Role of alcohol dehydrogenase 3 and cytochrome P-4502E1 genotypes in susceptibility to cancers of the upper aerodigestive tract

Alcohol is a recognized risk factor for upper aerodigestive tract (UAT) cancers, but the mechanism by which alcohol causes cancer remains obscure. Ethanol is oxidized to acetaldehyde (the suspected carcinogenic agent in alcohol) by alcohol dehydrogenases (ADHs) and cytochrome P-4502E1 (CYP2E1), both of which exhibit great inter-individual variability in activity. The hypothesis that these polymorphisms influence susceptibility to alcohol-related cancers remains poorly documented. We investigated whether ADH(3) and CYP2E1 DraI and RsaI genotypes modified the risk of UAT cancers among 121 oral cavity/pharyngeal cancer patients, 129 laryngeal cancer patients, and 172 controls, all French Caucasians. Cancer risks and gene-alcohol interactions were analyzed by unconditional logistic regression, accounting for potential confounders. ADH(3) genotype was not associated with UAT cancer. In contrast, a 2-fold risk of oral cavity/pharyngeal (OR = 2.0, 95% CI 1.0-3.9) and laryngeal (OR = 1.8, 95% CI 1.0-3.5) cancers was observed for carriers of the CYP2E1 DraI C variant allele compared with other individuals. The risk associated with the CYP2E1 RsaI c2 variant allele also increased for oral cavity/pharyngeal cancer (OR = 2.6, 95% CI 1.0-6. 6). The effects of ADH(3) or CYP2E1 genotype and alcohol or tobacco were independent. The highest risk of oral cavity/pharyngeal cancer was observed among the heaviest drinkers (>80 g/day) with the CYP2E1 DraI C allele (OR = 5.8, 95% CI 1.9-18.2) or the CYP2E1 RsaI c2 allele (OR = 7.2, 95% CI 1.4-38.2) compared with lighter drinkers with other genotypes. Our study suggests that CYP2E1 genotype modifies the risk of UAT cancers, but due to the low frequency of CYP2E1 variant alleles, large-scale studies are needed to confirm our findings.     

A cytochrome P4502E1 genetic polymorphism and tobacco smoking in breast cancer

Known breast-cancer risk factors account for only part of the variability in breast-cancer incidence. Tobacco smoke is not commonly considered a breast carcinogen, but many of its constituents, such as N-nitrosamines, are carcinogenic in laboratory animal studies. Herein, we assessed a cytochrome P4502E1 (CYP2E1) genetic polymorphism (a Dral restriction enzyme site in intron 6) as a risk factor for breast cancer in both premenopausal and postmenopausal women. Because N-nitrosamines are metabolically activated by CYP2E1, the risk among women smokers was investigated. Caucasian women were enrolled in a case-control study of breast cancer between 1986 and 1991. A subset of the women (219 premenopausal and 387 postmenopausal women) consented to phlebotomy. The allelic frequencies for the premenopausal women (D allele = 0.91 and C allele = 0.09) and postmenopausal women (D allele = 0.93 and C allele = 0.07) were similar to those previously reported. There was no statistically significant association between the CYP2E1 polymorphism and breast-cancer risk for premenopausal or postmenopausal women (adjusted odds ratio (OR) = 1.04, 95% confidence interval (CI) = 0.48, 2.24, and OR = 1.01, 95% CI = 0.55, 1.84, respectively). When the women were categorized as nonsmokers versus smokers (those who smoked more than one cigarette per week for more than 1 yr), premenopausal women with one or two C alleles who had a history of smoking were found to be at increased risk (unadjusted OR = 7.00, 95% CI = 0.75, 14.53, and adjusted OR = 11.09, 95% CI = 1.51, 81.41), although the number of study subjects with those genotypes was small. The small number of study subjects with a C allele precluded meaningful classification by level of smoking, but categorizing the smokers into two groups (above and below the median) also suggested an increased risk. Premenopausal women with the DD genotype and postmenopausal women with any genotype were not at increased risk. Breast-cancer risk was not related to the CYP2E1 genotype in either premenopausal nonsmokers or smokers (adjusted OR = 0.66, 95% CI = 0.20, 2.17, and OR = 2.13, 95% CI = 0.60, 7.59, respectively) or postmenopausal nonsmokers or smokers (OR = 0.90, 95% CI = 0.34, 2.35, and OR = 1.02, 95% CI = 0.46, 2.23, respectively), although the difference in the ORs for premenopausal nonsmokers and smokers suggests an increased risk for smokers. While there are limitations to this study, particularly related to the small number of subjects with the DC and CC genotypes, the study suggests that some women may be susceptible to tobacco smoke because of a CYP2E1 polymorphism. However, these results are preliminary and must be replicated. © 1996 Wiley-Liss, Inc.

1 This article is a US Government work and, as such, is in the public domain in the United States of America.

     

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.     

Increased risk of oral leukoplakia and cancer among mixed tobacco users carrying XRCC1 variant haplotypes and cancer among smokers carrying two risk genotypes: one on each of two loci, GSTM3 and XRCC1 (Codon 280).

An individual's susceptibility to oral precancer and cancer depends not only on tobacco exposure but also on the genotypes/haplotypes at susceptible loci. In this hospital-based case-control study, 310 cancer patients, 197 leukoplakia patients, and 348 controls were studied to determine risk of the disease due to polymorphisms at three sites on XRCC1 and one site on XRCC3. Independently, variant genotypes on these loci did not modulate risk of leukoplakia and cancer except for the XRCC1 (codon 280) risk genotype in exclusive smokeless tobacco users with leukoplakia [odds ratios (OR), 2.4; 95% confidence intervals (CI), 1.0-5.7]. But variant haplotypes, containing one variant allele, on XRCC1 increased the risk of leukoplakia (OR, 1.3; 95% CI, 1.0-1.7). Among stratified samples, mixed tobacco users, carrying variant haplotypes, also had increased risk of both leukoplakia (OR, 2.2; 95% CI, 1.3-3.9) and cancer (OR, 1.9; 95% CI, 1.2-3.1). In a previous study on this population, it was shown that the GSTM3 (A/A) genotype increased the risk of oral leukoplakia and cancer among smokers, which has also been substantiated in this study with expanded sample sizes. The simultaneous presence of two risk genotypes in smokers, one on each of two loci, GSTM3 and XRCC1 (codon 280), increased the risk of cancer (OR, 2.4; 95% CI, 1.0-5.8). Again, smokers carrying two risk genotypes, one on each of two loci, GSTM3 and XRCC1 (codon 399), were also overrepresented in both leukoplakia and cancer populations (P(trend) = 0.02 and 0.04, respectively) but enhancement of risks were not observed; probably due to small sample sizes. Therefore, the presence of variant haplotypes on XRCC1 and two risk genotypes, one on each of two loci, GSTM3 and XRCC1, could be useful to determine the leukoplakias that might progress to cancer in a group of patients.     

CYP1A1 Polymorphisms and Risk of Lung Cancer in the Ethnic Kashmiri Population

The CYP1A1 category of enzymes plays a central role in the metabolic activation of major tobaccocarcinogens. Several polymorphisms within the CYP1A1 locus have been identified and have been shownto be associated with lung cancer risk, particularly in Asian populations. Here we focused on the influenceof three polymorphisms on lung cancer in ethnic Kashmiris, genotyping 109 lung cancer cases and 163healthy controls by PCR-RFLP methods. While no polymorphic alleles in CYP1A1m4 (exon 7 thr toasn) site were detected in our population, the allele frequency of CYP1A1m1 (Msp1) and CYP1A1m2(exon 7 ile to val) were 30.1 and 26.6 in controls and 44.5 and 38.9 in cases. The CYP1A1m1 andCYP1A1m2 variants were significantly associated with lung cancer susceptibility (ORs; 2.65, CI 95% =1.562-4.49 and 2.24,CI 95%=1.35-3.73).This risk was prominent in case of SCC compared with AC orother types of lung cancer. Stratified analysis showed a multiplicative interaction between tobaccosmoking and variant CYP1A1m1 genotype on the risk of SCC. The ORs of SCC for non-smokers were2.08 and 3.15 for smokers. When stratified by pack years, effect was stronger in the heaviest smokers(ORs=6.00,95% CI=1.672-21.532).The interaction between tobacco smoking and variant CYP1A1m2genotype followed similar pattern. Our findings thus support the conclusion that CYP1A1m1 and m2polymorphisms are associated with the smoking related lung cancer risk in Kashmiri population.     

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.     

Polymorphisms at XPD and XRCC1 DNA repair loci and increased risk of oral leukoplakia and cancer among NAT2 slow acetylators

Polymorphisms at N-acetyl transferase 2 locus (NAT2) lead to slow, intermediate and rapid acetylation properties of the enzyme. Improper acetylation of heterocyclic and aromatic amines, present in tobacco, might cause DNA adduct formation. Generally, DNA repair enzymes remove these adduct to escape malignancy. But, tobacco users carrying susceptible NAT2 and DNA repair loci might be at risk of oral leukoplakia and cancer. In this study, 389 controls, 224 leukoplakia and 310 cancer patients were genotyped at 5 polymorphic sites on NAT2 and 3 polymorphic sites on each of XRCC1 and XPD loci by PCR-RFLP method to determine the risk of the diseases. None of the SNPs on these loci independently could modify the risk of the diseases in overall population but variant genotype (Gln/Gln) at codon 399 on XRCC1 and major genotype (Lys/Lys) at codon 751 on XPD were associated with increased risk of leukoplakia and cancer among slow acetylators, respectively (OR = 4.2, 95% CI = 1.2-15.0; OR = 1.6, 95% CI = 1.1-2.3, respectively). Variant genotype (Asn/Asn) at codon 312 on XPD was also associated with increased risk of cancer among rapid and intermediate acetylators (OR = 1.9, 95% CI = 1.2-2.9). Variant C-G-A haplotype at XRCC1 was associated with increased risk of leukoplakia (OR = 1.7, 95% CI = 1.2-2.4) but leukoplakia and cancer in mixed tobacco users (OR = 3.1, 95% CI = 1.4-7.1, OR = 2.4, 95% CI = 1.1-5.4, respectively) among slow acetylators. Although none of the 3 loci could modulate the risk of the diseases independently but 2 loci in combination, working in 2 different biochemical pathways, could do so in these patient populations.     

Association between CYP2E1 polymorphisms and susceptibility to prostate cancer.

Several genetic alterations have been associated with sporadic prostate cancer (PCa). In this study, the association between RsaI and DraI polymorphisms of CYP2E1 and PCa risk was analysed in a case-control study of 227 individuals using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Regarding DraI polymorphisms, the DD genotype is over-represented in PCa cases when compared with the control group (odds ratio (OR) 2.12; 95% confidence interval (CI) 1.11-4.05; P=0.022). Regarding the RsaI polymorphism, no significant differences were found. The results of this study indicate that DraI polymorphisms of the CYP2E1 gene may be associated with a twofold increased risk for the development of PCa.     

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.     

Effects of cytochrome P450 (CYP) 2A6 gene deletion and CYP2E1 genotypes on gastric adenocarcinoma

Cytochrome P450 (CYP) 2A6 and CYP2E1 are enzymes with a high ability to activate a nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), to its potent and ultimate carcinogens. The polymorphic CYP2A6 and CYP2E1 have been implicated in increased susceptibility to certain malignancies. In our study, 120 Japanese patients with gastric adenocarcinoma and 158 healthy controls were compared for frequencies of CYP2A6 and CYP2E1 genotypes. The frequency with which the subjects carried homozygotes of the CYP2A6 gene deletion allele, which causes lack of the enzyme activity, was significantly higher in the gastric cancer patients than in the healthy control subjects (OR = 3.14, 95% confidence interval (95% CI) = 1.05-9.41). Subdividing gastric adenocarcinoma according to tumor differentiation, patients with the well-differentiated type were 4.9-fold more likely to have the CYP2A6 homozygote deletion genotype (OR = 4.91, 95% CI 1.17-20.52). Stratifying by smoking status, we did not find the risk of CYP2A6 gene deletion allele in gastric adenocarcinoma. The CYP2E1 polymorphism detected by RsaI was not significantly different between gastric adenocarcinoma patients (40.8%) and the control population (44.3%). No statistically significant changes were observed when the CYP2E1 genotype was examined relative to tumor differentiation and smoking status. These results suggest that the CTY2A6 deletion is associated with gastric adenocarcinoma among Japanese populations.     

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.     

Association of CYP2E1 and NAT2 Polymorphisms with Lung Cancer Susceptibility among Mongolian and Han Populations in the Inner Mongolian Region

Purpose: To explore associations of CYP2E1 and NAT2 polymorphisms with lung cancer susceptibilityamong Mongolian and Han populations in the Inner Mongolian region. Materials and Methods: CYP2E1 andNAT2 polymorphisms were detected by PCR-RFLP in 930 lung cancer patients and 1000 controls. Results: (1)Disequilibrium of the distribution of NAT2 polymorphism was found in lung cancer patients among Han andMongolian populations (p=0.031). (2) Lung cancer risk was higher in individuals with c1, D allele of CYP2E1RsaI/PstI, DraI polymorphisms and slow acetylation of NAT2 (c1 compared with c2, OR=1.382, 95%CI: 1.178-1.587, p=0.003; D compared with C, OR=1.241, 95%CI: 1.053-1.419, P<0.001; slow acetylation compared withrapid acetylation, OR=1.359, 95%CI:1.042-1.768, p=0.056) (3) Compared with c2/c2 and rapid acetylation, c1/c1together with slow acetylation synergetically increased risk of lung cancer 2.83 fold. (4) Smokers with CYP2E1c1/c1, DD, and NAT2 slow acetylation have 2.365, 1.916, 1.841 fold lung cancer risk than others with c2/c2, CCand NAT2 rapid acetylation, respectively. (5) Han smokers with NAT2 slow acetylation have 1.974 fold lungcancer risk than others with rapid acetylation. Conclusions: Disequilibrium distribution of NAT2 polymorphismwas found in lung cancer patients among Han and Mongolian populations. Besides, Han smokers with NAT2slow acetylation may have higher lung cancer risk compared with rapid acetylation couterparts. CYP2E1 c1/c1, DD and NAT2 slow acetylation, especially combined with smoking, contributes to the development of lungcancer. CYP2E1 c1/c1 or DD genotype and NAT2 slow acetylation have strong synergistic action in increasinglung cancer risk.     

CYPlAl和CYPlA2基因多态性与汉族女性乳腺癌的关系

目的 探讨CYP1A1基因MspⅠ位点与CYP1A2基因C734A位点多态性与汉族女性乳腺癌的关系.方法 应用聚合酶链反应-限制性片段长度多态性技术和限制性核酸内切酶酶切的方法,检测2011年9月至2012年8月在四川省医学科学院四川省人民医院确诊的144例女性乳腺癌患者（乳腺癌组）和152例同期健康体检正常女性（对照组）CYP1A1基因MspⅠ与CYP1A2基因C734A多态性位点的基因型,用χ2检验比较两组等位基因频率的差异.结果 在乳腺癌组与对照组中,CYP1A1基因MspⅠ位点T等位基因频率分别为0.73和0.65,两者差异有统计学意义（χ2=4.94,P=0.03）,C等位基因与T等位基因相比,乳腺癌发病风险OR为0.67 （95%CI：0.47～0.96）;CYP1A2基因C734A位点C等位基因频率分别为0.26和0.29,两者差异无统计学意义 （χ2=0.63,P=0.43）.将乳腺癌组按照ER、PR表达与否进一步分组后,CYP1A1基因MspⅠ与CYP1A 2基因C734A 2个多态性位点的等位基因频率在ER（＋）与ER（-）组之间以及PR（＋）与PR（-）组之间差异均无统计学意义[ER（＋）组比ER（-）组：χ2=0.34、0.01;PR（＋）组比PR（-）组：χ2=0.60、0.68;P均〉0.05].结论 汉族女性CYP1A1基因MspⅠ位点多态性与乳腺癌相关联.     

CYP2D6 and CYP2E1 Gene Polymorphisms and their Association with Cervical Cancer Susceptibility: A Hospital Based Case-Control Study from South-Western Maharashtra

Background: In last few years several studies all over the world discovered the genetic polymorphisms in different cytochrome P450 genes associated with risk of various cancers, but contradictory outcomes were evidenced in case of cervical cancer risk.  In this case-control study we aimed to see whether the polymorphism of CYP2D6 or CYP2E1 genes may or may not be associated with cervical cancer risk in women of rural Maharashtra. Methods: In this case-control study, the association of CYP2D6 and CYP2E1 gene polymorphism with cervical cancer risk was studied by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The study was conducted with 350 clinically confirmed cervical cancer patients and 350 healthy women in a population of South-Western Maharashtra. The Odds ratio (OR) with 95% confidence interval and p-value were evaluated, where p ≤0.005 was considered as statistically significant. Results: After the analysis of SNP (rs389209) of CYP2D6 and SNPs (rs2031920, rs6413432, rs6413420) of CYP2E1, we noticed that variant allele A of CYP2E1*6 showed significant increase in cervical cancer cases (OR=4.81; 95% CI: 1.57- 14.77; p=0.005). The genotypic distribution of heterozygote G/A genotype of CYP2D6*4 showed negative association with cervical cancer development when age of cancer occurrence (OR=0.41; 95% CI: 0.27- 0.61; p<0.0001) and tobacco history (OR=0.35; 95% CI: 0.20- 0.59; p=0.0001) was considered. Conclusion: The findings from this study supported that rs6413432 SNP of CYP2E1*6 increased cervical cancer risk in the studied rural women population.     

Betel quid not containing tobacco and oral leukoplakia: a report on a cross-sectional study in Papua New Guinea and a meta-analysis of current evidence

Leukoplakia is an asymptomatic, potentially malignant change in the oral mucosa. Previous studies have reported that smoking and betel quid chewing are associated with increased risk of leukoplakia; few studies have reported on these associations in populations where betel quid does not contain tobacco. We conducted a case-control study nested in a cross-sectional study in Papua New Guinea and a systematic review of studies that included chewers of betel quid without tobacco. Our study recruited 1,670 adults. We recorded betel quid chewing and smoking. The prevalence of leukoplakia was 11.7%. In the nested case-control study of 197 cases and 1,282 controls, current betel chewing was associated with increased risk of leukoplakia with an adjusted odds ratio for current chewers of 3.8 (95% CI 1.7, 8.4) and in the heaviest chewers of 4.1 (95% CI 1.8, 9.1) compared to non-chewers. Current smoking was associated with an increased risk of leukoplakia with an adjusted odds ratio for current smokers of 6.4 (95% CI 4.1, 9.9) and amongst heaviest smokers of 9.8 (95% CI 5.9, 16.4) compared to non-smokers. The systematic review identified 5 studies examining risk of leukoplakia associated with betel quid chewing in populations where betel quid did not contain tobacco and that controlled for smoking. In studies that adjusted for smoking, the combined random effect odds ratio was 7.9 (95% CI 4.3, 14.6) in betel quid chewers. The results of this study and systematic review of similar studies provide evidence of the role of betel quid not containing tobacco and leukoplakia.     

Polymorphisms of GSTP1 and GSTT1, but not of CYP2A6, CYP2E1 or GSTM1, modify the risk for esophageal cancer in a western population

Esophageal cancer is among the most common and fatal tumors in the world. Eighty percent of esophageal tumors are esophageal squamous cell carcinoma (ESCC). Brazil is one of the high incidence areas in the West, where tobacco and alcohol consumption have been associated with ESCC. However, polymorphisms in xenobiotic metabolizing genes may also contribute to the risk. Therefore, in this study, we analyzed the risk of ESCC associated with tobacco and alcohol consumption and with polymorphisms of CYP2A6 (CYP2A6*2), CYP2E1 (CYP2E1*5B, CYP2E1*6), GSTP1 (Ile105Val), GSTM1 and GSTT1 null genotypes in 126 cases and 252 age- and gender-matched controls. Data on the amount, length and type of tobacco and alcohol consumed were collected, and DNA was extracted from blood lymphocytes from all individuals. Polymorphisms were analyzed by polymerase chain reaction (PCR)-multiplex (GSTM1 and T1), PCR-Restriction Fragment Length Polymorphism (CYP2E1*5B and *6 and GSTP1 Ile105Val) or allele-specific PCR amplification (CYP2A6*2). Risks were evaluated by multivariate conditional regression analysis. As expected, tobacco [odds ratio (OR) = 6.71, 95% confidence interval (95% CI) 3.08-14.63] and alcohol (OR = 16.98, CI 7.8-36.98) consumption, independently or together (OR = 26.91, CI 13.39-54.05) were risk factors. GSTP1 Ile105Val polymorphism was an independent risk factor (OR = 2.12, CI 1.37-3.29), whereas GSTT1 wild-type was an independent protective factor for ESCC (OR = 0.37, CI 0.16-0.79). There was approximately 80% statistical power to detect both results. There was no risk associated with CYP2A6, CYP2E1 and GSTM1 polymorphisms. In conclusion, this study suggests an opposite role of GSTP1 and GSTT1 polymorphisms for the risk for ESCC.     

Oral cancer susceptibility associated with the CYP1A1 and GSTM1 genotypes in Chilean individuals

Polycyclic aromatic hydrocarbons (PAHs) contained in tobacco smoke acquire carcinogenicity following their activation by xenobiotic-metabolizing enzymes to highly reactive metabolites. The cytochrome P4501A1 (CYP1A1) enzyme is central to the metabolic activation of these PAHs, and GSTM1 is the main enzyme responsible for its detoxification. CYP1A1 and GSTM1 polymorphisms were evaluated in 124 Chilean healthy controls and 48 oral cancer patients through PCR-based restriction fragment length polymorphism. In the healthy controls, frequencies of the CYP1A1 variant alleles for m1 (CYP1A1(*)2A) and the GSTM1null genotype were found to be 0.25 and 0.19, respectively. In the oral cancer patients, these frequencies were 0.33 and 0.50, respectively. Thus, the GSTM1 and m1 rare alleles were significantly more frequent in the oral cancer patients compared to the controls. The estimated relative risk for oral cancer associated with the single genotype CYP1A1 or GSTM1 was 2.08 for wt/m1, 1.04 for m1/m1 and 4.16 for the GSTM1null genotype. For smokers, the estimated relative risk (adjusted by age and gender) was higher in the individuals carrying the m1 allele of CYP1A1 [wt/m1: odds ratio (OR)=5.68, P=0.0080; m1/m1: OR=7.77, P=0.0420] or GSTM1null genotype (OR=20.81, P<0.0001). Combined genotypes CYP1A1 and GSTM1 increased the risk significantly (wt/m1/GSTM1null: OR=19.14, P=0.0030; m1/m1/GSTM1null: OR=21.39, P=0.0130). Taken together, these findings suggest that Chilean individuals carrying single or combined GSTM1 and CYP1A1 polymorphisms may be more susceptible to oral cancer induced by environmental tobacco smoking.     

Influence of the CYP1A1 T3801C Polymorphism on Tobacco and Alcohol-Associated Head and Neck Cancer Susceptibility in Northeast India

Background: Tobacco and alcohol contain or may generate carcinogenic compounds related to cancers.CYP1A1 enzymes act upon these carcinogens before elimination from the body. The aim of this study was toinvestigate whether CYP1A1 T3801C polymorphism modulates the relationship between tobacco and alcoholassociatedhead and neck cancer (HNC) susceptibility among the northeast Indian population. Materials andMethods: One hundred and seventy histologically confirmed HNC cases and 230 controls were included withinthe study. The CYP1A1 T3801C polymorphism was determined using PCR-RFLP, and the results were confirmedby DNA sequencing. Logistic regression (LR) and multifactor dimensionality reduction (MDR) approaches wereapplied for statistical analysis. Results: The CYP1A1 CC genotype was significantly associated with HNC risk(P=0.045). A significantly increased risk of HNC (OR=6.09; P<0.0001) was observed in individuals with combinedhabits of smoking, alcohol drinking and tobacco-betel quid chewing. Further, gene-environment interactionsrevealed enhanced risks of HNC among smokers, alcohol drinkers and tobacco-betel quid chewers carryingCYP1A1 TC or CC genotypes. The highest risk of HNC was observed among smokers (OR=7.55; P=0.009)and chewers (OR=10.8; P<0.0001) carrying the CYP1A1 CC genotype. In MDR analysis, the best model forHNC risk was the three-factor model combination of smoking, tobacco-betel quid chewing and the CYP1A1variant genotype (CVC=99/100; TBA=0.605; P<0.0001); whereas interaction entropy graphs showed synergisticinteraction between tobacco habits and CYP1A1. Conclusions: Our results confirm that the CYP1A1 T3801Cpolymorphism modifies the risk of HNC and further demonstrated importance of gene-environment interaction.     

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.     

CYP1A1 and CYP2E1 genotypes and risk of esophageal squamous cell carcinoma in a high-incidence region,Kashmir

The study analyzed the relationship between genetic polymorphisms of phase I xenobiotic metabolizing enzymes, cytochromes P450 (CYP) 1A1 and CYP2E1 and esophageal squamous cell carcinoma (ESCC) in Kashmir, India. The different genotypes of CYP1A1 and CYP2E1 were analyzed by polymerase chain reaction and restriction fragment length polymorphism in 526 ESCC cases and equal number of matched controls. Conditional logistic regression models were used to assess the association of various genotypes with ESCC, gene–gene, and gene–environment interactions. High risk of ESCC was found in participants who carried CYP1A1 Val/Val genotype (OR?=?2.87; 95 % CI?=?1.00–8.44) and the risk increased in such individuals when c1/c1 of CYP2E1 genotype was also present (OR?=?5.68; 95 % CI?=?1.09–29.52). Risk due to CYP1A1 Val/Val genotype was further enhanced (OR?=?8.55; 95 % CI?=?1.86–42.20) when the analysis was limited to ever smokers. Participants who carried CYP2E1 c1/c2 genotype showed an inverse relation (OR?=?0.27; 95 % CI?=?0.17–0.43) with ESCC. The inverse association of CYP2E1 c1/c2 genotype was retained when CYP1A1 Ile/Ile was also present (OR?=?0.18; 95 % CI?=?0.09–0.32), as well as when analysis was limited to ever smokers (OR?=?0.45; 95 % CI?=?0.23–0.90). Significant interaction was found between CYP1A1 (Val/Val) and CYP2E1 (c1/c1) genotypes (OR?=?1.30; 95 % CI?=?1.12–1.51; P?=?0.001) and between CYP1A1 (Val/Val) and smoking (OR?=?1.31; 95 % CI?=?1.01–1.69; P?=?0.043). The study suggests CYP1A1 Val/Val and CYP2E1 c1/c1 genotypes are significantly associated with ESCC risk.