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  • 1
    Keywords: CANCER ; EXPRESSION ; tumor ; BLOOD ; CELL LUNG-CANCER ; Germany ; PROSTATE ; THERAPY ; SUPPORT ; RISK ; DISTINCT ; GENE ; GENE-EXPRESSION ; GENES ; RNA ; transcription ; PATIENT ; DNA ; MESSENGER-RNA ; MARKER ; IMPACT ; primary ; prognosis ; RISK-FACTORS ; CARCINOGENESIS ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; VARIANTS ; lifestyle ; DIFFERENCE ; PLASMA ; REPAIR ; risk factors ; COLORECTAL-CANCER ; prostate cancer ; PROSTATE-CANCER ; MARKERS ; LYMPHOCYTES ; MDM2 ; CANCER-PATIENTS ; POLYMERASE-CHAIN-REACTION ; PREDICTION ; CANCER PATIENTS ; PERIPHERAL-BLOOD ; POLYMERASE CHAIN-REACTION ; NUCLEOTIDE EXCISION-REPAIR ; DNA repair ; TP53 ; BETA-CAROTENE ; molecular ; CHAIN ; ONCOLOGY ; REGRESSION ; RE ; TUMOR-SUPPRESSOR ; VARIANT ; THERAPIES ; mRNA ; LEVEL ; SUPPRESSOR ; GENOTYPE ; HAPLOTYPE ; OXIDATIVE DNA-DAMAGE ; RISK-FACTOR ; ENGLAND ; COEFFICIENTS ; quantitative ; outcome ; VALUES ; tumor suppressor ; MDM2 SNP309 ; genetic variants ; treatment outcome
    Abstract: Both genetic variants and messenger RNA (mRNA) expression of DNA repair and tumor suppressor genes have been investigated as molecular markers for therapy outcome. However, the phenotypic impact of genetic variants often remained unclear, thus the rationale of their use in risk prediction may be limited. We therefore analyzed genetic variants together with anthropometric and lifestyle factors to see how these affect mRNA levels of ERCC1, MDM2 and TP53 in primary blood lymphocytes. mRNA expression was measured in 376 prostate cancer patients by quantitative real-time polymerase chain reaction after reverse transcription, and ERCC1 rs11615 T 〉 C, ERCC1 rs3212986 C 〉 A, MDM2 rs2279744 T 〉 G and TP53 rs17878362 (p53PIN3) polymorphisms were determined. Considerable interindividual differences in mRNA expression were found (coefficients of variation: ERCC1, 45%; MDM2, 43% and TP53, 35%). ERCC1 expression was positively correlated with plasma levels of beta-carotene (P = 0.03) and negatively correlated with canthaxanthin (P = 0.02) and lutein (P = 0.02). Overall, the polymorphisms affected mRNA expression only weakly. Carriers of a distinct ERCC1 haplotype (CC) showed, however, significantly lower expression values than non-carriers (P = 0.001). Applying logistic regression, we found that CC haplotype carriers had a 1.69-fold increased odds ratio (95% confidence interval: 1.06-2.71) for reduced ERCC1 mRNA levels. This low ERCC1 expression might be associated with reduced DNA repair and better therapy response. In summary, the association we have found between ERCC1 genotype and mRNA expression supports recent clinical observations that genetic variation in ERCC1 can affect treatment outcome and prognosis. Our study further revealed a modulating effect by nutritional factors
    Type of Publication: Journal article published
    PubMed ID: 18332046
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  • 2
    Keywords: CANCER ; EXPRESSION ; IN-VITRO ; IONIZING-RADIATION ; radiotherapy ; BLOOD ; Germany ; THERAPY ; TOXICITY ; RISK ; GENE ; GENES ; transcription ; radiation ; PATIENT ; RESPONSES ; DNA ; RISK-FACTORS ; PATTERNS ; DNA-REPAIR ; REPAIR ; risk factors ; prostate cancer ; PROSTATE-CANCER ; PCR ; DAMAGE ; LYMPHOCYTES ; PROBES ; DNA-DAMAGE ; CANCER-PATIENTS ; RT-PCR ; INTENSITY-MODULATED RADIOTHERAPY ; sensitivity ; CANCER PATIENTS ; PERIPHERAL-BLOOD ; DNA repair ; CONSTITUTIVE EXPRESSION ; NORMAL-TISSUE RADIOSENSITIVITY ; PERIPHERAL-BLOOD LYMPHOCYTES ; radiosensitivity ; CLUSTER ; BRCA2 ; GRADE ; CLUSTER-ANALYSIS ; LEVEL ; DNA damage ; cluster analysis ; PROFILES ; EXPRESSION PATTERNS ; CRITERIA ; HUMAN-CELLS ; prospective ; GAMMA-IRRADIATION ; RISK-FACTOR ; SKIN REACTIONS ; peripheral blood ; GENOTOXIC STRESS ; gene expression profiles ; radio-resistance
    Abstract: Purpose: Repair of radiation-induced DNA damage is believed to play a critical role in the development of adverse reactions in radiotherapy patients. Constitutive mRNA expression of repair genes was investigated in such patients to analyze whether expression patterns are predictive for therapy-related acute side effects. Materials and methods: Prostate cancer patients (n = 406) receiving intensity-modulated radiotherapy were recruited in a prospective epidemiological study. Adverse effects were monitored during therapy using common toxicity criteria. For expression analyses, samples from 58 patients were selected according to their observed grade of clinical side effects to radiotherapy. Expression profiles were generated from peripheral blood lymphocytes using customized cDNA-arrays which carried probes for 143 DNA repair or repair-related genes. In addition, expression of selected genes was confirmed by quantitative real-time reverse transcription PCR (RT-PCR). Constitutive mRNA expression profiles were analyzed for predicting acute clinical radiosensitivity or radio-resistance. Results: Cluster analysis identified 19 differentially expressed genes. Many of these genes are involved in DNA double strand break repair. Expression levels of these genes differed up to 7-fold from the mean of all patients whereas expression levels of housekeeping genes varied only up to 2-fold. High expression of the identified genes was associated with a lack of clinical radiation sensitivity thus indicating radio-resistance. Conclusions: Constitutive expression of DNA repair-related genes may affect the development of acute side effects in radiotherapy patients, and high expression levels of these genes seem to support protection from adverse reactions
    Type of Publication: Journal article published
    PubMed ID: 16966187
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  • 3
    Keywords: CANCER ; CELLS ; EXPRESSION ; IN-VITRO ; IONIZING-RADIATION ; radiotherapy ; CELL ; Germany ; PROSTATE ; TOXICITY ; VITRO ; COMMON ; RISK ; GENE ; GENES ; transcription ; radiation ; TIME ; PATIENT ; DNA ; RISK-FACTORS ; INDUCTION ; STRESS ; DNA-REPAIR ; REPAIR ; risk factors ; smoking ; prostate cancer ; PROSTATE-CANCER ; MODULATION ; PCR ; DAMAGE ; LYMPHOCYTES ; DNA-DAMAGE ; CANCER-PATIENTS ; side effects ; CANCER PATIENTS ; real-time PCR ; NUCLEOTIDE EXCISION-REPAIR ; DNA repair ; NORMAL-TISSUE RADIOSENSITIVITY ; PERIPHERAL-BLOOD LYMPHOCYTES ; radiosensitivity ; ONCOLOGY ; GRADE ; quantitative RT-PCR ; REAL-TIME ; development ; ionizing radiation ; DAMAGE RECOGNITION ; LEVEL ; biomarker ; INTERVAL ; analysis ; CRITERIA ; BREAST-CANCER PATIENTS ; USA ; HUMAN-CELLS ; DNA damage response ; INCREASED RISK ; NEVER SMOKERS ; odds ratio ; RISK-FACTOR ; PREDICT ; quantitative ; REPAIR GENES ; LYMPHOBLASTOID-CELLS ; GROUP-C PROTEIN
    Abstract: Repair of radiation-induced DNA damage is believed to play a critical role in developing adverse reactions during radiotherapy. Ionizing radiation induces transcription of several DNA repair genes including XPC as a part of the p53-transmitted stress response. XPC gene induction was measured to analyze whether it predicts occurrence of therapy-related acute side effects. Prostate cancer patients (n = 406) receiving radiotherapy were monitored for development of acute adverse effects using common toxicity criteria. For gene induction analysis, lymphocytes from 99 patients were selected according to their observed grade of clinical side effects. Cells were irradiated in vitro with 5 Gy and analyzed after 4 hr for XPC gene induction using reverse transcription and quantitative real-time PCR. Analysis of modulation of XPC induction by personal, clinical or lifestyle factors was included. Inter-individual induction of XPC expression by ionizing radiation varied up to 20-fold (0.29-5.77) and was significantly higher in current or exsmokers than in never-smokers (p value: 0.008). Patients with XPC induction above the 90th percentile compared to those with lower induction levels were at increased risk of suffering from adverse reactions during radiotherapy (odds ratio 5.3, 95% confidence interval 1.2-24.5; adjusted for smoking). In summary, XPC mRNA levels induced by ionizing radiation were shown for the first time to be strongly affected by smoking and to be associated with an approximately 5-fold increased risk for developing acute side effects of radiotherapy. The predictive value of DNA damage-induced XPC levels as a possible biomarker for radiosensitivity has to be further investigated. (c) 2007 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 17657713
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