Aromatic DNA adducts and polymorphisms of CYP1A1, NAT2, and GSTM1 in breast cancer

Previous studies by us and others have shown a significantly higher level of aromatic DNA adducts in normal adjacent breast tissue samples obtained from breast cancer patients than in those obtained from non-cancerous controls. The increased amount of DNA damage could be related to excess environmental carcinogen exposure and/or genetic susceptibility to such exposure. In the current study, we investigated the relationship between the levels of aromatic DNA adducts in breast tissues and polymorphisms of the drug-metabolizing genes cytochrome P4501A1 (CYP1A1), N-acetyltransferase-2 (NAT2), and glutathione S-transferase M1 (GSTM1), in 166 women having breast cancer. DNA adducts were measured using (32)P-postlabeling and information on smoking status was obtained from medical records. When pooled data of smokers and non-smokers were analyzed by multiple regression analyses, no significant correlation was found between the level of total DNA adducts and age, race, or polymorphisms of CYP1A1, GSTM1, and NAT2. The only significant predictor of the level of DNA adducts in breast tissues was smoking (P = 0.008). When data were analyzed separately in smokers and non-smokers, however, a significant gene-environment interaction was observed. Smokers with CYP1A1*1/*2 or *2/*2 genotypes had a significantly higher level of DNA adducts than those with the CYP1A1*1/*1 genotype. This effect was not seen among non-smokers. There was also a gene-gene interaction, as smokers with combined CYP1A1*1/*2 or CYP1A1*2/*2 genotypes and GSTM1 null had a much higher level of adducts than those with either CYP1A1 or GSTM1 polymorphism. Genetic polymorphisms of CYP1A1 and NAT2 were also significantly correlated with the frequency of certain types of DNA adducts. For example, a bulky benzo[a]pyrene (B[a]P)-like adduct was detected in 26% of the samples, the presence of which was not related to age, race, smoking status, or GSTM1 and NAT2 genotype. However, a significantly higher frequency of the B[a[P-like adduct was found in individuals having CYP1A1*1/*2 or *2/*2 genotypes than in those having the *1/*1 genotype (P = 0.04). In addition, individuals having slow NAT2 alleles had a significantly higher frequency of the typical smoking-related DNA adduct pattern, i.e. a diagonal radioactive zone (DRZ), than others did (P = 0.008). These findings suggest that polymorphisms of CYP1A1, GSTM1, and NAT2 significantly affect either the frequency or the level of DNA adducts in normal breast tissues of women having breast cancer, especially in smokers. Further large-scale studies are required to determine the exact role of these polymorphisms and types of DNA damage in breast cancer susceptibility.     

Prospective study of NAT1 and NAT2 polymorphisms, tobacco smoking and meat consumption and risk of colorectal cancer

Heterocyclic amines in tobacco smoke and fried meat are activated or detoxified by N-acetyltransferases (NAT1 and NAT2). We identified 379 cases with colorectal cancer (CRC) and 769 sub-cohort members among a cohort of 57,000 members. There were no statistically significant associations between tobacco smoking, consumption of meat (red, processed and fried) and CRC risk. Preference for brown-dark pan-fried meat increased the CRC risk. NAT1 fast acetylators had a significantly higher risk of CRC than NAT1 slow acetylators, whereas NAT2 acetylator status did not affect the CRC risk. There were no statistically significant interactions between tobacco smoking and either NAT1 or NAT2 acetylator status in relation to CRC risk. However, smoking intensity increased CRC risk among carriers of both NAT1 and NAT2 fast. This indicates that N-acetylator status affects the relationship between smoking and CRC risk.     

Cigarette smoking, CYP1A1 MspI and GSTM1 genotypes, and colorectal adenomas

Cigarette smoking has been related to increased risk of colorectal adenomas, but the underlying mechanisms are unknown. Genetic polymorphisms are known for enzymes involved in the activation of polycyclic aromatic hydrocarbons and other tobacco-related carcinogens. Polycyclic aromatic hydrocarbons are activated by cytochrome P4501A1 (CYP1A1) and detoxified by glutathione S-transferases. We investigated the relation of CYP1A1 MspI and GSTM1 genotypes to the risk of colorectal adenomas with special reference to interaction with cigarette smoking among 205 cases of colorectal adenomas and 220 controls with normal total colonoscopy in a male Japanese population. Cigarette smoking was strongly associated with increased risk of colorectal adenomas. Overall, neither the CYP1A1 MspI genotype nor the GSTM1 genotype was related to colorectal adenomas. A significant trend for increased risk of colorectal adenomas associated with smoking was observed for each of the CYP1A1 MspI genotypes, and the increasing trends did not differ by MspI genotype. The positive association between smoking and colorectal adenomas did not vary much with GSTM1 genotypes. Among former and current smokers, adenoma risk did not differ according to the combination of CYP1A1 MspI and GSTM1 genotypes. CYP1A1 MspI and GSTM1 genotypes do not seem to modify the risk of colorectal adenomas associated with cigarette smoking.     

Dietary isothiocyanates, GSTM1, GSTT1, NAT2 polymorphisms and bladder cancer risk

Isothiocyanates (ITCs) are nonnutrient compounds in cruciferous vegetables with anticarcinogenic properties. ITCs down-regulate cytochrome P-450 biotransformation enzyme levels, activate Phase II detoxifying enzymes and induce apoptosis. On the other hand, ITCs also serve as a substrate for GSTs. Experimental evidences suggest that ITCs have anticarcinogenic effect on bladder cancer. Therefore, we evaluated dietary intake of ITCs, GSTM1, GSTT1 and NAT2 polymorphisms, and bladder cancer risk in a case-control study. There were 697 newly diagnosed bladder cancer cases identified from The University of Texas M. D. Anderson Cancer Center and 708 healthy controls matched to cases by age (+/-5), gender and ethnicity. Participants underwent an in-person interview, in which epidemiologic and food frequency questionnaires were administered to collect demographic and dietary intake data. Median ITC intake per day was statistically significantly lower in cases than in controls (0.23 vs. 0.33, p < 0.001). High ITC intake was associated with 29% decreased risk of bladder cancer [Odds ratio (OR) = 0.71, 95% confidence interval (CI) = 0.57, 0.89]. The protective effect was more evident in older individuals (> or =64-years-old), men, ever smokers and heavy smokers in stratified analysis. Compared with NAT2 rapid acetylator, NAT2 slow acetylator had an increased risk of bladder cancer in Caucasians (OR = 1.31, 95% CI = 1.02, 1.69). There was no main effect associated with the GSTM1 or GSTT1 genotypes. The protective effect of ITCs against bladder cancer was not modified by GSTM1, GSTT1 or NAT2 genotypes. This is the first epidemiological report that ITCs from cruciferous vegetable consumption protect against bladder cancer.     

GSTM1和CYP1A1基因多态性与宫颈癌发生及发展的相关性

目的:探讨谷胱苷肽硫转移酶M1（GSTM1）和CYP1A1 Exon7基因多态性与宫颈癌发生发展的关系。方法:选取2013年5月至2015年5月我院收治的宫颈癌患者184例为宫颈癌组,203例进行体检的健康人群为参照组。用限制性片段长度多态性-聚合酶链反应（RFLP-PCR）检测所有受试者GSTM1和CYP1A1 Exon7基因型;记录无进展生存期（PFS）,并随访观察生存和死亡情况。结果:GSTM1分为野生型（wt）和突变缺失型（null）,CYP1A1 Exon7野生型为Ⅱe/Ⅱe,突变型包括突变纯合型（Val/Val）、突变杂合型（Ⅱe/Val）。宫颈癌组携带GSTM1突变型基因型比例与参照组间比较,差异无统计学意义（P＞0.05）;宫颈癌组携带CYP1A1 Exon7突变型基因型比例显著高于参照组（P＜0.05）,且携带突变型基因型个体患宫颈癌的风险是携带野生型基因型个体的2.333倍。GSTM1、CYP1A1 Exon7基因型与宫颈癌患者年龄、病理分期、肿瘤分化程度、肿瘤直径及淋巴结转移均无关（P＞0.05）,与患者病理类型有关（P＜0.05）。GSTM1、CYP1A1 Exon7突变型宫颈癌患者PFS中位数与野生型患者比较,差异均无统计学意义（P＞0.05）。GSTM1、CYP1A1 Exon7突变型宫颈癌患者基因型与宫颈癌患者预后无关（P＞0.05）。结论:GSTM1及CYP1A1 Exon7基因多态性是宫颈癌发生发展的危险因素,尤其是CYP1A1 Exon7突变型,为预防宫颈癌提供依据。     

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   

N-acetyltransferase (NAT1, NAT2) and glutathione S-transferase (GSTM1, GSTT1) polymorphisms in breast cancer

To evaluate the potential association between NAT1/NAT2 polymorphisms and breast cancer, a case-control study was conducted in Korean women (254 cases, 301 controls). NAT1 *4/*10 genotype (42%) was the most common NAT1 genotype in this Korean population. The frequencies of slow, intermediate and rapid NAT2 acetylator genotype were 16, 39 and 44% in cases and 16, 42 and 42% in controls. Neither NAT1 rapid (homozygous or heterozygous NAT1 *10) (OR=1.2, 95% CI=0.8-1.9) nor NAT2 rapid acetylator genotype (OR=1.2, 95% CI=0.8-1.7) showed significant association with breast cancer risk. Although the risk of NAT2 rapid acetylator genotype in postmenopausal women (OR=1.4, 95% CI=0.7-2.8) was higher than that in premenopausal women (OR=1.1, 95% CI=0.7-1.7), those were not statistically significant. However, combinations of NAT1, GSTM1 and GSTT1 genotypes showed a significant linear gene-dosage relationship with breast cancer (p for trend=0.04) and those women with NAT2 rapid acetylator and both GSTM1 and GSTT1 null genotypes were at the elevated risk (OR=3.1, 95% CI=1.0-9.1). These results suggest that genetic polymorphisms of NAT1 and NAT2 have no independent effect on breast cancer risk, but they modulate breast cancer risk in the presence of GSTM1 and GSTT1 null genotypes.     

GSTM1, GSTT1, GSTP1, CYP1A1, and NAT1 polymorphisms, tobacco use, and the risk of head and neck cancer.

Squamous cell carcinoma of the head and neck (SCCHN), including the oral cavity, pharynx, and larynx, provides an ideal tumor model to investigate gene-environment interaction. We conducted a hospital-based case-control study including 182 cases with newly diagnosed SCCHN and 202 controls with nonneoplastic conditions of the head and neck that required surgery. Lifetime tobacco use and risk of SCCHN were evaluated in relation to the polymorphisms of GSTM1, GSTT1, GSTP1, CYP1A1, and NAT1. The main effects of genotype were associated with a slightly increased risk of SCCHN for GSTP1 [age-, race-, and sex-adjusted odds ratio (OR), 1.2; confidence interval (CI), 0.8-1.9], GSTT1 (OR, 1.2; CI, 0.7-2.3), and NAT1 (OR, 1.1; CI, 0.7-1.7). The joint effects of genotype combinations showed some excess risk for the combination of the GSTM1 null genotype and the CYP1A1 Ile/Val polymorphism (OR, 2.6; CI, 0.7-10.3). The analysis of the joint effects (interaction) of the "at-risk" genotypes and tobacco use did not reveal any interaction on either the multiplicative or additive scale for GSTM1, GSTP1, or CYP1A1. However, there was a suggestion of an interaction on the additive scale between the pack-years of tobacco use and the GSTT1 null genotype. The combined heterozygote and homozygote NAT1*10 genotypes also had a suggestive interaction with tobacco smoking history. The results of this study suggest a possible gene-environment interaction for certain carcinogen metabolizing enzymes, but larger studies that fully evaluate the interaction are needed.     

Influence of CYP1A1, CYP2E1, GSTM3 and NAT2 genetic polymorphisms in oral cancer susceptibility: results from a case-control study in Rio de Janeiro

Xenobiotic metabolizing enzymes are involved in the detoxification of many carcinogens and may be important in modulating cancer susceptibility. CYP1A1, CYP2E1, GSTM3, and NAT2 polymorphisms were determined in peripheral blood DNA of 231 oral cancer patients and 212 hospital controls in Rio de Janeiro, Brazil, using the PCR-RFLP technique. NAT2 polymorphism distribution was different between cases and controls (P=0.035), with an overrepresentation of NAT2( *)11 mutant allele in controls. Risk analysis showed that NAT2 4/4 individuals (OR=1.95, 95% CI=1.05-3.60) and combined GSTM3 and NAT2 heterozygotes (OR=1.94, 95% CI=1.04-3.66) were at increased oral cancer risk. No statistically significant association was observed for CYP1A1 and CYP2E1 polymorphisms. Our results suggest that NAT2 polymorphism, alone or combined with GSTM3, may modulate susceptibility to oral cancer in Rio de Janeiro.     

Impact of GSTT1, GSTM1, GSTP1 and NAT2 genotypes on KRAS2 and TP53 gene mutations in colorectal cancer

Which carcinogens are of influence in the development of human colorectal cancers remains a question; one answer could be the finding that specific polymorphisms in xenobiotic metabolizing enzymes are related to particular mutations in cancer genes. KRAS2 and TP53 gene mutations as well as genotypes for GSTM1, GSTP1, GSTT1 and NAT2 were determined in an exploratory series of 165 stable colorectal cancers. Mutations in KRAS2 and TP53 were found in 34% and 57.5% of cases, respectively. The KRAS2 mutation frequency was significantly lower in patients with a GSTT1 null genotype than in those with a GSTT1 non-null genotype (18% vs. 38%, p = 0.03). The overall risk of KRAS2 mutation for patients with distal colorectal cancer and GSTT1 null genotype was 0.3 (95% CI 0.1-0.9) compared to patients with distal colorectal cancer and non-null GSTT1 genotype. The overall risk of KRAS2 mutation was similarly reduced (OR = 0.4, 95% CI 0.2-0.9) for patients with distal colorectal cancer and GSTP1 mutated genotypes compared to patients with distal colorectal cancer and wild-type genotype. Patients with GSTP1 wild-type genotype appeared to be at significantly lower risk for TP53 mutation compared to patients with mutated genotypes (p = 0.023). Our results suggest that GSTT1 and GSTP1 could play a role in the occurrence of KRAS2 and TP53 mutations in colorectal cancer and generate a hypothesis on the dietary factors that could be incriminated.     

CYP1A1, GSTM1, and GSTT1 polymorphisms, smoking, and lung cancer risk in a pooled analysis among Asian populations

To evaluate the roles of CYP1A1 polymorphisms [Ile 462Val and T 6235C (MspI)] and deletion of GSTM1 and GSTT1 in lung cancer development in Asian populations, a pooled analysis was conducted on 13 existing studies included in Genetic Susceptibility to Environmental Carcinogenesis database. This pooled analysis included 1,971 cases and 2,130 controls. Lung cancer risk was estimated as odds ratios (OR) and 95% confidence intervals (95% CI) using unconditional logistic regression model adjusting for age, sex, and pack-year. The CYP1A1 6235C variant was associated with squamous cell lung cancer (TC versus TT: OR, 1.42; 95% CI, 0.96-2.09; CC versus TT: OR, 1.97; 95% CI, 1.26-3.07; P trend = 0.003). In haplotype analysis, 462Val-6235T and Ile-C haplotypes were associated with lung cancer risk with reference to the Ile-T haplotype (OR, 3.41; 95% CI, 1.78-6.53 and OR, 1.39; 95% CI, 1.12-1.71, respectively). The GSTM1-null genotype increased squamous cell lung cancer risk (OR, 1.36; 95% CI, 1.05-1.77). When the interaction was evaluated with smoking, increasing trend of lung cancer risk as pack-year increased was stronger among those with the CYP1A1 6235 TC/CC genotype compared with those with TT genotype (P interaction = 0.001) and with the GSTM1-null genotype compared with the present type (Pinteraction = 0.08, when no genotype effect with no exposure was assumed). These results suggest that genetic polymorphisms in CYP1A1 and GSTM1 are associated with lung cancer risk in Asian populations. However, further investigation is warranted considering the relatively small sample size when subgroup analyses were done and the lack of environmental exposure data other than smoking.     

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.     

Association of NAT1 and NAT2 polymorphisms to urinary bladder cancer: significantly reduced risk in subjects with NAT1*10.

The role of hereditary polymorphisms of the arylamine N-acetyltransferase 1 (NAT1) gene in the etiology of urinary bladder cancer is controversial. NAT1 is expressed in the urothelium and may O-acetylate hydroxyl amines, particularly in subjects with low NAT2 activity. Thus, NAT1 polymorphisms may affect the individual bladder cancer risk by interacting with environmental factors (smoking and occupational risks) and by interacting with the NAT2 gene. We studied the frequencies of the NAT1 haplotypes *3, *4, *10, *11, *14, *15, *17, and *22 in 425 German bladder cancer patients and 343 controls by PCR-RFLP. NAT1*10 allelic frequency was lower in bladder cancer patients (15.1%) compared with controls (20.4%; P = 0.012). Genotypes that included NAT1*10 were significantly less frequent among the cases (odds ratio adjusted for age, gender, and smoking, 0.65; 95% confidence interval, 0.46-0.91; P = 0.013). Two subtypes of NAT1*11 were detected: *11A (-344T, -40T, 445A, 459A, 640G, and 1095A) and *11C (-344T, -40T, 459A, 640G, and 1095A). The allele frequency of NAT1*11 was 4.3% in the cases versus 3.9% in the controls. The rare low-active NAT1*14A was overrepresented in the cases (P = 0.026). With regard to the NAT2 genotype, our data showed: (a) a partial linkage of NAT1*10 to NAT2*4; (b) a clear underrepresentation of NAT1*10 genotypes among rapid NAT2 genotypes in the cases studied (odds ratio, 0.39; 95% confidence interval, 0.22-0.68; P = 0.001), and (c) a gene-gene-environment interaction. NAT2*slow/NAT1*4 genotype combinations with a history of occupational exposure were 5.96 (2.96-12.0) times more frequent in cancer cases than in controls without risk occupation (P < 0.0001). Hence, our data suggest that individuals provided with NAT2*4 and NAT1*10 are at a significantly lower risk for bladder cancer, particularly when exposed to environmental risk factors.     

Association between dietary heterocyclic amine levels, genetic polymorphisms of NAT2, CYP1A1, and CYP1A2 and risk of stomach cancer: a hospital-based case-control study in Japan

Background  

Although the associations between grilled (broiled) or barbecued meats or fish intake and stomach cancer risk have been investigated, the evidence implicating heterocyclic amine (HCA) intake as a cause of stomach cancer is limited. We conducted a case-control study to investigate the association between HCA intake and stomach cancer risk. We also investigated the possible effect of genetic polymorphisms of NAT2, CYP1A1, and CYP1A2 on stomach cancer.     

Association of GSTM1, CYP1A1 and CYP2E1 genetic polymorphisms with susceptibility to lung adenocarcinoma: a case-control study in Chinese population

A case-control study of 164 lung adenocarcinoma (AC) patients with 181 age- and gender-matched healthy controls was conducted in order to assess any associations between glutathione- S -transferase M1 (GSTM1), cytochrome P4501A1 (CYP1A1) and cyto-chrome P4502E1 (CYP2E1) polymorphisms and susceptibility to lung AC in Chinese. The presence of CYP2E1 variant allele was significantly less frequent in cases than in controls, while the distribution of GSTM1 null genotype and variant CYP1A1 Msp 1 allele did not vary between cases and controls. After adjustment for age, gender, smoking and all other genotypes, the CYP2E1 Rsa1 variant allele was significantly associated with decreased risk of lung AC [odds ratio 0.534 (95% confidence interval, 0.340–0.837)]. Furthermore, 3.0-fold increased risk was found in individuals with combined GSTM1 null genotype and CYP2E1 Rsa 1 wild type versus those with combined GSTM1 non-null type and CYP2E1 variant allele. Our results suggest that CYP2E1 Rsa 1 variant allele is associated with a decreased risk of lung AC, and combined GSTM1 null genotype and CYP2E1 Rsa1 wild type has a promoting effect on susceptibility to lung AC. (Cancer Sci 2003; 94: 448–452)     

Association of GSTM1, GSTT1, and GSTP1 gene polymorphisms with the risk of prostate cancer: a meta-analysis.

The glutathione S-transferase (GST) gene superfamily encodes for enzymes involved in conjugation of electrophilic compounds to glutathione. Several polymorphisms in the GST genes have been implicated as risk factors for prostate cancer. We did a meta-analysis of 11 studies with GSTM1 genotyping (2,063 prostate cancer cases and 2,625 controls), 10 studies with GSTT1 genotyping (1,965 cases and 2,554 controls), and 12 studies with GSTP1 genotyping (2,528 cases and 3,076 controls). The random effects odds ratio was 1.08 [95% confidence interval (95% CI), 0.93-1.25, no significant between-study heterogeneity] for the GSTM1 null versus nondeleted genotype and 0.90 (95% CI, 0.73-1.12; P = 0.03 for heterogeneity) for the GSTT1 null versus nondeleted genotype. Overall, the random effects odds ratio was 1.05 (95% CI, 0.90-1.21; P < 0.01 for heterogeneity) for the GSTP1-Val versus GSTP1-Ile allele. For all three polymorphisms, there was a trend for the presence of an association in the earliest published studies, but this did not seem to be validated in subsequent research. For GSTT1, larger studies gave different results than smaller ones. The meta-analysis shows that these three polymorphisms are unlikely to be major determinants of susceptibility to prostate cancer on a wide population basis.     

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).