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  • 1
    Keywords: treatment ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; single nucleotide polymorphism ; SUSCEPTIBILITY ; VARIANTS ; SKIN ; mechanisms ; prevention ; HEALTH ; PROMOTER ; BREAST ; breast cancer ; BREAST-CANCER ; cancer prevention ; smoking ; SNP ; REPAIR ; WOMEN ; LYMPHOCYTES ; DAMAGE ; GENOTYPES ; cancer risk ; CANCER-PATIENTS ; INDIVIDUALS ; case-control studies ; DNA-DAMAGE ; CANCER PATIENTS ; SUSCEPTIBILITY GENE ; BODY ; RISK ; GENE ; ENZYMES ; DISEASE ; lung cancer ; LUNG-CANCER ; PATIENT ; MECHANISM ; DNA ; TUMORS ; validation ; DRUG ; RNA ; GENES ; THERAPY ; VITRO ; LUNG ; COMBINATION ; CANCER ; EXPRESSION ; IN-VITRO ; CELLS ; CELL ; tumor ; AGENTS ; radiotherapy ; NSCLC ; CANCER-RISK ; cancer research ; RNA EXPRESSION ; ENZYME ; case control studies ; analysis ; GENOTYPE ; PROFILES ; single-nucleotide ; development ; PROMOTER POLYMORPHISM ; XRCC1 ; VARIANT ; WEIGHT ; SINGLE NUCLEOTIDE POLYMORPHISMS ; SNPs ; case-control study ; GEMCITABINE ; CAPACITY ; DEFICIENCY ; small cell lung cancer ; AGENT ; SINGLE ; DNA repair ; MPO ; APE1
    Abstract: Cells in the body are permanently attacked by DNA-reactive species, both from intracellular and environmental sources. Inherited and acquired deficiencies in host defense mechanisms against DNA damage (metabolic and DNA repair enzymes) can modify cancer susceptibility as well as therapy response. Genetic profiles should help to identify high-risk individuals who subsequently can be enrolled in preventive measures or treated by tailored therapy regimens. Some of our attempts to define such risk profiles are presented. Cancer susceptibility: Single nucleotide polymorphisms (SNPs) in metabolic and repair genes were investigated in a hospital-based lung cancer case-control study. When evaluating the risk associated with different genotypes for N-acetyltransferases (Wikman et al. 2001) and glutathione-S-transferases (Risch et al. 2001), it is mandatory to distinguish between the three major histological subtypes of lung tumors. A promoter polymorphism of the myeloperoxidase gene MPO was shown to decrease lung cancer susceptibility mainly in small cell lung cancer (SCLC) (Dally et al. 2002). The CYP3A4*1B allele was also linked to an increased SCLC risk and in smoking women increased the risk of lung cancer eightfold (Dally et al. 2003b). Polymorphisms in DNA repair genes were shown to modulate lung cancer risk in smokers, and reduced DNA repair capacity elevated the disease risk (Rajaee-Behbahani et al. 2001). Investigations of several DNA repair gene variants revealed that lung cancer risk was only moderately affected by a single variant but was enhanced up to approximately threefold by specific risk allele combinations (Popanda et al. 2004). Therapy response: Inter-individual differences in therapy response are consistently observed with cancer chemotherapeutic agents. Initial results from ongoing studies showed that certain polymorphisms in drug transporter genes (ABCB1) differentially affect response outcome in histological subgroups of lung cancer. Stronger beneficial effects were seen in non-small cell lung cancer (NSCLC) patients following gemcitabine and in SCLC patients following etoposide-based treatment. Several DNA repair parameters (polymorphisms, RNA expression, and DNA repair capacity) were measured in vitro in lymphocytes of patients before radiotherapy and correlated with the occurrence of acute side effects (radio-hypersensitivity). Our initial analysis of several repair gene variants in breast cancer patients (n = 446) who received radiotherapy revealed no association of single polymorphisms and the development of side effects (moist desquamation of the irradiated normal skin). The risk for this side effect was, however, strongly reduced in normal weight women carrying a combination of XRCC1 399Gln and APE1 148Glu alleles, indicating that these variants afford some protection against radio-hypersensitivity (Chang-Claude et al. 2005). Based on these data we conclude that specific metabolic and DNA repair gene variants can affect cancer risk and therapy outcome. Predisposition to hereditary cancer syndromes is dominated by the strong effects of some high-penetrance tumor susceptibility genes, while predisposition to sporadic cancer is influenced by the combination of multiple low-penetrance genes, of which as a major challenge, many disease-relevant combinations remain to be identified. Before translating these findings into clinical use and application for public health measures, large population-based studies and validation of the results will be required.
    Type of Publication: Book chapter
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  • 2
    Keywords: RISK ; ENZYMES ; lung cancer ; LUNG-CANCER ; LUNG ; human ; CANCER ; cancer risk ; risk factors ; SERIES ; RISK ASSESSMENT ; polymorphism ; POLYMORPHISMS ; GENETIC POLYMORPHISMS ; RISK-FACTORS ; HEALTH ; GENETIC-POLYMORPHISM ; ENZYME
    Type of Publication: Book chapter
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  • 3
    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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  • 4
    Keywords: CANCER ; LUNG ; PHASE-I ; lung cancer ; LUNG-CANCER ; EPIDEMIOLOGY ; CARCINOGENESIS ; ASSOCIATION ; polymorphism ; SUSCEPTIBILITY ; METABOLITES ; PROMOTER ; AGE ; genetics ; REDUCED RISK ; smoking ; DATABASE ; REGION ; heredity ; DEFICIENCY ; VARIANT ; CARCINOGEN ; METAANALYSIS ; INTERVAL ; ENZYME ; analysis ; PHASE ; MISSENSE MUTATION ; GENOTYPE ; USA ; female ; Male ; odds ratio ; E ; Phase I ; MPO ; cooperative studies ; metabolic gene polymorphisms ; ACID RESPONSE ELEMENT ; DNA ADDUCT LEVELS ; HUMAN SKIN FIBROBLASTS ; HYPOCHLOROUS ACID
    Abstract: Myeloperoxidase is a phase I metabolic enzyme that converts the metabolites of benzo[a]pyrene from tobacco smoke into highly reactive epoxides. A polymorphism in the promoter region of myeloperoxidase (463G -〉 A) has been found to be inversely associated with lung cancer; differences in the association with age and gender have been suggested. We conducted a pooled analysis of individual data from 10 studies (3688 cases and 3874 controls) from the Genetic Susceptibility to Environmental Carcinogens database. The odds ratio for lung cancer was 0.88 (95% confidence interval: 0.80-0.97) for the AG variant of myeloperoxidase G-463A polymorphism, and 0.71 (95% confidence interval: 0.57-0.88) for the AA variant after adjusting for smoking, age, gender, and ethnicity. The inverse association between lung cancer and myeloperoxidase G-463A polymorphism was equally found in males and females (odds ratio for the AA genotype 0.73 [95% confidence interval: 0.56-0.96] and 0.67 [95% confidence interval: 0.46-0.98], respectively), without differences in the association according to age in the two genders. The myeloperoxicase G-463A polymorphism was significantly protective in "ever" smokers but not in "never" smokers. Myeloperoxidase is a key enzyme in tobacco-induced carcinogenesis
    Type of Publication: Journal article published
    PubMed ID: 17304047
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  • 5
    Keywords: CANCER ; EXPRESSION ; SURVIVAL ; CELL ; COMBINATION ; Germany ; LUNG ; LUNG-CANCER ; RISK ; GENE ; GENES ; DRUG ; PATIENT ; MESSENGER-RNA ; IMPACT ; prognosis ; RISK-FACTORS ; CYCLE ; polymorphism ; POLYMORPHISMS ; single nucleotide polymorphism ; FREQUENCIES ; MEMBRANE ; SNP ; chemotherapy ; LOCALIZATION ; pharmacokinetic ; PHARMACOKINETICS ; CISPLATIN ; lung neoplasms ; PHASE-II ; SINGLE ; REGRESSION ; SINGLE NUCLEOTIDE POLYMORPHISMS ; PHARMACOGENETICS ; GENOTYPE ; RISK-FACTOR ; PROGRESSION-FREE SURVIVAL ; ABCG2 ; ABCC3 ; CONCENTRATIVE NUCLEOSIDE TRANSPORTER ; PLATINUM-BASED CHEMOTHERAPY ; CELL-LUNG-CANCER ; predictive factor ; CNT1 ; multidrug resistance-associated proteins ; RESISTANCE-ASSOCIATED PROTEIN-3 ; SCLC
    Abstract: The prognosis of lung cancer patients treated with chemotherapy is poor, motivating the search for predictive factors. Single nucleotide polymorphisms (SNPs) in membrane transporter genes could influence the pharmacokinetics of cytostatic drugs and therefore affect treatment outcome. We examined 6 SNPs with known or suspected phenotypic effect: ABCG2 G34A, C421A; ABCC3 C-211T, G3890A, C3942T and CNT1 G565A. For 349 Caucasian patients with primary lung cancer [161 small cell lung cancer (SCLC), 187 nonsmall cell lung cancer (NSCLC) and 1 mixed] receiving first-line chemotherapy 3 different endpoints were analyzed: response after the 2nd cycle (R), progression-free survival (PFS) and overall survival (OS). The prognostic value of the SNPs was analyzed using multivariable logistic regression, calculating odds ratios (ORs) when comparing genotype frequencies in responders and nonresponders after the 2nd cycle. Hazard ratios (HRs) for PFS and for OS were calculated using Cox regression methods. In all lung cancer patients, none of the investigated polymorphisms modified response statistically significant. The only significant result in the histological subpopulations was in SCLC patients carrying the ABCC3 -211T allele who showed significantly worsened PFS (HR: 1.79; 95% confidence interval (CI) 1.13-2.82). In an exploratory subgroup analysis significantly worse OS was seen for carriers of the ABCG2 421A-allele treated with platinum-based drugs (HR: 1.60; 95% CI 1.04-2.47; n = 256). In conclusion, this study prioritizes ABCC3 C-211T and ABCG2 C421A as candidate transporter SNPs to be further investigated as possible predictors of the clinical outcome of chemotherapy in lung cancer patients. (C) 2008 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 19107936
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  • 6
    Keywords: DISEASE ; POPULATION ; GENETIC POLYMORPHISMS ; SUSCEPTIBILITY ; ACID ; WOMEN ; REGION ; CARCINOGENS ; DNA-ADDUCTS ; VARIANT
    Abstract: MPO participates in the metabolic activation of tobacco carcinogens such as PAHs. A frequent MPO -463 G--〉A polymorphism in the promoter region reduces MPO transcription and has been correlated with 〉4-fold lower benzo[a]pyrene-DNA adduct levels in the skin of coal tar-treated patients. Four of 7 case-control studies found significantly reduced lung cancer risk associated with the A allele. Due to their different etiologies, we examined whether the MPO genotype affects histologic lung cancer types differentially. A case-control study was conducted in 625 ever-smoking lung cancer patients, including 228 adenocarcinomas, 224 SCCs, 135 SCLCs and 340 ever-smoking hospital controls. MPO genotyping was performed by capillary PCR followed by fluorescence-based melting curve analysis. Combining the MPO -463 (G/A+A/A) genotypes, a protective effect approaching significance (OR = 0.75, 95% CI 0.55-1.01) was observed when comparing all lung cancer cases to controls. Among histologic types of lung cancer, a weak protective effect was found for both adenocarcinoma (OR = 0.81, CI 0.55-1.19) and SCC (OR = 0.82, CI 0.56-1.21); a stronger and significant effect was found for SCLC (OR = 0.58, CI 0.36-0.95; p = 0.029). Our results also suggest that the MPO genotype varies among inflammatory nonmalignant lung diseases. In conclusion, our results emphasize the need for a separate analysis of lung cancer histologic types and an adjustment for inflammatory nonmalignant lung diseases in future MPO-related studies. We confirm that the MPO -463 A variant affords a protective effect against lung cancer risk in smokers, which was strongest for SCLC patients.
    Type of Publication: Journal article published
    PubMed ID: 12432558
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  • 7
    Keywords: CANCER ; THERAPY ; RISK ; SUSCEPTIBILITY ; CANCER SUSCEPTIBILITY ; PROFILES
    Type of Publication: Journal article published
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  • 8
    Keywords: EXPRESSION ; INHIBITOR ; SURVIVAL ; carcinoma ; Germany ; DISEASE ; RISK ; PROTEIN ; LINES ; DNA ; MARKER ; polymorphism ; resistance ; PROMOTER ; Bcl-2 ; SOLID TUMORS ; ABT-737 ; Small cell
    Abstract: INTRODUCTION: We investigated the single-nucleotide polymorphism C-938A in the apoptotic gene BCL-2 to assess the potential impact as a genetic marker for response to chemotherapy and outcome prediction in small cell lung cancer (SCLC) patients. Such a marker might help optimize lung cancer treatment in a tailored approach. METHODS: DNA derived from peripheral blood lymphocytes of 188 Caucasian SCLC patients treated at the Thoraxklinik Heidelberg was genotyped. Chemotherapy response, time to progression (TTP), and overall survival (OS) were evaluated using multivariable regression (unconditional logistic for response and Cox proportional hazard for TTP and OS) with odds ratios and hazard ratios (HRs) and their 95% confidence intervals (CIs) as quantitative outcome measures, respectively. RESULTS: Small cell lung cancer patients carrying the BCL-2 -938CC genotype showed significantly worse TTP than patients carrying the BCL-2 -938AA genotype (HR = 1.86; 95% CI = 1.10-3.13, p = 0.021). The same adverse effect was shown for OS (HR = 2.38; 95% CI = 1.38-4.12, p = 0.002). Also, patients with limited disease (HR = 2.57; 95% CI = 1.18-5.60, p = 0.017) showed worse OS with the BCL-2 -938CC genotype. CONCLUSION: BCL-2 -938CC genotype shows significantly worse outcome in small cell lung cancer patients. This genetic marker might particularly impact on treatment strategies using BCL-2 antisense approaches.
    Type of Publication: Journal article published
    PubMed ID: 21107291
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  • 9
    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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  • 10
    Keywords: APOPTOSIS ; CANCER ; EXPRESSION ; SURVIVAL ; carcinoma ; Germany ; LUNG ; PATHWAY ; lung cancer ; LUNG-CANCER ; SYSTEM ; DISEASE ; POPULATION ; RISK ; GENE ; GENES ; prognosis ; RISK-FACTORS ; CYCLE ; polymorphism ; POLYMORPHISMS ; single nucleotide polymorphism ; PROGRESSION ; risk factors ; chemotherapy ; RISK FACTOR ; CANCER-PATIENTS ; VARIANT ; PHARMACOGENETICS ; SUBGROUPS ; matrix metalloproteinase ; gelatinase B ; outcome ; single nucleotide ; journals ; ALLELE-SPECIFIC REGULATION ; ARTERY LUMINAL DIMENSIONS ; lung cancer chemotherapy ; MATRIX-METALLOPROTEINASE-3 ; STROMELYSIN
    Abstract: The prognosis for lung cancer patients treated with chemotherapy is poor. Single nucleotide polymorphisms (SNPS) in matrix metalloproteinase (MMP) genes could influence treatment outcome by altering apoptotic pathways. Eight SNPs with known or suspected phenotypic effect in six genes (MMP1, MMP2, MMP3, MMP7, MMP9 and MMP12) were investigated. For 349 Caucasian patients with primary lung cancer, receiving first-line chemotherapy, three different endpoints were analysed: response after the second cycle, progression free survival (PFS) and overall survival (OS). The prognostic value of the SNPs was analysed using multiple logistic regression for all patients and histology-, stage- and treatment-specific subgroups. Hazard ratio estimates for PFS and OS were calculated using Cox regression methods. None of the investigated polymorphisms modified response significantly in the whole patient population. However, tumour stage IIIB variant allele carriers of MMP2 C-735T showed a significantly worse response. PFS was significantly prolonged in MMP1 G-1607GG variant allele carriers and OS in small cell lung cancer patients carrying the MMP12 A-82G variant allele. In conclusion, this study identified SNPs in MMP1, MMP2, MMP7 and MMP12 for further investigation as possible predictors of chemotherapy outcome in lung cancer patients
    Type of Publication: Journal article published
    PubMed ID: 19643940
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