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  • EXPRESSION  (8)
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  • 1
    Keywords: CANCER ; EXPRESSION ; carcinoma ; CELL ; Germany ; human ; LUNG ; lung cancer ; LUNG-CANCER ; EXPOSURE ; RISK ; GENE ; PROTEIN ; METABOLISM ; TISSUE ; PATIENT ; RISK-FACTORS ; FREQUENCY ; polymorphism ; SUSCEPTIBILITY ; PROMOTER ; OVARIAN-CANCER ; WOMEN ; MEN ; risk factors ; smoking ; PROSTATE-CANCER ; cancer risk ; RISK FACTOR ; CYP3A4 ; LINKAGE DISEQUILIBRIUM ; CANCER-PATIENTS ; CARCINOMAS ; POLYMERASE-CHAIN-REACTION ; adenocarcinoma ; ADENOCARCINOMAS ; CARRIERS ; case-control studies ; CLINICAL PRESENTATION ; CYP3A,genetic polymorphism,lung cancer susceptibility,small cell lung cancer,LightCycler ; EXPRESSED HUMAN CYTOCHROME-P450S ; GENETIC VARIANT ; HUMAN LIVER-MICROSOMES ; PROSTATE TUMORS ; PROTEIN LEVELS ; squamous cell carcinoma ; TOBACCO
    Abstract: CYP3A isozymes are involved in tobacco carcinogen- and steroid-metabolism, and are expressed in human lung tissue showing interindividual variation in expression and activity. The CYP3A4* 1 B allele has been associated with a two-fold higher promoter activity and with high-grade prostate cancers. The very frequent intron 3 polymorphism in the CYP3A5 gene (CYP3A5*3) results in decreased CYP3A5 protein levels. A case-control study was conducted in 801 Caucasian lung cancer patients that included 330 adenocarcinomas, 260 squamous cell carcinomas, 171 small cell lung cancers (SCLC) and 432 Caucasian hospital-based controls. CYP3A-genotyping was performed by capillary polymerase chain reaction followed by fluorescence-based melting curve analysis. A significantly increased SCLC risk for CYP3A4* 1B allele carriers [odds ratio (OR) 2.25, 95% confidence interval (CI) 1.11-4.55, P = 0.02] was found. After dividing cases and controls by gender, an increased lung cancer risk for CYP3A4* 1B carriers (OR 3.04, 95% CI 0.94-9.90, P= 0.06) for women but not for men (OR 1.00, 95% CI 0.56-1.81) was revealed. Heavier smoking men (greater than or equal to 20 pack-years) with the CYP3A4* 1 B allele had a significant OR for lung cancer of 3.42 (95% CI 1.65-7.14, P= 0.001) compared to * 1A/1* 1A carriers with lower tobacco exposure (〈 20 pack-years). For women, the respective OR was 8.00 (95% CI 2.12-30.30, P = 0.005). Genotype frequencies were generally in Hardy-Weinberg equilibrium, except for CYP3A5 where a greater than expected number of CYP3A5* 1 homozygotes was observed among cases (P = 0.006). In addition, we observed linkage disequilibrium of CYP3A4 and CYP3A5 (P 〈 0.00001), but a nonsignificantly increased lung cancer risk was only found for homozygous CYP3A5* 1 allele carriers (OR 5.24,95% CI 0.85-102.28, P = 0.14) but not for heterozygotes. To confirm our observation that the CYP3A4* 1B allele increases SCLC risk and modifies the smoking-related lung cancer risk in a gender-specific manner, further studies, including CYP3A haplotype analysis, will be necessary. Pharmacogenetics 13:607-618 (C) 2003 Lippincott Williams Wilkins
    Type of Publication: Journal article published
    PubMed ID: 14515059
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  • 2
    Keywords: CANCER ; EXPRESSION ; carcinoma ; CELL ; Germany ; LUNG ; COMMON ; lung cancer ; LUNG-CANCER ; EXPOSURE ; RISK ; GENE ; GENES ; HYBRIDIZATION ; DNA ; MECHANISM ; primary ; RISK-FACTORS ; mechanisms ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; SUSCEPTIBILITY ; NO ; AMPLIFICATION ; AGE ; DNA-REPAIR ; REPAIR ; CIGARETTE-SMOKING ; risk factors ; smoking ; PCR ; cancer risk ; DAMAGE ; RISK FACTOR ; REGION ; CARCINOGENS ; adenocarcinoma ; case-control studies ; squamous cell carcinoma ; INDIVIDUALS ; CANCER-RESEARCH ; SMOKERS ; NUCLEOTIDE EXCISION-REPAIR ; CELL CARCINOMA ; case control study ; case-control study ; REGRESSION ; OCCUPATIONAL-EXPOSURE ; CARCINOGEN ; HEAVY ; LUNG ADENOCARCINOMA ; PIGMENTOSUM GROUP-A
    Abstract: Polymorphisms of genes coding for DNA repair can affect lung cancer risk. A common single nucleotide (-4) G-to-A polymorphism was identified previously in the 5' untranslated region of the XPA gene. In a case-control study in European Caucasians, the influence of this polymorphism on primary lung cancer risk overall and according to histologic subtypes was investigated. Four hundred sixty-three lung cancer cases (including 204 adenocarcinoma and 212 squamous cell carcinoma) and 460 tumor-free hospital controls were investigated using PCR amplification and melting point analysis of sequence-specific hybridization probes. Odds ratios (OR) were calculated by multiple logistic regression analysis adjusting for age, gender, smoking habits, and occupational exposure and showed a slightly enhanced risk for all lung cancer cases as well as for squamous cell carcinoma and adenocarcinoma cases. Gene-environment interactions were analyzed with respect to smoking and occupational exposure. A nearly 3-fold increased risk for adenocarcinoma associated with the XPA AA genotype was observed for occupationally exposed individuals (OR, 2.95; 95% confidence interval, 1.42-6.14) and for heavy smokers (OR, 2.52; 95% confidence interval, 1.17-5.42). No genotype-dependent increase in OR was found for nonexposed individuals or those smoking 〈20 pack-years. The significant effect of the XPA polymorphism in heavy smokers and occupationally exposed individuals suggests an important gene-environment interaction for the XPA gene. The underlying mechanisms as to why AA homozygotes are predisposed to lung adenocarcinoma and which specific carcinogens are involved remains to be determined
    Type of Publication: Journal article published
    PubMed ID: 15598786
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  • 3
    Keywords: CANCER ; EXPRESSION ; carcinoma ; lung cancer ; LUNG-CANCER ; SYSTEM ; TISSUE ; prognosis ; T-CELLS ; PROGRESSION ; LYMPHOCYTES ; PERIPHERAL-BLOOD ; microenvironment ; lymph nodes ; TRANSCRIPTION FACTOR FOXP3 ; tumor microenvironment ; NK-CELLS ; Foxp3(+) Tregs
    Abstract: INTRODUCTION: : Regulatory T cells (Tregs) can play a key role in suppressing T-cell-mediated immunity in patients with cancer. In this study, the immune cell composition of the lung tissue and draining lymph nodes from patients with non-small cell lung cancer was analyzed. METHODS: : Samples (solid tumor, tumor border, and tumor-free lung tissue, as well as intrapulmonal N1 and mediastinal N2 lymph nodes) from 30 patients subjected to curative resection were analyzed by immunohistochemistry and flow cytometry. RESULTS: : Immunohistochemistry showed the presence of Foxp3 Tregs in tumor-infiltrated lung tissue, scattered Tregs in tumor-free lung samples, and a large number of these cells in metastatic lymph nodes. Using flow cytometry, we observed a significant enhancement of CD4 T cells and Foxp3 Tregs in the tumor center of adenocarcinoma samples, when compared with tumor-free lung tissues and tumor periphery. This enrichment was associated with a drastic decrease in natural killer cell amounts. Metastatic lymph nodes also showed higher Treg numbers than tumor-free ones in patients with lung adenocarcinomas. In contrast, patients with squamous cell carcinomas displayed less profound accumulation of Tregs. CONCLUSION: : Accumulation of Tregs in the center of lung tumors and in metastatic lymph nodes in combination with a decrease in the natural killer cell numbers suggests a critical role of Treg in the formation of immunosuppressive tumor microenvironment. Therefore, lung cancer immunotherapy may be improved by a specific Treg elimination or suppression.
    Type of Publication: Journal article published
    PubMed ID: 21258248
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  • 4
    Keywords: RECEPTOR ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; carcinoma ; FACTOR RECEPTOR ; Germany ; human ; THERAPY ; TYROSINE KINASE ; microarray ; TISSUE ; treatment ; antibodies ; antibody ; STAGE ; immunohistochemistry ; MALIGNANCIES ; microarrays ; NUMBER ; COLORECTAL-CANCER ; CARCINOMAS ; SQUAMOUS-CELL CARCINOMAS ; TARGETS ; gene amplification ; COX-2 ; EPIDERMAL-GROWTH-FACTOR ; INHIBITORS ; MALIGNANCY ; thymus ; EGFR ; CYCLOOXYGENASE-2 ; LEVEL ; SUBTYPES ; tissue microarray ; EPITHELIAL TUMORS ; CYCLOOXYGENASE-2 INHIBITORS ; correlation ; PROSTAGLANDIN-E SYNTHASE ; VARIETIES ; epidermal growth factor ; epidermal growth factor receptor ; GROWTH-FACTOR-RECEPTOR ; PRIMARY MALIGNANCIES ; thymoma ; E-2 PRODUCTION ; mPGES ; thymic carcinoma
    Abstract: The treatment of advanced stage thymomas and thymic carcinomas is a multimodal therapy. New therapeutic targets are currently under investigation, including the epidermal growth factor receptor (EGFR) as well as KIT. A number of studies have shown protumorigenic potential of Cyclooxygenase-2 (COX-2) in a variety of human malignancies, but so far it is unknown whether COX-2 is expressed in primary malignancies of the thymus. Using tissue microarrays, the expression of COX-2, microsomal-PGES-1 and -PGES-2 (mPGES-1 and mPGES-2), as well as EGFR was evaluated in different subtypes of thymoma and thymic carcinomas. COX-2 was expressed in all subtypes as determined by immunohistochemistry. Some cases of type B2 and thymic carcinomas had COX-2 staining levels classified as mild to moderate. However, when measuring the optical color intensity, no significant differences could be detected. Concerning the expression levels, a weak correlation between the expression of COX-2, mPGES-1 and mPGES-2 as well as EGFR was found. Furthermore, additional cases of thymomas and thymic carcinomas were analyzed by COX-2 Western immunoblot analysis and were compared to normal thymi. The analysis showed that thymomas and thymic carcinomas had a significantly stronger COX-2 expression than that of the normal thymi (p 〈 0.04). In summary, COX-2 is expressed in all subtypes of thymomas and thymic carcinomas and thus represents, in addition to EGFR and KIT, a potential therapeutic target. Further studies are needed in order to determine whether a combined therapy using COX-2 inhibitors in addition to the evolving anti-EGFR antibody therapy may be considered as a treatment option. (c) 2006 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 16823844
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  • 5
    Keywords: CANCER ; EXPRESSION ; Germany ; human ; LUNG ; lung cancer ; LUNG-CANCER ; POPULATION ; RISK ; GENE ; GENES ; DRUG ; FAMILY ; GENETIC POLYMORPHISMS ; SEQUENCE ; polymorphism ; POLYMORPHISMS ; PROMOTER ; EFFICACY ; cancer risk ; REGION ; CARRIERS ; VARIANT ; ALLELE ; CHINESE ; CYP3AP1,CYP3A5,CYP3A4,pseudogene,polymorphism,linkage disequilibrium
    Abstract: Genetic polymorphisms of the human CYP3A family affect clinical drug efficacy and may modify cancer risk. CYP3A genes show high sequence similarity that had previously lead to misallocation of CYP3A polymorphisms. Recent studies indicated a high degree of or even complete linkage for certain CYP3A alleles. Reliable LightCycler-based genotyping methods were developed and their degree of linkage in a large Caucasian population (n = 1210) investigated. Strong linkage disequilibrium was confirmed between CYP3A4, CYP3A5, and CYP3AP1 (each at P 〈 10(-5)). Contrary to some previous results claiming complete linkage between the phenotypically relevant CYP3A5(*) 1 and a variant in a pseudogene promoter region CYP3AP1(*) 1, we found among 428 controls (15 of 66) and 782 lung cancer cases (25 of 115) approximately 22% of CYP3AP1(*) 1/(*) 3 carriers to be homozygous for CYP3A5(*) 3. We conclude that contrary to previous assumptions, the CYP3AP1 genotype is not a reliable predictor for CYP3A5 activity. (C) 2004 Elsevier Ireland Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 15050738
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  • 6
    Keywords: CANCER ; CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; SURVIVAL ; tumor ; TUMOR-CELLS ; carcinoma ; CELL ; evaluation ; Germany ; SYSTEM ; SYSTEMS ; HISTORY ; GENES ; SURGERY ; TIME ; PATIENT ; murine ; FAMILY ; MARKER ; IMPACT ; ANTIGEN ; STAGE ; IDENTIFICATION ; LESIONS ; PROGRESSION ; AGE ; WOMEN ; METASTASIS ; colorectal cancer ; MEN ; COLORECTAL-CANCER ; metastases ; MARKERS ; MELANOMA ; PROGNOSTIC-FACTORS ; RESECTION ; PARAMETERS ; ONCOGENE ; INVOLVEMENT ; PROGNOSTIC FACTORS ; SELECTION ; SERUM ; SUBSET ; COLORECTAL-CARCINOMA ; PATIENT SURVIVAL ; MAGE ; lung metastases ; PROGNOSTIC-FACTOR ; LEVEL ; PROGNOSTIC MARKER ; FOS ; EVENTS ; vascular endothelial growth factor ; colorectal ; PROMOTES ; colorectal carcinoma ; growth factor ; PULMONARY METASTASES ; metastasectomy ; OPINION ; thoracic surgery ; TUMOR LYMPHANGIOGENESIS
    Abstract: Background: Although aggressive resection of pulmonary metastases prolongs the survival of patients with metastatic colorectal cancer, there is a need for predictive pathologic parameters to understand the key molecular events of metastatic progression. The aim of this study was to verify immunohistochemical markers in addition to established clinical parameters after surgery. Methods: From our subset of patients undergoing resection of pulmonary metastases from metastatic colorectal carcinoma, we analyzed 39 patients (23 men and 16 women) between 2003 and 2007. Only patients who met the criteria for a potentially curative operation were included. All patients were analyzed with regard to age and sex, primary tumor location, stage of the primary tumor, history of hepatic metastases, number of pulmonary metastases, pre-thoracotomy carcinoembryonic (CEA) serum antigen level, and the presence of thoracic lymph node metastasis. Furthermore, we immunohistochemically investigated the expression of vascular endothelial growth factor (VEGF)-D, FBJ murine osteosarcoma viral oncogene homolog B (FOS-B), and melanoma antigen (MAGE)-A in the Surgical specimens of pulmonary metastatic lesions. Results: The overall 3-year survival was 50.6%. A significantly longer survival was observed with multivariate analysis in patients with a pre-thoracotomy serum carcinoembryonic antigen level of no more than 4.2 ng/mL (p=0.001), and Dukes stage A or B primary tumor (p=0.001). A significantly longer recurrence-free survival was observed with multivariate analysis in patients without thoracic lymph node involvement compared to patients with pulmonary and/or mediastinal lymph node metastases (p=0.006). The stage of the primary tumor remained significant (p=0.029), and FOS-B expression in tumor cells showed a trend towards favorable recurrence-free survival after pulmonary metastasectomy (p=0.059). No statistically significant difference was found in the overall survival rate or recurrence-free survival rate of patients with expression of VEGF-D or MAGE-A antigen in pulmonary metastatic tumor cells. Conclusions: Our results suggest that in addition to clinically prognostic factors, FOS-B expression has a debatable impact on patient Survival. We conclude that the evaluation of molecular and clinical prognostic parameters at the time of pulmonary metastasectomy offers a greater understanding of the metastatic process and provides important information for patient selection
    Type of Publication: Journal article published
    PubMed ID: 19795327
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  • 7
    Keywords: SYSTEM ; lung cancer ; LUNG-CANCER ; TISSUE ; GENE ; GENE-EXPRESSION ; CANCER ; CELLS ; EXPRESSION ; LUNG ; CELL ; non-small cell lung cancer ; DISPLAY ; gene expression ; STROMAL CELLS ; USA ; EXPRESSION PROFILES ; PROFILES ; STEM-CELL ; CELL-LUNG-CANCER
    Type of Publication: Meeting abstract published
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  • 8
    Keywords: APOPTOSIS ; CANCER ; EXPRESSION ; GROWTH ; INHIBITOR ; CELL ; Germany ; LUNG ; MODEL ; MODELS ; lung cancer ; LUNG-CANCER ; POPULATION ; RISK ; GENE ; PROTEIN ; PATIENT ; MECHANISM ; CARCINOGENESIS ; mechanisms ; CELL-CYCLE ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; SUSCEPTIBILITY ; NO ; DIFFERENCE ; PROMOTER ; AGE ; WOMEN ; CIGARETTE-SMOKING ; smoking ; p53 ; REGION ; MDM2 ; HEALTHY ; DNA repair ; protein expression ; CELL-GROWTH ; ONCOLOGY ; RE ; SUBTYPES ; GENOTYPE ; GENDER ; PROMOTER REGION ; ENGLAND ; CIGARETTE ; interactions ; ACCELERATES TUMOR-FORMATION ; SNP309
    Abstract: The polymorphism SNP309 (rs2279744) in the promoter region of the MDM2 gene has been shown to alter protein expression and may play a role in the susceptibility to lung cancer. The MDM2 protein is a key inhibitor of p53 and several mechanisms of MDM2/p53 interactions are presently known: modulating DNA-repair, cell-cycle control, cell growth and apoptosis. We used 635 Caucasian patients diagnosed with lung cancer before 51 years of age and 1300 healthy gender and age frequency matched population Caucasian controls to investigate the association between the MDM2 SNP309 and the risk of developing early onset lung cancer. Conditional logistic models were applied to assess the genotype-phenotype association, adjusted for smoking. Compared to the GG genotype, the adjusted ORs for the TG and TT genotype were 0.9 (95% CI: 0.7-1.5) and 1.0 ( 95% CI: 0.7-1.5), respectively. Also no association was found for histological subtypes of lung cancer. The strength of this study is that within young cases the genetic component to develop lung cancer may be greater. Our results indicate that the MDM2 SNP309 is not significantly associated with lung carcinogenesis but point towards gender-specific differences
    Type of Publication: Journal article published
    PubMed ID: 18433484
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