CYP2D6 and CYP1A1 mutations in the Turkish population

Drugs and carcinogens are substrates of a group of metabolic enzymes including cytochrome p450 enzymes and gluthatione S-transferases. Many of the genes encoding these enzymes exhibit functional polymorphisms that contribute individual cancer susceptibility and drug response. Molecular studies based on these polymorphic enzymes also explain the aetiology of cancer and therapeutic management in clinics. We analysed the cytochrome p4501A1 (CYP1A1) and 2D6 (CYP2D6) variant genotype and allele frequencies by PCR-RFLP in Turkish individuals (n=140). The frequency of the CYP1A1*2A mutant allele was found to be 15.4%, and the CYP2D6*3 and *4 mutant allele (poor metabolizer) frequencies were 2.5% and 13.9%, respectively. This study presents the first results of CYP1A1 and CYP2D6 mutant allele distributions in the Turkish population and these data provide an understanding of epidemiological studies that correlate therapeutic approaches and aetiology of several types of malignancy in Turkish patients.     

Human catecholamine sulfotransferase (SULT1A3) pharmacogenetics: functional genetic polymorphism

Sulfotransferase (SULT) 1A3 catalyzes the sulfate conjugation of catecholamines and structurally related drugs. As a step toward studies of the possible contribution of inherited variation in SULT1A3 to the pathophysiology of human disease and/or variation in response to drugs related to catecholamines, we have resequenced all seven coding exons, three upstream non-coding exons, exon-intron splice junctions and the 5'-flanking region of SULT1A3 using DNA samples from 60 African-American (AA) and 60 Caucasian-American (CA) subjects. Eight single nucleotide polymorphisms (SNPs) were observed in AA and five in CA subjects, including one non-synonymous cSNP (Lys234Asn) that was observed only in AA subjects with an allele frequency of 4.2%. This change in amino acid sequence resulted in only 28 +/- 4.5% (mean +/- SEM) of the enzyme activity of the wild-type (WT) sequence after transient expression in COS-1 cells, with a parallel decrease (54 +/- 2.2% of WT) in level of SULT1A3 immunoreactive protein. Substrate kinetic studies failed to show significant differences in apparent Km values of the two allozymes for either dopamine (10.5 versus 10.2 micro m for WT and variant, respectively) or the cosubstrate 3'-phosphoadenosine 5'-phosphosulfate (0.114 versus 0.122 micro m, respectively). The decrease in level of immunoreactive protein in response to this single change in amino acid sequence was due, at least in part, to accelerated SULT1A3 degradation through a proteasome-mediated process. These observations raise the possibility of ethnic-specific inherited alterations in catecholamine sulfation in humans.     

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.     

Genetic polymorphism of cytochrome P450 2E1 in the Turkish population.

CYP 2E1 is involved in metabolic activation of carcinogenic N-nitrosamines, benzene, urethane and other low molecular weight compounds. CYP2E1 gene is present in the population in various polymorphic forms. We detected the RFLP of the human CYP2E1 gene with the restriction endonuclease PstI, RsaI and DraI in a group of 153 Turkish individuals. According to the results of the PstI/RsaI analysis, 96.07% of the subjects were of the c1/c1 genotype, and 3.93% were of the c1/c2 genotype. In the DraI RFLP analysis, 84.30% DD genotype, 15.03% CD genotype and 0.66% CC genotype were determined. The data obtained may be useful in epidemiological studies of the influence of CYP2E1 polymorphism on carcinogenesis.     

Genetic polymorphism of manganese superoxide dismutase (MnSOD) and breast cancer susceptibility

Within mitochondria, manganese superoxide dismutase (MnSOD) provides a major defence against oxidative damage by reactive oxygen species (ROS). An alanine-9valine (Ala-9Val) polymorphism in the mitochondrial targeting sequence of MnSOD has been described and has recently been associated with risk of human breast cancer. Our present case-control study was performed to explore the association between MnSOD genetic polymorphism and individual susceptibility to breast cancer. Ala-9Val polymorphism in the signal sequence of the protein for MnSOD was determined using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay in a study population. There was no significant difference in risk for breast cancer development between patients positive and negative for the MnSOD Ala allele with adjusted odds ratio (OR): 0.86 (95% confidence interval (CI(0.43 to 1.72). When MnSOD Ala was combined with either cytochrome P450 1B1 CYP1B1*1 and catechol O-methyltransferase COMT-L (V158M) genotypes, the risk for developing breast cancer was significantly increased in patients with a body mass index (BMI) greater than 24 kg m(-2) (OR: 1.42 (95%CI=1.04-1.93)).     

Association of SULT1A1 and UGT1A1 polymorphisms with breast cancer risk and phenotypes in Russian women

Estrogens are critical for breast cancer initiation and development. Sulfotransferase 1A1 (SULT1A1) and UDP-glucuronosyltransferase 1A1 (UGT1A1) conjugate and inactivate both estrogens and their metabolites, thus preventing estrogen-mediated mitosis and mutagenesis. SULT1A1 and UGT1A1 are both polymorphic, and different alleles encode functionally different allozymes. We hypothesize that low-activity alleles SULT1A1*2 and UGT1A1*28 are associated with higher risk for breast cancer and more severe breast tumor phenotypes. We performed a case-control study, which included 119 women of Russian ancestry with breast cancer and 121 age-matched Russian female controls. We used PCR followed by pyrosequencing to determine the SULT1A1 and UGT1A1 genotypes. Allele UGT1A1*28 was present at a higher frequency than the wild-type UGT1A1*1 allele in breast cancer patients as compared to controls (P = 0.002, OR = 1.79, CI 1.23–2.63). Consistently, the frequency of genotypes that contain allele UGT1A1*28 in the homozygous or the heterozygous state was greater in breast cancer patients as compared with the frequency of the wild-type UGT1A1*1/*1 genotype (P = 0.003, OR = 4.00, CI 1.49–11.11 and P = 0.014, OR = 2.04, CI 1.14–3.57, respectively). Individuals carrying allele UGT1A1*28 in the homo-or heterozygous state had larger breast tumors (>2 cm) as compared to the group with high-activity genotypes (P = 0.011, IR = 3.44, CI 1.42–8.36). No association was observed between any of the SULT1A1 genotypes and breast cancer risk or phenotypes. Our data suggest that UGT1A1, but not SULT1A1, genotypes are important for breast cancer risk and phenotype in Russian women. Published in Russian in Molekulyarnaya Biologiya, 2006, Vol. 40, No. 2, pp. 263–270. The article was translated by the authors.     

SULT1A1 Arg213His polymorphism and susceptibility of environment-related cancers: a meta analysis of 5,915 cases and 7,900 controls

The common genetic polymorphism for SULT1A1 is Arg213His polymorphism, which may affect the sulfation process of various environmental carcinogens and thus is suggested to be related to susceptibility of several cancers. However, studies on the association between SULT1A1 Arg213His polymorphism and cancer susceptibility are inconsistent. To assess the relationship between Arg213His polymorphism and environmental-related cancers systematically, we performed a meta analysis from 20 case–control studies including 5,915 cases and 7,900 controls. The odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate the strength of risk, we found a significant association between SULT1A1 Arg213His polymorphism and environment-related cancers (for dominant model: OR 1.22, 95% CI 1.07–1.39, P = 0.003). When stratified by ethnicity, a significant risk was observed in Asian cases, compared with controls (for dominant model: OR 1.69, 95% CI 1.17–2.43, P = 0.005). When we chose only smokers in our analysis, we also found a significantly increased risk between Arg213His polymorphism and susceptibility of environment-related cancers for participants exposed to a smoking environment. In conclusion, SULT1A1 Arg213His polymorphism, ethnicity, smoking may modulate environment-related cancer risk. Studies on gene–gene interactions in the sequential or concurrent metabolic pathway and gene-environment interactions need to be further conducted to explore the susceptibility of cancer occurrence.     

SULT1A1 Arg213His polymorphism, smoked meat, and breast cancer risk: a case-control study and meta-analysis

SULT1A1 is involved in both detoxification of estrogens and bioactivation of carcinogens in smoked meat. SULT1A1 Arg213His polymorphism's effect on breast cancer risk is still unclear. We recruited 400 case-control pairs to investigate the association between SULT1A1 genotypes and breast cancer risk, and the combined effect of SULT1A1 polymorphism and daily intake of smoked meat. Participants were questioned about their dietary habits and other risk factors, and their SULT1A1 genotypes were determined. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated by multivariable unconditional logistic regression. We also performed a meta-analysis of relevant published studies to test these associations. In the case-control study, no significant associations were observed between SULT1A1 polymorphism and breast cancer risk. In the meta-analysis, SULT1A1 His/His genotype slightly increased risk among both overall and postmenopausal women (OR(pooled-overall)=1.12, 95% CI: 1.02-1.24; OR(pooled-post)=1.17, 95% CI: 1.03-1.32). A larger positive association was observed in Asian populations (OR(pooled-Asian)=2.01, 95% CI: 1.24-3.26). In our case-control study, high energy-adjusted daily intake of smoked meat was significantly associated with breast cancer risk in overall, pre- and postmenopausal women (aORs: 2.31-3.13, OR 95% CIs exclude 1). High smoked meat intake interacted positively with the His variant allele (all γ>1). These results correlated with those of the meta-analysis (γ(pooled-overall)=1.27). The SULT1A1 His/His genotype may increase the risk of breast cancer among Asian women, and dietary exposure to heterocyclic amines and polycyclic aromatic hydrocarbons, along with the SULT1A1 His/His variant genotype, may synergistically increase the risk of breast cancer.     

Genetic polymorphism of the human cytochrome CYP2A13 in a French population: implication in lung cancer susceptibility

The human cytochrome CYP2A13, which is mainly expressed in the respiratory tract, has been shown to be highly efficient in vitro in the metabolism of tobacco-smoke carcinogens and procarcinogens such as 4-methylnitroso-1-(3-pyridyl)-1-butanone (NNK). In order to investigate the extent of CYP2A13 genetic polymorphism in a French Caucasian population of 102 individuals, a screening for sequence variations in the 5'-untranslated and protein encoding regions of its gene was performed using a polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) strategy. Six polymorphisms in the coding region were identified, including two rare missense mutations (C474G or Asp158Glu, G967T or Val323Leu) and one nonsense mutation (Arg101Stop). This deleterious mutation, the most frequent (5%) in our population, presumably encodes a severely truncated protein. The influence of the nonsense mutation in lung cancer susceptibility was examined by PCR-SSCP using peripheral blood DNA from 204 cases of lung cancer and 201 controls. The CYP2A13*7 allele, which harbours the C301T mutation, was present in 2.0% of controls and 3.4% of cases. However, multivariate analysis showed an elevated risk for small cell lung cancer in subjects heterozygous for the null allele (odds ratio OR=9.9; 95% confidence interval CI=1.9-52.2). This increased risk was not linked to other histological types of lung cancer.     

中国北方人群谷胱甘肽转硫酶P1基因多态性及其与胃癌遗传易感性的关系

为了分析中国北方人群谷胱甘肽转硫酶P1基因(glutathione-S-transferase P1, GSTP1)多态性分布, 同时探讨GSTP1基因多态性及其与幽门螺杆菌(H. pylori)既往感染联合作用对胃癌发病风险的影响, 采用多聚酶链反应-限制性片段长度多态性(PCR-RFLP)技术检测1,612例外周血DNA GSTP1的多态性; 采用ELISA方法检测血清H. pylori IgG。结果显示, (1) 中国北方人群GSTP1基因Val等位基因分布频率为22%, 胃癌高、低发区GSTP1 Val等位基因分布频率有显著性差异(0.23/0.20); (2) 以Ile/Ile基因型为参照组与其他两种基因型比较进行胃癌的风险分析, 结果显示携带Val/Val基因型的个体患胃癌的危险性最大, 其OR为5.588 (3.256 ~ 9.591); 携带Val等位基因的个体患胃癌危险性是非携带Val等位基因个体的1.587倍; (3) 以H. pylori IgG(-)并携带GSTP1基因纯合野生型(Ile/ Ile)的个体为参照, H. pylori IgG(+)并携带纯合多态基因型(Val/Val)的个体患胃癌的风险最高, OR为17.571(6.207 ~ 49.742)。说明GSTP1 Val等位基因的分布存在人群及地区差异。携带GSTP1 Val等位基因的个体胃癌发病风险增高。GSTP1 Val等位基因纯合型与H. pylori感染对于胃癌的发生具有交互作用。     

Meta-analysis of the relationship between p21 Ser31Arg polymorphism and lung cancer susceptibility

The cyclin-dependent kinase inhibitor 1A (also known as p21) is thought to be involved in tumor development by mediating cell cycle arrest through the inhibition of cyclin/CDK activity. To explore the relationship of Ser31Arg polymorphism in the p21 gene with the risk of developing lung cancer, we performed an overall and stratified meta-analysis based on ethnicity, lung cancer subtypes and source of controls, with six eligible studies (2366 cases and 3320 controls). No significant variation in lung cancer risk was detected in any of the genetic models in the overall, and the ethnicity-based and cancer subtype-based subgroup analyses. However, in the subgroup analysis based on source of controls, significant opposite associations were observed; a significantly increased lung cancer risk was observed in the hospital-based control subgroup, while a significantly decreased lung cancer risk was detected in the mixed-source control and unknown-source control subgroups. In summary, based on our meta-analysis, p21 Ser31Arg polymorphism does not appear to act as an independent lung cancer risk factor and is more likely to act together with other genetic and non-genetic factors in the development of lung cancer; this needs further investigation.     

Association of glutathione S-transferase P1 gene polymorphism with the risk of small-cell carcinoma of lung cancer

Abstract

The conclusions of the published reports on the relationship between glutathione S-transferase P1 (GSTP1) gene polymorphism and the risk of small-cell carcinoma of lung cancer are still debated. GSTP1 is one of the important mutant sites reported at present. This meta-analysis was performed to evaluate the association between GSTP1 and the risk of small-cell carcinoma of lung cancer. The association investigations were identified from PubMed and Cochrane Library, and eligible studies were included and synthesized using meta-analysis method. Ten reports were included into this meta-analysis for the association of GSTP1 A/G gene polymorphism and small-cell carcinoma of lung cancer. The G allele and GG genotype were not associated with the susceptibility of risk of small-cell carcinoma in overall populations, East-Asians and Turkish population. However, there was an association between GG genotype with the risk of small-cell carcinoma in Caucasians. In conclusion, GG genotype was associated with the risk of small-cell carcinoma in Caucasian patients with lung cancer. However, GSTP1 A/G gene polymorphism is not associated with the susceptibility of small-cell carcinoma in overall populations, East-Asians and Turkish population.     

Polymorphisms associated with the risk of lung cancer in a healthy Mexican Mestizo population: Application of the additive model for cancer

Lung cancer is the leading cause of cancer mortality in Mexico and worldwide. In the past decade, there has been an increase in the number of lung cancer cases in young people, which suggests an important role for genetic background in the etiology of this disease. In this study, we genetically characterized 16 polymorphisms in 12 low penetrance genes (AhR, CYP1A1, CYP2E1, EPHX1, GSTM1, GSTT1, GSTPI, XRCC1, ERCC2, MGMT, CCND1 and TP53) in 382 healthy Mexican Mestizos as the first step in elucidating the genetic structure of this population and identifying high risk individuals. All of the genotypes analyzed were in Hardy-Weinberg equilibrium, but different degrees of linkage were observed for polymorphisms in the CYP1A1 and EPHX1 genes. The genetic variability of this population was distributed in six clusters that were defined based on their genetic characteristics. The use of a polygenic model to assess the additive effect of low penetrance risk alleles identified combinations of risk genotypes that could be useful in predicting a predisposition to lung cancer. Estimation of the level of genetic susceptibility showed that the individual calculated risk value (iCRV) ranged from 1 to 16, with a higher iCRV indicating a greater genetic susceptibility to lung cancer.     

Association between the flap endonuclease 1 gene polymorphisms and cancer susceptibility: An updated meta-analysis

Flap endonuclease 1 (FEN1) has emerged as an important enzyme in the maintenance of genomic instability and preventing carcinogenesis. The relationship between FEN1 −69G>A (rs174538)+4150G>T (rs4246215) polymorphisms and cancer susceptibility has been reported; however, results were inconclusive. In the present study, a meta-analysis of data from eligible reports was carried out to summarize the possible relationship between FEN1 polymorphisms and cancer risk. A total of 11 articles, including 20 studies with 7366 cases and 9028 controls and 18 studies with 6649 cases and 8325 controls for FEN1 rs174538 and FEN1 rs4246215 polymorphisms, respectively, were recruited for meta-analysis. Overall, meta-analyses showed that FEN1 rs174538 and rs4246215 polymorphisms are significantly associated with the decreased risk of cancer. The stratified analysis proposed that both variants were associated with protection against gastrointestinal cancer, breast cancer, hepatocellular cancer, esophageal cancer, gastric cancer, colorectal cancer, and lung cancer. In conclusion, this meta-analysis revealed an association between FEN1 polymorphisms and cancer risk. Additional studies in a larger study population that include subjects from a variety of ethnicities are warranted to further verify our findings.     

CYP17 gene polymorphism and prostate cancer susceptibility in a Tunisian population

Prostate cancer (PCa) formation has been reported to be associated with androgen. Two key steps in the sex steroid synthesis are mediated by the enzyme cytochrome P450c 17α which is encoded in the CYP17 gene. The A2 allele of the CYP17 gene has been thought to be associated with increased functional activity of this steroidogenic enzyme. Consequently, the A2 allele has been examined as a biomarker of individual susceptibility to hormone-related diseases among men. We prospectively assessed the association between the A2 allele of CYP17 and PCa risk among 125 cases and 125 controls in a case–control study. Our aim was to investigate whether a polymorphism of CYP17 gene could be used as a genetic marker for associating PCa. The result revealed a significant association between the CYP17 polymorphic genotypes and PCa. Therefore, CYP17 gene polymorphism is likely contributed to the pathogenesis of PCa but not to disease severity.     

RASSF1A Ala133Ser polymorphism is associated with increased susceptibility to hepatocellular carcinoma in a Turkish population

Aim

The tumor suppressor gene Ras association domain family 1 isoform A (RASSF1A) regulates cell cycle regulation, apoptosis and microtubule stability and is inactivated by promoter hypermethylation at a high frequency in hepatocellular carcinoma (HCC). A guanine (G)/thymine (T) common single nucleotide polymorphism (SNP) at first position of codon 133 in RASSF1A gene determines an alanine (Ala) to serine (Ser) (Ala133Ser) amino acidic substitution which may alter cancer risk by influencing the function of RASSF1A protein.

Methods

To determine the association of the RASSF1A Ala133Ser polymorphism with the risk of HCC development in a Turkish population, a hospital-based case–control study was designed consisting of 236 subjects with HCC and 236 cancer-free control subjects matched for age, gender, smoking and alcohol status. The genotype frequency of the RASSF1A Ala133Ser polymorphism was determined by using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay.

Results

Allele and genotype associations of RASSF1A Ala133Ser polymorphism with HCC susceptibility were observed in comparisons between the patient and control samples (P < 0.001). Risk of HCC development in this Turkish population was significantly increased in carriers of the Ser133 variant allele of Ala133Ser polymorphism (Ala/Ser and Ser/Ser genotypes) when compared with homozygote Ala/Ala genotype (OR = 5.47, 95% CI = 3.63–8.25, P = 0.001).

Conclusion

Because our results suggest for the first time that the Ser133 allele of RASSF1A Ala133Ser polymorphism may be a genetic susceptibility factor for HCC in the Turkish population, further independent studies are required to validate our findings in a larger series, as well as in patients of different ethnic origins.     

Q192R polymorphism in the PON1 gene and nasal polyp in a Turkish population

The pathogenesis of nasal polyps is not completely understood. Oxidative damage contributes to polyp formation in the nasal mucosa. The paraoxonase 1 (PON1) enzyme is an important liver enzyme with high antioxidant activity. In this study, we investigated the correlation between Q192R genotypic polymorphism of the PON1 enzyme and nasal‐polyp disease. The study examined 62 nasal‐polyp patients and 88 controls. PON1 Q192R polymorphism was determined using polymerase chain reaction‐restriction fragment length polymorphism. The genotype distribution of the PON1 gene was significantly different between nasal‐polyp patients (QQ = 69.35%, QR = 25.81%, RR = 4.83%) and healthy controls (QQ = 52.27%, QR = 44.31%, RR = 3.40%). Our results suggest that the PON1 QQ genotype (odds ratio [OR] = 2.066, P = .036) is associated with a higher risk of developing the nasal‐polyp disease while QR genotype (OR = 0.437, P = .021) showed a lower risk.     

Retracted: CYP2E1 Rsa Ι/Pst Ι polymorphism and lung cancer susceptibility: a meta‐analysis involving 10,947 subjects

Many studies have examined the association between the CYP2E1 Rsa Ι/Pst Ι (rs3813867) polymorphism gene polymorphisms and lung cancer risk in various populations, but their results have been inconsistent. The PubMed and CNKI database was searched for case–control studies published up to October 2013. Data were extracted and pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated. In this meta‐analysis, we assessed 23 published studies involving comprising 4727 lung cancer cases and 6220 controls of the association between CYP2E1 Rsa Ι/Pst Ι polymorphism and lung cancer risk. For the homozygote c2/c2 and c2 allele carriers (c1/c2 + c2/c2), the pooled ORs for all studies were 0.73(95% CI = 0.62–0.84; P = 0.005 for heterogeneity) and 0.84 (95% CI = 0.77–0.92; P = 0.001 for heterogeneity) when compared with the homozygous wild‐type genotype (c1/c1). In the stratified analysis by ethnicity, the same significantly risks were found among Asians and mixed population for both the c2 allele carriers and homozygote c2/c2. However, no significant associations were found in Caucasian population all genetic models. This updated meta‐analysis suggests that CYP2E1 Rsa Ι/Pst Ι c2 allele is a decreased risk factor for the developing lung cancer among Asians and mixed population.     

Interactions between the OGG1 Ser326Cys polymorphism and intake of fruit and vegetables in relation to lung cancer

The enzyme 8-oxoguanine glycosylase 1 (OGG1) repairs oxidatively damaged DNA and a polymorphism in the OGG1 gene (Ser³²⁶Cys) has been associated with lung cancer. We examined associations between the polymorphism and intake of fruits and vegetables and smoking in the development of lung cancer, by genotyping blood samples from 431 lung cancer cases and 796 comparison persons, which were identified within a prospective cohort on 57,000 cohort members. We found no overall association between the OGG1 polymorphism and lung cancer. There was a statistically significant interaction between the polymorphism and dietary intake of vegetables, with a 54% decrease in lung cancer risk per 50% increase in vegetable intake among homozygous Cys³²⁶Cys carriers and no decrease in risk among carriers of Ser³²⁶Ser or Ser³²⁶Cys. The same tendency was seen in relation to intake of fruit. There were no statistically significant interactions between the OGG1 polymorphism and smoking.