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  • GENE  (22)
  • polymorphism  (16)
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  • 11
    Keywords: brain ; CANCER ; IRRADIATION ; radiotherapy ; tumor ; Germany ; PROSTATE ; THERAPY ; TOXICITY ; COHORT ; RISK ; GENE ; GENES ; TISSUE ; TUMORS ; validation ; radiation ; PATIENT ; MARKER ; RISK-FACTORS ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; BREAST ; MUTATION ; prostate cancer ; PROSTATE-CANCER ; MARKERS ; cancer risk ; RISK FACTOR ; HEAD ; NETHERLANDS ; NORMAL TISSUE ; NECK-CANCER ; brain tumor ; BRAIN-TUMORS ; head and neck cancer ; THERAPIES ; brain tumors ; RISK-FACTOR ; CANCERS ; CANCER-RISK ; GENOME-WIDE ASSOCIATION ; Genetic ; Genome-wide association studies ; cellular response ; CELLULAR-RESPONSE ; BRAIN-TUMOR
    Abstract: Radiotherapy is an important weapon in the treatment of cancer, but adverse reactions developing in the co-irradiated normal tissue can be a threat for patients. Early reactions might disturb the usual application schedule and limit the radiation dose. Late appearing and degenerative reactions might reduce or destroy normal tissue function. Genetic markers conferring the ability to identify hyper-sensitive patients in advance would considerably improve therapy. Association studies on genetic variation and occurrence of side effects should help to identify such markers. This survey includes published studies and novel data from our own laboratory. It illustrates the presence of candidate polymorphisms in genes involved in the cellular response to irradiation which could be used as predictive markers for radiosensitivity in breast or prostate cancer patients. For other tumor types such as head and neck cancers or brain tumors, the available data are much more limited. In any case, further validation of these markers is needed in large patient cohorts with systematically recorded data on side effects and patient characteristics. Genetic variation contributing to radiosensitivity should be screened on a broader basis using newly developed, more comprehensive approaches such as genome-wide association studies
    Type of Publication: Journal article published
    PubMed ID: 19022265
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  • 12
    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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  • 13
    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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  • 14
    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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  • 15
    Keywords: CANCER ; CANCER CELLS ; CELLS ; radiotherapy ; BLOOD ; CELL ; MODEL ; MODELS ; THERAPY ; FOLLOW-UP ; LONG-TERM ; RISK ; GENE ; GENES ; SAMPLE ; SAMPLES ; TISSUE ; radiation ; TIME ; PATIENT ; MECHANISM ; GENETIC POLYMORPHISMS ; mechanisms ; SKIN ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; SUSCEPTIBILITY ; BREAST ; breast cancer ; BREAST-CANCER ; RADIATION-THERAPY ; WOMEN ; CANCER-CELLS ; MULTIVARIATE ; NORMAL TISSUE ; PREDICTORS ; OXIDATIVE STRESS ; RANDOMIZED TRIAL ; OXYGEN ; COMPLICATIONS ; DNA-REPAIR GENES ; reactive oxygen species ; fibrosis ; ONCOLOGY ; THERAPIES ; radiation therapy ; analysis ; USA ; POSTMASTECTOMY RADIOTHERAPY ; INDUCED SUBCUTANEOUS FIBROSIS ; long-term toxicities ; LUMPECTOMY ; NORMAL TISSUE COMPLICATIONS
    Abstract: Telangiectasia and subcutaneous fibrosis are the most common late dermatologic side effects observed in response to radiation treatment. Radiotherapy acts on cancer cells largely due to the generation of reactive oxygen species (ROS). ROS also induce normal tissue toxicities. Therefore, we investigated if genetic variation in oxidative stress-related enzymes confers increased susceptibility to late skin complications. Women who received radiotherapy following lumpectomy for breast cancer were followed prospectively for late tissue side effects after initial treatment. Final analysis included 390 patients. Polymorphisms in genes involved in oxidative stress-related mechanisms (GSTA1, GSTM1, GSTT1, GSTP1, MPO, MnSOD, eNOS, CAD were determined from blood samples by MALDI-TOF. The associations between telangiectasia and genotypes were evaluated by multivariate unconditional logistic regression models. Patients with variant GSTA1 genotypes were at significantly increased risk of telangiectasia (OR 1.86, 95% CI 1.11-3.11). Reduced odds ratios of telangiectasia were noted for women with lower-activity eNOS genotype (OR 0.58, 95% CI 0.36-0.93). Genotype effects were modified by follow-up time, with the highest risk observed after 4 years of radiotherapy for gene polymorphisms in ROS-neutralizing enzymes. Decreased risk with eNOS polymorphisms was significant only among women with less than 4 years of follow-up. All other risk estimates were nonsignificant. Late effects of radiation therapy on skin appear to be modified by variants in genes related to protection from oxidative stress. The application of genomics to outcomes following radiation therapy holds the promise of radiation dose adjustment to improve both cosmetic outcomes and quality of life for breast cancer patients. (C) 2007 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 18027873
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  • 16
    Keywords: CANCER ; IONIZING-RADIATION ; tumor ; PATHWAY ; HISTORY ; incidence ; NEW-YORK ; POPULATION ; RISK ; GENE ; GENES ; radiation ; DNA ; FAMILY ; INDEX ; BASE ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; SUSCEPTIBILITY ; VARIANTS ; BREAST ; breast cancer ; BREAST-CANCER ; AGE ; family history ; WOMEN ; REPAIR ; smoking ; cancer risk ; DAMAGE ; DNA-DAMAGE ; PARAMETERS ; MULTIVARIATE ; INDIVIDUALS ; sensitivity ; ALCOHOL ; TOBACCO SMOKING ; education ; DNA repair ; EXCISION-REPAIR ; POSTMENOPAUSAL WOMEN ; BODIES ; ONCOLOGY ; case-control study ; REGRESSION ; RE ; FAMILIES ; VARIANT ; CAPACITY ; XRCC1 POLYMORPHISMS ; XRCC1 ; ALLELES ; analysis ; DNA damage ; GENOTYPE ; MASS ; FAMILY-HISTORY ; USA ; CANCER INCIDENCE ; CANCER-RISK ; OGG1 ; CONTRACEPTIVES ; postmenopausal ; body mass ; ALCOHOL-DRINKING ; breast cancer risk ; oxidative DNA damage ; APEX1 ; MENOPAUSAL STATUS ; HOGG1 GENE ; SER326CYS POLYMORPHISM
    Abstract: DNA repair plays an important role in tumor development. The base excision repair (BER) pathway mainly removes DNA damage caused by ionizing radiation and reactive oxidative species. Here, we examined possible associations between polymorphisms in three important BER genes (OGG1 Ser326Cys, APEX1 Asp148Glu, XRCC1 Arg194Trp, XRCC1 Arg280His, XRCC1 Arg399Gln) and breast cancer incidence in Thai women. The study population consisted of 507 breast cancer cases and 425 controls. Odds ratios (OR) were adjusted by multivariate logistic regression analysis for age, body mass index, age at menarche, family history of breast cancer, menopausal status, reproduction parameters, use of contraceptives, tobacco smoking, involuntary tobacco smoking, alcohol drinking, and education. For homozygous carriers of the Glu allele in APEX1, a significant protective effect was found when compared to Asp/Asp carriers (odds ratio (OR) = 0.60, 95% confidence interval (CI) = 0.38-0.94). Subgroup analysis based on menopausal status revealed increased breast cancer risk in postmenopausal women and OGG1 (OR = 2.05, 95% CI 1.14-3.69). Reconstructed diplotypes for XRCC1 showed that CGA/CGA carriers had an increased risk of breast cancer compared with carriers of the wild type diplotype CGG/CGG (OR = 2.56, 95% CI 1.28-5.15). When the joint effects of XRCC1, APEX1 and OGG1 polymorphisms were evaluated, individuals homozygous for two or three risk alleles were at increased risk (OR = 1.88, 95% CI 1.26-2.82). In conclusion, our data suggest that Thai women with a certain XRCC1 diplotype or homozygous for two or three variant alleles of XRCC1, OGG1, and APEX1 are likely to have an increased susceptibility to breast cancer
    Type of Publication: Journal article published
    PubMed ID: 17922186
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  • 17
    Keywords: APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; IN-VITRO ; IONIZING-RADIATION ; radiotherapy ; PATHWAY ; TOXICITY ; COHORT ; GENE ; GENE-EXPRESSION ; radiation ; MESSENGER-RNA ; mechanisms ; BREAST-CANCER ; LYMPHOCYTES ; CANCER-PATIENTS ; EPSTEIN-BARR-VIRUS ; Epstein-Barr virus ; ONCOLOGY ; immortalization ; BLOOD-CELLS ; Individual radiosensitivity ; Ionizing irradiation ; LYMPHOBLASTOID CELL-LINES ; mRNA expression ; White blood cell subtypes
    Abstract: The majority of patients tolerate radiotherapy well, but some of them suffer from severe side effects. To find genes possibly predictive for radiosensitivity, mRNA profiles were generated before and 6h after in vitro irradiation with 5Gy. We analyzed lymphocytes from four head and neck and eight breast cancer patients with strong acute radiation toxicity and from 12 matching normal reacting patients in a blind study. Expression was also measured in lymphocyte subpopulations and Epstein-Barr transformed lymphocytes. Radiation response in whole lymphocyte populations was most similar to that of B cells. In peripheral blood lymphocytes of all patients; 153 genes were identified which were statistically significantly altered by a fold change of more than 50% by irradiation. The signatures of radio-responsive genes differed tremendously between primary and transformed cells. Pathway analysis revealed genes involved in p53 signalling, cell cycle control and apoptosis in response to radiation in primary lymphocytes. In these cells, a set of 67 radiation-induced genes was identified capable of differentiating between severe radiosensitive and normal reacting patients. More than one third of such classifying genes belong to the group of apoptosis or cell cycle regulating genes. The classifying potential of the expression signature has now to be validated in further patient cohorts.
    Type of Publication: Journal article published
    PubMed ID: 21236564
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  • 18
    Keywords: CANCER-RISK ; pharmacology ; polymorphism ; POLYMORPHISMS ; cancer risk ; TOBACCO ; LUNG ; CANCER ; LUNG-CANCER ; lung cancer ; RISK ; GENE ; GENES
    Type of Publication: Meeting abstract published
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  • 19
    Keywords: EXPRESSION ; radiotherapy ; DNA ; IMPACT ; GENE ; GENE-EXPRESSION ; gene expression ; genetics ; REPAIR ; DNA-REPAIR ; heredity ; DNA repair ; side effects ; USA ; TOXICOLOGY ; PREDICT ; LEVEL ; mutagen
    Type of Publication: Meeting abstract published
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  • 20
    Keywords: CANCER ; carcinoma ; CELL ; COMBINATION ; Germany ; LUNG ; PATHWAY ; INFORMATION ; lung cancer ; LUNG-CANCER ; EXPOSURE ; RISK ; GENE ; GENES ; PATIENT ; DNA ; RISK-FACTORS ; recombination ; polymorphism ; POLYMORPHISMS ; SUSCEPTIBILITY ; VARIANTS ; IDENTIFICATION ; HUMANS ; AGE ; REPAIR ; risk factors ; smoking ; cancer risk ; DAMAGE ; RISK FACTOR ; HIGH-RISK ; ADDUCTS ; adenocarcinoma ; case-control studies ; squamous cell carcinoma ; INDIVIDUALS ; sensitivity ; EXCISION-REPAIR ; ACID SUBSTITUTION VARIANTS ; non-small cell lung cancer ; CELL CARCINOMA ; case-control study ; VARIANT ; OCCUPATIONAL-EXPOSURE ; CAPACITY ; ALLELE ; SINGLE NUCLEOTIDE POLYMORPHISMS ; XRCC1 POLYMORPHISMS ; XPD ; XRCC1
    Abstract: Several polymorphisms in DNA repair genes have been reported to be associated with lung cancer risk including XPA (-4G/A), XPD (Lys751Gln and Asp312Asn), XRCC1 (Arg399Gln), APE1 (Asp148Glu) and XRCC3 (Thr241Met). As there is little information on the combined effects of these variants, polymorphisms were analyzed in a case-control study including 463 lung cancer cases [among them 204 adenocarcinoma and 212 squamous cell carcinoma (SCC)] and 460 tumor-free hospital controls. Odds ratios (OR) adjusted for age, gender, smoking and occupational exposure were calculated for the variants alone and combinations thereof. For homozygous individuals carrying the Glu variant of APE1, a protective effect was found (OR = 0.77, CI = 0.51-1.16). Individuals homozygous for the variants XPA (-4A) (OR = 1.53, CI = 0.94-2.5), XPD 751Gln (OR = 1.39, CI = 0.90-2.14) or XRCC3 241Met (OR = 1.29, CI = 0.85-1.98) showed a slightly higher risk for lung cancer overall. In the subgroup of adenocarcinoma cases, adjusted ORs were increased for individuals homozygous for XPA (-4A) (OR = 1.62, CI = 0.91-2.88) and XRCC3 241Met (OR = 1.65; CI = 0.99-2.75). When analyzing the combined effects of variant alleles, 54 patients and controls were identified that were homozygous for two or three of the potential risk alleles [i.e. the variants in nucleotide excision repair, XPA (-4A) and XPD 751Gln, and in homologous recombination, XRCC3-241Met]. ORs were significantly increased when all patients (OR = 2.37; CI = 1.26-4.48), patients with SCC (OR = 2.83; CI = 1.17-6.85) and with adenocarcinoma (OR = 3.05; CI = 1.49-6.23) were analyzed. Combinations of polymorphisms in genes involved in the same repair pathway (XPA + XPD or XRCC1 + APE1) affected lung cancer risk only in patients with SCC. These results indicate that lung cancer risk is only moderately increased by single DNA repair gene variants investigated but it is considerably enhanced by specific combinations of variant alleles. Analyses of additional DNA repair gene interactions in larger population-based studies are warranted for identification of high-risk subjects
    Type of Publication: Journal article published
    PubMed ID: 15333465
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