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。     

细胞色素P450 2E1和1A1多态性与肺癌关系的病例对照研究

目的 :探讨细胞色素P45 0 2E1和P45 0 1A1的多态性与肺癌的关系。方法 :采用聚合酶链式反应和限制性片段长度多态性技术检测新发肺癌患者91例及非肺部疾患同性别的患者 91例的细胞色素CYP 2E1和CYP 1A1的基因多态性 ,并分析比较。结果 :在 2组间平衡吸烟的因素后 ,CYP 2E1和CYP 1A1基因多态性分别单独分析时 ,与肺癌关系较弱 ,其OR值分别为 1 46和 1 5 1,与对照组相比差异无统计学意义 ,P >0 0 5 ;而两者联合分析时 ,CYP2E1C1C1型和CYP 1A1突变型的OR值为 3 0 0 ,95 %CI为 1 0 3～ 8 78,差异有统计学意义 ,χ2 =4 0 2 ,P <0 0 5。结论 :CYP 2E1和CYP 1A1单一基因的多态性不能增加患肺癌的危险 ,而两者联合作用时则可增强患肺癌的风险。     

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。     

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。     

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P45 0 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 (PolymeraseChainReaction ,PCR)和限制性片段长度多态性 (RestrictionFregmentLengthPolymorphisms ,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 (χ2 =1 35 5 ,P >0 0 5 ) ;CYP 2E1C1/C1基因型或饮酒单因素作用的比值比 (OddsRatil,OR)分别为 1 389和 3 33,而两者联合作用的OR为 5 4 1。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。     

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.     

细胞色素CYP2E1和GST M1与肺癌易感性的病例对照研究

目的探讨谷胱甘肽转硫酶(GST)和细胞色素CYP2E1多态性与肺癌易感性的关系.方法选取广州市广东籍新发肺癌病人91例及同期非肺部疾患及相同性别的病人91例作匹配,调查他们的吸烟、饮酒等因素的暴露情况.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CYP2E1和GST的基因多态性.结果CYP2E1 C1C1基因型与C1C2基因型比较,其OR为1.82(95%CI=0.95～3.40),GSTM1基因缺失型的OR值为1.26(0.69～2.30),而两者联合分析时,则可增加患肺癌的危险,其OR值为2.13(0.82～5.56),但无统计学意义(P＞0.05).吸烟与肺癌关系密切,其OR值为2.82(1.56～5.12),当吸烟与这两种基因型协同作用时,可明显提高患肺癌的危险性,携带CYP2E1 C1C1基因型的吸烟者的OR值为5.42(2.05～14.32),GSTM1基因缺失型的吸烟者的OR值为4.38(1.81～10.61).多因素logistic回归分析结果表明:文化程度(OR为0.63,0.45～0.86)、吸烟量(OR为1.56,1.14～2.14)、元抽油烟机(OR为3.77,1.48～9.56)、食用动物油(OR为1.67,1.25～2.24)、胡萝卜(OR为0.47,0.22～0.98)、饮酒(OR为6.58,1.53～28.3)、直系亲属肺癌史(OR为3.75,1.64～8.58)等因素与肺癌有关,而上述两种基因均未进入模型.结论CYP2E1和GSTM1在单因素分析中未显示出与肺癌风险的联系.这两种基因分别与吸烟协同作用时明显提高肺癌的危险性.然而在多因素分析中均未进入logistic模型,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.     

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。     

细胞色素P450 2E1基因多态性与食管癌易感性关系的Meta分析

目的探讨细胞色素P450 2E1（CYP2E1）基因多态性与食管癌易感性的关系。方法检索CBMdisc、CMCC、CNKI、Medline、Pubmed等数据库,并收集未公开发表的文章及硕、博士学位论文,获得有关CYP2E1基因多态性与食管癌易感性的关系的文献进行Meta分析,以病例组及对照组CYP2E1基因型分布的比值比（OR值）为效应指标,确定纳入标准,对文献进行筛选,异质性检验,然后应用Meta分析软件RevMan4．2．2对各研究原始数据进行统计处理,计算合并OR值及95％可信区间。结果按照纳入标准,最终进入系统评价的文献共有11篇病例对照研究,其中食管癌患者1094例,对照1329例,Meta分析结果合并OR=2．61,95％可信区间为1．68—4．05,说明CYP2E1基因型频率分布与食管癌的关联有统计学意义。结论对目前相关研究结果的Meta分析显示,CYP2E1基因多态性与食管癌易感性之间存在相关,即携带Rsa Ⅰ／PstⅠ识别的野生型CYP2E1基因纯合子的个体发生食管癌的危险性较高。     

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。     

Effects of cytochrome P450 1A1 and uridine-diphosphate-glucuronosyltransferase 1A1 allelic polymorphisms on the risk of development and the prognosis of head and neck cancers

We studied the effect of allelic polymorphisms of cytochrome P450 1A1 (CYP1A1) and uridine-diphosphate-glucuronosyltransferase 1A1 (UGT1A1) on the risk of development of head and neck cancers and overall survival. One hundred and forty-two head and neck cancer patients (48 with laryngeal, 42 with hypopharyngeal and 52 with mesopharyngeal tumours) were included in the study. The control group (150 individuals) included volunteers without malignant tumours. There was no statistically significant difference in age, sex distribution, or smoking habits between the two groups. The participants were genotyped for the CYP1A1 isoleucine/valine (Ile/Val) polymorphism in exon 7 and for the UGT1A1 thymine-adenine-repeat polymorphism (*1 and *28 alleles) in the promoter region of the gene. The effect of the allelic variants on survival was studied using the log-rank test, whereas the χ-test and odds ratios (OR) with 95% confidence intervals (CI) were used to compare the allelic frequencies between patients and controls. Our study revealed a significant link between the occurrence of the CYP1A1 Ile/Val, Val/Val (OR: 1.72, 95% CI: 1.02-2.96, P=0.044) and UGT1A1*28 alleles (OR: 2.74, 95% CI: 1.45-5.18, P=0.002) and an increased risk of head and neck cancers. These alleles decreased the duration of survival significantly (P=0.018 and 0.006). The survival was significantly more strongly reduced when the two high-risk alleles were carried simultaneously (OR: 2.149, 95% CI: 1.111-4.157, P=0.001). Our results suggest that the use of the CYP1A1 Ile/Val and Val/Val variants and UGT1A1*28 as biomarkers can aid risk assessment while their prognostic value can aid planning of individual therapy.     

磺基转移酶1A1基因多态性和饮食暴露与结直肠癌易感性的关系

目的 研究磺基转移酶（SULT）1A1基因Arg213His多态性与结直肠癌易感性,及其与结直肠癌相关危险因素的交互作用。方法 对140例结直肠癌患者和343例正常对照进行病例对照研究,运用PCR—RFLP方法检测SULT1A1基因Arg213His多态。结果 SULT1A1的Arg／Arg、Arg／His和His／His的分布频率在对照组和结肠癌、直肠癌组中差异无统计学意义（P〉0．05）。红肉、过度烹饪肉类的摄入与结肠癌和直肠癌的发生,在控制年龄、性别、吸烟和既往病史后,关联无统计学意义。红肉摄入量〉5kg／年组结合SULT1A1突变基因型在对照组和直肠癌组差异有统计学意义,OR值为3．78（95％CI：1．08～13．20）。结论 磺基转移酶1A1基因Arg213His多态性与肉类摄入联合在直肠癌发生过程中起着一定作用。     

Bmi-1基因及其编码蛋白在SKM-1细胞系中的表达

目的探讨人类Blymphoma Mo-MLVinsertion region(Bmi-1)基因及其编码蛋白在骨髓增生异常综合征(myelodysplasia syndrome,MDS)发病中的地位和作用。方法以正常骨髓和白血病细胞系K562为对照,利用半定量RT-PCR和Western Blot研究MDS细胞系SKM-1中Bmi-1基因在mRNA和蛋白水平的改变。结果SKM-1中Bmi-1在mRNA和蛋白水平均较正常组织有明显表达(P<0.05),二者表达水平与K562细胞系无显著差异(P>0.05)。结论Bmi-1基因在MDS亚型RAEB细胞系SKM-1中有明显表达,其在RAEB发病中可能具有重要意义。     

A Study on the Association of Cytochrome-P450 1A1 Polymorphism and Breast Cancer Risk in North Indian Women

Cytochrome P-450 1A1 (CYP1A1) is involved in the 2-hydroxylation of estrogens and mammary carcinogens into 2-hydroxy catechol metabolites. Many commonly occurring single nucleotide polymorphism (SNP) are reported in CYP1A1 in various populations that include, isoleucine to valine substitution at 462 codon in heme binding region in exon 7 (A to G transition at position 2455; M2), threonine to asparagine substitution at codon 461 (C to A transversion at position 2453; M4), T to C transition at 3801 position (M1) and T to C transition at position 3205 (M3) in 3′ non-coding region. Epidemiological studies have shown inconsistent patterns between CYP1A1 polymorphism and breast cancer risk among various populations. Most of the studies have shown significant association between CYP1A1 genotype polymorphism and breast cancer risk. The present investigation was therefore undertaken to investigate the association of M1, M2, M3 and M4 polymorphisms and their subsequent contribution in premenopausal and postmenopausal women with breast cancer risk in north Indian women. Genomic DNA was isolated from case controls and breast cancer patients, specific segments of genomic DNA were amplified and restriction fragment length polymorphism (RFLP) was performed. CYP1A1 expression and catalytic activity were also assessed in premenopausal and postmenopausal case controls and patients. Polymorphism at M1, M2 and M4 alleles was detected and odds ratio for W/M1 and␣M1/M1 was calculated as 1.07 (95% CI, 0.59–1.87) and 0.74 (95% CI, 0.28–1.96) respectively. Odds ratio for W/M1 and M1/M1 alleles in premenopausal and postmenopausal women was 1.09 (95% CI, 0.45–2.49)/0.62 (95% CI, 0.10–2.66) and 1.60 (95% CI, 0.60–4.22)/1.06 (95% CI, 0.22–7.33) respectively. Odds ratio for W/M4 and M4/M4 allele was 1.20 (95% CI, 0.65–2.24)/4.55 (95% CI, 0.44–226.2) and 0.96 (95% CI, 0.36–2.64)/4.51 (95% CI, 0.23–273.0) respectively in total and premenopausal women. In postmenopausal women odds ratio was calculated as 1.16 (95% CI, 0.45–2.94) for M4/W but it could not be detected for M4/M4 since this genotype was not found in any postmenopausal case controls. Odds ratio for W/M2 genotype was calculated 0.57 (95% CI, 0.28–1.02), 1.06 (95% CI, 0.40–2.47) and 0.33 (95% CI, 0.12–0.89) respectively for total, premenopausal and postmenopausal women, however, in any group the odds ratio for M2/M2 could not be detected as M2/M2 genotype was not found in breast cancer patients. Polymorphism at M1 and M4 alleles was not found significantly associated with breast cancer risk and only wild type genotype was found in case controls and patients for M3 allele. Lack of protective association between CYP1A1 M2 genotype was also observed, however, in postmenopausal women a significant protective association with breast cancer risk was found (odds ratio, 0.33; 95% CI, 0.12–0.89; P-value 0.03). Similarly, no significant alteration in CYP1A1 expression and catalytic activity was observed in wild type and variant genotypes both in premenopausal and postmenopausal patients as compared with their respective controls. The results obtained from the present investigation thus suggest that probably CYP1A1 (M1, M2, M3, and M4) polymorphism alone does not play a significant role in the breast cancer risk in north Indian women.     

Clinical Observations on Associations Between the UGT1A1 Genotype and Severe Toxicity of Irinotecan

Background: Severe toxicity is commonly observed in cancer patients receiving irinotecan (CPT-11)UDPglucuronosyltransferase1A1 (UGT1A1) catalyzes the glucuronidation of the active metabolite SN-38 but therelationship between UGT1A1 and severe toxicity remains unclear. Our study aimed to assess this point to guideclinical use of CPT-11. Materials and Methods: 89 cancer patients with advanced disease received CPT-11-basedchemotherapy for at least two cycles. Toxicity, including GI and hematologic toxicity was recorded in detail andUGT1A1 variants were genotyped. Regression analysis was used to analyse relationships between these variablesand tumor response. Results: The prevalence of grade III-IV diarrhea was 10.1%, this being more common inpatients with the TA 6/7 genotype (5 of 22 patients, 22.7%) (p<0.05). The prevalence of grade III-IV neutropeniawas 13.4%and also highest in patients with the TA 6/7 genotype (4 of 22 patients; 18.2%) but without significance(p>0.05). The retreatment total bilirubin levels were significantly higher in TA6/7 patients (mean, 12.75μmol/L)with compared to TA6/6 (mean, 9.92 μmol/L) with p<0.05. Conclusions: Our study support the conclusion thatpatients with a UGT1A1*28 allele (s) will suffer an increased risk of severe irinotecan-induced diarrhea, whetherwith mid-or low-dosage. However, the UGT1A1*28 allele (s) did not increase severe neutropenia. Higher serumtotal bilirubin is an indication that patients UGT1A1 genotype is not wild-type, with significance for clinic usageof CPT-11.     

二甲双胍对LKB1基因过表达的子宫内膜癌HEC-1A细胞的影响

目的 研究二甲双胍对LKB1基因过表达的子宫内膜癌HEC-1A细胞的增殖与细胞周期的影响。方法 以不同浓度的二甲双胍作用于LKB1基因过表达的子宫内膜癌HEC-1A细胞（LKB组）与缺失LKB1基因表达的HEC-1A细胞（CON组）。用流式细胞术仪检测各组HEC-1A细胞的细胞周期;RT-PCR法和Western blot技术检测各组HEC-1A细胞的LKB1、mTOR基因与蛋白的表达;以平板克隆法与细胞迁移实验检测各组细胞的细胞增殖水平。结果 与缺失LKB1基因表达的HEC-1A细胞比较,LKB1基因过表达的HEC-1A细胞随着二甲双胍浓度的升高明显降低细胞克隆形成率、细胞迁移率、S 期细胞比例及mTOR基因与蛋白的表达,而增加G₀ /G₁期细胞比例及LKB1基因与蛋白的表达,差异均有统计学意义（P均<0.05）。结论 二甲双胍抑制LKB1基因过表达的子宫内膜癌HEC-1A细胞的生长和侵袭,其机制可能为介导LKB1/mTOR信号传导通路而抑制子宫内膜癌细胞的增殖。