and in the major histology subtypes. We tested the combined effect of multiple SNPs on lung cancer risk and on gene expression. Findings were prioritized based on significance thresholds and consistency across different analyses, and accounted for multiple testing and prior knowledge. Two haplotypes in EPHX1 were significantly associated with lung cancer risk in the overall population. In addition, CYP1B1 and CYP2A6 polymorphisms were inversely associated with adenocarcinoma and squamous cell carcinoma risk, respectively. Moreover, the association between CYP1A1 rs2606345 genotype and lung cancer was significantly modified by intensity of cigarette smoking, suggesting an underling dose-response mechanism. Finally, increasing number of variants at CYP1A1/A2 genes revealed significant protection in never smokers and risk in ever smokers. Results were supported by differential gene expression in non-tumor lung tissue samples with down-regulation of CYP1A1 in never smokers and up-regulation in smokers from CYP1A1/A2 SNPs. The significant haplotype associations emphasize that the effect of multiple SNPs may be important despite null single SNP-associations, and warrants consideration in genome-wide association studies (GWAS). Our findings emphasize the necessity of post-GWAS fine mapping and SNP functional assessment to further elucidate cancer risk associations.     

Genetic polymorphisms and possible gene-gene interactions in metabolic and DNA repair genes: effects on DNA damage

We investigated in a central European population, the association between genetic polymorphisms in several genes coding for xenobiotic metabolizing enzymes (CYP1A1, CYP2E1, EPHX1, GSTP1, GSTM1 and GSTT1) and in DNA repair genes (XPD, XPG, XPC and XRCC1) and the levels of single-strand breaks (SSBs) and SSB endonuclease III sensitive sites (endoIII sites) in peripheral blood lymphocytes. No significant differences in the mean levels of SSBs and endoIII sites after stratification for main confounders and occupational exposure were observed in the studied population. Significantly higher levels of SSBs were observed in individuals bearing the wild-type alleles (AA) (0.75+/-0.51SSB/10(9)Da) and heterozygous (AC) genotypes (0.67+/-0.49SSB/10(9)Da) compared to those with homozygous XPD (CC) genotype (0.43+/-0.28SSB/10(9)Da, P=0.033). A moderate increase in the levels of SSBs was also found in individuals with the homozygous XPG exon 15 wild type (GG) and heterozygous (GC) genotypes in comparison to those with the homozygous (CC) genotype (P=0.066) and in individuals with low activity EPHX1 genotype in comparison to those with high activity genotype. Nevertheless, these differences were not statistically significant. No other significant association was found. When gene-gene interactions were evaluated, a combination of EPHX1 activity genotypes with that of either XPD or XPG significantly (P=0.003 and 0.016, respectively) modulated SSB levels resulting in a three-fold difference between the "protective" and the "adverse" genotype-combinations. Almost three-fold differences in SSB levels were found between the "protective" and the "adverse" genotype-combinations of EPHX1 activity genotype and GSTM1 or GSTT1 genotypes, respectively. In conclusion, our results suggest a relation between markers of genotoxicity and polymorphisms in genes coding for xenobiotic metabolizing and DNA repair enzymes as well as a modulating effect of combinations of these polymorphisms.     

Cytochrome P4501A1 and microsomal epoxide hydrolase gene polymorphisms: gene-environment interaction and risk of prostate cancer

The role of low penetrance genes and environmental factors in the etiology of prostate cancer (PCa) is unclear. Most procarcinogens require metabolic activation by CYP4501A1, whereas microsomal epoxide hydrolase (mEH) is involved in the detoxification. In our case-control study, we assessed whether CYP1A1 and mEH susceptibility genotypes, tobacco use, and age factors contribute to PCa risk. One hundred thirty patients with PCa and 140 control subjects were analyzed by polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP) method from genomic DNA samples. Binary logistic regression model was used for assessing differences in genotype prevalence and their association between patient and the control group. T/C polymorphism of CYP1A1 gene revealed significant association with the tobacco users (p < 0.005) for PCa risk. Our results demonstrated significant association with exon 3 variant genotypes of the mEH alone or in combination with tobacco users (p < 0.005), whereas in exon 4 genotypes, no association was observed. Haplotype analysis projected significant associations with very slow haplotypes of mEH gene (OR = 2.48, 95% CI = 1.41-4.38, p = 0.002). In conclusion, our study demonstrated that exon 3 of mEH and CYP1A1 T/C gene polymorphism are predisposing risk factors for susceptibility of sporadic PCa in northern India. It also suggests that a combination of smoking plays a significant role in modified PCa risk on the study population, which means that smokers carrying susceptible genotypes may be subjected to higher risk than those carrying nonsusceptible genotypes.     

CYP1A1 MspI polymorphisms and lung cancer risk: an updated meta-analysis involving 20,209 subjects

Published data describing the association between CYP1A1 MspI gene polymorphism and lung cancer risk are inconclusive. To determine a more conclusive relationship, we performed an updated meta-analysis of all eligible studies and conducted the subgroup analysis by stratification according to the ethnicity source, histological types of lung cancer, gender and smoking status of case and control populations. A total of 51 studies comprising 20,209 subjects were included in the analysis. A significantly elevated lung cancer risk was associated with two variant genotypes (for TT vs CC: OR=1.24, 95% CI=1.11-1.40; for CT and TT combined vs CC: OR=1.19, 95% CI=1.12-1.27) in the overall population. In the stratified analysis, significantly higher risks associated with lung cancer were found in Asians, Caucasians, lung SCC, lung AC and the male population. In contrast, negligible risks were found in the mixed population, lung SCLC and the female population. Additionally, a significant association was found in the smoker population, whereas no association was found in non-smoker populations. This meta-analysis suggests that the MspI polymorphisms of CYP1A1 correlate with increased lung cancer susceptibility, and that there is an interaction between the CYP1A1 polymorphism and smoking. However, the associations vary in different ethnic populations, histological types of lung cancer and the gender of case and control populations.     

Association of functionally important polymorphisms in cytochrome P4501B1 with lung cancer

In the present study, genotype and haplotype frequencies of four polymorphisms of cytochrome P450 1B1 (CYP1B1) that cause amino acid changes (Arg-Gly at codon 48, Ala-Ser at codon 119, Leu-Val at 432 and Asn-Ser at codon 453) were studied in 200 patients suffering from lung cancer and equal number of controls. A significant difference was observed for the distribution of variant genotypes of CYP1B1Arg48Gly and Ala119Ser polymorphisms (CYP1B1*2) in cases when compared to the controls. No significant difference was observed for the distribution of variant genotypes of CYP1B1Leu432Val (CYP1B1*3) and CYP1B1Asn453Ser (CYP1B1*4) polymorphism. When the four SNPs were analyzed using a haplotype approach, SNPs at codon 48 (Arg48Gly) and codon 119 (Ala119Ser) exhibited complete linkage disequilibrium (LD) in all the cases and controls. Significant differences in the distribution of the three haplotypes (G-T-C-A, G-T-G-A and G-T-C-G) were observed in the cases when compared to controls. Tobacco use in the form of smoking as well as chewing was found to significantly increase the risk of lung cancer in patients by interacting with CYP1B1Ala119Ser genotypes demonstrating the role of gene-environment interaction in lung cancer. Further, the risk of lung cancer increased several fold in the patients carrying the genotype combinations of CYP1B1Ala119Ser and CYP1B1Leu432Val with GSTM1, a phase II enzyme suggesting the importance of gene-gene interactions in enhancing the susceptibility to lung cancer.     

Effect of CYP17 and PSA gene polymorphisms on prostate cancer risk and circulating PSA levels in the Slovak population

Cytochrome P-450c17α (CYP17) and prostate-specific antigen (PSA) genes, which are involved in the androgen metabolism cascade, have been studied as possible candidates for genetic influences on prostate cancer development. Contradictory results prompted us to evaluate the frequencies of polymorphisms in the CYP17 and PSA genes as well as the association between these genetic variants and serum PSA levels in prostate cancer patients and men routinely screened for prostate cancer with PSA in the Slovak male population. The CYP17 and PSA polymorphisms were determined by the PCR-RFLP analysis in 197 Caucasian prostate cancer patients and 256 Caucasian controls. We did not find any association between the CYP17 and PSA genotypes and prostate cancer risk overall, or by grade. Also the total serum PSA levels in the cases with the AG or AA genotype were not significantly higher than in the men with the GG genotype (P > 0.05). Our study did not provide support for the hypothesized relationship between CYP17 and PSA gene polymorphisms and prostate cancer in the Slovak male population.     

CYP1A1 *2B and *4 polymorphisms are associated with lung cancer susceptibility in Mexican patients

BACKGROUND: CYP1A1 is a gene involved in the high aryl hydrocarbon hydroxylase -inducible phenotype, which is a genetically-determined variation among individuals that has been associated with lung cancer risk. More specifically, CYP1A1 *2B and *4 polymorphisms have been associated with high susceptibility to lung cancer among cigarette smokers. MATERIALS AND METHODS: DNA was obtained from blood samples and we studied by PCR-RFLP the distribution of CYP1A1 *2B (n=248) and *4 (n=222) polymorphisms in healthy controls and 222 lung cancer patients from a Mexican population. RESULTS: Comparisons between groups showed an increased risk for lung cancer patients of *2B/*2B (18%; OR 7.6; 95% CI 3.0-19.2) and *4/ *4 genotypes (15%; OR 11.45; 95% CI 2.19-59.85) compared to the control group (1% for *2B/ *2B and 4.4% for *4/ *4). A significant association between lung cancer and homozygous *2B/ *2B passive smokers and *4/*4 ever (cigarettes) and passive smokers was also observed (p<0.05). Multivariate analysis revealed an increased risk for the *2B/*2B genotype (OR 6.83), as well as for *4/*4 (OR 28.8). CONCLUSION: The results of the study indicate a significant association between *2B/*2B and *4/*4 genotypes and the risk of developing lung cancer among Mexicans.     

CYP1A1 and CYP2D6 polymorphism and risk of lung cancer in a North Indian population.

This case-control study was conducted to examine the association between the CYP1A1 and CYP2D6 genotypes and lung cancer risk among North Indians. The estimated relative risk for lung cancer associated with the CYP1A1 Val/Val allele was 2.68, and was four-fold when cases with small cell lung cancer (SCLC) were considered alone. With regard to the metabolism of debrisoquine, no poor metabolizers were found amongst the subjects. The odds ratio of risk with the heterozygous extensive metabolizer (HEM) genotype was 1.5. However, in the presence of at least a single copy of the variant CYP1A1 MspI allele and the CYP2D6 HEM genotype, the risk was two-fold for squamous cell carcinoma (SQCC). When the CYP1A1 Val/Val and CYP2D6 HEM genotypes were taken together, the risk for SCLC was four-fold. Stratified analysis indicated an interaction between bidi smoking and variant CYP1A1 genotypes on the risk for SQCC and SCLC. Heavy smokers (Brinkman index>400) with Val/Val genotypes were at a very high risk of developing lung cancer (odds ratio 29.30, 95% confidence interval 2.42-355, p=0.008). Heavy smokers with CYP1A1 MspI (CYP1A1*1/2A or CYP1A1*2A/*2A) genotype had a seven-fold risk for SCLC compared with non-smokers. This study is the first to be carried out on a North Indian population, and, although small, suggests that CYP1A1 and CYP2D6 polymorphisms might have a role in determining the risk for lung cancer and should be investigated further.     

Impact of genetic variations of the CYP1A1, GSTT1, and GSTM1 genes on the risk of coronary artery disease

Carcinogenic and toxic molecules produce DNA adducts that contribute to the development of atherosclerosis. Genetic polymorphisms of xenobiotic-detoxified enzymes, which control the level of DNA adducts, may affect both enzymatic activity and individual susceptibility to coronary artery disease (CAD). In this study we investigated the effects of genetic polymorphisms of the CYP1A1*2C, GSTT1, and GSTM1 enzymes on CAD risk in a Turkish population. Genotypes were determined for 132 CAD patients and 151 healthy controls by the polymerase chain reaction/restriction fragment length polymorphism method. There were no significant differences between patients and controls in terms of CYP1A1, GSTT1, and GSTM1 genotypes. Analysis of the possible interactions between the genotypes, after adjustment for the risk factors, demonstrated that individuals carrying CYP1A1 variant GSTT1 null genotypes had an 8.907-fold increased CAD risk compared to their wild status (p<0.05). We suggest that genetic polymorphisms of xenobiotic-metabolizing enzymes could play an important role in CAD. Therefore, CYP1A1 and GSTM1 polymorphisms should be considered as important parameters for the prediction of CAD.     

The association of 5alpha-reductase II (SRD5A2) and 17 hydroxylase (CYP17) gene polymorphisms with prostate cancer patients in the Turkish population

To date, research has led to the invention of multiple genes and their single nucleotide polymorphisms (SNPs) and environmental factors that influence the prostate cancer (PCa) pathogenesis. Therefore, the genes involved in these pathways are candidates for PCa predisposition. It is thought that polymorphisms of 5alpha-reductase II (SRD5A2) and 17 hydroxylase (CYP17) genes are likely to increase susceptibility. The aim of this study was to investigate the risk association of SRD5A2 and CYP17 gene polymorphisms in the development and progression of PCa in the Turkish population. In this study, 100 PCa patients and 105 healthy controls were studied. SRD5A2 and CYP17 gene polymorphisms were determined by real-time PCR and polymerase chain reaction-restriction length polymorphisms (PCR-RFLP) techniques. First, the AT and TT genotypes of SRD5A2 gene at codon 49 were not observed. Second, there was no significant association between the polymorphisms at codon 89 and the risk of PCa. Third, in the CYP17 gene, the A1A1 genotype is more common (46%) in cases than controls (32.4%). The odds ratios (ORs) of the A1A1 genotype was found at 1.69 (95% confidence interval [CI], 0.77-3.74) compare with the A2A2 genotype. Genotyping results of the SRD5A2 and CYP17 genes were also analyzed in relation to prostate-specific antigen (PSA) levels, Gleason score (GS), and tumor stage, but no statistically significant difference was observed (P > 0.05). Finally, we conclude that there was no evidence of an association between CYP17 (P = 0.134) and SRD5A2 (P = 0.784) polymorphism and PCa risk in the Turkish population.     

Multiple analytical approaches reveal distinct gene-environment interactions in smokers and non smokers in lung cancer

Complex disease such as cancer results from interactions of multiple genetic and environmental factors. Studying these factors singularly cannot explain the underlying pathogenetic mechanism of the disease. Multi-analytical approach, including logistic regression (LR), classification and regression tree (CART) and multifactor dimensionality reduction (MDR), was applied in 188 lung cancer cases and 290 controls to explore high order interactions among xenobiotic metabolizing genes and environmental risk factors. Smoking was identified as the predominant risk factor by all three analytical approaches. Individually, CYP1A1*2A polymorphism was significantly associated with increased lung cancer risk (OR = 1.69;95%CI = 1.11–2.59,p = 0.01), whereas EPHX1 Tyr113His and SULT1A1 Arg213His conferred reduced risk (OR = 0.40;95%CI = 0.25–0.65,p<0.001 and OR = 0.51;95%CI = 0.33–0.78,p = 0.002 respectively). In smokers, EPHX1 Tyr113His and SULT1A1 Arg213His polymorphisms reduced the risk of lung cancer, whereas CYP1A1*2A, CYP1A1*2C and GSTP1 Ile105Val imparted increased risk in non-smokers only. While exploring non-linear interactions through CART analysis, smokers carrying the combination of EPHX1 113TC (Tyr/His), SULT1A1 213GG (Arg/Arg) or AA (His/His) and GSTM1 null genotypes showed the highest risk for lung cancer (OR = 3.73;95%CI = 1.33–10.55,p = 0.006), whereas combined effect of CYP1A1*2A 6235CC or TC, SULT1A1 213GG (Arg/Arg) and betel quid chewing showed maximum risk in non-smokers (OR = 2.93;95%CI = 1.15–7.51,p = 0.01). MDR analysis identified two distinct predictor models for the risk of lung cancer in smokers (tobacco chewing, EPHX1 Tyr113His, and SULT1A1 Arg213His) and non-smokers (CYP1A1*2A, GSTP1 Ile105Val and SULT1A1 Arg213His) with testing balance accuracy (TBA) of 0.6436 and 0.6677 respectively. Interaction entropy interpretations of MDR results showed non-additive interactions of tobacco chewing with SULT1A1 Arg213His and EPHX1 Tyr113His in smokers and SULT1A1 Arg213His with GSTP1 Ile105Val and CYP1A1*2C in nonsmokers. These results identified distinct gene-gene and gene environment interactions in smokers and non-smokers, which confirms the importance of multifactorial interaction in risk assessment of lung cancer.     

Smoking related risk involved in individuals carrying genetic variants of CYP1A1 gene in head and neck cancer

Background: CYP1A1 is one of the commonest genes which had been widely investigated to find the risk of various malignancies in different ethnic groups. The polymorphism in these genes with a combination of environmental exposure has been hypothesized to confer a differential risk of cancer for individuals carrying these genetic variants. Based on this model, individuals with higher CYP1A1 activity would be at increased risk of cancer when exposed to high levels of smoke components. The proposed mechanism involves cytochrome P450 1A1 (CYP1A1), a gene that is inducible by xenobiotics to produce genetic susceptibility for malignancies. Patients and procedures: We performed a case–control study in 205 cases with histopathologically confirmed squamous cell carcinoma of head and neck and reported habits of bidi or cigarettes smoking and 245 similar controls to investigate the role of CYP1A1 polymorphisms in the risk of head and neck cancers especially among smokers of Hyderabad Indian population. Venous blood samples (5 ml) were collected from patients and control groups; genomic DNA was extracted and used for polymerase chain reaction (PCR) to determine the genotypes. RFLP assays were designed to detect each of the variant CYP1A1 alleles. Results and discussion: CYP1A1m1/m1 genotype (OR = 8.12, 95% CI: 3.27–21.30) and CYP1A1w1/m1 showed elevated risk when compared with CYP1A1w1/w1. Similarly CYP1A1w2/m2 (OR = 1.58, 95% CI: 0.94–2.67) and CYP1A1m2/m2 (OR = 6.31, 95% CI: 2.74–18.69) genotypes also showed elevated risk when compared with CYP1A1w2/w2 genotype. This data demonstrated that smoking was a risk factor for head and neck cancers. The m2 mutations were in close linkage disequilibrium with the m1 mutations; 53% m1 mutants had the mutation in the m2 site. Conclusion: Those individuals carrying at least one CYP1A1 m1 or m2 variant allele were at a 2-fold elevated risk for head and neck cancer. Our data clearly demonstrates that CYP1A1 is an important determinant in susceptibility to tobacco-induced head and neck carcinogens and there is an association between genetic polymorphism in the CYP1A1 locus and elevated risk of the type of smoking among Indians. This appears to be a new and important prognostic and diagnostic marker for determining the risk of head and neck cancers genetically.     

Polymorphisms in genes of the steroid hormone biosynthesis and metabolism pathways and endometrial cancer risk

Objectives: The incidence of endometrial cancer has recently increased substantially and studies have shown that altered levels of exogenous and endogenous hormones are associated with individual variation in endometrial cancer risk. The environmental and reproductive risk factors that influence these hormones are well known, however, genetic variants involved in hormone biosynthesis and estrogen metabolism have not been well established in endometrial cancer. Methods: To determine whether polymorphisms in genes of the steroid hormone biosynthesis and metabolism pathways are associated with endometrial cancer risk, 28 polymorphisms in 18 genes were genotyped in 191 endometrial cancer cases and 291 healthy controls. Results: The GSTM1 deletion and the variant (GG) genotype of the CYP1B1 rs1800440 polymorphism were associated with a decreased risk of developing endometrial cancer. Furthermore, combinations of haplotypes in CYP1A1, CYP1B1 and GSTs were associated with a decreased risk. The analysis of the repeat polymorphisms revealed that women with the long repeat allele length of the ESR1 (GT)n repeat polymorphism were at an increased risk of developing endometrial cancer. Conversely, women with two long repeat length alleles of the (CAG)n repeat polymorphism in the AR correlated with a decrease in endometrial cancer risk compared to women with one or two alleles with the short repeat length. Conclusions: The findings are consistent with our hypothesis that variability in genes involved in steroidogenesis and estrogen metabolism may alter the risk of developing endometrial cancer, suggesting that they may be useful as biomarkers for genetic susceptibility to endometrial cancer.