CYP1B1、NQO1基因多态性与肺癌易感性关系的研究

目的研究内蒙古地区蒙古族与汉族人群的CYP1B1和NQO1基因多态性及吸烟状况与肺癌易感性的关系。方法采用PCR-RFLP技术对CYP1B1基因L432V位点和NQO1基因C609T位点多态性进行检测。结果 (1)CYP1B1基因L432V位点基因型分布频率在蒙古族和汉族健康人群中差异无统计学意义(χ2=1.220,P> 0.05);NQO1基因C609T位点基因型分布频率在蒙古族和汉族健康人群中差异无统计学意义(χ2=0.221,P> 0.05)。(2)在蒙古族和汉族人群中,NQO1 C/T和T/T基因型有明显增加患肺癌风险性的作用(汉族人群OR:1.461,2.278,P <0.05;蒙古族人群OR:1.493,2.040,P <0.05),而CYP1B1 C/G和G/G基因型无明显增加患肺癌风险性的作用(汉族人群OR:1.271,1.614,P> 0.05;蒙古族人群OR:0.970,1.758,P> 0.05)。(3)在汉族人群中,携带CYP1B1 C/G+G/G基因型的吸烟者患肺癌的危险性高于携带C/C的非吸烟者(OR:2.152,P <0.05);携带NQO1 C/C、C/T+T/T基因型的吸烟者患肺癌的危险性高于携带C/C的非吸烟者(OR:2.172,2.613,P <0.05)。在蒙古族人群中,携带CYP1B1 C/C、C/G+G/G基因型的吸烟者患肺癌的危险性高于携带C/C的非吸烟者(OR:1.409,1.765,P <0.05);携带NQO1 C/C、C/T+T/T基因型的吸烟者患肺癌的危险性高于携带C/C的非吸烟者(OR:2.479,2.729,P <0.05)。结论 (1)CYP1B1基因L432V位点基因型以及NQO1基因C609T位点基因型在内蒙古地区蒙古族和汉族健康人群中的分布不具有种族差异。(2)NQO1 C/T和T/T基因型显著增加内蒙古地区蒙古族和汉族患肺癌的易感性。(3)在蒙古族和汉族人群中,CYP1B1 C/G+G/G基因型以及NQO1 C/T+T/T基因型显著增加吸烟者患肺癌的易感性。     

髓过氧化物酶基因多态性与肺癌易感性的研究

目的研究内蒙古地区蒙汉族人群中髓过氧化物酶(myeloperoxidase,MPO)基因多态性分布频率差异及其与肺癌易感性的关系,同时探讨基因多态性与吸烟在肺癌易感性中的交互作用。方法PCR-RFLP技术检测内蒙古地区蒙古族和汉族人群MPO基因G463A位点的多态性,运用SPSS统计软件对数据分析,计数资料组间差异采用χ2检验及Binary Logistic回归分析进行统计处理,并探讨基因多态性与肺癌易感性的关系。结果 (1) MPO基因G463A位点G/G、G/A和A/A基因型在内蒙古地区汉族健康人群的分布频率分别为63.71%、30.57%和5.72%;在蒙古族健康人群中分布频率分别为64.86%、30.00%和5.14%,两组比较差异无统计学意义(P> 0.05)。(2)内蒙古地区蒙古族和汉族人群中MPOG/A和A/A基因型与MPO G/G基因型比较差异有统计学意义,有明显降低患肺癌风险性的作用(P<0.05)。(3)基因多态性联合吸烟分析发现,在内蒙古地区蒙古族和汉族人群中,吸烟能增加携带各种基因型个体患肺癌的风险性,其中携带MPO G/G、G/A基因型的非吸烟者以及携带G/A、A/A和G/G基因型的吸烟者与携带MPO A/A基因型的非吸烟者比较差异有统计学意义,患肺癌的危险性增加(P<0.05)。结论 (1) MPO基因G463A位点多态性在内蒙古地区蒙古族和汉族人群中的分布差异无统计学意义;(2) MPO G/A和A/A基因型能显著降低内蒙古地区蒙古族和汉族肺癌的易感性;(3) MPO G/G基因型显著增加吸烟者患肺癌的易感性,其与吸烟在肺癌发生中存在交互作用。     

DNA修复基因XPD单核苷酸多态性与肺癌遗传易感性

目的探讨XPD基因单核苷酸多态性与肺癌遗传易感性的关系。方法以聚合酶链反应-限制性片段长度多态性方法分析肺癌患者(n=114)和按性别、年龄频数配比的对照者(n=114)XPD基因Asp312Asn和Lys751Gln位点的多态性,比较不同基因型与肺癌风险的关系,并探讨吸烟在其中的影响。结果与携带XPD312Asp/Asp基因型者比较,携带至少1个312Asn等位基因的个体罹患肺癌的风险增加1.55倍(95%CI1.02～2.39)。而与携带XPD751Lys/Lys基因型者比较,携带至少1个751Gln等位基因的个体罹患肺癌的风险并没有显著增加(校正OR=0.96;95%CI0.53～1.72)。交互作用分析显示,携带至少1个312Asn等位基因并吸烟者肺癌风险增加5.14倍(95%CI1.82～9.16),其中重度吸烟者肺癌风险增加高达7.32倍(95%CI2.17～21.18)。结论DNA修复基因XPD Asp312Asn多态性可能与山东地区汉族人群肺癌遗传易感性有关,并可显著增加吸烟对肺癌的危险性。     

谷胱甘肽硫转移酶M1基因多态与肺癌易感性的关系

目的探讨谷胱甘肽硫转移酶M1（GSTM1）基因多态与支气管肺癌癌变的关系。方法采用回顾性“病例—对照”设计和限制性片段多态检测法（PCR—RFLP）,检测肺癌病例组103例和正常对照组138例的G卯Ml基因多态,以非条件性logistic回归模型分别对年龄、性别进行校正后计算比数比（OR）及95％可信区间（CI）。结果GSTM1的缺陷型基因（D）频率在对照组、肺癌组分别为44.2％和61．2％。logistic回归分析表明．GSTMl缺陷型（D）患肺癌的危险度升高2．09倍,差异有统计学意义。GSTM1（D）可显著增加鳞癌和小细胞癌的患病危险度。结论GSTM1（D）是患肺癌的危险因素,GSTM1（D）存在与吸烟有协同作用。     

MIF-173G＞C基因多态性与卵巢癌易感性的关系

目的 研究巨噬细胞移动抑制因子(MIF)基因-173G＞C多态性与江苏人群卵巢癌遗传易感性的关系.方法 采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术,检测MIF-173G＞C多态性在130例卵巢癌患者和145例年龄相匹配正常对照者的频率和分布,比较不同基因型携带者患卵巢癌的危险性;通过分层分析探讨年龄、初潮年龄、产次、流产数及绝经状态对罹患卵巢癌的影响.结果 与携带MIF-173GG基因型相比,携带MIF-173GC/CC基因型者罹患卵巢癌的风险降低了43.2％(OR=0.568,95％CI=0.323～0.997).分层分析结果显示,产次0～1次、流产≥2次及已绝经的女性携带-173GC/CC基因型较携带GG基因型者罹患卵巢癌的风险降低尤为显著(产次0～1:OR=0.392,95％CI=0.179～0.860;流产≥2次:OR=0.394,95％CI=0.166～0.934;已绝经:OR=0.436,95％CI=0.221～0.861).结论 MIF-173G＞C多态性可能与江苏人群卵巢癌的发生有关.     

髓过氧化物酶基因G-463A多态性与脑梗死易感性的研究

目的 探讨髓过氧化物酶(MPO)基因G-463A位点多态性与颈动脉斑块患者易发脑梗死的相关性.方法 用二维超声测量97例颈动脉斑块患者和68名健康者内-中膜厚度(IMT)及颈动脉斑块指数(PI),限制性片段长度多态性-聚合酶链反应(RFLP-PCR)技术检测MPO基因G-463A多态性.结果 MPO-463位点G/A多态性有3种基因型(GG,GA,AA),2组间基因型分布和等位基因频率分布差异有统计学意义(P＜0.05).具有GG基因型者发生脑梗死的危险性较具有AA基因型者显著增高[x2=6.925,P=0.008,相对危险度(OR)=4.030,95％可信区间(CI):1.465～11.236];杂合子GA发生脑梗死的危险性较纯合子AA仍有升高趋势(x2=3.43,P=0.006,OR=2.748,95％CI:0.952～7.800);将GA和GG基因型合并计算,发现携带至少1个等位基因G者其患脑梗死的风险仍显著增高(x2=6.20,P=0.013,OR=3.488,95％CI:1.302～9.468).结论 MPO基因G-463A位点多态性与颈动脉斑块程度关系明显.MPO基因G-463A位点多态性与颈动脉斑块患者易发脑梗死的关系明显.     

hOGG1基因多态性与川北地区肺癌易感性关系的研究

目的探讨四川北部地区汉族人群8-羟基鸟嘌呤糖苷酶(hOGG1)基因Ser326Cys位点多态性状况及其与该地区肺癌易感性的关系,并与其他地区人群进行比较。方法采用病例对照研究方法和聚合酶链式反应-限制性片段长度多态性(polymerise chain reaction-restriction fragment length polymorphism,PCR-RFLP)方法检测四川北部地区肺癌患者125例和非肿瘤患者125例(对照组)hOGG1基因第326位点Ser/Cys基因型分布,并比较不同基因型与肺癌发病危险的关系。结果病例组的Ser/Ser、Ser/Cys、Cys/Cys基因型频率分别为15.2%、27.2%、57.6%,而对照组分别为32.0%、42.4%、25.6%。χ2检验显示两组基因型分布差异有统计学意义(P<0.05)。与携带Ser/Ser基因型相比,携带Ser/Cys基因型者患肺癌风险增加(OR=1.351,95%CI=0.674～2.707,P=0.397),而携带Cys/Cys基因型者肺癌风险增加3倍(OR=4.737,95%CI=2.384～9.413,P=0.000)。结论 hOGG1基因Ser326Cys多态性可能与四川北部肺癌易感性有关,携带Cys/Cys基因型肺癌风险明显增加。     

MBL2关键遗传变异对肺癌发病风险的影响

目的分析MBL2基因启动子区rs11003125C>G遗传变异与肺癌易感性的关系。方法使用聚合酶链式反应-限制性片段长度多态性分析(PCR-RLFP)的方法对2008年1月-2012年12月华北理工大学附属唐山工人医院收治的肺癌患者706例(病例组)及健康对照706例(对照组)的MBL2 rs11003125多态位点进行基因分型。用Logistic回归分析统计两个位点各基因型影响肺癌发病风险的OR值及95%CI。结果与MBL2 rs11003125CC基因型携带者相比,携带rs11003125CG基因型的个体发生肺癌的风险显著降低(OR=0.73,95%CI=0.57~0.93,P=0.010)。年龄分层显示,在≤60岁组中,携带rs11003125CG基因型的个体具有较低的肺癌发病风险(OR=0.67,95%CI=0.48~0.92,P=0.015)。吸烟分层显示,在吸烟组中,携带rs11003125CG基因型的个体肺癌发病风险较低(OR=0.61,95%CI=0.40~0.92,P=0.023)。结论 MBL2基因启动子区rs11003125 CG基因型降低肺癌的发病风险。     

TGF-β1基因多态性与高级别宫颈上皮内瘤变易感性的关系

目的研究转化生长因子β1(TGF-β1)基因多态性与高级别宫颈上皮内瘤变(CINⅡ-Ⅲ)遗传易感性的关系。方法选择191例CINⅡ-Ⅲ患者为病例组,207例年龄相匹配的正常者为对照组,采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术检测TGF-β1基因C509T和T869C多态性在两组中的频率和分布,比较不同基因型携带者患CINⅡ-Ⅲ的危险性。结果与携带T869CTT基因型相比,携带T869CTC/CC基因型者罹患CINⅡ-Ⅲ的风险升高1.582倍(OR=1.582,95%CI=1.026-2.438,P<0.05)。产次0-1次和不吸烟的女性携带T869CTC/CC基因型较携带TT基因型者罹患CINⅡ-Ⅲ的风险升高更为显著(P<0.05)。结论 TGF-β1T869C多态性可能与人群CINⅡ-Ⅲ的遗传易感性相关。     

血管紧张素Ⅱ受体基因多态性与醛固酮腺瘤发病风险的相关性

目的 探讨血管紧张素Ⅱ 1型受体及2型受体基因(AT1R、AT2R)多态性与中国汉族人群肾上腺醛固酮腺瘤(APA)发病风险的相关性.方法 提取148例APA组织DNA及192例正常人群外周血DNA;采用MGB-Taqman探针法对AT1R基因(rs5182、rs5186)和AT2R基因(rs5194、rs1403543) 4个SNP位点进行基因型检测.SNPassoc 1.5-3软件分析Hardy-Weinberg平衡以及AT1R、AT2R基因多态性与APA发病危险的关联性.结果 4个位点基因型分布均符合Hardy-Weinberg平衡(P均＞0.05).APA组AT2R基因rs5194位点A等位基因频率(0.49)要高于正常人群组(0.35)(x2=12.08,P==0.001).以rs5194纯合子基因型GG为参照,纯合子基因型AA和杂合子基因型GA的APA发病风险均增高(OR=2.66,95％ CI=1.45-4.87和OR=1.67,95％ CI=1.02-2.74).rs5194位点多态性在显性模型、隐性模型以及加性模型中均与APA发病相关联(OR=1.94,95％CI=1.23-3.06,P=0.003; OR=2.01,95％ CI=1.17-3.45,P=0.01; OR=1.64,95％CI=1.21-2.20,P=0.001).结论 AT2R基因rs5194位点多态性和APA发病相关联,对该SNP位点的检测可能可以对预测APA的发病危险提供有用的遗传信息.     

Glutathione S-transferases mu 1, theta 1, pi 1, alpha 1 and mu 3 genetic polymorphisms and the risk of colorectal and gastric cancers in humans

INTRODUCTION: Glutathione S-transferases (GSTs) are considered to be cancer susceptibility genes as they play a role in the detoxification of carcinogenic species. This study aimed to elucidate the influence of several GST polymorphisms on colorectal and gastric cancer risk. PATIENTS AND METHODS: GST mu1 (GSTM1), theta1 (GSTT1), pi1 (GSTP1), alpha1 (GSTA1) and mu3 (GSTM3) genotypes were determined in 144 colorectal cancer patients, 98 gastric cancer patients and 329 healthy control individuals. RESULTS: Colorectal cancer: the risk is greater for carriers of the GSTM1 null genotype (odds ratio [OR] = 1.91, 95% confidence interval [CI] = 1.25-2.91), for carriers of the GSTT1 null genotype (OR = 3.62, 95% CI = 2.34-5.62), and for simultaneous carriers of both GSTM1 and GSTT1 null genotypes (OR = 4.98, 95% CI = 2.77-9.00). Carriers of the GSTP1 104 Val/Val genotype are at a lower risk (OR = 0.31, 95% CI = 0.09-0.88). Among carriers of the GSTP1 Ile/Ile genotype, smoking increases the risk compared with nonsmoking (OR = 2.35, 95% CI = 1.11-4.99). Gastric cancer: the risk is greater for carriers of the GSTT1 null genotype (OR = 2.58, 95% CI = 1.53-4.36) and for simultaneous carriers of both GSTM1 and GSTT1 null genotypes (OR = 3.32, 95% CI = 1.62-6.77). Carriers of the GSTP1 104 Val/Val genotype are at a lower risk (OR = 0.20, 95% CI = 0.02-0.86). DISCUSSION: The GSTT1 null genotype, particularly if it is associated with the GSTM1 null genotype, greatly increases the risk for colorectal and gastric cancers. The GSTP1 104 Val/Val genotype may protect from both malignant tumors. CONCLUSION: This study indicates that GST polymorphisms, in particular the GSTM1/GSTT1 double-null haplotype, can be considered low-penetrance genes for gastrointestinal cancer.     

The human 8-oxoguanine DNA N-glycosylase 1 (hOGG1) DNA repair enzyme and its association with lung cancer risk

OBJECTIVE: The human 8-oxoguanine DNA N-glycosylase 1 gene encodes a DNA glycosylase that is involved in the base excision repair of 8-hydroxy-2-deoxyguanine from oxidatively-damaged DNA and expressed in lung tissue. The codon 326 polymorphism in the hOGG1 gene has been suggested to reduce DNA repair enzyme activity based on in vitro functional analysis. The goal of the present study is to determine whether the codon 326 polymorphism was significantly associated with alterations in individual risk for lung cancer. METHODS: To determine whether hOGG1 plays a role in risk for lung cancer, we measured the prevalence of the Ser326Cys polymorphism in incident lung cancer patients and matched non-cancer controls. hOGG1 genotyping was performed by PCR-restriction fragment length polymorphism analysis of genomic DNA isolated from 179 Caucasian lung cancer cases and 358 controls individually matched in a 1:2 ratio by race-, sex- and age (+/- 5 years). RESULTS: Significantly increased risk for lung cancer was observed for both the hOGG1 326 (odds ratio [OR] = 1.9, 95% confidence interval [CI] = 1.2-2.9) and hOGG1 326 genotypes (OR = 3.8, 95% CI = 1.4-10.6). The increased risk for lung cancer was observed for subjects with both the hOGG1 326 (OR = 1.7, 95% CI = 1.1-2.8) and hOGG1 326 genotypes (OR = 4.9, 95% CI = 1.5-16.1) in ever-smokers. A significant association was found between hOGG1 genotypes and lung cancer risk with a dose-dependent effect with smoking. Significantly increased risk for variant hOGG1 genotypes was observed for all non-small cell lung cancer patients. CONCLUSION: These results suggest that the hOGG1 Ser326Cys polymorphism plays an important role in the risk for lung cancer and is linked to exposure to tobacco smoke.     

NAT2 slow acetylation and GSTM1 null genotypes may increase postmenopausal breast cancer risk in long-term smoking women

N-acetyltransferase (NAT) 1 and 2 and glutathione S-transferase (GST) M1 and T1 are phase II enzymes that are important for activation and detoxification of carcinogenic heterocyclic and aromatic amines, as present in cigarette smoke. We studied whether genetic polymorphisms in these genes modifies the relationship between smoking and breast cancer. A nested case-control study was conducted among participants in a Dutch prospective cohort. Breast cancer cases (n=229) and controls (n=264) were frequency-matched on age, menopausal status and residence. Compared to never smoking, smoking 20 cigarettes or more per day increased breast cancer risk statistically significant only in postmenopausal women [odds ratio (OR)=2.17; 95% confidence interval (CI) 1.04-4.51]. Neither NAT1 slow genotype, or GSTT1 null genotype, alone or in combination with smoking, affected breast cancer risk. However, compared to individuals with rapid NAT2 genotype, women with the very slow acetylator genotype (NAT2*5), who smoked for 20 years showed an increased breast cancer risk (OR=2.29; 95% CI 1.06-4.95). Similarly, the presence of GSTM1 null genotype combined with high levels of cigarette smoking (OR=3.00; 95% CI 1.46-6.15) or long duration (OR=2.53; 95% CI 1.24-5.16), increased rates of breast cancer. The combined effect of GSTM1 null genotype and smoking high doses was most pronounced in postmenopausal women (OR=6.78; 95% CI 2.31-19.89). In conclusion, our results provide support for the view that women who smoke and who have a genetically determined reduced inactivation of carcinogens (GSTM1 null genotype or slow NAT2 genotype (especially very slow NAT2 genotype)) are at increased risk of breast cancer.     

Alcohol consumption, glutathione S-transferase M1 and T1 genetic polymorphisms and breast cancer risk

To evaluate the potential association between GSTM1 and GSTT1 genotypes and development of breast cancer, a hospital based case-control study was conducted in a South Korean study population consisting of 189 histologically confirmed incident breast cancer cases and their 189 age-matched control subjects with no present or previous history of cancer. A multiplex polymerase chain reaction method was used for the genotyping analyses and statistical evaluations were performed by unconditional logistic regression model. The GSTM1 null genotype was significantly associated with breast cancer risk in premenopausal women [odds ratio (OR) = 2.0, 95% confidence interval (CI) = 1-3.7], but not in the postmenopausal women (OR = 0.9, 95% CI = 0.5-1.9), nor in all women grouped together (OR = 1.3, 95% CI = 0.8-1.1). The GSTT1 null genotype posed a similar risk of breast cancer with an OR of 1.6 (95% CI = 1.0-2.5) for the total breast cancer group, OR of 1.7 (95% CI = 0.9-3.2) for pre-menopausal women, and OR of 1.3 (95% CI = 0.6-2.8) for post-menopausal women. The breast cancer risk associated with concurrent lack of both GSTM1 and GSTT1 genes was 2.2 (95% CI = 1.1-4.5), and the risk increased as the number of null genotype increased (P for trend = 0.03). When the data were stratified by the known risk factors of breast cancer, a significant interaction was observed between the GSTM1 genotypes and alcohol consumption (P for interaction = 0.03). An especially remarkable risk of breast cancer was observed for alcohol-consuming premenopausal women lacking both the GSTM1 and GSTT1 genes (OR = 5.3, 95% CI = 1.0-27.8) compared to those with both of the genes. Our findings thus suggest a novel gene-environment interaction which plays an important role in the individual susceptibility to breast cancer. p6     

Polymorphism in cytochrome P450 CYP2D6, CYP1A1, CYP2E1 and glutathione S-transferase, GSTM1, GSTM3, GSTT1 and susceptibility to tobacco-related cancers: studies in upper aerodigestive tract cancers

Glutathione S-transferase GSTM1, GSTM3 and GSTT1 and cytochrome P450 CYP2D6, CYP1A1 and CYP2E1 loci are susceptibility candidates for cancers of the upper aerodigestive tract because putatively protective and risk genotypes have been identified from studies in other diseases associated with alcohol and tobacco consumption. We describe genotype frequencies in 398 oral, pharyngeal and laryngeal squamous cell carcinoma patients and 219 control individuals. Of the genotypes presumed to be protective, only GSTM1 A/B influenced susceptibility; the GSTM1 A/B frequency was lower in the patients than the control individuals both before [odds ratio = 0.3, 95% confidence interval (CI) 0.1-0.7] and after correction for imbalances in age, sex, smoking and alcohol consumption (odds ratio = 0.2, 95% CI 0.1-0.5). Of the putatively risk genotypes, GSTM3 AA, previously associated with susceptibility to skin cancer, was higher in the cases (odds ratio = 1.6, 95% CI 1.1-2.4). Dividing cases into oral/pharyngeal and laryngeal squamous cell carcinoma showed the GSTM3 AA frequency was higher in laryngeal squamous cell carcinoma than control individuals (odds ratio = 1.6, 95% CI 1.1-2.5) and the difference between control individuals and oral/pharyngeal squamous cell carcinoma approached significance (odds ratio = 1.7, 95% CI 1.0-2.8). The putatively protective GSTM3 BB genotype was lower in patients with glottic (1.0%) than supraglottic (3.0%) squamous cell carcinoma. We identified no differences between patients and control individuals in the frequencies of presumed risk genotypes (e.g. CYP2D6 EM, CYP1A1 m1/m1, CYP1A1 Ile/Ile, CYP2E1 DD, CYP2E1 c1c1, GSTT1 null) or, interactions between genotypes and smoking or alcohol consumption. We conclude, first, that mu class glutathione S-transferase influence risk of upper aerodigestive tract cancers thereby complementing studies in skin cancer patients showing GSTM1 A/B is protective, while GSTM3 AA moderately increases risk. The influence of GSTM1 A/B, but not GSTM1 A or GSTM1 B (mostly heterozygotes with GSTM1*0) suggests that two expressed alleles may attenuate risk. While we found immunohistochemical evidence of GSTM3 expression in the cilia lining the larynx, the biochemical consequences of the polymorphism are unclear. Indeed, the influence of the gene may reflect linkage disequilibrium with another gene. However, we did not find an association with GSTM1 genotypes. Second, we conclude that the CYP2D6, CYP2E1, CYP1A1 and GSTT1 alleles studied, although putatively good candidates, either do not determine the effectiveness of detoxification of tobacco-derived carcinogens in the upper aerodigestive tract or, that chronic consumption of tobacco and alcohol overwhelms enzyme defences, irrespective of genotype.     

Polymorphisms of glutathione S-transferase genes (GSTM1, GSTP1 and GSTT1) and bladder cancer susceptibility in the Turkish population

We investigated the effect of the GSTM1 and GSTT1 null genotypes, and GSTP1 313 A/G polymorphism on bladder cancer susceptibility in a case control study of 121 bladder cancer patients, and 121 age- and sex-matched controls of the Turkish population. The adjusted odds ratio for age, sex, and smoking status is 1.94 [95% confidence intervals (CI) 1.15-3.26] for the GSTM1 null genotype, and 1.75 (95% CT 1.03-2.99) for the GSTP1 313 A/G or G/G genotypes. GSTT1 was shown not to be associated with bladder cancer. Combination of the two high-risk genotypes. GSTM1 null and GSTP1 313 A/G or G/G, revealed that the risk increases to 3.91-fold (95% CI 1.88-8.13) compared with the combination of the low-risk genotypes of these loci. In individuals with the combined risk factors of cigarette smoking and the GSTM1 null genotype, the risk of bladder cancer is 2.81 times (95% CI 1.23-6.35) that of persons who both carry the GSTM1-present genotype and do not smoke. Similarly, the risk is 2.38-fold (95% CI 1.12-4.95) for the combined GSTP1 313 A/G and G/ G genotypes and smoking. These findings support the role for the GSTM1 null and the GSTP1 313 AG or GG genotypes in the development of bladder cancer. Furthermore, gene-gene (GSTM1-GSTP1) and gene-environment (GSTM1-smoking, GSTP1-smoking) interactions increase this risk substantially.     

Glutathione-S-transferase M1, M3, T1 and P1 polymorphisms and susceptibility to non-small-cell lung cancer subtypes and hamartomas.

Polymorphic glutathione-S-transferase (GST) genes causing variations in enzyme activity may influence individual susceptibility to lung cancer. In this case-control study (consisting of 389 Caucasian lung cancer patients, including 151 adenocarcinomas (ACs) and 172 squamous cell carcinomas (SCCs), and 353 hospital control subjects without malignant disease, genotype frequencies for GSTM1, GSTM3, GSTP1 and GSTT1 were determined by polymerase chain reaction (PCR)/ restriction fragment length polymorphism (RFLP)-based methods. While adjusted odds ratios (ORs) indicated no significantly increased risk for lung cancer overall due to any single GST genotype, the risk alleles for GSTM1, GSTM3 and GSTP1 conferring reduced enzyme activity were present at higher frequency in SCC than in AC patients. This is consistent with a reduced detoxification of carcinogenic polycyclic aromatic hydrocarbons (PAHs) from cigarette smoke that are more important for the development of SCC than for AC. An explorative data analysis also identified statistically significantly increased ORs for the combinations GSTT1 non-null and GSTP1 GG or AG for lung cancer overall (OR 2.23, CI 1.11-4.45), and for SCC (OR 2.69, CI 1.03-6.99). For lung cancer overall, and especially among SCC patients, the GSTT1 null genotype was underrepresented (SCC 11.2% v. control subjects 19%, P = 0.026, OR 0.57, CI 0.30-1.06). Additionally, in 28 patients with hamartomas, the GSTT1 null genotype was also protective (P = 0.013), while GSTP1 variant allele carriers were overrepresented (OR 2.48, CI 1.06-6.51). In conclusion, GST genotypes may act differently, either by detoxifying harmful tobacco carcinogens and/or by eliminating lung cancer chemopreventive agents. The latter role for GSTT1 would explain the observed lower risk of SCC and hamartoma associated with GSTT1 null. Further confirmatory studies are required.     

SNPs of GSTM1, T1, P1, epoxide hydrolase and DNA repair enzyme XRCC1 and risk of urinary transitional cell carcinoma in southwestern Taiwan

A hospital-based case-control study was conducted near a former black-foot disease (BFD)-endemic area in southwestern Taiwan to examine the possible risk factors and genetic susceptibility for urinary transitional cell carcinoma (TCC). A total of 221 patients with pathologically confirmed TCC and 223 age-sex-matched control subjects from urology outpatient clinics were recruited between 1998 and 2002. The results showed that residency in the BFD area and consumption of well water for more than 10 years was a strong factor on urinary cancer risk (odds ratio [OR],8.16, 95% confidence interval [CI],3.34-19.90, p<0.0001). Dose response relationship between average arsenic concentration in well water and TCC risk was also observed. Cigarette smoking played a relatively minor role in urinary carcinogenesis in this study. The GSTP1 Ile105Val A-->G polymorphism was significantly associated with cancer risk (A/G+G/G: OR=0.60, 95%CI=0.39-0.94, p=0.02), and the effect of Val105 allele was largely confined to the subjects diagnosed earlier than 55 years old (A/G+G/G: OR,0.29; 95% CI, 0.09-0.87, p=0.03). The results suggest that GSTP1 is a candidate for susceptibility locus and Ile105 allele may predispose individuals to early-onset urinary TCC. The GSTM1 null genotype was associated with tumors of high-invasiveness (OR,2.21; 95% CI, 1.34-4.73) as well as with early-onset TCC risk (OR,2.53; 95% CI, 0.97-6.59). Our preliminary results showed the XRCC1 Arg194Trp were associated with arsenic-related urinary TCC and the interaction between the genotype and the exposure was statistically significant. The modulating effect of the GSTM1, GSTT1, GSTP1 Ile105Val, EPHX Tyr113His and XRCC1 Arg280His on arsenic-related TCC risk was also suggestive. These observations implied that impaired metabolism of carcinogenic exposure as well as impaired DNA repair function play an important role in arsenic-related urinary transitional cell carcinogenesis.