吸烟、N-乙酰基转移酶2与结直肠癌的关系

流行病学研究已表明，环境因素是结直肠癌发生过程中的危险因素，然而并非所有暴露在相同环境中的人都患结直肠癌，提示遗传易感性在其中起重要作用。N-乙酰基转移酶2(NAT2)是药物代谢酶系重要的Ⅱ相酶，参与内外源性物质在体内的代谢和解毒，其活性改变与结直肠癌易感性可能相关。我们采用检测NAT2多态性方法，研究NAT2基因多态     

代谢酶NAT2基因多态性与肺癌易感性关系的研究

目的 探讨代谢酶N-乙酰化转移酶2(NAT2)基因多态性与肺癌易感性的关系.方法 采用聚合酶链式反应-限制性片段长度多态性技术检测152名正常人和150例原发性肺癌患者的外周血NAT2基因型.应用病例对照研究分析NAT2基因多态性与肺癌易感性的关系.结果 ①NAT2等位基因型WT/WT、WT/Mx、Mx/Mx在对照组中分布频率分别为28.9%、52.0%和19.1%;在肺癌组中分布频率分别为22.0%、45.3%和32.7%,两组比较差异有统计学意义(P=0.023).②携带NAT2慢乙酰化基因型个体患肺癌的风险是携带NAT2快乙酰化基因型个体的1.84倍(95%CI为1.044～3.231,P=0.035).③携带慢乙酰化基因型个体患肺腺癌的风险进一步升高,是携带快乙酰化基因型个体的2.49倍(95%CJ为1.242～4.973,P=0.010).④携带NAT2慢乙酰化基因型吸烟者患肺癌的风险是携带快乙酰化基因型吸烟者的2.34倍(95%CI为1.007～5.424,P=0.048).结论 NAT2慢乙酰化基因型显著增加中国汉族人群尤其是吸烟者患肺癌的风险.     

细胞色素P450基因多态性与宫颈癌易感性关系的研究进展

在宫颈癌的发生过程中,人乳头瘤病毒感染宫颈是必要的条件。对肿瘤的易感性则影响最终的疾病结局。细胞色素P450(CYP450)是体内重要的代谢酶,与许多前致癌物和致癌物的活化有关,是目前肿瘤研究的热点之一。基因多态性是遗传易感性的物质基础,深入研究CYP450在宫颈癌肿瘤发生、发展的机制及遗传多态性与肿瘤易感性的关系,使易感患者脱离不良环境因素,可将宫颈癌控制在预防阶段。     

Ⅰ、Ⅱ相代谢酶基因多态性与肺癌遗传易感性研究进展

代谢酶基因多态性在人类恶性肿瘤发病中的作用已为越来越多的研究所证实,近几年,国内外开展了许多有关基因多态性和肺癌易感性的研究,本文就近年来对Ⅰ、Ⅱ相代谢酶基因多态性和肺癌遗传易感性关系的研究作一简要综述。     

基因的多态性与食管癌的易感性

食管癌的癌变机制仍不清楚,值得关注的是遗传因素在食管癌发生中起的作用,本文主要介绍参与致癌物代谢的相关基因(CYP、ADH、GST、ALDH、NAT)、与DNA稳定性有关的基因(MTHFR、XRCC1、HOGG1)以及某些抑癌基因(P53),探讨它们的多态性与食管癌的易感性关系。     

基因的多态性与食管癌的易感性

食管癌的癌变机制仍不清楚，值得关注的是遗传因素在食管癌发生中起的作用，本主要介绍参与致癌物代谢的相关基因(CYP、ADH、GST、ALDH、NAT)、与DNA稳定性有关的基因(MTHFR、XRCCl、HOGGl)以及某些抑癌基因(P53)，探讨它们的多态性与食管癌的易感性关系。     

细胞色素P450 2E1和谷胱甘肽转硫酶P1基因的多态性与食管癌的易感性

我国是食管癌高发国家之一,食管癌的发生与环境致癌物有关。但并非所有暴露于致癌物者最后都发生食管癌。提示个体易感性差异所起的重要作用。 前致癌物进入人体后,需经过Ⅰ相代谢酶的活化或转化,才可被Ⅱ相代谢酶解毒。Ⅰ相代谢酶主要由细胞色素     

谷胱甘肽转硫酶基因型与浙江汉族人群散发性大肠癌的易感性

大肠癌的发生机制涉及环境、遗传两方面,而环境因素致癌主要取决于个体的易感性.毒物代谢酶的基因多态性是影响人类肿瘤遗传易感性的重要因素之一.     

细胞色素P4502C19基因多态性与肺癌易感性的关系

研究证明致癌物代谢酶的遗传多态性在决定环境致癌物的效应时起着关键性的作用,ＣＹＰ酶体系中许多酶参与致癌物的代谢,其基因的多态性与肿瘤的易感性有关,如ＣＹＰ２Ｄ６、ＣＹＰ１Ａ１、ＣＹＰ２Ｅ１等。１９９４年,ｄｅＭｏｒａｉｓ等发现细胞色素Ｐ４５０２Ｃ１９（ＣＹＰ２Ｃ１９）等位基因的两个突变位点：ＣＹＰ２Ｃ１９ｍ１和ＣＹＰ２Ｃ１９ｍ２,并证明ＣＹＰ２Ｃ１９基因的多态性与ＣＹＰ２Ｃ１９酶活性的多态性有关［１］。我们应用等位基因特异扩增法（ＡＳＡ）原理,建立了ＣＹＰ２Ｃ１９等位基因分型法［２,３］,并对７…     

CYP2E1 Rsa Ⅰ/Pst Ⅰ多态性与亚洲人肺癌发病风险的关系

细胞色素P450 2E1(CYP2E1)是细胞色素P450基因家族中的重要成员,参与亚硝胺等前致癌物在体内的代谢活化.CYP2E1基因具有多态性,其中Rsa Ⅰ/Pst Ⅰ基因多态性与肺癌的危险性关系目前尚未明确,各地研究结果不一致.我们通过检索Pub Med,Embase,Web of Science和CNKI数据库中相关研究的文献,提取相关数据,采用荟萃分析量分析CYP2E1多态性与肺癌发生风险.     

Association Between NAT2 Polymorphisms and Lung Cancer Susceptibility

To further investigate the association between NAT2 polymorphisms and lung cancer susceptibility.In terms of phenotypes, we investigated the acetylator status of NAT2 polymorphisms associated with lung cancer risk. Additionally, in view of genotypes, we mainly analyzed 5 single nucleotide polymorphisms (SNPs) in NAT2 gene, namely C282T, A803G, C481T, G590A, and G857A. Twenty-six eligible studies were included in our meta-analysis by searching PubMed, Embase, and CNKI databases. We used odds ratios (ORs) with corresponding 95% confidence intervals (CIs) to evaluate the susceptibility to lung cancer associated with NAT2 polymorphisms.Overall, based on phenotypes, the pooled ORs showed no significant association between NAT2 polymorphisms and lung cancer susceptibility. In the subgroup analyses by ethnicity and source of control, there was still no significant association. In terms of genotypes, overall, no obvious relationship was observed between NAT2 polymorphisms and lung cancer risk. But increased risk of lung cancer was found in association with NAT2 C282T polymorphism (TT vs. CC + TC: OR = 1.58, 95% CI = 1.11–2.25).Our meta-analysis demonstrates that TT genotype in NAT2 C282T polymorphism may be a risk factor for lung cancer susceptibility. Additionally, the acetylator status of 5 SNPs in NAT2 gene may not be associated with lung cancer risk.     

Molecular epidemiology of non-small cell lung cancer

Although smoking is the primary risk factor for most lung cancers, genetic predisposition may play an important role. Familial aggregation studies suggest a greater genetic component in the risk for younger individuals developing lung cancer, for lifetime nonsmokers, and possibly for women. Low-penetrance, high-prevalence polymorphic genes may explain part of this genetic predisposition. Functional polymorphisms of xenobiotic metabolism may alter the total exposure of tobacco carcinogens in the host. Subtle alterations in the DNA repair, inflammatory, and cell cycle pathways may also alter lung cancer susceptibility. The role of individual polymorphisms has been evaluated for several genes including the CYP and glutathione s-transferase superfamilies, and the NAT genes; DNA repair genes such as XPD (nucleotide excision pathway), XRCC1 (base excision pathway), and MGMT; and tumor suppressor or cell cycle genes such as p53. Molecular epidemiological studies are now focused on building larger databases from existing smaller studies and developing strategies to simultaneously evaluate multiple polymorphisms and genes within the same pathway.     

A slow acetylator genotype associated with an increased risk of advanced cervical cancer

PURPOSE: Human papillomavirus (HPV) is the major etiological agent associated with cervical cancer. However, other risk factors have been indicated, including carcinogen exposure, oral contraceptive usage, certain nutritional deficiencies, and genetic factors. N-acetyltransferase 2 (NAT2) has an important role in the metabolism of several carcinogens. NAT2 polymorphism modulates the activity of the enzyme, by activation, via O-acetylation, or through detoxification, via N-acetylation. This case-control study was designed to evaluate the association between NAT2 polymorphism and genetic susceptibility to cervical cancer. METHODS: Genomic DNA was obtained from 125 women with advanced cervical cancer and 170 healthy women. PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphisms) was used to analyse two common mutant alleles at NAT2 loci. RESULTS: The NAT2*6/NAT2*6 genotype, which corresponds to a slow acetylator genotype, was found to be associated with a 3.41-fold (95% CI: 1.35-8.94; P= 0.007) increase in the risk of cervical cancer. For the entire case groups the proportion of cervical cancer cases attributable (attributable proportion) to the NAT2*6/NAT2*6 genotype was 10.2%. CONCLUSIONS: The results reported in this study suggest that NAT2 polymorphism is a genetic susceptibility factor involved in the carcinogenesis of cervical cancer, and also that the analysis of the allelic profile of populations in different geographic locations may help to understand the incidence of cervical cancer worldwide.     

A pilot study testing the genetic polymorphism of N-acetyltransferase 2 as a risk factor in lung cancer

NAT2 as phase II enzyme is involved in the detoxification/activation of various drugs, environmental substances and carcinogenic compounds. A genotyping approach has been used to investigate NAT2 genotype with putative relevance in lung cancer in population of 110 Slovak-Caucasians patients and 167 non-malignant individuals from the same region. Slow acetylation was not observed to be a significant risk factor of lung cancer development (OR=1.19; 95% CI: 0.71-1.99). However, one genotype responsible for slow acetylation (NAT2*5B/*6) was observed significantly more frequently in lung cancer patients with squamous cell carcinoma compared with control subjects (OR=2.24; 95% CI: 1.14-4.34). Stratified analysis showed an increasing impact of the specific allelic combination NAT2*5B/*6 in non-smokers (OR=6.5; 95% CI: 1.25-15.08). In the case of squamous lung carcinoma an analysis revealed a tendency to adversely affect cancer risk in the individuals with the mentioned genotype in younger than 60 years (OR=3.14; 95% CI: 0.98-9.72) non-smokers (OR=10.40; 95% CI: 1.35-118.89) and in females (OR=4.25; 1.08-16.25). Additional studies are needed to confirm the results we observed and to assess the impact of other effects (specific allelic combinations, sex differences and histological subtype of lung cancer) on NAT2 susceptibility in lung carcinogenesis.     

Possible association of NAT2 polymorphism with laryngeal cancer risk: an evidence-based meta-analysis

Purpose

N-acetyltransferase 2 (NAT2) plays an important role in the metabolism of various potential carcinogens, which can be subdivided into rapid and slow acetylation phenotype according to the different genotypes. A number of studies have been devoted to the association of NAT2 polymorphism with susceptibility to laryngeal carcinoma; however, the results were inconsistent and inconclusive. The aim of the present study was to conduct a meta-analysis assessing the possible association of NAT2 polymorphism with laryngeal cancer risk.

Methods

The relevant studies were identified through a search of PubMed, Embase, ISI Web of Knowledge, and Chinese National Knowledge Infrastructure until February 2011 and selected on the basis of the established inclusion criteria for publications, and then a meta-analysis was performed to quantitatively summarize the association of NAT2 polymorphism with laryngeal cancer susceptibility.

Results

Seven studies were included in the present meta-analysis, which described a total of 980 laryngeal cancer cases and 1,487 controls. The overall odds ratio (OR) for NAT2 slow and rapid acetylators was 0.99 (95% CI?=?0.71?C1.38) and 1.01 (95% CI?=?0.72?C1.40), respectively. When stratifying for race, the pooled ORs for NAT2 slow acetylator were 1.99 (95% CI?=?1.10?C3.63) in Asians and 0.85 (95% CI?=?0.62?C1.15) in Caucasians, and the pooled ORs for NAT2 rapid acetylator were 0.50 (95% CI?=?0.28?C0.91) in Asians and 1.18 (95% CI?=?0.87?C1.60) in Caucasians.

Conclusions

This meta-analysis suggested that there was overall lack of association between NAT2 polymorphism and laryngeal cancer risk; however, NAT2 slow acetylation may contribute to a risk factor for laryngeal cancer in Asians but not in Caucasians.     

The impact of smoking and polymorphic enzymes of xenobiotic metabolism on the stage of bladder tumors: a generalized ordered logistic regression analysis

Cigarette smoking is the predominant risk factor for bladder cancer in males and females. The tobacco carcinogens are metabolized by various xenobiotic metabolizing enzymes such as N-acetyltransferases (NAT) and glutathione S-transferases (GST). Polymorphisms in NAT and GST genes alter the ability of these enzymes to metabolize carcinogens. In this paper, we conduct a statistical analysis based on logistic regressions to assess the impact of smoking and metabolizing enzyme genotypes on the risk to develop bladder cancer using a case–control study from Tunisia. We also use the generalized ordered logistic model to investigate whether these factors do have an impact on the progression of bladder tumors.     

Genetic polymorphism of N-acetyltransferase and glutathione S-transferase related to neoplasm of genitourinary system. Minireview

Genetically determined risk factors may considerably contribute to the development of neoplastic diseases, including neoplasm of urinary organs, e.g. bladder and prostate cancers. It is believed that they may result, among others, from the differences in the metabolism of environmental carcinogens and mechanisms of DNA repair. There is a clear evidence that the kind and rate of metabolism is genetically determined by polymorphic enzyme coding genes participating in the process of xenobiotic transformation. Genetic polymorphism has been confirmed for a number of enzymes involved in the reaction of oxidation or conjugation of exo- and endogenous xenobioties. Gene variability may alter the expression or enzymatic activity of coded enzymes. Therefore, the cancer risk assessment should also be based on individual differences in the ability to activate (phase I) or to detoxify (phase II) possible carcinogens. In the present study, the information on the significance of glutathione 5-transferase (GST) and N-acetyltransferase (NAT) gene families in protection of human health and incidence of various diseases is summarized. The role of hereditary polymorphisms of GST and NAT genes involved in the etiology of neoplasm of urinary organs is controversial. That is why, special attention has to be focused on the recent information on a possible role of GST and NAT polymorphisms in the predisposition to urinary bladder, prostate and urothelial transitional cell carcinoma.     

Lung cancer: genetics of risk and advances in chemoprevention

PURPOSE OF REVIEW: The current article reviews recent advances in genetic susceptibility and chemoprevention of lung cancer. RECENT FINDINGS: Linkage analysis has identified a locus on chromosome 6q23-25 that determines susceptibility to lung cancer in families with multiple members with cancer of the lung, throat, and larynx. Obligate gene carriers are sensitive to even small tobacco smoke exposure in terms of increased lung cancer risk. Variation in other genes, particularly those regulating the activation or inactivation of carcinogens, has been implicated in determining lung cancer risk. Epidemiologic and preclinical studies suggest that chemoprevention of lung cancer is an achievable goal. Early trials with beta-carotene supplementation, however, have revealed a harmful effect. Promising new agents must be evaluated in both preclinical models and in intermediate end point biomarker trials before being taken to large primary prevention trials, and lung cancer chemoprevention should only be attempted within controlled clinical trials. SUMMARY: We are poised to learn a great deal about the genetic susceptibility to lung cancer, which will not only allow definition of groups with extremely high risk, but may also yield new insights into processes that determine innate susceptibility or resistance to lung carcinogenesis. Chemoprevention of lung cancer is not yet ready for clinical application. As a result of the large number of lung cancer deaths and the large number of at-risk individuals, even modestly effective chemoprevention could save many lives.     

Genetic susceptibility to lung cancer

Lung cancer is the most common cause of cancer death in the world. Environmental factors, particularly cigarette smoking, are of paramount importance in determining lung cancer risk. Lung cancer and chronic obstructive lung disease are likely to share some common susceptibility genes, but these have not yet been identified. Evidence from various sources, including twin studies, segregation analyses, and case-control studies, support a heritable component to lung cancer risk in humans. As with many common diseases, susceptibility genes for lung cancer appear to be of low penetrance. Family studies of lung cancer susceptibility using linkage analysis and positional cloning have not been reported; however, a consortium is currently carrying out such studies, and results may soon be available. Association studies support lung cancer risk being partly determined by genes that control the metabolism of carcinogens found in tobacco smoke, with the heritable effects being most prominent in smokers with shorter smoking histories. Of these, the CYP1A1 and GSTM1 polymorphisms have been most consistently implicated. In the mouse, an oligonucleotide repeat polymorphism within an intron of the Ki-ras oncogene is the major lung cancer susceptibility locus; however this locus is not clearly involved in susceptibility to lung cancer in the human. Further understanding of the genetic basis of lung cancer susceptibility has many important implications, ranging from targeting prevention and screening efforts to the most highly susceptible population to developing novel chemopreventive therapies.