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)

Several polymorphic genes have been reported to be possibly involved in modifying lung cancer risk in smokers. The gene GSTM1 is frequently deleted in human populations, and the null genotype has been reported to be a risk factor for developing lung carcinoma. A germline polymorphism of p53 with a single-base change at codon 72 that causes an amino acid replacement of arginine (Arg; CGC) by proline (PRO; CCC) has also been reported to be associated with cancer susceptibility in a Japanese population. Both polymorphisms were genotyped by PCR in a northwestern Mediterranean healthy population (n = 147) and in a group of lung cancer patients (n = 139). The results showed that the frequency of the GSTM1 null genotype was higher in the lung cancer patients compared to the controls [odds ratio (OR), 1.57; 95% confidence interval (CI), 0.99-2.51]. The histological subtypes most clearly modified were small cell carcinoma (OR, 1.89; CI, 0.97-3.65) and adenocarcinoma (OR, 1.93; CI, 0.90-4.14). The null GSTM1 genotype was more frequent among those cancer patients who were medium/ light smokers (< or = 50 pack-years) and in those who showed an onset of the disease at a more advanced age. The study of the p53 polymorphism in the healthy population showed allele frequencies of 0.79 (Arg) and 0.21 (Pro). The frequencies found in the lung cancer patients were statistically similar. Both polymorphisms were studied together, and the relative risk of the combination null GSTM1 and Pro/Pro or Arg/Pro genotypes was calculated taking the combination of GTSM1 + together with Arq/Arg as a baseline. The OR found (1.97; CI, 1.03-3.73) suggests that the Pro allele of the p53 germline polymorphism may slightly increase the risk fo the GSTM1 null genotype among smokers.
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PMID:Glutathione-S-Transferase M1 and codon 72 p53 polymorphisms in a northwestern Mediterranean population and their relation to lung cancer susceptibility. 916 98

Deficiencies of the glutathione transferase isoenzymes GSTM1-1 and GSTT1-1 have been shown to be risk modifiers in a number of different cancers but there have been no similar studies with GSTP1-1, the only member of the Pi class of glutathione S-transferases expressed in humans. Over-expression of GSTP1-1 in tumours suggests that it may be a significant factor in acquired resistance to certain anticancer drugs. We previously identified a cDNA clone with two amino acid substitutions (I105V, A114V). This clone suggests that the GSTP1 gene is polymorphic and it is possible that the different genotypes may be associated with altered cancer risk or drug resistance. In the present study, we report methods for genotyping individuals at codons 105 and 114 of GSTP1 and demonstrate that these two loci are polymorphic in several different racial groups. We also detected significant linkage disequilibrium between these two loci. To determine if either of the alleles at these two loci were associated with altered cancer susceptibility, we genotyped individuals with colorectal cancer or lung cancer. A total of 131 colorectal and 184 lung cancer patients were compared with 199 control individuals. Overall, there were no significant associations between the GSTP1 polymorphisms and either form of cancer.
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PMID:Polymorphism of the Pi class glutathione S-transferase in normal populations and cancer patients. 951 Nov 78

The activity of chemical carcinogens is a complex balance between metabolic activation by cytochrome P450 monooxygenases and detoxification by enzymes such as glutathione S-transferase (GST). Regulation of these proteins may have profound effects on carcinogenic activity, although it has proved impossible to ascribe the observed effects to the activity of a single protein. GstP appears to play a very important role in carcinogenesis, although the precise nature of its involvement is unclear. We have deleted the murine GstP gene cluster and established the effects on skin tumorigenesis induced by the polycyclic aromatic hydrocarbon 7, 12-dimethylbenz anthracene and the tumor promoting agent 12-O-tetradecanoylphorbol-13-acetate. After 20 weeks, a highly significant increase in the number of papillomas was found in the GstP1/P2 null mice [GstP1/P2(-/-) mice, 179 papillomas, mean 9.94 per animal vs. GstP1/P2(+/+) mice, 55 papillomas, mean 2.89 per animal, (P < 0.001)]. This difference in tumor incidence provides direct evidence that a single gene involved in drug metabolism can have a profound effect on tumorigenicity, and demonstrates that GstP may be an important determinant in cancer susceptibility, particularly in diseases where exposure to polycyclic aromatic hydrocarbons is involved, for instance in cigarette smoke-induced lung cancer.
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PMID:Increased skin tumorigenesis in mice lacking pi class glutathione S-transferases. 956 Feb 66

Although several genes that cause monogenic familial cancer syndromes have been identified, susceptibility to sporadic cancer remains unresolved. Animal experiments have demonstrated multigenic control of tumor susceptibility. Recently, we described four mouse lung cancer susceptibility (Sluc) loci, the main effects of which are masked by their mutual interactions. Because such interactions can considerably affect the strategies for identification of cancer susceptibility genes in humans, it is necessary to establish whether they are common or rare. Here, we report the mapping of 10 additional Sluc loci and show that 13 of the 14 Sluc loci are involved in one or more interactions, demonstrating that interactions of tumor susceptibility genes are frequent and that they probably form complex networks.
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PMID:High frequency of interactions between lung cancer susceptibility genes in the mouse: mapping of Sluc5 to Sluc14. 980 79

An association between the BstUI (Pro/Pro) genotype of the p53 codon 72 polymorphism and lung cancer has been reported previously (X. Jin et al., Carcinogenesis (Lond.), 16: 2205-2208, 1995). However, the genotype distribution of p53 codon 72 polymorphism as well as the association of this polymorphism with lung cancer risk and prognosis remain undefined in the Taiwanese population. Therefore, we investigated the genotype distribution of p53 codon 72 polymorphism in 194 lung cancer patients and 152 noncancer controls. The genotype frequencies in Taiwanese noncancer controls were 0.56 (Arg) and 0.44 (Pro). Chi2 analysis indicated significant differences in genotype distribution of p53 from other reports in Swedish (P < 0.001), Spanish (P < 0.001), Caucasians in the United States (P = 0.002), and African-Americans (P = 0.027). In addition, our data suggest that the Pro allele of the p53 codon 72 polymorphism increased the risk of lung cancer among female Taiwanese. The female patients with genotype Pro/Pro showed a significantly increased odds ratio (3.14; confidence interval, 1.48-6.64; P = 0.003) of having lung adenocarcinoma, compared with normal controls with the other genotypes. Patients with the Pro/Pro genotype had an odds ratio of 2.63 (confidence interval, 1.22-5.68; P = 0.01) higher than those with the other genotypes to be diagnosed with lung cancer at the early ages. We further investigated the association of p53 codon 72 polymorphism with prognosis in 133 lung cancer patients. Patients with the Pro/Pro genotype tended to have poorer prognosis than those with the Arg/Pro genotype (P = 0.05, by the log-rank test). Our data suggested that p53 codon 72 polymorphism may play a role in cancer susceptibility and prognosis in specific classes of lung cancer patients in Taiwan.
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PMID:p53 codon 72 polymorphism in Taiwanese lung cancer patients: association with lung cancer susceptibility and prognosis. 991 10

The characterization of genetic determinants for cancer susceptibility is important for understanding disease pathogenesis and for preventive measures. There is growing evidence that a group of predisposing polymorphic genes exists, such as those involved in carcinogen metabolism and repair, which may increase cancer in certain environmentally exposed subjects, even those exposed only to low levels of carcinogens. In developing preventive strategies, it is therefore necessary to identify these vulnerable members in our society, particularly those suffering from an unfortunate combination of high carcinogen exposure, cancer-predisposing genes and lack of protective (dietary) factors. Thus, molecular epidemiology faces the difficult task of analyzing carcinogen-exposed individuals for a combination of genotypes associated with cancer susceptibility. Once identified, combinations of cancer-predisposing genes can then be used as intermediate risk markers rather than taking cancer as an endpoint. In case-control studies, simultaneous measurements were carried out in each subject to determine exposure/early effect markers, e.g. polycyclic aromatic hydrocarbons (PAH)-DNA adducts, and susceptibility markers, e.g. genetic polymorphism, in drug-metabolizing enzymes related to cytochrome P450 1A1 (CYP1A1) and glutathione S-transferase (GSTM1) genes. The genotype dependence of human lung (+)-anti-benzo[a]pyrene diol-epoxide (BPDE)-DNA adducts in lung cancer patients was examined. BPDE-DNA adduct levels in bronchial tissue of smokers with high pulmonary CYP1A1 inducibility (by immunohistochemistry) and GSTM1 inactive were approximately 100-fold higher than in subjects with an active GSTM1 at similar smoking dose. Further genetic analyses confirmed that the combination of CYP1A1 homozygous mutants and GSTM1 inactive leads to high levels of BPDE-DNA adducts in human lung of smokers and white blood cells of PAH-exposed coke oven workers. Thus, BPDE-DNA adduct levels resulting from the "at risk" genotype combinations may serve as markers to identify high-risk subjects among smokers and individuals occupationally and/or environmentally exposed to PAH.
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PMID:Impact of adduct determination on the assessment of cancer susceptibility. 1002 94

Genetically polymorphic xenobiotic metabolizing enzymes are supposed to be host factors for an individual's cancer susceptibility. A total of 255 laryngeal cancer patients was genotyped for NAT1 and NAT2 and compared with 510 reference individuals, matched by age and gender. NAT1 genotypes (NAT1*3, *4, *10, and *11 ) were found equally distributed between cases and control individuals. However, there was a significant overrepresentation of 20 (7.8%) homozygous NAT2 genotypes coding for rapid acetylation (NAT2*4/*4 and NAT2*4/*12A) amongst laryngeal cancer patients versus 19 (3.7%) such individuals in the control group (odds ratio 2.18, 95% confidence limits 1.13, 4.22; P = 0.018). Furthermore, an increasing NAT2*4/*4 frequency in cases with strong cigarette consumption was observed, but also in non-smokers. Heterozygous genotypes of NAT2*4/slow were not overrepresented. These results correspond with earlier findings in lung cancer. Analysis of NAT1 and NAT2 combinations revealed a linkage disequilibrium between NAT1*10 and NAT2*4; NAT1*10 frequency was twofold higher in NAT2*4/*4 carriers than in slow NAT2 coding genotypes. In conclusion, the distinct genotype NAT2*4/*4 proved to be a rare, but powerful host risk factor for larynx carcinoma. These data support the notion that an individual's specific NAT2 genotype may be decisive for the organ of his smoking-initiated cancer.
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PMID:Association of arylamine N-acetyltransferases NAT1 and NAT2 genotypes to laryngeal cancer risk. 1020 49

The p53 tumour suppressor gene is at the crossroads of a network of cellular pathways including cell cycle checkpoints, DNA repair, chromosomal segregation, and apoptosis. These pathways have evolved to maintain the stability of the genome during cellular stress from DNA damage, hypoxia, and activated oncogenes. The high frequency of p53 mutations in human cancer is a reflection of the importance of p53 involvement in this network of pathways during human carcinogenesis. An electronic database containing p53 mutations from more than 9000 cancers (http:/(/)www.iarc.fr/p53/homepage.html) can be used to generate hypotheses for further clinical, epidemiological, and laboratory investigations. For example, one can hypothesize that (a) p53 mutations vary in their pathobiological significance; (b) cellular content influences the selection of p53 mutations in clonally derived cancers; (c) the location and type of mutation within the p53 gene provide clues to functional domains in the gene product; and (d) the p53 mutation spectrum can be a molecular link between aetiological agents and human cancer. This review will focus on the role of p53 and cancer susceptibility genes in the molecular pathogenesis and epidemiology of human lung cancer.
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PMID:Molecular epidemiology of human cancer risk: gene-environment interactions and p53 mutation spectrum in human lung cancer. 1034 2

Genomic instability is a driving force for tumorigenesis. p53 and telomerase play central roles in maintaining genomic integrity. The purpose of this study was to assess the associations among p53 protein overexpression, telomerase activity and genetic instability in lung cancer. We found that telomerase activity was detectable in 80% of 100 lung tumours, but only 7.7% of 91 paired adjacent normal tissues. p53 protein was overexpressed in 63% of the tumours but only 2% of the normal tissues. p53 was overexpressed in 56 of the 80 (70%) tumour tissues with telomerase activity but only seven of the 20 (35%) without telomerase activity. p53 protein overexpression carried a 6.7-fold (95% confidence interval, 1.7-27.7) increased risk for positive telomerase activity after adjustment by age, sex, ethnicity, smoking status and family history of lung cancer. The mean in vitro bleomycin-induced breaks per cell (a marker of cancer susceptibility) was significantly higher (0.92) for patients who overexpressed p53 in lung tumour tissue than that for patients with no detectable p53 expression in lung tumour tissue (0.65). Our data suggest that p53 protein overexpression may be common in individuals genetically susceptible to carcinogen exposure. p53 status may be related to telomerase expression.
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PMID:Associations among telomerase activity, p53 protein overexpression, and genetic instability in lung cancer. 1040 53

Lung cancer is the leading cause of cancer death in Taiwan. Potential molecular markers associated with cancer susceptibility and prognosis are the genes involved in tumorigenesis. Therefore, we investigated the association of p53 codon 72 polymorphism with prognosis in 114 lung cancer patients. The estimated median survival times for patients with proline (Pro)/Pro, arginine (Arg)/Arg, and Arg/Pro genotypes were 25, 26 and 36 months, respectively. We also found that patients with the Pro/Pro genotype had a worse prognosis compared with those with Arg/Pro genotypes, especially for patients with squamous cell lung cancer (P = 0.013), male patients (P = 0.028) and those aged 60-69 years (P = 0.052). In patients with early stage lung cancer, patients with Pro/Pro and Arg/Arg genotypes had a tendency for a worse prognosis than those with the Arg/Pro genotype (P = 0.057). Our data suggest that p53 codon 72 polymorphism may be a potential prognostic factor in certain sub groups of lung cancer patients in Taiwan.
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PMID:Prognostic significance of p53 codon 72 polymorphism in lung carcinomas. 1044 64


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