Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytochrome P450 (CYP) CYP1A1 activates tobacco-related carcinogens. A point mutation at codon 462 in exon 7 of CYP1A1 results in a substitution of isoleucine by valine near the heme binding site. This mutation is rare in Caucasians but common in Japanese populations, in which association with increased risk of lung cancer has been reported. There are few data in other Asian populations. We investigated this I462V polymorphism using DNA from 214 incident cases of lung cancer and 669 controls in a prospective cohort study of 18,244 middle-aged and older men in Shanghai, China. The valine allele frequency was 0.138 among the control population. The I462V genotype was not appreciably associated with lung cancer risk overall. There was some suggestion that having at least one valine allele might be related to increased risk of lung cancer among smokers of <20 cigarettes/day (odds ratio, 1.72; 95% confidence interval, 0.82-3.62), particularly among those with homozygous deletion of GSTM1 (odds ratio, 2.80; 95% confidence interval, 1.07-7.33), which is involved in the detoxification of activated tobacco carcinogens. In this Chinese cohort, with CYP1A1 valine allele frequency intermediate between Japanese and Caucasian populations, the I462V polymorphism is not related to lung cancer overall, but it might play a role at lower levels of cigarette smoking among subjects with impaired carcinogen detoxification as assessed by the GSTM1-null genotype.
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PMID:CYP1A1 I462V genetic polymorphism and lung cancer risk in a cohort of men in Shanghai, China. 1100 20

Smoking is the principal cause of lung cancer. However, not all smokers will develop this disease. Individual susceptibility to chemically induced cancer may be explained in part by genetic differences in the activation and detoxification of procarcinogens. The activation phase of polycyclic aromatic hydrocarbon (PAH) metabolism is governed by the enzyme CYP1A1, induced by PAH when it enters the body. The extent to which PAH induces CYP1A1 activity varies greatly from one subject to another. CYP1A1 inducibility has long been associated, although inconsistently, with an increased risk of lung cancer. In 1982, Kouri corroborated Kellerman's results with a new method for measuring inducibility, but few studies have reported using this method. The glutathione S-transferases (GSTs) are involved in the detoxification phase of PAH, and the allelic deletion of GSTM1 has been also associated with an increased risk of lung cancer. We conducted a case-control study to examine the risk of lung cancer related, separately and together, to CYP1A1 inducibility, GSTM1 polymorphism and cigarette smoking in a French population. The 611 subjects were 310 incident lung cancer cases and 301 hospital control subjects. We were able to constitute a DNA bank for 552 subjects (89.5%) and gather detailed information on smoking history for all of them. Inducibility could be measured for 195 cases and 183 control subjects. Results for GSTM1 polymorphism concern 247 cases and 254 control subjects. GSTM1 polymorphism and inducibility could both be assessed for 179 cases and 166 control subjects. The odds ratio related to inducibility was 1.7 [1.0-3.0] for medium and 3.1 (1.3-7.4) for hyper inducers. The association with GSTM1 was 1.6 (1.0-2.6). With a reference category of subjects who were both low inducers and GSTM1(+), we found an odds ratio for lung cancer of 8.1 (2-31) for the subjects with both risk factors [i.e. GSTM1(-) and hyper inducers]. Our data did not reveal evidence of interaction between smoking and inducibility. On the other hand, we found an interaction of 3.6 (0.6-21) between inducibility and GSTM1.
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PMID:Relation between inducibility of CYP1A1, GSTM1 and lung cancer in a French population. 1103 3

Isothiocyanates (ITCs) are nonnutrient compounds in cruciferous vegetables with anticarcinogenic properties. One proposed mechanism for their protective action is through down-regulation of cytochrome P-450 biotransformation enzyme levels and induction of phase II detoxifying enzymes. Because ITCs also serve as a substrate for GSTs, we evaluated dietary intake of ITCs and GSTM1 and GSTT1 genotype information in a lung cancer case-control study. There were 503 newly diagnosed lung cancer cases (264 men and 239 women) identified from The University of Texas M. D. Anderson Cancer Center and 465 controls (252 men and 213 women) recruited from enrollees in a local managed care organization. Subjects had an in-person interview including a semiquantitative food frequency questionnaire, and blood samples were obtained for genotyping. Cases reported significantly lower ITC intake per day compared with controls (P = 0.009). There was no main effect associated with the GSTM1 null genotype [odds ratio (OR) = 1.09]. However, there was a statistically significant OR of 1.41 associated with the GSTT1 null genotype. On stratified analysis, low ITC intake and the GSTM1 null genotype were associated with increased lung cancer risk in current smokers, with an OR of 2.22 [confidence interval (CI) = 1.20-4.10). For current smokers with the GSTT1 null genotype, the OR with low ITC intake was 3.19 (CI = 1.54-6.62). The comparable OR in the presence of both null genotypes was 5.45 (CI = 1.72-17.22). These effects were not demonstrable for former smokers by GSTM1 genotype, although the risk for low ITC intake and GSTT1 null genotype was 1.79 (CI = 0.95-3.37). Thus, current smokers who are homozygous null for the GST null genotype and who consume less carcinogenic blocking compounds are at higher lung cancer risk. Some of the inconsistencies reported in the role of GST genotypes in lung cancer risk could be due to unexpected confounding from dietary factors.
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PMID:Dietary intake of isothiocyanates: evidence of a joint effect with glutathione S-transferase polymorphisms in lung cancer risk. 1104 82

This two-by-two factorially designed study evaluate approaches for communicating feedback of lung cancer susceptibility to smokers as a method for motivating smoking cessation. The study factors were: method of communicating feedback (by mail with telephone follow-up or in-person) and carbon monoxide feedback (yes or no). One-hundred-forty-four smokers were stratified on race and randomized to one of four conditions. Participants were surveyed at baseline and 2-month follow-up. Polymerase chain reaction (PCR) testing for the absence of the glutathione S transferase mu (GSTM1) gene was the susceptibility marker. Regardless of counseling method or carbon monoxide (CO) feedback, the majority (90%) of smokers accurately recalled the test result and 66% accurately interpreted the meaning of the test result. Smokers who received their result in person were significantly less likely to have read the result booklet than those in the telephone counseling group (OR = .28, 95%; CI .12-.62; p < .05). Neither counseling method nor CO feedback increased smokers' perceived risks for lung cancer. However, at the counseling session those who received in-person counseling were significantly less frightened by the test result than those who received telephone counseling (OR = .42, 95%; CI .20-86; p < .05) and at the 2-month follow-up those who received a CO test were significantly less frightened by their susceptibility result (OR = .40, 95%; CI .17-.92; p < .05) than those who did not have a CO test. Evaluation of further refinements in communicating the meaning of susceptibility results to motivate smoking cessation is warranted.
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PMID:Maximizing the motivational impact of feedback of lung cancer susceptibility on smokers' desire to quit. 1118 23

The published studies of onco-associated genetic polymorphisms are characterized by insufficient interlaboratory reproducibility. The inconsistency of the results can be partially attributed to some characteristics of patients and control groups, which are used for the comparison of allele frequencies. For instance, many investigations involve so-called "healthy donors" as a standard. However, the efficiency of such a comparison can be questioned; indeed, as an individual life-time risk of malignancy reaches as high as 40-50%, a significant part of "healthy donors" would soon or later become the oncological patients. Here we tested the advantage of using "true" oncologically tolerant individuals as an additional control, e.g. tumor-free people, who succeeded to achieve an elderly age without signs of any neoplastic disease. GSTM1 gene polymorphism was used as a "positive control" for this novel design of molecular epidemiological study, as the GSTM1-null genotype displays slight but reproducible association with lung cancer risk. In the present investigation, GSTM1-deficiency was detected in 45% elderly tumor-free individuals, 55% healthy middle-aged donors, and 59% lung cancer patients. The minimal frequency (43%) of GSTM1(-) genotype was detected in elderly tumor-free smokers, and the maximal one (100%) was found in never-smoking lung cancer patients. Thus, the comparison of lung cancer patients to the "true" oncologically tolerant cohort (elderly tumor-free individuals, especially smokers) revealed more demonstrative deviations for the unfavorable genotype, than the traditional comparative analysis between oncological patients and healthy donors.
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PMID:[Polymorphism of the GSMT1 gene in lung cancer resistance and susceptibility]. 1120 85

We have studied the influence of GSTM1 and NAT2 genotypes on aromatic DNA adduct level (AL) and HPRT mutant frequency (MF) in smokers with newly diagnosed lung cancer and matched population controls. AL was analyzed in relation to genotypes in 170 cases and 144 controls (113 current/recent smokers and 201 former/never smokers), and MF in 157 cases and 152 controls (155 ever smokers and 154 never smokers). Both genotypes exhibited the a priori expected effects on AL and MF among controls only, especially among smoking controls [significantly lower pack-years (a pack-year is defined as 1 pack of cigarettes/day for 1 year) than among cases]. Among the 42 currently smoking controls, the NAT2 slow genotype [odds ratio (OR), 7.5; 95% confidence interval (CI), 1.5-38.4], in particular in combination with the GSTM1 null genotype (OR, 19.3, 95% CI, 1.1-338.6 for null/slow versus positive/rapid) was strongly associated with high AL. The null/slow combination was also significantly associated with high MF among ever smokers (cases and controls pooled) with lower pack-years (OR, 3.7; 95% CI, 1.3-10.7 versus all of the other genotypes; OR, 5.1; 95% CI, 1.2-22.4 versus positive/rapid). In contrast, an antagonistic gene-gene interaction was seen among smoking cases for both AL and MF. Only currently smoking cases with the combined GSTM1 null and NAT2 rapid genotype showed a positive correlation between InAL and InMF (r, 0.64; P = 0.1), and an increase of AL with both age and daily cigarette use. This genotype combination was also associated with high MF among ever-smoking cases (OR, 4.0; 95% CI, 0.9-17.7 versus positive/rapid). There was a significant interaction between NAT2 genotype and pack-years of smoking among cases, so that the rapid genotype was associated with high MF among ever-smoking cases diagnosed at higher pack-years, whereas the slow genotype was associated with high MF at lower pack-years. These findings suggest that the influence of NAT2 genotype on AL and MF and its interaction with GSTM1 genotype may be dose dependent. The NAT2 slow genotype, in particular when combined with the GSTM1 null genotype, may confer increased susceptibility to adduct formation, gene mutation, and lung cancer when the smoking dose is low.
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PMID:Differential interactions between GSTM1 and NAT2 genotypes on aromatic DNA adduct level and HPRT mutant frequency in lung cancer patients and population controls. 1121 70

Lung cancer is the leading cause of cancer mortality in Taiwanese women. Cigarette smoking cannot explain the high lung cancer mortality in this population because less than 10% of women in Taiwan are smokers. Therefore, environmental factors other than smoking may play an important role in lung cancer development in female nonsmokers. The purpose of this study was to elucidate the role of environmental carcinogen exposure in lung cancer development in Taiwanese female nonsmokers, based on DNA adduct formation. We collected nontumorous lung tissues resected from 62 nonsmoking lung cancer patients and 20 noncancer controls to investigate whether differences in susceptibility to DNA adduct formation exist between men and women. (32)P-postlabeling and ELISA (enzyme-linked immunosorbent assay) with polyclonal antibody against BPDE (7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene)-DNA adduct were used to evaluate DNA adduct levels in lung tissues of study subjects. Our data showed that the DNA adduct levels of lung cancer patients determined by both assays were significantly higher than those of noncancer controls (P = 0.0001 for (32)P-postlabeling; P = 0.01 for ELISA). Moreover, DNA adduct levels in females were markedly greater than those in males (P = 0.014 for (32)P-postlabeling; P = 0.001 for ELISA). The difference in DNA adduct levels could not be explained by genetic polymorphisms of cytochrome P-4501A1 (CYP1A1) or glutathione S-transferase (GSTM1), as determined by polymerase chain reaction and restriction fragment length polymorphism. These results demonstrate that lung cancer patients have a higher susceptibility to DNA damage than that of noncancer controls. In addition, differences in susceptibility to DNA damage derived from environmental carcinogen exposure were observed between male and female nonsmokers. In conclusion, high susceptibility to DNA damage in females may partially explain the high mortality rate of lung cancer in nonsmoking Taiwanese women.
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PMID:Gender difference in DNA adduct levels among nonsmoking lung cancer patients. 1142 80

A vast number of studies are focused on investigating genetic polymorphism in order to estimate genetic contribution to the development of cancer. Possible cancer susceptibility genes have been sought among oncogenes, tumor suppressor genes, DNA repair genes and genes encoding phase I and phase II enzymes. Large individual differences in the biotransformation of xenobiotics have been explained on the basis of genetic polymorphisms in some detoxifying enzymes, regardless of environmental and occupational exposure. Among these enzymes, glutathione S-transferases (GST) constitute a large multigene family of phase II enzymes involved in detoxification of potentially genotoxic chemicals. Five genetic polymorphisms of GST have been well documented. Total or partial deletions and (or) single nucleotide polymorphisms in alleles encoding GSTM1, GSTM3, GSTPI, GSTT1, GSTZ1 are associated with reduction of enzymatic activity toward several substrates of different GST isoenzymes. In addition, molecular epidemiology studies indicate that a single genetic polymorphism of glutathione S-transferase appears to be a moderate lung cancer risk factor. However, the risk is higher when interactions with more GST polymorphisms and other risk factors (e.g. cigarette smoking) occur. Individuals with decreased rate of detoxification, with "high risk" glutathione S-transferase genotypes have a slightly higher level of carcinogen-DNA adducts and more cytogenetic damages.
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PMID:Significance of genetic polymorphisms in glutathione S-transferase multigene family and lung cancer risk. 1154 73

Chinese populations consume a diet relatively high in isothiocyanates (ITCs), a derivative of cruciferous vegetables known to have cancer-protective effects. This class of compounds is metabolized by the glutathione S-transferase family of enzymes, which are also involved in the detoxification of tobacco-related carcinogens such as polycyclic aromatic hydrocarbons and alkyl halides. We evaluated the association between dietary isothiocyanate intake, GSTM1 and GSTT1 polymorphisms, and lung cancer risk in 420 Chinese women: 233 histologically confirmed lung cancer patients and 187 hospital controls. Among these, 58.8% of cases and 90.3% of controls were lifetime nonsmokers. An allele-specific PCR method was used to detect the presence or absence of the GSTM1 and GSTT1 genes in DNA isolated from peripheral blood. Higher weekly intake of ITCs (above the control median value of 53.0 micromol) reduced the risk of lung cancer to a greater extent in smokers [adjusted odds ratio (OR), 0.31; 95% confidence interval (CI), 0.10-0.98] than nonsmokers (OR, 0.70; 95% CI, 0.45-1.11). The inverse association was stronger among subjects with homozygous deletion of GSTM1 and/or GSTT1. Among nonsmokers with GSTM1-null genotype, higher intake of ITCs significantly reduced the risk of lung cancer (OR, 0.54; 95% CI, 0.30-0.95), an effect not seen among those with detectable GSTM1 (OR, 1.07; 95% CI, 0.50-2.29). Our results, in a Chinese female population, are consistent with the hypothesis that ITC is inversely related to the risk of lung cancer, and we show that among nonsmokers this effect may be primarily confined to GST-null individuals. Conjugation and elimination of ITCs is enhanced in GST-non-null relative to -null individuals, such that the GST metabolic genotype modifies the protective effect of ITCs on lung cancer development.
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PMID:Dietary isothiocyanates, glutathione S-transferase -M1, -T1 polymorphisms and lung cancer risk among Chinese women in Singapore. 1158 32

Human microsomal epoxide hydrolase (mEH) catalyzes a key step in the biotransformation of benzo[a]pyrene that yields the highly mutagenic (+)-anti-7,8-diol-9,10 epoxide (BPDE). Two polymorphisms have been described in the coding region of the mEH gene (EPHX1) that produce two protein variants: 113Tyr-->113His (exon 3) and 139His-->139Arg (exon 4). We performed a case-control study among Northwestern Mediterranean Caucasians to investigate a possible association between these EPHX1 variants and lung cancer risk. Both EPHX1 polymorphisms were analyzed in a group of lung cancer patients (n=176) and in a control group of healthy smokers (n=187). The results showed a significantly decreased risk for the rare homozygous 113His/113His (adjusted odds ratio (OR): 0.44, 95% confidence interval (CI): 0.27-0.71) and 139Arg/139Arg (adjusted OR: 0.55, 95% CI: 0.33-0.91) compared with the major wild-types 113Tyr/113Tyr and 139His/139His, respectively, as the references. Thereafter, we analyzed the EPHX1 variants in combination with three glutathione S-transferase polymorphic genes (GSTM1, GSTT1, and GSTP1) and we found a significant overepresentation of cancer patients with a combination of exon 3 113Tyr/113Tyr EPHX1 and exon 5 105Ile/105Ile GSTP1 (adjusted OR: 2.34, 95% CI: 1.21-4.52). The polymorphic site within the exon 5 of GSTP1 results in a Ile-->Val substitution, and the isoleucine GSTpi isoform has been found in vitro to be less active than the valine isoform towards the conjugation of BPDE. The 113 Tyr/Tyr EPHX1 encodes for a high-activity mEH. Our results agree with these observations in vitro and suggest that a genetically determined combination of a high-activity mEH and a low-activity GSTpi may increase lung cancer risk among smokers.
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PMID:Lung cancer susceptibility in relation to combined polymorphisms of microsomal epoxide hydrolase and glutathione S-transferase P1. 1159 90


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