p27~(Kip1)和细胞周期蛋白D1在胃癌中的表达及其预后意义

目的 :研究p2 7Kip1、细胞周期蛋白D1(cyclinD1)在胃癌组织中的表达水平以及与生物学行为的关系和对预后评价的意义。方法 :以免疫组化方法检测 92例胃癌组织中p2 7Kip1、cyclinD1蛋白的表达水平。结果 :本组 92例胃癌中 ,p2 7Kip1蛋白阳性 39例 ,占 42 .4% ;cyclinD1蛋白表达阳性 44例 ,占 47.8% ;胃癌组织中 ,p2 7Kip1蛋白水平与胃壁浸润深度、TNM分期、病理组织学分级、区域淋巴结转移均相关 (P <0 .0 5 ) ;cyclinD1蛋白表达与病理组织学分级负相关 (P <0 .0 5 ) ;p2 7Kip1与cyclinD1蛋白阳性表达显著相关 (P <0 .0 5 ) ;单变量生存分析结果 ,p2 7Kip1高表达组三年、五年生存率分别为 77.1%、5 7.8% ,明显高于低表达组的 33.7%、2 6 .3 % (P =0 .0 0 7) ,多变量分析显示p2 7Kip1是一个独立的预后指标 (P =0 .0 0 0 3)。结论 :p2 7Kip1可作为反映肿瘤恶性表型的指标 ,对胃癌预后具有一定的价值 ;cyclinD1是胃癌发生、发展过程中早期的分子事件 ;p2 7Kip1在胃癌进展中起着比cyclinD1更重要的作用。     

cyclin D1、p53蛋白在胃癌组织中的表达

目的 研究cyclin D1、p53蛋白在胃癌组织中的表达及两者的相关性。方法 采用原位杂交技术及免疫组化技术，分别检测73例胃癌组织中cyclin D1 mRNA及p53蛋白的表达。结果 cyclin D1在胃癌组织及癌旁组织中的阳性表达率分别为54．79％（40／73）及28．77％（21／73），两者有显著性差异。cyclin D1 mRNA表达强度与肿瘤分化、浸润深度、淋巴结转移及病理分期无关（P＞0．05），p53蛋白在胃癌组织中的阳性表达率为32．88％（24／73），cyclin D1表达强度与p53表达无关（P＞0．05）。结论 cyclin D1及p53蛋白的过表达在胃癌的发生发展过程中均起重要作用。     

小鼠前胃癌组织形成中VEGF和cyclin D1及p27^kip1的表达

目的：研究VEGF、cyclin D1和p27^kip1在小鼠前胃癌组织形成过程中的表达及意义，初步探讨维甲酸对小鼠前胃癌的干预机制。方法：建立ICR小鼠前胃癌模型，SABC法测定VEGF、cyclin D1和p27^kip1表达。结果：cyclin D1在小鼠前胃癌组织中的表达（64．7％）明显高于癌前期病变（29．4％）。X^2=4．3447，P=0．0371；VEGF表达在癌前期病变（47．1％）高于增生期病变（33．3％），X^2=4．836，P=0．0381；cyclin D1、p27^kip1和VEGF阳性表达与小鼠胃癌组织学分级无相关性。维甲酸抑制组癌及癌前期病变发生率（23．5％）低于单纯诱导组（76．9％），X^2=14．3549．P=0．0002。结论：VEGF、cyclin D1和p27^kip1是小鼠前胃癌组织形成过程中重要的分子事件；维甲酸对亚硝胺类致癌物诱发的小鼠前胃鳞状上皮癌及癌前期病变具有抑制作用，但与对VEGF、cyclin D1和p27^kip1表达的调控无明显相关。     

非小细胞肺癌组织中表达p^27kipl的临床意义

目的：研究p^27kipl在非小细胞肺癌（NSCLC）组织中的表达水平及其与生物学行的关系和对预后的影响。方法：用免疫组化法检测102例NSCLC组织和10例正常肺组织中的p^27kipl蛋白表达水平。结果：102例肺癌组织标本中,p^27kipl阳性38例,占37．3％,其中强阳性13例占12．75,10例正常肺组织中的阳性6例,占60．0％,其中强阳性4例,占40．0％,比较肺癌组织与正常肺组织表达水平有显著性差异（P＜0．05）;并与组织学分级,有无淋巴结转移,癌周浸润、复发和转移明显相关（P＜0．05）。p^27kipl蛋白高表达组的生存期均明显高于低表达组（P＜0．01）。结论p^27kipl蛋白表达水平与非小细胞肺癌的发生,发展密切相关,可作为断预的重要指标。     

淋巴结阴性乳腺癌p21waf1、c-erbB-2和p53蛋白表达及其临床意义

目的：探讨腋淋巴结阴性乳腺癌组织中p21^waf1、c-erbB-2和p53基因蛋白表达及其与临床病理参数和预后的关系。方法：应用免疫组化LSAB方法检测121例腋淋巴结阴性乳腺部石蜡切片中p21^waf1、c-erbB-2和p53蛋白的表达情况;同时应用Kaplan-Meier法及多变量Cox比例风险模型,分析3种蛋白表达与预后的关系。结果：（1）p21^waf1蛋白表达率为48．8％,与病理组织学分级、ER状态有关;p53蛋白表达率为36．4％,c-erbB－2蛋白表达率为26．4％,与组织学分级有关;（2）p21^waf1阳性表达与p53表达呈负相关（P＜0．01）;Cox阳性组患者无瘤生存率高于阴性组（P＜0．05）;c-erbB－2阳性组患者无瘤生存率明显低于阴性组（P＜0．01）;Cox模型分析显示仅有c-erbB－2表达对预后有显著影响。结论：乳腺癌组织p21^waf1、c-erbB-2表达与病理组织学分级有相关性;p^21waf1表达依赖于p53途径刺激;p^21waf1、c-erbB－2表达与腋淋巴结阴性乳腺癌预后有关,且c-erbB-2表达是一个独立的预后指标。     

褪黑素对小鼠肝癌细胞增殖及p27Kip1、cyclin D1基因表达的影响

目的探讨褪黑素(melatonin MT)抑制H22小鼠肝癌细胞增殖的可能机制.方法通过体外细胞培养,分别采用不同剂量MT作用不同的时间,MTT显色技术检测细胞的增殖;RT-PCR检测MT作用4 d后,H22细胞中p27Kip1、cyclin D1mRNA的表达;免疫组化检测H22细胞中p27Kip1、cyclin D1蛋白的表达.结果MT具有抑制肝癌细胞的生长和增殖的作用,且具有时间依赖关系.MT诱导细胞凋亡的过程中,与对照组相比,MT药理剂量组H22细胞中的p27Kip1 mRNA及蛋白表达升高(P＜0.01);cyclin D1 mRNA及蛋白表达下降(P＜0.01).MT生理剂量组p27Kip1mRNA表达升高(P＜0.01),而p27Kip1蛋白表达水平与对照组相比差异无显著性(P＞0.05),cyclinD1 mRNA及蛋白表达均下降,差异元显著性(P＞0.05).结论MT抑制肝癌细胞的增殖可能与上调细胞周期抑制因子p27Kip1的表达,降低周期蛋白cyclin D1表达,进而延迟细胞周期的进程有关.     

胃癌中Cks1 、p27 Kip1和Skp2 蛋白的表达

 目的 探讨Cks1在胃癌发生及其在Skp2调节p27 ^Kip1降解过程中的作用。方法 应用流式细胞术测定正常胃粘膜和胃癌组织中Cks1、p27^Kip1、Skp2蛋白表达。结果胃癌组织中Cks1、Skp2表达明显高于正常胃粘膜（x²=22．69，P〈0．05；x²=13．42，P〈0．05），而p27 ^Kip1表达则低于正常胃粘膜（x²=14．83，P〈0．05）。胃癌中Cks1、Skp2表达与p27 ^Kip1表达呈负相关（r=-0．649，P〈0．05；r=-0．732，P〈0．05）；而Cks1蛋白表达与Skp2蛋白缺乏相关性（P〉0．05）。胃癌中Cks1的表达与肿瘤分化程度相关（x²=5．05，P〈0．05），而与肿瘤浸润深度、淋巴结转移及临床分期不相关（P〉0．05）。结论Cks1可能参与了胃癌的发生；胃癌中Cks1可能参与了Skp2调节p27 ^Kip1泛素化降解过程。     

HIF-1α、CD44在胃癌组织中的表达及临床意义

目的：探讨缺氧诱导因子1α（ hypoxia inducible factor-1α,HIF-1α）、CD44在胃癌组织中的表达及临床意义。方法采用免疫组织化学法检测184例胃癌组织中HIF-1α和CD44的表达,并分析其与患者临床病理特征及预后的关系。结果 HIF-1α、CD44在胃癌组织中的阳性表达率分别为55．4％（102/184）、62．4％（116/184）;HIF-1α的表达与肿瘤浸润深度及淋巴结转移密切相关（ P＜0．05）,CD44表达与肿瘤大小、肿瘤浸润深度及淋巴结转移密切相关（ P＜0．05）;相关分析结果显示,CD44和HIF-1α在胃癌组织中的表达呈正相关（ r＝0．71,P＝0．003）。多因素分析显示,HIF-1α阳性表达、CD44阳性表达、淋巴结转移和肿瘤浸润深度为胃癌的独立预后因素（ P＜0．05）。结论 HIF-1α、CD44在胃癌组织中的表达呈正相关且与胃癌预后密切相关。     

肝细胞癌组织中PTEN和p27Kip1及cyclinD1蛋白表达及临床意义

目的:研究肝细胞癌(hepatocellular carcinoma, HCC)中PTEN、p27Kip1和cyclinD1蛋白的表达及相互关系,初步探讨它们在肝细胞癌的发生发展中的生物学意义。方法:应用Elivision免疫纽化方法检测53例肝细胞癌组织及癌旁肝组织中PTEN、p27Kip1和cyclinD1蛋白表达。结果: 53例肝细胞癌组织中p27Kip1和cyclinD1蛋白表达的阳性率分别为65％和53％,均高于癌旁肝组织(x2=34．11,x2=29．05,P值均为0．000),肝细胞癌组织中PTEN蛋白表达的阳性率(57％)明显低于癌旁肝组织中的阳性率(96．2％)(x2=20．94, P=0．000),PTEN和cyclinD1蛋白表达与肿瘤大小、TNM分期和是否伴肝硬化无关;与组织分化程度、有无侵袭性呈显著相关(P值分别为0．014、0．003、0．026和0．042)。p27Kip1蛋白表达与肿瘤大小和是否伴肝硬化无关,与肝细胞癌组织分化程度、TNM分期和有无侵袭性呈显著相关(P值分别为0．000、0．008和0．001)。PTEN蛋白表达与p27Kip1和cyclinD1蛋白表达无相关性。结论: PTEN、p27Kip1和cyclinD蛋白在肝细胞癌的发生发展中发挥重要作用。PTEN、p27Kip1和cyclinD蛋白的联合检测对评估肝细胞癌的恶性程度有参考价值。     

β-Catenin，cyclinD1及c—myc的表达在肝细胞癌中的表达

目的 探讨β-Catenin、cyclinD1及c—myc蛋白的表达与肝癌临床病理参数的关系。方法 采用EnVisions^TMplus免疫组织化学方法研究β-Catenin、cyclinD1及c—myc蛋白在52例HCC及癌旁肝组织中的表达情况。结果 52例HCC中β-Catenin、cyclinD1及c-myc蛋白染色阳性率分别为55．8％、48．1％及53．8％，癌旁肝组织的阳性率为36．5％、25．0％及32．7％，β-Catenin、cyclinD1及c-myc在HCC及癌旁肝组织两者间有显着性差异（P（0．05）。在HCC中β-Catenin的阳性表达与cyclinD1、c-myc的阳性表达密切相关（P=0．0108，r=0．3920；P=0．0295，r=0．3406）且呈正相关；β-Catenin、cyclinD1及cmyc在人肝癌组织中的检出率与肝外转移、术后复发及肿瘤分化程度明显有关（P〈0．05），cyclinD1的检出率与门静脉癌栓也明显有关（P〈0．05），β-Catenin的检出率与临床分期和门静脉癌栓也有显著性差异（P〈0．05）。结论 β-Catenin、cyclin D1及c-myc蛋白的过表达可促使肝癌细胞增殖，使肝癌细胞具有更强的侵袭力，与肝癌的发生发展关系密切。     

Polymorphisms in GSTM1, GSTT1 and CYP1A1 and risk of pancreatic adenocarcinoma

A prospective study of 149 unselected incident cases of pancreatic adenocarcinoma and 146 ethnically-matched controls found no associations between GSTM1 (adjusted odds ratio (AOR) 1.14), GSTT1 (AOR: 1.19) and CYP1A1 (AOR: 1.08) polymorphisms and pancreatic cancer susceptibility. Smoking and drinking status did not affect results. These polymorphisms do not appear to be important gene modifiers in pancreatic cancer.     

GSTM1, GSTT1 and GSTP1 polymorphisms and lung cancer risk

Previous studies have suggested that GST genotypes may play a role in determining susceptibility to lung cancer, though the data are often conflicting. In this study we investigated GSTM1, GSTT1 and GSTP1 status in relation to lung cancer risk in patients attending a Manchester bronchoscopy clinic. Cases were all patients (n=94) currently with, or with a history of, tumours of the lung, trachea or bronchus. The control group were all other patients (n=165) who were free of benign and malignant tumours both at the time of, or prior to, diagnosis. All patients were interviewed for information on lifestyle risk factors, and DNA extracted from bronchial lavage and blood samples was used for genotyping. GSTM1 null genotype was associated with decreased lung cancer risk (odds ratio (OR) 0.50, 95% confidence interval (CI) 0.29–0.87), particularly among men (OR 0.43, 95% CI 0.21–0.87) and those above the median age (OR 0.33, 95% CI 0.15–0.70). No difference in GSTT1 and GSTP1 genotype distribution was seen between cases and controls. The GSTM1 null genotype was associated with a decreased risk of squamous cell carcinoma: the OR, adjusted for age, sex and pack years was 0.32 (95% CI 0.12–0.82). As previous studies have reported that the GSTM1 null genotype is associated with an increased lung cancer risk, further work is required to determine whether the observed association is true, or whether it arises from bias or confounding factors.     

Polymorphisms in CYP1B1, GSTM1, GSTT1 and GSTP1, and susceptibility to breast cancer

Polymorphisms in the cytochrome P450 1B1 (CYP1B1) and glutathione S-transferase (GST) drug metabolic enzymes, which are responsible for metabolic activation/detoxification of estrogen and environmental carcinogens, were analyzed for their association with breast cancer risk in 541 cases and 635 controls from a North Carolina population. Each polymorphism, altering the catalytic function of their respective enzymes, was analyzed in Caucasian and African-American women. As reported in previous studies, individual polymorphisms did not significantly impact breast cancer risk in either Caucasian or African-American women. However, African-American women exhibited a trend towards a protective effect when they had at least one CYP1B1 119S allele (OR=0.53; 95% CI=0.20-1.40) and increased risk for those women harboring at least one CYP1B1 432V allele (OR=5.52; 95% CI=0.50-61.37). Stratified analyses demonstrated significant interactions in younger (age < or =60) Caucasian women with the CYP1B1 119SS genotype (OR=3.09; 95% CI=1.22-7.84) and younger African-American women with the GSTT1 null genotype (OR=4.07; 95% CI=1.12-14.80). A notable trend was also found in Caucasian women with a history of smoking and at least one valine allele at GSTP1 114 (OR=2.12; 95% CI=1.02-4.41). In Caucasian women, the combined GSTP1 105IV/VV and CYP1B1 119AA genotypes resulted in a near 2-fold increase in risk (OR=1.96; 95% CI=1.04-3.72) and the three way combination of GSTP1 105IV/VV, CYP1B1 119AS/SS and GSTT1 null genotypes resulted in an almost 4-fold increase in risk (OR=3.97; 95% CI=1.27-12.40). These results suggest the importance of estrogen/carcinogen metabolic enzymes in the etiology of breast cancer, especially in women before the age of 60, as well as preventative measures such as smoking cessation.     

Genetic polymorphisms of CYP1A1, GSTM1 and GSTT1 genes and lung cancer risk

Genetic polymorphisms of the genes encoding for the xenobiotic metabolizing enzymes result in individual variations in the efficiency of detoxification of environmental carcinogens, and have been extensively associated with variable risk for lung neoplasms in different ethnic and environmental backgrounds. In this study, using PCR-RFLP based assays, we investigated the distribution of genetic polymorphisms in CYP1A1, GSTM1 and GSTT1 genes in Greek lung cancer patients (N=122) and healthy controls (N=178). The frequency of CYP1A1 m1 homozygous genotype was 0.04 in patients and 0.02 in controls (detected in 4.10% of patients and in 1.69% of controls, respectively), that of GSTM1 null genotype was 0.52 in patients and 0.54 in controls, whereas those of GSTT1 null genotype was 0.17 and 0.11, in patients and controls, respectively. The GSTM1 null genotype was more frequent in adenocarcinoma, as well as in lung cancer patients with history of chronic obstructive pulmonary disease (COPD). The GSTT1 null genotype correlated with advanced age of the patients at the time of diagnosis. Three combinations of rare genotypes - in subjects carrying simultaneously deviations from the common genotype in more than one gene - were over-represented in lung cancer patients, compared to control population, and were furthermore significantly associated with history of heavy tobacco consumption in lung cancer patients. The results imply involvement of specific genotype combinations of CYP1A1, GSTM1 and GSTT1 alleles in the development of lung cancer in heavy smokers.     

CYP1B1 and hormone-induced cancer

Cancers in hormone-responsive tissues (e.g., breast, ovary, endometrium, prostate) occur at high incidence rates worldwide. However, their genetic basis remains poorly understood. Studies to date suggest that endogenous/exogenous oestrogen and environmental carcinogens may play a role in development and/or progression of hormone-induced cancers via oxidative oestrogen metabolism. Cytochrome P450 1B1 is a key enzyme in its oestrogen metabolism pathway, giving rise to hydroxylation and conjugation. Although CYP1B1 is expressed in many cancers, particularly high levels of expression are observed in oestrogen-mediated disease. CYP1B1 is more readily found in tumour tissue compared to normal. Given the role of CYP1B1 in pro-carcinogen and oestrogen metabolism, polymorphisms in CYP1B1 could result in modifications in its enzyme activity and subsequently lead to hormone-mediated carcinogenesis. CYP1B1 may also be involved in progression of the disease by altering the tissue response to hormones and clinical response to chemotherapy. The exact mechanism behind these events is complex and unclear. Only a few functional single nucleotide polymorphisms of CYP1B1 are known to result in amino acid substitutions and have been extensively investigated. Studies examining the contribution of different CYP1B1 alleles to hormone-mediated cancer risks are inconsistent. The main focus of this review is to appraise the available studies linking the pathogenesis of the hormone-induced cancers to various CYP1B1 polymorphisms. Additionally, we explore the role of a neuronal protein, γ-synuclein, in CYP1B1-mediated pathogenesis.     

Genetic polymorphisms of SULT1A1 and SULT1E1 and the risk and survival of breast cancer.

We examined whether common single nucleotide polymorphisms (SNP) in SULT1A1 (c.779G>A, *14A>G, and *85C>T) and SULT1E1 (IVS1-447C>A, IVS4-1653T>C, and *959G>A) genes influenced the risk and survival of breast cancer. Our study population consisted of 989 histologically confirmed sporadic breast cancer patients and 1,054 controls without history of cancer recruited from three teaching hospitals in Seoul. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by logistic regression model. In the survival analysis for 529 breast cancer patients with completed treatments, the hazard ratios (HR) were calculated with Cox proportional hazard model. Women with the SULT1E1 *959 GA/AA genotype had a moderately decreased breast cancer risk compared with those with the GG genotypes (OR, 0.8; 95% CI, 0.70-1.00). When the haplotypes were considered, the homozygous *959 AA genotype together with the IVS4-1653 T>C base change (CTA-CCA haplotype) was associated with halved breast cancer risk (OR, 0.5; 95% CI, 0.24-0.88) compared with the wild type CTG-CTG haplotype. No other significant overall association was observed between the SULT1A1 and SULT1E1 SNPs nor haplotypes and breast cancer risk. When stratified by survival, patients with the SULT1E1 IVS4-1653 TC/CC genotypes showed a >3-fold risk of recurrence (HR, 3.2; 95% CI, 1.39-7.48) compared with those with the TT genotype. Moreover, when the haplotypes were considered, the SULT1E1 *959 G>A base change together with the IVS4-1653 T>C base change (CTG-CCA haplotype) was associated with a >4-fold risk of breast cancer (OR, 4.2; 95% CI, 1.15-15.15). These findings suggest that genetic polymorphisms of SULT1E1 are associated with increased risk and a disease free survival of breast cancer in Korean women.     

CYP1A1, GSTM1, and GSTP1 genetic polymorphisms and urinary 1-hydroxypyrene excretion in non-occupationally exposed individuals.

The CYP1A1 and glutathione S-transferase enzymes (e.g., GSTM1 and GSTP1) are involved in the activation and conjugation of polycyclic aromatic hydrocarbons (PAHs), respectively, and are controlled by genes that are polymorphic. The CYP1A1*2 allelic variant has been associated with elevated urinary 1-hydroxypyrene (1-OHP), a proposed marker for internal dose of activated PAHs, in coke-oven workers. We investigated whether this association could be observed at low exposure levels, such as those experienced by the general population. We conducted a cross-sectional study among 188 individuals (106 Japanese, 60 Caucasians, and 22 Hawaiians) who were selected as controls in a population-based case-control study and provided lifestyle information, a 12-h urine specimen, and a blood sample. 1-OHP was analyzed by high-performance liquid chromatography after enzymatic hydrolysis. Lymphocyte DNA was used for PCR-based genotyping. Smokers excreted twice as much 1-OHP (geometric mean, 0.51 nmol/12 h) as nonsmokers (geometric mean, 0.27 nmol/12 h; P = 0.006). Overall and among nonsmokers, 1-OHP urinary levels did not differ by CYP1A1, GSTM1, or GSTP1 genotypes. However, after adjusting for age, ethnicity, and number of cigarettes per day, smokers with at least one CYP1A1*2 variant allele excreted 2.0-fold more 1-OHP than smokers with the wild-type genotype (P = 0.02). Similar results were obtained for the CYP1A1*3 variant allele. The present data add to the growing evidence suggesting that individuals with the (linked) CYP1A1*2 or *3 variant alleles have a greater capacity to activate PAHs from tobacco smoke and occupational exposure and, as a result, are at greater risk for PAH-related cancers, especially certain respiratory cancers.     

Methoxyestrogens exert feedback inhibition on cytochrome P450 1A1 and 1B1

Cytochrome P450 1A1 (CYP1A1) and 1B1 (CYP1B1) catalyze the oxidative metabolism of 17 beta-estradiol (E2) to catechol estrogens (2-OHE2 and 4-OHE2) and estrogen quinones, which may lead to DNA damage. Catechol-O-methyltransferase catalyzes the methylation of catechol estrogens to methoxyestrogens (2-MeOE2, 2-OH-3-MeOE2, and 4-MeOE2), which simultaneously lowers the potential for DNA damage and increases the concentration of 2-MeOE2, an antiproliferative metabolite. In this study, we showed that CYP1A1 and CYP1B1 recognized as substrates both the parent hormone E2 and the methoxyestrogens. Using purified recombinant enzymes, we demonstrated that CYP1A1 and CYP1B1 O-demethylated the methoxyestrogens to catechol estrogens according to Michaelis-Menten kinetics. Both CYP1A1 and CYP1B1 demethylated 2-MeOE2 and 2-OH-3-MeOE2 to 2-OHE2, whereas CYP1B1 additionally demethylated 4-MeOE2 to 4-OHE2. Because the P450-mediated oxidation of E2 and the O-demethylation of methoxyestrogens both yielded identical catechol estrogens as products, we used deuterated E2 (E2-d4), unlabeled methoxyestrogens, and gas chromatography/mass spectrometry to examine both reactions simultaneously. Kinetic analysis revealed that methoxyestrogens acted as noncompetitive inhibitors of E2 oxidation with K(i) ranging from 27 to 153 micro M. For both enzymes, the order of inhibition by methoxyestrogens was 2-OH-3-MeOE2 > or = 2-MeOE2 > 4-MeOE2. Thus, methoxyestrogens exert feedback inhibition on CYP1A1- and CYP1B1-mediated oxidative estrogen metabolism, thereby reducing the potential for estrogen-induced DNA damage.     

CYP1A1, GSTM1, and GSTT1 polymorphisms and breast cancer risk in Brazilian women

The frequency of CYP1A1 (CYP1A1*2A), GSTM1, and GSTT1 polymorphisms, as well as the main risk factors associated with breast cancer were studied in Brazilian women, with malignant breast cancer (n=128), or age-matched controls (n=256). Only a family history of breast cancer presented a significant risk (OR=3.00, CI=1.27-7.06). Among non-whites, the CYP1A1*2A allele was underrepresented among patients. Statistical analysis indicated that this polymorphism may decrease the risk of breast cancer among these individuals, particularly after adjusting for the risk presented by selected risk factors (OR=0.30, 95% CI=0.12-0.76).     

Meta- and pooled analyses of GSTM1, GSTT1, GSTP1, and CYP1A1 genotypes and risk of head and neck cancer.

Sequence variation in the GSTM1, GSTT1, GSTP1, and CYP1A1 genes may potentially alter susceptibility to head and neck cancers, although evidence from previous studies has not been consistent. To explore these associations, we conducted a meta-analysis of 31 published case-control studies (4635 cases and 5770 controls) and a pooled analysis of original data from nine published and two unpublished case-control studies (2334 cases and 2766 controls). In the meta-analysis, the summary odds ratios (ORs) for head and neck cancer were 1.23 [95% confidence interval (95% CI), 1.06-1.42] for the GSTM1 null genotype, 1.17 (95% CI, 0.98-1.40) for the GSTT1 null genotype, 1.10 (95% CI, 0.92-1.31) for carrying the GSTP1 Val105 allele, and 1.35 (95% CI, 0.95-1.82) for carrying the CYP1A1 Val462 allele. The pooled analysis ORs were 1.32 (95% CI, 1.07-1.62) for the GSTM1 null genotype, 1.25 (95% CI, 1.00-1.57) for the GSTT1 null genotype, 1.15 (95% CI, 0.86-1.53) for carrying the GSTP1 Val105 allele, and 0.98 (95% CI, 0.75-1.29) for carrying the CYP1A1 Val462 allele. Increasing risk of head and neck cancer was observed with inheritance of increasing numbers of modest risk genotypes at the three GST loci (P for trend = 0.04), with the combination of carrying the GSTM1 null, GSTT1 null, and GSTP1 Val105 alleles conferring an OR of 2.06 (95% CI, 1.11-3.81). In conclusion, both the meta- and pooled analysis support modest associations of GSTM1 and GSTT1 genotypes with head and neck cancer risk, and our pooled analysis supports the notion of greater risk when genotypes at multiple GST loci are considered in a multigenic model.