GSTM1和CYP2E1基因多态性与肺癌遗传易感性关系的研究

背景与目的肺癌是中国人群恶性肿瘤死因的首位，其发病可能与肺癌人群中某些肺癌相关基因的遗传多态性有关。本研究旨在探讨细胞色素P4502E1(CYP2E1)基因RsaⅠ／PstⅠ多态性和谷胱甘肽转移酶M1(GSTM1)基因多态性与肺癌易感性之间是否存在相关性。方法应用PCR-RFLP和PCR法检测99例人非小细胞肺癌患者和66例同期住院的肺良性疾病患者CYP2E1基因的RsaⅠ／PstⅠ多态性和GSTM1基因多态性，并分析其与肺癌遗传易感性的相关性。结果(1)CYP2E1基因RsaⅠ／PstⅠ多态性的三种基因型在肺癌组和对照组的频率差异没有统计学意义(χ^2=1．374，P=0．241)。(2)肺癌组GSTM1(-)基因型频率显著高于对照组(分别为57．6％和40．9％)(χ^2=4．401，P=0．036)。(3)携带GSTM1(-)基因型的个体患肺癌的危险性显著高于GSTM1( )基因型的个体(OR=1．96，95％CI=1．042～3．689，P=0．037)。(4)与携带c1／c2或c2／c2基因型的不吸烟个体比较，携带c1／c1基因型的吸烟者患肺癌的风险显著增加(OR=3．525，95％CI=1．168～10．638，P=0．025)。(5)联合分析CYP2E1基因RsaⅠ／PstⅠ多态性和GSTM1基因多态性，携带有c1／c1和GSTM1(-)基因型的个体患肺癌的风险显著高于携带GSTM1( )和c1／c2或c2／c2基因型的个体(OR=3．449，95％CO=1．001～11．886，P=0．050)。按照吸烟因素分层，携带有GSTM1(-)和c1／c1基因型的不吸烟个体患肺癌的风险显著高于携带GSTM1( )和c1／c2或c2／c2基因型的不吸烟个体(OR=11．553，95％CI=1．068-124．944，P=0．044)，携带有GSTM1(-)和c1／c2或c2／c2基因型的不吸烟个体患肺癌的风险同样显著高于携带GSTM1( )和c1／c2或c2／c2基因型的不吸烟个体(OR=13．374，95％CI=1．258～142．166，P=0．032)。结论(1)GSTM1(-)基因型增加人群患肺癌的风险；(2)CYP2E1的c1／c1基因型和GSTM1(-)基因型的联合可增加吸烟和不吸烟人群患肺癌的风险。     

广州地区汉族人群肺癌易感性标记物CYP1A1、CYP2E1和GSTM1与肺癌关系的病例对照研究

[目的]探讨广州地区汉族人群谷胱苷肽硫转移酶（GSTM1）、细胞色素P4501A1（CYP1A1）和细胞色素P4502E1（CYP2E1）基因多态性与肺癌易感性的关系。[方法]选取中山大学附属第一医院、广州市肿瘤医院、广州市红十字会医院等医院的广州籍新发肺癌病人91例及同期上述各医院的同性别非肺部疾患病人91例作对照，采用聚合酶链式反应（PCR）和限制性片段长度多态性（RFLP）技术检测CYP1A1、CYP2E1和GSTM1的基因多态性。[结果]与野生型的CYP1A1相比，突变型肺癌OR为1．51（0．76～3．011。CYP2E1C2C2基因型与C1C1基因型比较，其OR为5．48（1．21～25．23）．GSTM1基因缺失型的OR值为1．26（0．69～2.30）．而三者联合作用时．则可增加患肺癌的危险，其OR值为3．97（0．94-16．791，但无统计学意义（P〉0．05）。[结论]CYP1A1、CYP2E1和GSTM1的某些基因型增加了患肺癌的危险性，但尚未达到统计学的显著性水平，说明它们均不是肺癌个体易感性的主效基因．而是次效基因。     

CYP1A1 GSTM1基因多态性和吸烟与肺癌易感性关系的病例对照研究

目的:探讨天津市居民致癌物代谢酶CYP1A1和GSTM1基因多态性对肺癌易感性的影响。方法:利用限制性片断长度多态性-聚合酶链反应(RFLP-PCR)方法检测原发性肺癌患者和健康对照者细胞色素P450酶基因CYP1A1Msp位点和谷胱甘肽硫转移酶基因GSTM1的多态性情况。结果:肺癌组与对照组之间CYP1A1和GSTM1基因型分布差异均存在统计学显著意义(P<0.05)。携带CYP1A1变异基因型或GSTM1阴性基因型的个体患肺癌的危险性增高,比值比(OR)分别达到2.44(1.04～5.81)和1.84(1.03～3.29)。多因素分析结果显示具有CYP1A1变异基因型、GSTM1阴性基因型的吸烟个体患肺癌的风险较大。结论:CYP1A1Msp位点变异基因型和GSTM1阴性基因型可能是肺癌的易感因素,吸烟与肺癌易感基因之间具有协同作用。     

CYP1A1和GSTM1基因多态性与内蒙古人群肺癌易感性的关系

背景与目的 肺癌是严重危害人类健康的恶性肿瘤之一，其发病与肺癌人群中某些肺癌相关基因的遗传多态性有关。本研究旨在探讨细胞色素P4501A1（CYP1A1）基因多态性和谷胱甘肽硫转移酶M1（GSTM1）基因多态性与内蒙古人群肺癌易感性的关系。方法 用PCR-RFLP技术分析了原发性肺癌组和住院对照组（各163例）的CYP1A1、GSTM1基因的多态性、基因型分布频率和交互作用。结果 CYP1A1突变型和GSTM1基因缺陷型EGSTM1（-）]频率分布分别为36．8％、65．0％（病例组）和19．0％、48．9％（对照组），二者经χ^2检验差异有显著性（χ^2=12．82，P=0．000；χ^2=9．78，P=0．002）。CYP1A1突变型患肺癌的风险显著增加（OR=2．48，95％CI为1．51～4．08）。GSTM1（-）者患肺癌的风险也显著增加（OR=2．03，95％CI为1．30～3．17）。基因突变的协同分析发现CYP1A1突变型／GSTM1（-）在肺癌组和对照组中的分布频率分别为28．8％和8．0％，二者经χ^2检验有显著性差异（χ^2=23．883，P=0．000）。CYP1A1突变型／GSTM1（-）患肺癌的风险显著增加（OR=4．90，95％CI为2．50～9．83）。无论是在肺癌组还是在对照组，CYP1A1突变型／GSTM1（-）和CYP1A1非突变型／GSTM1（-）在性别间分布频率的差异均无显著性（肺癌组χ^2=0．797，P=0．372；对照组χ^2=0．670，P=0．761）。吸烟与肺癌易感性的统计学分析，结果显示吸烟与肺癌易感性有关（χ^2=14．197，P=0．000），吸烟者患肺癌的风险显著增加（OR=2．33，95％CI为1.50～3．62）。CYP1A1突变型与吸烟关系的协同分析发现，携带CYP1A1突变型基因的吸烟者较携带CYP1A1突变型基因不吸烟者易患肺癌（OR=4．44，95％CI为2．40～8．32，χ^2=23．843，P=0．000）。GSTM1（-）与吸烟关系的协同分析中也发现，携带GSTM1（-）的吸烟者患肺癌的风险显著增加（OR=7．32，95％CI为3．39～15．50，χ^2=36．708，P=0．000）。结论 CYP1A1突变型和GSTM1（-）是内蒙古地区肺癌的易患因素，二者对肺癌的发生有协同作用，吸烟与肺癌的易感性也有关，CYP1A1突变型、GSTM1（-）与吸烟在肺癌的发生上也有相互促进作用。     

代谢酶基因多态性与肺癌易感性关系的研究

目的　探讨代谢活化酶细胞色素P45 0 1A1(CYP1A1)、2D6(CYP2D6)、2E1(CYP2E1)和代谢解毒酶谷胱甘肽硫转移酶 (GSTM 1)基因多态性与肺癌易感性的关系及重度吸烟对肺癌易感性的影响。方法　采用PCR、PCR RFLP等技术检测 180例原发性肺癌患者及 2 2 4例肺部良性疾病患者和正常人 (对照组 )外周血代谢酶基因型。结果　CYP1A1突变等位基因 (m )、CYP2D6野生型等位基因 (w )、CYP2E1A基因型和GSTM 1功能缺失型 ( -)可使患肺癌的危险性增加到 1.5 0～ 1.5 8倍 (P <0 .0 5 )。携带GSTM 1( -)者若同时携带CYP1A1、2D6或 2E1中任意 1个易感基因型 ,可使患肺癌的危险性升高到 2 .2 4～ 2 .69倍 (P <0 .0 5 )。携带相同基因型者 ,重度吸烟比不吸烟者患肺癌的危险性显著升高。重度吸烟人群中携带 4种易感基因型者患肺癌的危险性显著增高 ,达 9.85倍 ( 95 %CI =2 .3 0～ 45 .71)。结论　代谢酶基因的易感等位基因携带者患肺癌的危险性上升 ,且与烟草致癌物暴露剂量呈正相关。     

CYP2C9、GSTM1基因多态性与肺癌易感性的关系

目的探讨细胞色素P4502C9(CYP2C9)基因、谷胱甘肽硫转移酶M1(GST M1)基因多态性与肺癌易感性的关系。方法用PCR-RFLP法分析56例肺癌(简称肺癌组)和42例健康对照组NsiⅠ识别的CYP2C9基因型;用PCR法分析其GST M1基因型。结果突变型CYP2C9*3型基因发生频率在肺癌组中为8.93%,高于对照组的4.76%,其差异无显著性(P>0.05)。肺癌组GST M1基因缺失型〔GST M1(-)〕发生率为71.43%,高于对照组的45.24%,其差异有显著性(P<0.01);GST M1(-)型与肺癌呈高度联系强度,OR=3.09(95%CI=1.32~6.94);GST(-)基因型在吸烟的肺癌组(81.08%)与对照组(52.18%)之间的频率差异有显著性(P<0.05)。结论突变型CYP2C9*3型基因与肺癌无显著性联系;GST M1(-)基因型是肺癌发生的遗传易患性因素;吸烟可显著提高GST(-)基因型个体患肺癌的危险性。     

CYP1A1、GSTM1基因多态性与肺癌易感性的研究

目的:探讨CYP1A1、GSTM1基因多态性与肺癌易感性之间的相关性。方法:利用RFLP-PCR(限制性片段长度多态性-聚合酶链反应)方法检测65例原发性肺癌和60例非肿瘤患者CYP1A1、GSTM1基因,再用NcoI及HinfI两种内切酶识别CYP1A1等位基因亚型。结果:1)肺癌组与对照组CYP1A1等位基因型Ile/Ile、Ile/Val、Val/Val的频率总体分布无显著性差异;但肺癌组CYP1A1(Val/Val)基因型频率(18.5%)明显高于对照组(8.3%),两组差异有显著性(P<0.05)。2)肺癌组GSTM1(-)基因型的频率(63.1%)明显高于对照组(45.0%),P<0.05。3)两种等位基因联合分析发现,与携带CYP1A1(Ile/Ile)/GSTM1(+)基因型的个体相比:CYP1A1(Ile/Ile)/GSTM1(-)以及CYP1A1(Ile/Val+Val/Val)/GSTM1(+)基因型个体患肺癌的风险度较高,OR分别为3.82(95.0%CI,1.27～11.45)和3.5(95.0%CI,1.18～10.41);而CYP1A1(Val/Val)/GSTM1(-)基因型个体患肺癌的风险度最高,OR为10.5(95.0%CI,1.70～64.73)。4)进一步分层分析发现,CYP1A1(Ile/Val+Val/Val)等位基因型主要增加鳞癌的危险性;而GSTM1基因型组织类型无明显的相关性。5)在分析吸烟对肺癌易感性的影响时发现,CYP1A1(Ile/Val+Val/Val)及GSTM1(-)等位基因型与吸烟有协同作用,并与至发病时的累积吸烟量有关。结论:CYP1A1(Val/Val     

广西壮族人群GSTM1和GSTT1基因多态性与肺癌易感性关系的研究

[目的]探讨广西壮族人群谷胱甘肽硫转移酶（glutathione S-transferase,GST）中的GSTM1和GSTT1基因多态性与肺癌易感性的关系。[方法]以病例对照研究方法,采用聚合酶链式反应（PCR）分别检侧58例肺癌患者和60例健康对照的GSTM1、GSTT1基因多态性;χ2检验分析各种基因型频率在肺癌组和对照组之间的差异;用Logistic回归分析吸烟与GSTM1、GSTT1基因型多态性的联合作用。[结果]单独分析GSTM1、GSTT1基因多态性与肺癌相关性无统计学意义,而两者联合则与肺癌有相关性（χ2=4.085,P=0.043）。吸烟与GSTM1缺陷型基因对肺癌易感有协同作用,OR为3.778（95%CI：1.170～12.194,P=0.026）;吸烟与GSTT1缺陷型基因对肺癌易感无协同作用,OR为2.833（95%CI：0.982～8.173）。[结论]GSTM1、GSTT1的单一基因多态性不增加患肺癌的危险,而两者联合作用时可增加患肺癌的风险。GSTM1缺陷型有吸烟行为的人更易患肺癌。     

细胞色素P450 2E1基因多态性与肺癌易感性的研究

目的:研究与致癌物有关的代谢酶细胞色素P450 2E1(CYP 2E1)基因多态性和饮酒与肺癌易感性的关系.方法:采用聚合酶链反应(Polymerase Chain Reaction,PCR)和限制性片段长度多态性(Restriction FregmentLength Polymorphisrms,RFLP)方法,分析91例肺癌患者和138例对照的Rsal认别的CYP 2E1基因型.结果:本次研究结果为CYP 2E1基因型频率在肺癌组和对照组的分布差异无显著性意义(X2=1.355,P＞0.05);CYP 2E1C1/C1基因型或饮酒单因素作用的比值比(Odds Ratil,OR)分别为1.389和3.33,而两者联合作用的OR为5.41.结论:CYP 2E1基因多态性与肺癌无明显相关性,但与饮酒有联合作用.     

CYP2D6遗传多态性与肺癌易感性关系的研究

目的探讨CYP2D6Ch基因多态性的频率分布,以及与肺癌的遗传易感性关系.方法应用病例-对照研究及PCR-RFLP等技术,检测肺癌及正常对照各50例的CYP2D6Ch基因型,并应用Logistic回归分析基因多态性与肺癌易感性的关系.结果(1)CYP2D6Ch T/T型(突变型)频率在病例组中为36.0%,在对照组中为50.0%;非T/T型(即C/C合并C/T基因型)与肺癌风险临界升高相关(OR=3.06;95%CI=0.94～9.92).(2)对病例组进行相关变量的分层分析后发现,在肺鳞癌,或轻度吸烟组中,CYP2D6Ch非T/T型与肺癌风险升高显著相关(分别为:OR=3.20,CI=1.04～9.85;OR=7.07,CI=1.16～42.85).结论本文提示CYP2D6Ch基因型分布规律与欧美人群差异较大,且T/T型在肺鳞癌或轻度吸烟者中可作为保护因素而降低肺癌的易感性.     

细胞色素P450 1A1和谷胱苷肽硫转移酶基因多态性与肺癌关系的病例对照研究

目的　探讨细胞色素P4 5 0 1A1(CYP 1A1)和谷胱苷肽硫转移酶 (GST) M1基因多态性与肺癌易感性的关系。方法　选取新发肺癌患者 91例及同期非肺部疾患同性别患者 91例作匹配 ,另选取体检正常者 4 7例做频数对照 ,采用聚合酶链式反应 (PCR)和限制性片段长度多态性 (RFLP)技术检测CYP 1A1和GST M1的基因多态性。结果　单独分析CYP 1A1和GST M1基因多态性与肺癌的关系 ,其OR值分别为 1.5 3和 1.4 2 ,与对照组比较 ,差异均无显著性 (P >0 .0 5 ) ,表明与肺癌的发生无相关性。而将二者联合分析时 ,其OR值为 2 .4 7,95 %CI为 1.0 3～ 5 .90 ,与对照组比较 ,差异有显著性(P <0 .0 5 ) ,表明与肺癌的发生有一定相关性。结论　CYP 1A1和GST M1的单一基因多态性不增加患肺癌的危险 ,而两者联合作用时 ,则可增强患肺癌的风险。     

Genetic Polymorphisms of Xenobiotic Metabolizing Genes (GSTM1, GSTT1, GSTP1), Gene-Gene Interaction with Association to Lung Cancer Risk in North India; A Case Control Study

Aim: In this case control study involving, 220 human subjects; polymorphisms in xenobiotic metabolizing genes (GST-M1, -T1 and -P1) and their association to lung cancer risk is being analysed among smokers and non-smokers. GSTM1 or GSTT1 gene polymorphism and amino acid changes in GSTP1 have been correlated and may be associated to lung cancer risk. Other factor includes exposure to environmental pollutants and life style choices. We have explored gene-gene and gene-environment interaction in the aetiology of lung cancer risk among north Indian population. Patients and Methods: For the study we have collected 120 lung cancer patient blood samples from Kamala Nehru Memorial Cancer Hospital, Allahabad, Uttar Pradesh and 100 matched controls. DNA was isolated and GST-M1 and - T1 genotyping were assessed by multiplex PCR whereas the GSTP1 polymorphism was analysed using restriction fragment length polymorphism. The risk of lung carcinogenesis was assessed using logistic regression analysis calculating the odd ratio (OR) with 95% confidence interval (CI). Results: The risk of lung carcinogenesis was three fold higher for null GSTT1 (OR=3.045, 95%CI=1.750-5.301, p-value <0.001) genotype; whereas other two types; GSTM1 (OR= 1.342, 95% CI=0.788-2.284, p-value=0.270) and GSTP1 (OR=0.806, 95% CI=0.526-1.236, p-value=0.323) showed no association to lung cancer susceptibility respectively. Smokers diagnosed with lung cancer had more null genotypes for GSTT1 (OR=4.773, 95%CI=1.939-11.751, p<0.001). The ‘at risk’ genotype combination GSTM1 (null) /GSTT1 (null) (OR=1.76, 95%CI; 0.920-3.370, p-value=0.03) showed increased susceptibility to lung cancer risk. The genotype combination of GSTT1 (null)/GSTP1 (Ile/Ile) (p=0.009) was associated with increased lung cancer risk. Conclusion: The results of this study suggest that; GSTT1 null genotype were more susceptible for lung cancer risk and smoking increases the susceptibility for lung cancer several folds among the North Indian population. Gene-gene interaction for null genotypes of GSTM1 and GSTT1 were correlated with higher risk of having lung cancer.     

Interactive effect of genetic polymorphism of glutathione S-transferase M1 and smoking on squamous cell lung cancer risk in Korea

To evaluate the role of the genetic polymorphisms of CYP2E1, GSTM1 and GSTT1, and their interaction with smoking in lung cancer development in Korean males, a hospital-based case-control study was conducted. Histologically confirmed male lung cancer patients (n=171) and male patients with no present or previous history of systemic illness who visited the urology department (n=196) were recruited from Seoul National University Hospital, Korea (1998-1999). CYP2E1 genotypes were determined by PCR-RFLP using RsaI digestion and GSTM1 and T1 genotypes were determined by multiplex PCR. Risks were estimated as odds ratios (ORs) and 95% confidence intervals (CIs) using a logistic regression model adjusting for age and pack-year. Smoking was a significant risk factor for lung cancer (P<0.001). Although genetic polymorphisms of CYP2E1, GSTM1 and T1 were not associated with the overall risk of lung cancer, the GSTM1 null genotype significantly increased the risk of squamous cell lung cancer (OR=1.9, 95% CI=1.04-3.60). An interactive effect between the GSTM1 null genotype and smoking was observed (P=0.04). These results suggest that the GSTM1 null genotype is associated with squamous cell lung cancer and modifies the effect of smoking on squamous cell lung cancer development in Korean males.     

GSTM1 and NAT2 polymorphisms in operable and non-operable lung cancer patients

We have genotyped 657 Norwegian men, including 282 lung cancer patients (147 non-operable and 135 operable) and 375 healthy referents (210 smokers and 165 non-smokers), to study the possibility that glutathione S-transferase M1 (GSTM1)-null and/or N-acetyl transferase 2 (NAT2)-slow genotypes confer susceptibility towards lung cancer in smokers. Compared with smoking referents, there was a significant over-representation of the GSTM1-null genotype among patients with squamous cell carcinoma (SQ) [odds ratio (OR) = 1.7, 95% confidence interval (95%CI) = 1.1-2.7], and the NAT2-slow genotype among patients with large cell carcinoma or mixed histological diagnosis (LM) (OR = 2.5, 95%CI = 1.0-6.1). In contrast to operable patients, non-operable patients showed a clear over-representation of slow genotypes if they were younger (相似文献   

中国人肺癌易患性与CYP2E1基因多型性相关

目的　研究致癌物代谢酶细胞色素P45 0 2E1基因 (CYP2E1)多型性与肺癌风险的关系。方法　以PCR RFLP方法 ,分析 92例肺癌患者和 137例正常对照者RsaI识别的CYP2E1基因型。结果　c1/c1基因型频率在肺癌病例组为 72 8% ,显著 (P <0 0 1)高于对照组的 5 4 7%。多因素分析表明 ,携带c1/c1的个体发生肺癌的危险性比携带c1/c2和c2 /c2的个体高 2 5倍 (OR 2 5 ,95 %CI 1 8～ 3 8)。分层分析发现 ,c1/c1基因型主要增加肺鳞状细胞癌的危险性 (OR 2 6 ,95 %CI 2 3～ 5 8)。重要的是 ,研究发现CYP2E1c1/c1基因型与吸烟有协同作用。c1/c1基因型或吸烟单因素作用的OR分别为 3 9和 4 1,而二者联合作用的OR为 7 9;当吸烟量 <2 0包 年时 ,c1/c2和c2 /c2基因型的OR为 2 4,而c1/c1基因型的OR为 7 6 ;当吸烟量≥ 2 0包 年时 ,前者的OR为 5 5 ,而后者的OR增加到8 7。结论　CYP2E1c1/c1基因型是中国人肺癌的遗传易患性因素 ,此种基因型与吸烟有协同作用。     

Effect of vitamin intervention on the relationship between GSTM1, smoking, and lung cancer risk among male smokers.

The GSTM1 (glutathione S-transferase mu-1) null genotype is suspected of increasing an individual's susceptibility to tobacco smoke carcinogens because of impaired carcinogen detoxification. We were interested in whether there were differences in lung cancer susceptibility to smoking within the GSTM1 genotypes and the impact of antioxidant supplementation on this. For this purpose, we conducted a nested lung cancer case-control study and evaluated the role of GSTM1 within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. GSTM1 genotype status was determined for 319 cases and 333 controls using a PCR-based approach. GSTM1 was evaluated as an independent risk factor and as an effect modifier of smoking using logistic regression analyses. The GSTM1 null genotype itself was unrelated to risk of lung cancer, odds ratio (OR) = 1.09 and 95% confidence interval (CI), 0.79-1.50, but it may have modified the effect of smoking. There was a suggestion for a stronger association between years of smoking and lung cancer among the GSTM1 null genotype, but the differences between GSTM1 null and present genotypes were not statistically significant (P = 0.12). Furthermore, the smoking association was strongest among those with the GSTM1 null genotype not receiving alpha-tocopherol supplementation, whereas among those receiving alpha-tocopherol, there was no modification by GSTM1 on the association between smoking duration and lung cancer risk. Beta-carotene supplementation did not modify the relationship between GSTM1, smoking years, and lung cancer risk. In conclusion, GSTM1 is not associated with lung cancer risk in male smokers but may confer a higher susceptibility to cumulative tobacco exposure. This association may be attenuated by alpha-tocopherol but not by beta-carotene supplementation.     

Association of CYP1A1, CYP1A2, GSTM1 and NAT2 gene polymorphisms with colorectal cancer and smoking.

We investigated CYP1A1*2A, CYP1A1*2C, CYP1A2*1C, CYP1A2*1F, GSTM1 and NAT2 gene polymorphisms, involving enzymes which metabolize many carcinogens, with reference to colorectal cancer risk. The distribution of these genotypes was not associated with risk overall. However, the CYP1A1*2A T/C genotype showed a significant association with colorectal cancer risk in never-smokers (odds ratio [OR], 3.06; 95% confidence interval [95% CI], 1.11-8.40; p = 0.030). The risk of the NAT2 rapid genotype in never-smokers was also statistically significantly increased (OR, 5.38; 95%CI, 1.80-16.1; p = 0.003). Furthermore, the joint effects of NAT2 rapid plus other genotypes were associated with colorectal cancer overall (OR, 3.12; 95%CI, 1.15-8.51; p = 0.026, for NAT2 rapid plus combined CYP1A1*2C Ile/Val and Val/Val, OR, 3.25; 95%CI, 1.09-9.74; p = 0.035, for NAT2 rapid plus CYP1A2*1C G/G, and OR, 4.20; 95%CI, 1.09-16.1; p = 0.037, for NAT2 rapid plus GSTM1 null, respectively). In never-smokers, the joint effects of NAT2 rapid plus other genotypes were remarkable (OR, 15.9; 95%CI, 1.87-135.8; p = 0.011, for NAT2 rapid plus combined CYP1A1*2A T/C and C/C, OR, 5.71; 95%CI, 1.49-21.9; p = 0.011, for NAT2 rapid plus combined CYP1A1*2C Ile/Val and Val/Val, and OR, 9.14; 95%CI, 2.05-40.7; p = 0.004, for NAT2 rapid plus CYP1A2*1F A/A, respectively). The joint effect of CYP1A2*1F A/A plus CYP1A2*1C G/G genotypes was also increased in never-smokers (OR, 6.16; 95%CI, 1.26-30.1; p = 0.025). Our findings suggest that the CYP1A1*2A T/C and NAT2 rapid genotypes is associated with colorectal cancer susceptibility without smoking exposure. These results also indicate that the NAT2 in combination with CYP1A1*2C, CYP1A2*1C, or GSTM1 genotypes may strongly confer susceptibility to colorectal cancer. In particular, the combination of NAT2 plus CYP1A1*2A, CYP1A1*2C, or CYP1A2*1F genotypes, and that of CYP1A2*1F plus CYP1A2*1C genotype may define a group of persons who are genetically susceptible to colorectal cancer in never smokers.     

GSTM1, GSTT1, and GSTP1 polymorphism and lung cancer risk in relation to tobacco smoking

The impact of genetic polymorphisms in GSTM1, GSTP1 or GSTT1 on susceptibility to lung cancer has received particular interest since these enzymes play a central role in detoxification of major classes of tobacco carcinogens. In the current German study we investigated the role of GSTM1, GSTT1 and GSTP1 polymorphisms as a genetic modifier of risk for individuals with lung cancer as susceptible genotypes especially in relation to tobacco smoking. The GSTM1, the GSTP1 as well as GSTT1-polymorphism were determined by real time PCR analysis in 446 lung cancer patients and 622 controls. The observed allele frequencies of the GSTP1 polymorphism in the population were within the range described for Caucasians. Multivariate analyses of lung cancer patients, who carried at least one mutant variant allele of GSTP1 (OR=1.03; 95%-CI: 0.76-1.39) did not show any elevated risks. GSTM1 or GSTT1 null-genotypes were found in 47.3% resp. 18.5% of the controls and in 52.5% resp. 16.8% of the cancer patients. The estimated risk of the GSTM1 null genotype for lung cancer was OR=1.34 (95%-CI: 0.99-1.81) and for the GSTT1 null genotype OR=0.88 (95%-CI: 0.59-1.32). When analyzed by histology no individual subtype of lung cancer was strongly associated with the polymorphisms. Lung cancer risk rose significantly with higher cumulative cigarette consumption confirming the association with smoking-related lung cancer risk. Stratified analysis between tobacco smoking and variant genotypes revealed for heavy smokers (>60 pack-years) increasing risks at the presence for at least one copy of the GSTP1 variant allele OR=50.56 (95%-CI: 15.52-164.79). The corresponding risks for GSTM1 null genotypes were OR=112.08 (95%-CI: 23.02-545.71) and for the GSTT1 null-genotype OR=158.49 (95%-CI: 17.75-1415.06) in smokers >60 pack-years. Analysing the interaction between tobacco smoking and the genotypes, combined smoking and having the susceptible genotypes did not show a joint effect. In this study polymorphisms of the GSTM1, GSTT1 or GSTP1 had no relevant modifying effect on lung cancer risk and cumulative smoking dose.     

Associations between cytochrome P4502E1 genotype, mutagen sensitivity, cigarette smoking and susceptibility to lung cancer

Cytochrome P4502E1 (CYP2E1) is involved in the metabolic activation of carcinogenic N-nitrosoamines. We therefore assessed the genotype frequencies of PstI or RsaI CYP2E1 restriction fragment length polymorphisms and another susceptibility marker, mutagen sensitivity, in 137 lung cancer cases (92 African American and 45 Mexican American) and 206 controls (114 African American and 92 Mexican American) identified in a molecular epidemiological study of lung cancer. The CYP2E1 c1/c1 genotype was found in 86.7% of Mexican American cases, 70.6% of Mexican American controls, 89.1% of African American cases and 86.8% of African American controls. By multivariate analysis, this genotype was found to be associated with a 14.0-fold increased risk of lung cancer in Mexican Americans but not in African Americans; a 9.9- fold increased risk of lung cancer in Mexican American former smokers, but not in non-smokers or current smokers; a 15-fold increased risk of lung cancer in Mexican American males, but not in females. Patients with the susceptible genotype appeared to have developed cancer at an earlier age and with lower cigarette pack-year of exposure than did patients with the c1/c2 or c2/c2 genotypes. Stratified analysis suggested a greater than multiplicative interaction between cigarette smoking and CYP2E1 c1/c1 genotype, although not statistically significant. The odds ratios (ORs) for the CYP2E1 c1/c1 genotype, cigarette smoking and both risk factors combined were 1.3, 6.7 and 16.3, respectively. The association between CYP2E1 c1/c1 genotype and pack-years of smoking followed the same pattern. The interaction between mutagen sensitivity and CYP2E1 c1/c1 genotype was especially strong in former smokers (the ORs for the CYP2E1 c1/c1 genotype, mutagen sensitivity and both risk factors combined were 3.9, 5.4 and 23.0, respectively). Therefore, the data suggest that individuals who lack a c2 allele might be at higher risk for developing lung cancer.