雌激素代谢基因COMT和CYP17单核苷酸多态与女性乳腺癌风险的关系

目的：研究参与雌激素合成的细胞色素P450c17(CYP17)和雌激素代谢解毒的儿茶酚-O-甲基转移酶(COMT)基因多态与乳腺癌发生的关系。方法：以聚合酶链反应和限制性片段长度多态方法,对250例乳腺癌患者和250例正常对照者的COMT基因第4外显子第158位密码子G／A(Val／Met)多态和CYP17基因启动子区-1931T／C多态进行分析。以logistic回归模型计算各种基因型的乳腺癌风险(DR)及其95％可信区限(95％CI)。结果：乳腺癌患者的COMT Met／Met基因型频率为10．4％,显著高于对照组的5．2％(P=0．03)。多因素分析显示,COMT Met／Met基因型患乳腺癌的风险比Val／Val或Val／Met基因型高2．1倍(95％a为1．1～4．5)。分层分析显示,COMT Met／Met基因型主要增加绝经前女性患乳腺癌的风险(OR4．1,95％CI为1．2～17.3),而不增加绝经后女性患乳腺癌的风险(OR 1．3,95％CI为0．5～3．5),提示该基因多态对乳腺癌风险的影响与雌激素水平有关。CYP17基因型频率在病例和对照组中的分布差异无显著性(P=O．83)。结论：COMT基因单核苷酸多态与乳腺癌易感性相关,Met／Met基因型增加乳腺癌风险,而CYP17基因多态与中国女性乳腺癌风险无相关性。     

Interactions between genetic polymorphism of cytochrome P450-1B1, sulfotransferase 1A1, catechol-o-methyltransferase and tobacco exposure in breast cancer risk

Genetic polymorphisms of enzymes involved in the metabolism of xenobiotics and estrogens might play a role in breast carcinogenesis related to environmental exposures. In a case-only study on 282 women with breast cancer, we studied the interaction effects (ORi) between smoking habits and the gene polymorphisms of Cytochrome P450 1B1 (Val432Leu CYP1B1), Phenol-sulfotransferase 1A1 (Arg213His SULT1A1) and Catechol-O-methyltransferase (Val158Met COMT). The smokers carrying the Val CYP1B1 allele associated with a high hydroxylation activity had a higher risk of breast cancer than never smokers with the Leu/Leu genotype (ORi=2.32, 95%CI: 1.00-5.38). Also, the smokers carrying the His SULT1A1 allele associated with a low sulfation activity had a 2-fold excess risk compared to never smokers carrying Arg/Arg SULT1A1 common genotype (ORi= 2.55, 95%CI: 1.21-5.36). The His SULT1A1 allele increased the risk only in premenopausal patients. The Met COMT allele with a lower methylation activity than Val COMT did not modify the risk among smokers. The excess risk due to joint effect could result from a higher exposure to activated tobacco-compounds for women homo/heterozygous for the Val CYP1B1 allele. Also, a lower sulfation of the tobacco carcinogens among women with His SULT1A1 could increase exposure to genotoxic compounds. Alternatively, the Val CYP1B1 or His SULT1A1 allele with modified ability to metabolize estrogens could increase the level of genotoxic catechol estrogen (i.e., 4-hydroxy-estradiol) among smokers. Our study showed that gene polymorphisms of CYP1B1 and SULT1A1 induce an individual susceptibility to breast cancer among current smokers.     

CYP2E1 rs2031920, COMT rs4680 Polymorphisms,Cigarette Smoking,Alcohol Use and Lung Cancer Risk in a Japanese Population

Background Cytochrome P450 2E1 (CYP2E1) and catechol-O-methyltransferase (COMT) genes may contribute to susceptiblity to lung cancer becuase of their critical involvement in mechanisms of carcinogenesis. Materials and Methods We evaluated the role of CYP2E1 rs2031920 and COMT rs4680 in a case-control study involving 462 lung cancer cases and 379 controls in Japanese. Logistic regression was used to assess adjusted odds ratios (OR) and 95% con dence intervals (CI). Multiplicative and additive interactions with cigarette smoking or alcohol use were also examined. Results Neither CYP2E1 rs2031920 nor COMT rs4680 was associated with lung cancer risk overall. However, smokers with the CC genotype of CYP2E1 rs2031920 (OR 3.57, 95% CI 2.26-5.63) presented a higher risk of lung cancer than those with at least one T allele (OR 2.91, 95% CI 1.70-4.98) as compared to never-smokers with at least one T allele (reference). Subjects with excessive drinking and the CC genotype of CYP2E1 rs2031920 had a signi cantly higher risk (OR2.22, 95% CI 1.39-3.56) than appropriate drinkers with at least one T allele. A similar tendency was observed between COMT rs4680 and either smoking or drinking habits. There were no multiplicative or additive interactions between the polymorphisms and either smoking or alcohol use. Conclusions Our ndings indicate that CYP2E1 rs2031920 and COMT rs4680 are not major contributors to lung cancer risk in our Japanese population. Future studies on the genetics of lung cancer in Japanese and their environment interactions are required.     

Polymorphisms in estrogen bioactivation, detoxification and oxidative DNA base excision repair genes and prostate cancer risk

To date, the potential impact of hormones on prostate cancer has predominantly focused on receptor-mediated events. However, catechol estrogens, if not inactivated by catechol-O-methyltransferase (COMT), can generate large quantities of reactive oxygen species (ROS). ROS may cause a spectrum of damage including oxidative DNA base lesions, which can lead to irreversible mutation(s) if they are not repaired by base excision repair (BER) systems. hOGG1 is a key enzyme in short patch BER because it recognizes and performs initial excision of the most common form of oxidative DNA base damage, 8-hydroxyguanine (8-oxo-dG). To investigate potential non-receptor-mediated estrogen effects, we evaluated the association between COMT Val158Met and hOGG1 Ser326Cys polymorphisms and prostate cancer in a family-based case-control study (439 prostate cancer cases, 479 brother controls). We observed no noteworthy associations between these polymorphisms and prostate cancer risk in the total study population. However, among men with more aggressive prostate cancer, the hOGG1 326 Cys/Cys genotype was inversely associated with disease (OR=0.30; 95% CI=0.09-0.98). Combining the lower activity CYP1B1 432 Leu/Leu or Leu/Val genotypes (which may decrease the level of catechol estrogens and ROS generated) with the hOGG1 326 Cys/Cys genotype and the XRCC1 399 Arg/Arg or Arg/Gln genotypes (which may enhance BER) resulted in an even further reduced risk in Caucasians with more aggressive disease (OR=0.09; 95% CI=0.01-0.56). Including the high-activity COMT 158Val allele to this combination also lowered aggressive prostate cancer risk but the effect was not as strong (OR=0.20; 95% CI=0.05-0.88). The decreased risk we observed with the hOGG1 326 Cys/Cys genotype confirms an earlier report and the further reduced risk found with the CYP1B1 (432 Leu/Leu or Leu/Val)-hOGG1 (326 Cys/Cys)-XRCC1 (Arg/Arg or Arg/Gln) genotype combination may lend new insights to the importance of ROS generated from non-receptor-mediated estrogenic mechanisms in more aggressive prostate cancer.     

Lack of Associations of the COMT Val158Met Polymorphism with Risk of Endometrial and Ovarian Cancer: a Pooled Analysis of Case-control Studies

This meta-analysis was conducted to examine whether the genotype status of Val158Met polymorphism in catechol-O-methyltransferase (COMT) is associated with endometrial and ovarian cancer risk. Eligible studies were identified by searching several databases for relevant reports published before January 1, 2014. Pooled odds ratios (ORs) were appropriately derived from fixed-effects or random-effects models. In total, 15 studies (1,293 cases and 2,647 controls for ovarian cancer and 2,174 cases and 2,699 controls for endometrial cancer)were included in the present meta-analysis. When all studies were pooled into the meta-analysis, there was no evidence for significant association between COMT Val158Met polymorphism and ovarian cancer risk (Val/Met versus Val/Val: OR=0.91, 95% CI=0.76-1.08; Met/Met versus Val/Val: OR=0.90, 95% CI=0.73-1.10; dominant model: OR=0.90, 95% CI=0.77-1.06; recessive model: OR=0.95, 95% CI=0.80-1.13). Similarly, no associations were found in all comparisons for endometrial cancer (Val/Met versus Val/Val: OR 0.97, 95% CI=0.77-1.21; Met/Met versus Val/Val: OR=1.02, 95% CI=0.73-1.42; dominant model: OR=0.98, 95% CI=0.77-1.25; recessive model: OR=1.02, 95% CI=0.87-1.20). In the subgroup analyses by source of control and ethnicity, no significant associations were found in any subgroup of population. This meta-analysis strongly suggests that COMT Val158Met polymorphism is not associated with increased endometrial and ovarian cancer risk.     

Case-control study of ovarian cancer and polymorphisms in genes involved in catecholestrogen formation and metabolism.

Steroid hormones, such as estrogens, appear to be associated with ovarian carcinogenesis, but the precise biological mechanisms are unclear. Polymorphisms in genes that regulate the concentration of estrogens and their metabolites may contribute directly to the individual variation in ovarian cancer risk through a mechanism involving oxidative stress or indirectly by influencing ovarian cancer susceptibility associated with ovulation and reproduction. We conducted a population-based, case-control study of primary ovarian cancer between 1993 and 1999 in Hawaii to test several genetic and related hypotheses. A personal interview and blood specimen were obtained in the subjects' homes. In a sample of 129 epithelial ovarian cancer cases and 144 controls, we compared the frequencies of several polymorphisms in genes that regulate steroid hormone metabolism and catecholestrogen formation. Multivariate unconditional logistic regression was used to model the association of each genetic polymorphism separately after adjusting for age, ethnicity, and other covariates. The high-activity Val432 allele of the CYP1B1 gene, which may be linked to oxidative stress through elevated 4-hydroxylated catecholestrogen formation, was associated with an increased risk of ovarian cancer. The Val/Leu genotype for CYP1B1 was associated with an odds ratio of 1.8 (95% confidence interval, 1.0-3.3) and the Val/Val genotype with an odds ratio of 3.8 (95% confidence interval, 1.2-11.4) compared with the Leu/Leu genotype (P = 0.005). Tobacco smokers with at least one CYP1A1 (MspI) m2 allele, one CYP1B1 Val allele, one COMT Met allele, or two CYP1A2 A alleles were at significantly increased risk of ovarian cancer compared to never-smokers with CYP1A1 (MspI) ml/ml, CYP1B1 Leu/Leu, COMT Val/Val, or CYP1A2 A/A genotypes, respectively. We found a positive statistical interaction (P = 0.03) between tobacco smoking and the CYP1A1 (MspI) polymorphism on the risk of ovarian cancer. None of the other gene-environment (pregnancy, oral contraceptive pill use) or gene-gene interactions were statistically significant. Although not significant, there was a suggestion that the effect of the CYP1B1 Val allele was reduced substantially in the presence of the high-activity COMT Met allele. These findings suggest that the CYP1B1-Val allele and perhaps other genetic polymorphisms in combination with environmental or hormonal exposures are susceptibility factors for ovarian cancer.     

Lack of Association Between the CYP1A1 Ile462Val Polymorphism and Endometrial Cancer Risk: a Meta-analysis

Purpose: Any association between the CYP1A1 Ile462Val polymorphism and endometrial cancer risk remainsinconclusive. For a more precise estimate, we performed the present meta-analysis. Methods: PUBMED, OVIDand EMBASE were searched for the studies which met inclusion criteria. Data in all eligible studies wereevaluated and extracted by two authors independently. The meta-analysis estimated pooled odds ratio (OR) with95% confidence interval (CI) for endometrial cancer risk attributable to the CYP1A1 Ile462Val polymorphism.Results: A total of 7 studies were included in this meta-analysis. The results indicated no association betweenendometrial cancer risk and the CYP1A1 Ile462Val polymorphism (for Val vs Ile allele model [OR 1.09, 95%CI 0.73-1.62]; for Val.Val vs Ile.Ile genotype model [OR 1.54, 95% CI 0.56-4.23]; for (Ile.Val + Val.Val) vs Ile.Ilegenotpye model [OR 1.08, 95% CI 0.71-1.63]; for Val.Val vs (Ile.Ile + Ile.Val) genotype model [OR 1.46, 95% CI0.53-4.04]). Conclusions: This meta-analysis suggests that there is no association between endometrial cancerrisk and the CYP1A1 Ile462Val polymorphism.     

CYP1A1 Val462 and NQO1 Ser187 polymorphisms, cigarette use, and risk for colorectal adenoma

Cigarette use is a risk factor for colorectal adenoma, a known precursor of colorectal cancer. Polymorphic variants in NQO1 and CYP1A1 influence the activation of carcinogenic substances in tobacco smoke, possibly impacting on tobacco-associated risks for colorectal tumors. We investigated the association of cigarette smoking with risk for advanced colorectal adenoma in relation to the CYP1A1 Val(462) and NQO1 Ser(187) polymorphic variants. Subjects were 725 non-Hispanic Caucasian cases with advanced colorectal adenoma of the distal colon (descending colon, sigmoid and rectum) and 729 gender- and ethnicity-matched controls, randomly selected from participants in the prostate, lung, colorectal and ovarian cancer screening trial. Subjects carrying either CYP1A1 Val(462) or NQO1 Ser(187) alleles were weakly associated with risk of colorectal adenoma; however, subjects carrying both CYP1A1 Val(462) and NQO1 Ser(187) alleles showed increased risks (OR = 2.2, 95% CI = 1.1-4.5), particularly among recent (including current) (OR = 17.4, 95% CI = 3.8-79.8, P for interaction = 0.02) and heavy cigarette smokers (>20 cigarettes/day) (OR = 21.1, 95% CI = 3.9-114.4, P for interaction = 0.03) compared with non-smokers who did not carry either of these variants. These genotypes were unassociated with risk in non-smokers. In analysis of adenoma subtypes, the combined gene variants were most strongly associated with the presence of multiple adenoma (P = 0.002). In summary, joint carriage of CYP1A1 Val(462) and NQO1 Ser(187) alleles, particularly in smokers, was related to colorectal adenoma risk, with a propensity for formation of multiple lesions.     

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.     

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.     

Ovarian cancer risk and polymorphisms involved in estrogen catabolism.

Polymorphisms within genes responsible for estrogen catabolism could alter cellular levels of genotoxic 4-hydroxylated catechol estrogens and antiangiogenic 2-methoxyestradiol, thus influencing risk of developing ovarian cancer. We carried out a population-based case-control study of 310 epithelial ovarian cancer cases and 585 controls in African-American and Caucasian women ages 35 to 54 years from Seattle, Atlanta, and Detroit metropolitan areas. Subjects were interviewed and genotyped for CYP1A1 m1, m2, m3, and m4; CYP1B1 Arg(48)Gly, Ala(119)Ser, Val(432)Leu, and Asn(453)Ser; COMT Val(158)Met; UGT1A1 A(TA)nTAA; and SULT1A1 Arg(213)His polymorphisms. Unconditional logistic regression was used to calculate odds ratios (OR). Haplotypes were inferred and analyzed using models based on expectation-maximization with progressive ligation and Bayesian coalescence theory. CYP1B1 Leu(432) carriers were at increased risk of ovarian cancer, with an adjusted OR of 1.5 (95% confidence interval, 1.1-2.3) compared with Val(432) homozygotes. The most common CYP1B1 haplotype was Arg(48)-Ala(119)-Val(432)-Asn(453). All other haplotypes with frequencies >5% contained the Leu(432) allele. In diplotype analyses, relative to women homozygous for Arg(48)-Ala(119)-Val(432)-Asn(453), women with diplotypes containing at least one Leu(432) allele had adjusted ORs ranging from 1.3 to 2.2. Among women homozygous for COMT Met(158), carriers of CYP1B1 Leu(432) had a 2.6-fold increase in risk relative to CYP1B1 Val(432) homozygotes (95% confidence interval, 1.1-5.9). This latter result is opposite in direction from a similar analysis conducted by other investigators in a different study population. No association of ovarian cancer risk was observed with any of the other polymorphisms examined, either alone or in combination.     

CYP1B1, CYP1A1, MPO, and GSTP1 polymorphisms and lung cancer risk in never-smoking Korean women

Polymorphisms in metabolic genes encoding phase I and phase II enzymes are thought to modulate the risk of lung cancer via changes in enzymatic activity. Recently, the effect of these metabolic enzymes and their interaction with environmental factors has been studied in both smokers and also never-smokers, since never-smokers are a good model in which to study genetic susceptibility at low-dose carcinogen exposure. Here, we investigated the association of CYP1A1 Ile462Val, CYP1B1 Leu432Val, GSTP1 Ile105Val, MPO G-463A polymorphisms and lung cancer risk in never-smoking Korean women. In this case-control study of 213 lung cancer patients and 213 age-matched healthy controls, we found that carrying one variant allele of the CYP1A1 Ile462Val polymorphism was associated with a significantly decreased risk of lung adenocarcinoma (adjusted odds ratio (OR)=0.63; 95% confidence interval (CI), 0.41-0.99). Furthermore, the combination of risk genotypes of CYP1B1 Leu432Val with CYP1A1 Ile462Val was associated with the risk of lung adenocarcinoma (adjusted OR=2.16; 95% CI, 1.02-4.57) as well as overall lung cancer (adjusted OR=2.23; 95% CI 1.01-4.89). The polymorphisms of GSTP1 Ile105Val and MPO G-463A showed no significant association with lung cancer. Theses results suggest that the CYP1A1 Ile462Val polymorphism is associated with a reduced risk of lung adenocarcinoma in never-smoking Korean women, whereas specific combinations of variant genotypes for metabolic enzymes increase lung cancer risk considerably.     

Metabolic polymorphisms, smoking, and oral cancer in Puerto Rico

Genetic polymorphisms resulting in variation in metabolism of tobacco carcinogens may influence oral cancer risk. In a population-based case-control study in Puerto Rico, genotypes of CYP1A1, GSTM1, and GSTT1 were determined by a PCR-based method for 132 oral cancer patients and 143 control subjects. Genotype-associated risks were estimated by logistic regression. The null variant of GSTM1 was associated with a marginally significant decrease in oral cancer risk [odds ratio (OR) = 0.6, 95% confidence interval (CI) = 0.3-1.0, and P for trend = 0.09]. Risks increased with increasing cigarette use among subjects with the GSTM1-present genotype (P for trend <0.0001), rising to OR = 9.5, 95% CI = 3.0-30, among the heaviest cigarette users. In contrast, among subjects with the GSTM1-null genotype, risks did not clearly increase with increasing cigarette use (P for trend <0.61; OR = 1.8, 95% CI = 0.6-5.2 among the heaviest tobacco users). The GSTT1-null variant (OR = 1.0, 95% CI = 0.5-1.9) and CYP1A1(462Val) variant (OR = 0.9, 95% CI = 0.5-1.7) were not associated with the risk. Risks rose with increasing cigarette use in a similar manner for subjects with or without the CYP1A1(462Val) variant (P for interaction = 0.3) and for subjects with or without the GSTT1-null genotype (P for interaction = 0.4). In conclusion, cigarette use significantly increased the risk of oral cancer in this population. The GSTM1-present genotype was associated with higher tobacco-associated risk for oral cancer among heavy smokers than the null genotype.     

Cytochrome P4501A1 and glutathione S-transferase M1 genotypes as risk factors for prostate cancer in Japan

BACKGROUND: The p53 mutation spectrum of prostate cancers developing in Japan indicates a role for environmental factors. This suggests there might be differences in susceptibility due to genetic polymorphisms in metabolic activation enzyme genes. We analyzed genetic polymorphisms of the xenobiotic-metabolizing enzymes, CYP1A1 and GSTM1. METHOD: Genotyping of CYP1A1 and GSTM1 was investigated by using allele-specific PCR in 115 prostate cancer (PCa) patients and 204 control patients. RESULTS: The CYP1A1 Val/Val genotype significantly increased the risk for PCa (OR = 2.6; 95% CI = 1.11-6.25) and the Ile/Val genotype showed a similar tendency (OR = 1.4; CI = 0.86-2.29). Individuals with the GSTM1 (0/0) genotype demonstrated a slightly increased risk (OR = 1.3; CI = 0.82-2.04). The combination of the CYP1A1 Val allele and GSTM1 (0/0) genotype was associated with a higher risk (OR = 2.3; CI = 1.18-4.48) than the CYP1A1 Val allele alone. When cases were analyzed by age at initial diagnosis, the relative risks with both the CYP1A1 Val allele and the GSTM1 (0/0) genotype were higher in the young group than in the old group (CYP1A1; OR = 1.7, CI = 0.89-3.17: GSTM1; OR = 1.6, CI = 0.84-2.99). The frequency of the GSTM1 (0/0) genotype was also higher in patients with advanced stage disease. In stage D, the OR was 1.7 with a CI of 0.93-3.17 and in stages A and B, the OR was 0.8 with a CI of 0.40-1.62. CONCLUSIONS: These results suggest that CYP1A1 and GSTM1 polymorphisms are linked to a propensity for PCa development.      

Catechol-O-methyltransferase gene polymorphism and post-menopausal breast cancer risk

Estrogen is involved in breast carcinogenesis. Hypotheses have been raised that its effect is modified by enzymes such as catechol-O-methyltransferase (COMT) that deactivate potentially genotoxic estrogen metabolites. We have investigated the association between the functional genetic Val108/158Met polymorphism in COMT and breast cancer risk in a large population-based case-control study performed in the genetically homogeneous Swedish population. We determined COMT genotype in 1534 women with invasive breast cancer and in 1504 control women and calculated odds ratios (OR) and 95% confidence intervals (CI) from logistic regression models. There was no overall association between COMT genotype and breast cancer risk. However, the L allele was associated with an increased risk for lobular breast cancer, with OR 2.0 (95% CI 1.2-3.5) for HL and 1.7 (95% CI 0.9-3.0) for LL. In exploratory subset analyses, we found no statistically significant interaction, but some indication of a positive association between HL and LL genotypes and breast cancer among women with diabetes mellitus and a negative association among nulliparous women. Based on our findings, COMT activity alone does not seem to play a major role in breast carcinogenesis, but may be of importance in certain histotypes or in conjunction with other exposures.     

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.     

CYP 1A1 polymorphism and risk of lung cancer in relation to tobacco smoking: a case-control study in China

The impact of genetic polymorphisms in CYP1A1 on susceptibility to lung cancer has received particular interest in recent years since this enzyme plays a central role in activation of major classes of tobacco carcinogens. Several polymorphisms in the CYP1A1 locus have been identified and their genotypes appear to exhibit population frequencies that depend on ethnicity. We have assessed the role of CYP1A1 genotype in lung cancer risk in the Chinese population via a case-control study. Three polymorphisms, m1 (MSP:I), m2 (exon 7 Ile-->Val) and m4 (exon 7 Thr-->Asn), were determined by PCR-RFLP in 404 controls and 217 lung cancer cases. While no polymorphic alleles were detectable in the m4 site among our study subjects, the allele frequencies for CYP1A1 m1 and CYP1A1 m2 were found to be 35.6 and 25.6% among controls, compared with 42.6 and 34.2% among cases. Multivariate analysis showed an elevated risk for lung cancer in subjects having at least one m1 allele [odds ratio (OR) = 2.0, 95% confidence interval (CI) = 1.4-2.8] or having at least one m2 allele (OR = 1.9, 95% CI = 1.3-2.7). However, this increased risk was limited to squamous cell carcinoma (SCC), but not adenocarcinoma or other histological types of lung cancer. Stratified analysis indicated a multiplicative interaction between tobacco smoking and variant CYP1A1 m1 genotypes on the risk of SCC. The ORs of SCC for the variant CYP1A1 m1 genotype, tobacco smoking and both factors combined were 2.8, 9.1 and 29.9, respectively. When the data was stratified by the pack-year values, this joint effect was consistent and stronger among the heaviest smokers. The interaction between tobacco smoking and the variant CYP1A1 m2 genotypes followed the same pattern. Our findings support the conclusion that CYP1A1 m1 and CYP1A1 m2 polymorphisms are associated with smoking-related lung cancer risk in Chinese.     

<Emphasis Type="Italic">CYP1A1</Emphasis> and <Emphasis Type="Italic">CYP1B1</Emphasis> genetic polymorphisms,smoking and breast cancer risk in a Finnish Caucasian population

We investigated the associations between two CYP1A1 polymorphisms (Ile462Val and Thr461Asn) and one CYP1B1 polymorphism (Leu432Val) and breast cancer risk. The study population consisted of 483 breast cancer patients and 482 healthy population controls, all of homogenous Finnish origin. No statistically significant overall associations were found between the CYP1A1 and CYP1B1 genotypes and breast cancer risk. However, a significant increase in the breast cancer risk was seen for women who had smoked 1–9 cigarettes/day and carried the CYP1B1 432Val allele; the OR was 2.6 (95% CI 1.07–6.46) for women carrying the Leu/Val genotype and 5.1 (95% CI 1.30–19.89, P for trend 0.005) for women with the Val/Val genotype compared to similarly smoking women homozygous for the 432Leu allele. Furthermore, when CYP1B1 genotypes were combined with the previously analyzed N-acetyl transferase (NAT2) genotypes, a significant increase in breast cancer risk was found among women who had at least one CYP1B1 432Val allele together with the NAT2 slow acetylator genotype (OR 1.52; 95% CI 1.03–2.24) compared to women carrying a combination of CYP1B1 Leu/Leu and NAT2 rapid acetylator genotypes. This risk was seen to be confined to ever smokers; the OR was 2.46 (95% CI 1.11–5.45) for ever smokers carrying at least one CYP1B1 432Val allele together with the NAT2 slow acetylator genotype compared to ever smokers with the CYP1B1 Leu/Leu and NAT2 rapid acetylator genotype combination. Our results suggest that the CYP1B1 polymorphism may be an important modifier of breast cancer risk in Finnish Caucasian women who have been exposed to tobacco smoke and/or carry the NAT2 slow acetylator genotype.     

Rapid detection of single nucleotide polymorphisms related with lung cancer susceptibility of Chinese population

Genetic variations have been thought to contribute to individual differences in lung cancer susceptibility. In our study, the possibility of an association of CYP1B1, GSTP1 and hOGG1 genetic polymorphisms with lung cancer was investigated in Chinese population of Nanjing, by a new single nucleotide polymorphism (SNP) typing approach of di-allele-specific-amplification with artificially modified primers (diASA-AMP) technique. A matched case-control study of 227 patients with lung cancer was conducted to detect CYP1B1 Leu432Val, GSTP1 Ile105Val and hOGG1 Ser326Cys polymorphisms. Genotypes were analyzed by diASA-AMP technique. Results did not show a significant difference in distributions of allele frequencies or genotypes of CYP1B1, GSTP1 and hOGG1 between two groups. However, stratifying on smoking status demonstrated that CYP1B1 432Val genotype had a slightly combined effect on lung cancer with smoker subjects (OR=2.78, 95%CI=1.46-5.29). The interaction between GSTP1 105Val mutation and smoking in the development of lung cancer were not detected, nor was hOGG1 326Cys mutation. Variant allele frequencies of CYP1B1, GSTP1 and hOGG1 in control group were similar to other reports of Chinese population. The sequencing results of CYP1B1, GSTP1 and hOGG1 matched the ones of diASA-AMP technique. CYP1B1 432Val polymorphism may modulate the individual susceptibility of lung cancer among smokers in Chinese population. GSTP1 Ile105Val and hOGG1 Ser326Cys polymorphisms were not found to be risk factors of lung cancer in this study. The method diASA-AMP is rapid, specific and cost-effective. It can be used for rapid detection of the genes related with tumor susceptibility of population.     

Polymorphisms in polycyclic aromatic hydrocarbon metabolism and conjugation genes, interactions with smoking and prostate cancer risk.

The relationship between cigarette smoking and prostate cancer remains unclear. Any potential association may depend on the individuals' ability to metabolize and detoxify cigarette carcinogens--such as polycyclic aromatic hydrocarbons. To investigate this, we studied the association between prostate cancer and smoking, as well as the main and modifying effects of functional polymorphisms in genes that metabolize polycyclic aromatic hydrocarbons (CYP1A1 Ile(462)Val, microsomal epoxide hydrolase His(139)Arg) and detoxify reactive derivatives (GSTM1 null deletion, GSTT1 null deletion, GSTP1 Ile(105)Val and Ala(114)Val) using a family-based case-control design (439 prostate cancer cases and 479 brother controls). Within the entire study population, there were no main effects for smoking or any of the polymorphisms. However, the nondeleted GSTM1 allele was inversely associated with prostate cancer [odds ratio (OR), 0.50; 95% confidence interval (95% CI), 0.26-0.94] among men with less aggressive disease (Gleason score < 7 and clinical tumor stage < T2c) and positively associated (OR, 1.68; 95% CI, 1.01-2.79) with prostate cancer in men with more aggressive disease (Gleason score > or = 7 or clinical tumor stage > or = T2c). We also found a statistically significant negative multiplicative interaction between the GSTM1 nondeleted allele and heavy smoking (> 20 pack-years) in the total study population (P = 0.01) and in Caucasians (P = 0.01). Among Caucasians, heavy smoking increased prostate cancer risk nearly 2-fold in those with the GSTM1 null genotype (OR, 1.73; 95% CI, 0.99-3.05) but this increased risk was not observed in heavy smokers who carried the GSTM1 nondeleted allele (OR, 0.95; 95% CI, 0.53-1.71). Our results highlight the importance of considering genetic modifiers of carcinogens when evaluating smoking in prostate cancer.