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)

The Fas/tumor necrosis factor (TNF)/TRAIL receptors signal death through a cytoplasmic death domain (DD) containing six alpha-helices with positively charged helix 2 interacting with negatively charged helix 3 of another DD. DD mutation occurs in head/neck and lung cancer (TRAIL receptor KILLER/DR5) and in lpr mice (Fas). We examined the apoptotic potential of known KILLER/DR5 lung tumor-derived mutants (n = 6) and DD mutants (n = 18) generated based on conservation with DR4, Fas, Fas-associated death domain (FADD), and tumor necrosis factor receptor 1 (TNFR1). With the exception of Arg-330 required in Fas or FADD for aggregation or for TNFR1 cytotoxicity, surprisingly major loss-of-function KILLER/DR5 alleles (W325A, L334A (lpr-like), I339A, and W360A) contained hydrophobic residues. Loss-of-function of I339A (highly conserved) has not been reported in DDs. Charged residue mutagenesis revealed the following points. 1) E326A, conserved in DR4, is dispensable for death; the homologous residue is positively charged in Fas, TNFR1, and FADD and is critical for DD interactions. 2) K331A, D336A, E338A, K340A, K343A, and D351A have partial loss-of-function suggesting multiple charges stabilize receptor-adapter interactions. Analysis of the tumor-derived KILLER/DR5 mutants revealed the following. 1) L334F has partial loss-of-function versus L334A, whereas E338K has major loss-of-function versus E338A, examples where alanine and tumor-specific substitutions have divergent phenotypes. 2) Unexpectedly, S324F, E326K, K386N, and D407Y have no loss-of-function with tumor-specific or alanine substitutions. Loss-of-function KILLER/DR5 mutants were deficient in recruitment of FADD and caspase 8 to TRAIL death-inducing signaling complexes. The results reveal determinants within KILLER/DR5 for death signaling and drug design.
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PMID:Death domain mutagenesis of KILLER/DR5 reveals residues critical for apoptotic signaling. 1127 61

Allelic loss of chromosome 8p21-22 occurs frequently in cancer, including lung and head and neck squamous cell cancer. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors, including proapoptotic DR4 and KILLER/DR5, are located on 8p21-22. TRAIL receptors are candidate tumor suppressor genes, because their inactivation would be expected to result in deficient apoptotic signaling. To investigate the involvement of DR4 in human cancer, we have determined the genomic structure of DR4 and screened 31 lung cancer cell lines [14 small cell lung cancer and 17 non-small cell lung cancer (NSCLC)], many with deletions at 8p21-22, and 21 primary NSCLC samples for mutations in DR4. We found two missense alterations in the ectodomain of DR4. One, at nucleotide 626, changes a cytosine to a guanine (C626G) and results in a substitution of an arginine for threonine. The other, at nucleotide 422, changes a guanine to adenine (G422A) and results in a substitution of a histidine for arginine. Using genomic DNA sequencing and RFLP analysis, we show that these two alterations cosegregated in 96% of all of the samples (n = 243) evaluated (tumor and normal). The frequency of being homozygous for both altered alleles was 35% in the lung cancer cell lines but only 13% in age- and race-matched controls, which was a significant increase (chi(2) = 5.2, P = 0.023). The frequency of homozygosity for both alleles was also significantly increased in the primary NSCLC samples (chi(2) = 9.2, P = 0.002) as compared with the age- and race-matched controls. To determine whether the altered alleles are specific for lung cancer, we evaluated 19 head and neck squamous cell cancer and 25 gastric adenocarcinoma samples. Forty-seven % of the former and 44% of the latter were homozygous for both the C626G and G422A alterations, and this was significantly elevated relative to age- and race-matched controls (chi(2) = 8.6, P = 0.003 and chi(2) = 8.2, P = 0.004). These alterations result in amino acid changes in or near the ligand-binding domain of DR4 and, based on the crystal structure of DR5 and its homology with DR4, have the potential to affect TRAIL binding to DR4. Our results suggest that the altered DR4 alleles may be associated with, and should be investigated additionally as potential markers for, predisposition to common malignancies.
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PMID:Nucleotide substitution in the ectodomain of trail receptor DR4 is associated with lung cancer and head and neck cancer. 1141 May 8

There are numerous conflicting epidemiological studies addressing correlations between cytochrome P450 1A1 (CYP1A1) genetic polymorphisms and lung cancer susceptibility, with associations plausibly linked to alterations in carcinogen bioactivation. Similarly, correlations between aryl hydrocarbon receptor gene (AHR) codon 554 genotype and CYP1A1 inducibility are controversial. The objective of this study was to determine whether smoking status, and CYP1A1, AHR, and glutathione S-transferase M1 gene (GSTM1) polymorphisms correlate with altered CYP1A1 activities. Lung microsomal CYP1A1-catalyzed 7-ethoxyresorufin O-dealkylation (EROD) activities were much higher in tissues from current smokers (n = 46) than in those from non-/former smokers (n = 24; 12.11 +/- 13.46 and 0.77 +/- 1.74 pmol/min/mg protein, respectively, mean +/- SD; P < 0.05). However, EROD activities in lung microsomes from current smokers CYP1A1*1/1 (n = 33) and heterozygous MspI variant CYP1A1*1/2A (n = 10) were not significantly different (12.23 +/- 13.48 and 8.23 +/- 9.76 pmol/min/mg protein, respectively, P > 0.05). Three current smokers were heterozygous variant CYP1A1*1/2B (possessing both *2A and *2C alleles), and exhibited activities similar to individuals CYP1A*1/1. One current smoker was heterozygous variant CYP1A1*4 and exhibited activities comparable with individuals CYP1A1*1/1 at that locus. EROD activities in microsomes from current smokers AHR(554)Arg/Arg (n = 41) and heterozygous variant AHR(554)Arg/Lys (n = 5) were not significantly different (12.13 +/- 13.56 and 12.01 +/- 14.23 pmol/min/mg protein, respectively; P > 0.05). Furthermore, microsomal EROD activities from current smokers with the GSTM1-null genotype (n = 28) were not significantly different from those (n = 18) carrying at least one copy of GSTM1 (12.61 +/- 14.24 and 11.34 +/- 12.53 pmol/min/mg protein, respectively; P > 0.05). Additionally, when genotypic combinations of CYP1A1, AHR, and GSTM1 were assessed, there were no significant effects on EROD activity. On the basis of microsomal enzyme activities from heterozygotes, CYP1A1*1/2A, CYP1A1*1/2B, CYP1A1*1/4, and AHR(554) Arg/Lys variants do not appear to significantly affect CYP1A1 activities in human lung, and we observed no association between CYP1A1 activity and the GSTM1-null polymorphism.
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PMID:Human lung microsomal cytochrome P4501A1 (CYP1A1) activities: impact of smoking status and CYP1A1, aryl hydrocarbon receptor, and glutathione S-transferase M1 genetic polymorphisms. 1148 50

The Ah receptor (AhR) is a ligand-dependent transcription factor that positively regulates the expression of the CYP1A1 gene. We investigated the genetic polymorphisms of the AhR gene including the promoter, and examined the link between these polymorphisms, CYP1A1 inducibility and the lung cancer incidence. The AhR promoter region and the 11 exons of 30 subjects were screened. Among the three polymorphisms found, two [(2417)(A/G) ((157)G/A)] have never been described previously. The (1721)(G/A) and (2417)(A/G) are localized in exon 10 and lead to Arg(554)Lys and Met(786)Val substitutions, respectively. The other polymorphism was found in the 5'-untranslated region, resulting in the substitution of a G by an A at position 157 (157)(G/A). To evaluate the frequency of this allelic variant found, a DNA library of a case-control study of lung cancer (162 controls and 177 patients) was studied. There is no significant association between (1721)(G/A), (157)(G/A) and lung cancer: (1721)(G/A) and (157)(G/A) were detected at the same allele frequency of 0.086 and 0.25, respectively in both controls and patients. (2417)(A/G) was found in only one control of 100 (allele frequency 0.005). Statistical analysis did not show any relationship between both (1721)(G/A) and (157)(G/A) polymorphisms found and CYP1A1 inducibility. Considering the rareness of the (2417)(A/G) allelic variant we were not able to evaluate its association with inducibility. In conclusion, none of the polymorphisms were found to play a key role in the CYP1A1 inducibility or in the susceptibility to develop lung cancer.
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PMID:Polymorphisms of human aryl hydrocarbon receptor (AhR) gene in a French population: relationship with CYP1A1 inducibility and lung cancer. 1169 44

Traditionally, non-small cell lung cancer (NSCLC) has been evaluated as a unique entity in genotyping studies. However, recent biological data suggest that different NSCLC subtypes, specifically adenocarcinomas (AC) and squamous cell carcinomas (SCC), differentially alter cancer behavior. Several studies have associated a p53 polymorphism at codon 72 with NSCLC susceptibility. This study investigated whether different p53 genotypes altered the overall risk of developing AC versus SCC. Polymorphisms in metabolizing enzymes, together with prolonged exposure to tobacco carcinogens, can result in accumulation of DNA damage; these effects may potentiate the effects of subtle differences in p53 function. Thus, interactions between polymorphisms of p53 and either GSTM1 or GSTT1 were also evaluated. We analyzed 1168 incident lung cancer cases and 1256 control subjects using multiple logistic regression. Histological data were available for 1144 cases (98%): 585 with AC, 284 with SCC, and 275 with other histological subtypes (large cell, small cell, mixed, and other). An increase in the NSCLC risk posed by the p53 Pro allele (versus Arg/Arg) was seen in AC compared with controls [adjusted odds ratio (OR), 1.36; 95% confidence interval (CI), 1.1-1.7] but not in SCC (adjusted OR, 1.04; 95% CI, 0.8-1.4). Among AC and SCC cancer patients, individuals with the GSTM1-null genotype had an OR of 1.80 (95% CI, 1.1-2.8; case-only analysis) of having AC versus SCC if they also carried a p53 Pro allele. We conclude that different genotype combinations of p53 and GSTM1 increase the risk of developing specific histological subtypes of NSCLC.
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PMID:Differential association of the codon 72 p53 and GSTM1 polymorphisms on histological subtype of non-small cell lung carcinoma. 1175 90

SULT1A1 enzyme is a member of the sulfotransferase family that alters biological activities of numerous carcinogenic and mutagenic compounds through sulfation. A genetic polymorphism in the coding region of SULT1A1 gene has been associated with modulated enzyme activity. There is a G-->A nucleotide polymorphism in SULT1A1 gene that codes for an Arg-->His substitution, which results in decreased activity and thermal stability of the SULT1A1 enzyme. Utilizing a case-control study design, we hypothesized that the variant allele of the SULT1A1 gene may be associated with lung cancer risk. The PCR-RFLP assay was used to successfully genotype the SULT1A1*2 allele (variant A-allele) in 463 Caucasian lung cancer cases and 485 frequency matched Caucasian controls. There was an overall significant difference between cases and controls when adjusted by sex and smoking status (adjusted OR=1.41, 95% CI: 1.04-1.91). The adjusted OR was higher for females (OR=1.64, 95% CI: 1.06-2.56) than for males (OR=1.23, 95% CI: 0.80-1.88). Furthermore, the risk was significantly higher in current smokers (OR=1.74, 95% CI: 1.08-2.29) and heavy smokers (OR=1.45, 95% CI: 1.05-2.00). Our results support the hypothesis that a genetic polymorphism in the SULT1A1 gene may be associated with increased lung cancer risk.
Lung Cancer 2002 Feb
PMID:Sulfotransferase (SULT) 1A1 polymorphism as a predisposition factor for lung cancer: a case-control analysis. 1180 85

The human REIC gene is a recently found mortalization-related gene and a candidate tumor suppressor gene expression of which is largely attenuated in many immortalized and tumor-derived cell lines (Biochem. Biophys. Res. Commun. 268 (2000) 20-24). To gain insight into the mechanisms of the down-regulation, we investigated the genomic structure and promoter activity of the human REIC gene. The gene, identical with the DKK-3 gene, resides on chromosome 11p15.1, consists of nine exons, and has two promoters. Methylation in the main promoter region was detected in 11 out of 21 cell lines tested (52%) derived from a variety of human tumors, in which the expression of the REIC gene was decreased. In ten of these 11 cell lines the minor promoter was also methylated. Similarly, the REIC gene expression was decreased in 14 of 24 fresh non-small cell lung cancer specimens (58%) compared to that in corresponding non-cancerous tissue, though allelic loss and tumor-specific mutation were rare. Of these 14 tumors, at least five tumors exhibited heavy methylation of the REIC promoter region. These results indicate that the down-regulation of the REIC gene expression is ascribed to the aberrant promoter hyper-methylation at least in a subset of human tumors. The expression was restored upon treatment of SQ5 cells with 5-aza-deoxycytidine, confirming DNA methylation as the mode of downregulation. A notable single nucleotide polymorphism in the coding region (cSNP) with an amino acid substitution of glycine (GGG) to arginine (AGG) was found at codon 335 of the REIC gene. However, the distribution of the cSNP showed no significant difference between lung cancer patients and healthy population.
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PMID:Reduced expression of the REIC/Dkk-3 gene by promoter-hypermethylation in human tumor cells. 1181 87

DNA repair plays a critical role in protecting the genome of the cell from insults of cancer-causing agents, such as those found in tobacco smoke. Reduced DNA repair capacity, therefore, can increase the susceptibility to smoking-related cancers. Recently, three coding polymorphisms in X-ray cross-complementing group 1 (XRCC1) DNA repair gene have been identified, and it is possible that these polymorphisms may affect DNA repair capacity and thus modulate cancer susceptibility. We investigated the relationship between the codon 399 polymorphism in XRCC1 gene and lung cancer risk in male smokers. The study population consisted of 192 lung cancer patients and 135 healthy controls. The distribution of XRCC1 genotypes was not significantly different between cases and controls. When the cases were categorized by histological type, however, the presence of at least one Gln allele was associated with a significant increased risk for squamous cell carcinoma [crude odds ratio (OR) = 1.77, 95% confidence interval (CI) = 1.06-2.93 and adjusted OR = 1.66, 95% CI = 0.99-2.79]. The risk for the disease increased as the number of Gln alleles increased (Arg/Gln genotype: adjusted OR = 1.45, 95% CI = 0.84-2.5; Gln/Gln genotype: adjusted OR = 3.26, 95% CI = 1.17-9.15). When the subjects dichotomized by cigarette consumption into two pack-year groups (< or =40 pack-years, >40 pack-years), the Gln allele was associated with an increased risk for squamous cell carcinoma only in the group of individuals having < or =40 pack-years of smoking (Arg/Gln genotype: adjusted OR = 1.48, 95% CI = 0.78-2.8; Gln/Gln genotype: adjusted OR = 5.75, 95% CI = 1.46-22.69). These results suggest that XRCC1 codon 399 polymorphism may be an important genetic determinant of squamous cell carcinoma of the lung in persons with lower degrees of cigarette use.
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PMID:Polymorphism of the DNA repair gene XRCC1 and risk of primary lung cancer. 1181 97

Substrates for CYP2C9 include fluoxetine, phenytoin, warfarin, losartam and numerous nonsteroidal anti-inflammatory drugs. Polymorphisms in the coding region of the CYP2C9 gene produce variants at amino-acid residues 144 Arg/Cys and 359 Ile/Leu of the CYP2C9 protein. Individuals homozygous for Leu359 have markedly diminished metabolic capacities for most CYP2C9 substrates, the frequency of this allele is, however, rather low. Consistently with the modulation of enzyme activity by genetic and other factors, wide interindividual variability occurs in the elimination and/or dosage requirements of prototypic CYP2C9 substrates. The polymorphic enzyme CYP2C9 takes part in the metabolism of alkylating agents and polycyclic aromatic hydrocarbons like benzo(a)pyrene, a carcinogen present in tobacco smoke. Although the impact of impaired enzyme activity in metabolism of carcinogens and procarcinogens has not been fully defined, an association of CYP2C9 variant alleles to DNA adduct levels in lung tissues as well as to lung cancer risk have been reported. In this study 64 healthy subjects (44M/22F) were analysed for CYP2C9 genotype with PCR-RFLP and for serum carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), CA 19-9, CA 15-3, ferritin, IL-6, IL-8 concentrations by chemiluminescence or electrochemiluminescence methods. CYP2C9*1 was found to be the most prevalent allele and CYP2C9*1/CYP2C9*1 was the most frequent genotype represented in 64% of the population in southeastern Anatolia (Gaziantep). Although slight differences in serum tumour marker and cytokine concentrations were observed for CYP2C9 genotypes the differences were statistically insignificant (P > 0.05). This could be due to the complexity of the role of CYP2C9 in benzo(a)pyrene metabolism as well as from other contributing factors like interindividual variability of diverse enzymes participating in the same metabolic pathway, unequal expression of the variant alleles and differences in exposure to carcinogens. However, determination of CYP2C9 phenotypes in a larger group of subjects might clarify these slight differences.
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PMID:Cytochrome P4502C9 genotype in Southeast Anatolia and possible relation with some serum tumour markers and cytokines. 1183 86

GSTP1 and GSTM1 are genes involved in Phase II metabolism, whereas p53 is a tumor suppressor gene. Individually, functional polymorphisms of these genes have been studied as risk factors for lung cancer. Small sample sizes have hindered the detection of possible increases in risk associated with having two or more "at risk" polymorphisms of these three genes. In a large Caucasian population, we examined the association of combined variant genotypes [or double-variants (DVs)] of these three genes and lung cancer risk, compared with their corresponding "double-wild-type" genotypes. Because these DVs may promote lung carcinogenesis at an earlier age, a subgroup of individuals aged 55 years or younger was examined separately. Using a case-control design, individuals were genotyped for GSTM1, GSTP1, and p53 codon 72 using PCR-RFLP techniques. All of the analyses used multiple logistic regression. Indicator variables were created to evaluate the risk for individuals with the following DVs: GSTP1 GG + GSTM1-null and GSTP1 GG + p53 Arg/Pro or Pro/Pro. A total of 1694 cases and controls were evaluated. In the whole population, those with the double variants have a higher risk of lung cancer when compared with those with the double-wild-type genotypes, supporting our original hypothesis. Individuals with the GSTP1 and GSTM1, DV (P1-M1 DV) had a marginally significant higher risk of lung cancer compared with their double-wild-type counterparts [adjusted odds ratio (AOR), 1.60; 95% confidence interval (CI), 0.95-2.70]. A significantly higher risk was found for the GSTP1, p53 DV (P1-p53 DV; AOR, 1.99; 95% CI, 1.12-3.53). Among individuals aged 55 or younger, these risks were even higher: for the P1-M1 DV the AOR was 4.03 (95% CI, 1.47-11.1); for the P1-p53 DV the AOR was 5.10 (95% CI, 1.42-18.30). Specific DVs of GSTM1, GSTP1, and p53 codon 72 are associated with a higher lung cancer risk. This susceptibility is highest among younger individuals.
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PMID:Combinations of the variant genotypes of GSTP1, GSTM1, and p53 are associated with an increased lung cancer risk. 1201 59


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