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  • DNA repair  (15)
  • 1
    Keywords: CANCER DIAGNOSIS ; THERAPIES ; DNA repair ; methods ; NEW-YORK ; GENE ; GENES ; PATIENT ; CANCER ; CELL ; carcinoma ; radiotherapy ; DIAGNOSIS ; THERAPY ; cell cycle ; CELL-CYCLE ; prognosis ; BREAST ; breast cancer ; BREAST-CANCER ; CANCER-PATIENTS ; side effects ; CANCER PATIENTS
    Type of Publication: Book chapter
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  • 2
    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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  • 3
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  Mainz//2011; 56. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie (gmds), 6. Jahrestagung der Deutschen Gesellschaft für Epidemiologie (DGEpi); 20110926-20110929; Mainz; DOC11gmds226 /20110920/
    Publication Date: 2011-09-20
    Keywords: genetic variants ; DNA repair ; lymphoma ; ddc: 610
    Language: English
    Type: conferenceObject
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  • 4
    Keywords: CANCER ; IRRADIATION ; radiotherapy ; Germany ; TOXICITY ; LUNG-CANCER ; RISK ; RISKS ; GENE ; GENES ; HYBRIDIZATION ; SURGERY ; radiation ; PATIENT ; DNA ; GENETIC POLYMORPHISMS ; SKIN ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; SUSCEPTIBILITY ; VARIANTS ; BREAST ; breast cancer ; BREAST-CANCER ; DESIGN ; DNA-REPAIR ; REPAIR ; DAMAGE ; PROBES ; CARRIERS ; CANCER PATIENTS ; body mass index ; NUCLEOTIDE EXCISION-REPAIR ; DNA repair ; radiation sensitivity ; ACID SUBSTITUTION VARIANTS ; radiosensitivity ; MASSES ; RE ; VARIANT ; CAPACITY ; CANCER SUSCEPTIBILITY ; XPD ; ALLELES ; INTERVAL ; DNA repair gene ; DNA repair genes ; GENETIC-POLYMORPHISM ; CARRIER ; GENOTYPE ; HAPLOTYPE
    Abstract: Purpose: Several DNA repair gene polymorphisms have been described, which affect DNA repair capacity and modulate cancer susceptibility. We evaluated the association of six polymorphisms in the DNA repair genes: XRCC1 (Arg(194) Trp, Arg(280)His, and Arg(399)GIn), APE1 (Asp(148)Glu), and XPD (Lys(751)Gln and Asp(312)Asn), with the risk of acute skin reactions following radiotherapy. Design: We conducted a prospective study of 446 female patients with breast cancer who received radiotherapy after breast-conserving surgery. Individual genetic polymorphisms were determined using melting point analysis of sequence-specific hybridization probes. The development of acute skin reactions (moist desquamation) associated with DNA repair gene polymorphisms was modeled using Cox proportional hazards, accounting for cumulative biologically effective radiation dose. Results: Overall, the development of acute toxicity, which presented in 77 patients, was not associated with the genetic variants studied, although the hazard ratios (HR) were generally below 1. Risks were however differential by body mass index. Among normal-weight patients only, both carriers of theAPE1 (148)Glu and the XRCC1 (399)Gln alleles had decreased risk of acute skin reactions after radiotherapy (HR, 0.49 and 0.51, respectively). The results for XRCC1 were confirmed by haplotype analysis. When considering joint effects, we observed that compared with homozygote carriers of the wild-type allele in both genes, the risk was most strongly reduced in carriers of both APE1 (148)Glu and XRCC1 (399)GIn alleles with normal weight [HR, 0.19; 95% confidence interval (95% CI), 0.06-0.56] but not in those with overweight (HR, 1.39; 95% CI, 0.56-3.45; P-interaction = 0-009). Conclusion: The XRCC1 (399)Gln or APE1 (148)Glu alleles may be protective against the development of acute side effects after radiotherapy in patients with normal weight
    Type of Publication: Journal article published
    PubMed ID: 16000577
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  • 5
    Keywords: CANCER ; IONIZING-RADIATION ; LUNG-CANCER ; EXPOSURE ; HISTORY ; POPULATION ; RISK ; GENE ; GENES ; radiation ; DNA ; FAMILY ; INDEX ; BIOMARKERS ; ASSOCIATION ; FREQUENCY ; polymorphism ; POLYMORPHISMS ; SUSCEPTIBILITY ; FREQUENCIES ; BREAST ; breast cancer ; BREAST-CANCER ; AGE ; family history ; WOMEN ; DNA-REPAIR ; REPAIR ; smoking ; COLORECTAL-CANCER ; BLADDER-CANCER ; cancer risk ; INSTABILITY ; PARAMETERS ; TRANSFORMATION ; genetic polymorphism ; case-control studies ; TOBACCO ; ALCOHOL ; BODY ; FLUORESCENCE ; DNA repair ; SKIN-CANCER ; POSTMENOPAUSAL WOMEN ; MASS INDEX ; MASSES ; BODIES ; case control study ; case-control study ; RE ; FAMILIES ; CAPACITY ; ALLELE ; SINGLE NUCLEOTIDE POLYMORPHISMS ; XPD ; individual susceptibility ; biomarker ; case control studies ; INTERVAL ; analysis ; PREMENOPAUSAL WOMEN ; FAMILY-HISTORY ; PREMENOPAUSAL ; odds ratio ; CANCER-RISK ; TOXICOLOGY ; microbiology ; CHINESE POPULATION ; - ; BODY-MASS ; BODY-MASS-INDEX ; biotechnology ; XRCC3 ; REPAIR GENE XRCC3
    Abstract: The X- ray repair cross- complementing group 3 gene ( XRCC3) belongs to a family of genes responsible for repairing DNA double- strand breaks caused by normal metabolic processes and exposure to ionizing radiation. Polymorphisms in DNA repair genes may alter an individual's capacity to repair damaged DNA and may lead to genetic instability and contribute to malignant transformation. We examined the role of a polymorphism in the XRCC3 gene ( rs861529; codon 241: threonine to methionine change) in determining breast cancer risk in Thai women. The study population consisted of 507 breast cancer cases and 425 healthy women. The polymorphism was analysed by fluorescence- based melting curve analysis. The XRCC3 241Met allele was found to be uncommon in the Thai population ( frequency 0.07 among cases and 0.05 among controls). Odds ratios ( OR) adjusted 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 were calculated for the entire population as well as for pre- and postmenopausal women. There was a significant association between 241Met carrier status and breast cancer risk ( OR 1.58, 95% confidence interval ( CI) 1.02 - 2.44). Among postmenopausal women, a slightly higher OR ( 1.82, 95% CI 0.95 - 3.51) was found than among premenopausal women ( OR 1.48, 95% CI 0.82 - 2.69). Our findings suggest that the XRCC3 Thr241Met polymorphism is likely to play a modifying role in the individual susceptibility to breast cancer among Thai women as already shown for women of European ancestry
    Type of Publication: Journal article published
    PubMed ID: 17701750
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  • 6
    Keywords: CANCER ; CELL ; LUNG ; PATHWAY ; PATHWAYS ; lung cancer ; LUNG-CANCER ; EPIDEMIOLOGY ; RISK ; GENE ; GENES ; validation ; DNA ; BIOMARKERS ; cell cycle ; CELL-CYCLE ; SEQUENCE ; ASSOCIATION ; SUSCEPTIBILITY ; SUSCEPTIBILITY LOCUS ; VARIANTS ; HEALTH ; NUMBER ; REPAIR ; smoking ; p53 ; cancer risk ; FRANCE ; genotyping ; DNA repair ; TP53 ; ONCOLOGY ; VARIANT ; METAANALYSIS ; XRCC1 ; SINGLE-NUCLEOTIDE POLYMORPHISMS ; biomarker ; analysis ; methods ; DNA repair genes ; pooled analysis ; USA ; cancer research ; CANCER-RISK ; OGG1 ; NOV ; GENOME-WIDE ASSOCIATION ; association study ; XRCC3 ; discussion ; POOLED-ANALYSIS ; CONSORTIUM ; genetic variants ; GENOME-WIDE ; APEX1
    Abstract: Background: The International Lung Cancer Consortium was established in 2004. To clarify the role of DNA repair genes in lung cancer susceptibility, we conducted a pooled analysis of genetic variants in DNA repair pathways, whose associations have been investigated by at least 3 individual studies. Methods: Data from 14 studies were pooled for 18 sequence variants in 12 DNA repair genes, including APEX1, OGG1, XRCC1, XRCC2, XRCC3, ERCC1, XPD, XPF, XPG, XPA, MGMT, and TP53. The total number of subjects included in the analysis for each variant ranged from 2,073 to 13,955 subjects. Results: Four of the variants were found to be weakly associated with lung cancer risk with borderline significance: these were XRCC3 T241M [heterozygote odds ratio (OR), 0.89; 95% confidence interval (95% CI), 0.79-0.99 and homozygote OR, 0.84; 95% Cl, 0.71-1.00] based on 3,467 cases and 5,021 controls from 8 studies, XPD K751Q (heterozygote OR, 0.99; 95% Cl, 0.89-1.10 and homozygote OR, 1.19; 95% CI, 1.02-1.39) based on 6,463 cases and 6,603 controls from 9 studies, and TP53 R72P (heterozygote OR, 1.14; 95% Cl, 1.00-1.29 and homozygote OR, 1.20; 95% CI, 1.02-1.42) based on 3,610 cases and 5,293 controls from 6 studies. OGG1 S326C homozygote was suggested to be associated with lung cancer risk in Caucasians (homozygote OR, 1.34; 95% CI, 1.01-1.79) based on 2,569 cases and 4,178 controls from 4 studies but not in Asians. The other 14 variants did not exhibit main effects on lung cancer risk. Discussion: In addition to data pooling, future priorities of International Lung Cancer Consortium include coordinated genotyping and multistage validation for ongoing genome-wide association studies. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3081-9)
    Type of Publication: Journal article published
    PubMed ID: 18990748
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  • 7
    Keywords: CANCER ; CELLS ; EXPRESSION ; IRRADIATION ; radiotherapy ; CELL ; Germany ; THERAPY ; TOXICITY ; COHORT ; RISK ; SURGERY ; radiation ; PATIENT ; DNA ; INDEX ; QUALITY ; SKIN ; treatment ; BREAST ; breast cancer ; BREAST-CANCER ; LESIONS ; RADIATION-THERAPY ; ASSAY ; WOMEN ; DNA-REPAIR ; REPAIR ; COMET ASSAY ; DAMAGE ; LYMPHOCYTES ; BEAM ; DNA-DAMAGE ; PARAMETERS ; CANCER-PATIENTS ; KINETICS ; body mass index ; DNA repair ; DNA repair capacity ; PERIPHERAL-BLOOD LYMPHOCYTES ; ATAXIA-TELANGIECTASIA ; HETEROZYGOTES ; INTRINSIC RADIOSENSITIVITY ; radiation tolerance,DNA repair capacity,breast neoplasms,body mass index
    Abstract: Background and purpose: Intrinsic and extrinsic factors can affect the occurrence of side effects of radiotherapy. The influence of therapy modalities, personal characteristics and individual DNA repair capacity on the risk of acute skin toxicity was thus evaluated.Materials and methods: In a prospective study of 478 female breast cancer patients receiving adjuvant radiotherapy of the breast after breast-conserving surgery, acute skin toxicity was documented systematically using a modified version of the common toxicity criteria. Prognostic personal and treatment characteristics were identified for the entire cohort. Individual DNA repair capacity was determined in a subgroup of 113 patients with alkaline comet assay using phytohemagglutinin stimulated lymphocytes. Using proportional hazards analysis to account for cumulative biologically effective radiation dose, the hazard for the development of acute skin reactions (moist desquamation) associated with DNA repair capacity was modeled.Results: Of the 478 participants, 84 presented with acute reactions by the end of treatment. Higher body mass index was significantly associated with an increased risk for acute reactions (hazard ratio = 1.09 per 1 kg/m(2)), adjusted for treating hospital and photon beam quality. The comet assay parameters examined, including background DNA damage in non-irradiated cells, DNA damage induced by 5 Gy, and DNA repair capacity, were not significantly associated with risk of acute skin toxicity.Conclusions: Higher BMI is predictive of acute skin toxicity, however, individual repair parameters as determined by the alkaline comet assay are not informative enough. More comprehensive analyses including late effects of radiotherapy and repair kinetics optimized for different radiation-induced DNA lesions are warranted. (C) 2003 Elsevier Ireland Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 14643951
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  • 8
    Keywords: APOPTOSIS ; CANCER ; tumor ; carcinoma ; CELL ; Germany ; LUNG ; lung cancer ; LUNG-CANCER ; SYSTEM ; EXPOSURE ; RISK ; GENE ; GENES ; PATIENT ; RISK-FACTORS ; cell cycle ; CELL-CYCLE ; CYCLE ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; SUSCEPTIBILITY ; VARIANTS ; BREAST-CANCER ; risk factors ; smoking ; p53 ; cancer risk ; MUTATIONS ; TRANSFORMATION ; SQUAMOUS-CELL CARCINOMA ; adenocarcinoma ; case-control studies ; squamous cell carcinoma ; GASTRIC-CANCER ; DNA repair ; DNA-REPAIR GENES ; molecular epidemiology ; ONCOLOGY ; case-control study ; REGRESSION ; RE ; TUMOR-SUPPRESSOR ; VARIANT ; INCREASE ; CARCINOGEN ; case control studies ; analysis ; SUPPRESSOR ; GENOTYPE ; adenocarcinoma of the lung ; HISTOLOGY ; RISK-FACTOR ; CANCER-RISK ; PROLINE ; SQUAMOUS-CELL ; INCREASES ; cell cycle control ; CODON-72 ; P53 POLYMORPHISM
    Abstract: Alterations in cell cycle regulation and apoptosis leading to malignant transformation could be caused by common genetic variants in tumor suppressor genes. The effects of the TP53 polymorphism Arg72Pro on lung cancer risk have been investigated in numerous studies with, however, conflicting results. In many studies, important risk modifiers such as smoking or tumor histology were not taken into account. We therefore investigated the combined effects of polymorphisms in TP53 (Arg72Pro) and p21/CDKN1A (Ser31Arg) and smoking on lung cancer risk. Our case-control study consisted of 405 patients with lung cancer, mainly squamous-cell carcinoma (185) and adenocarcinoma (177) and 404 unmatched tumor-free hospital controls. Multivariate regression analysis showed a moderate but statistically significant risk of lung cancer overall. and especially of squamous-cell carcinoma (OR, 1.65; CI, 1.10-2.47) for TP53 72Pro allele carriers. The risk was markedly increased in heavy smokers (〉 20 pack-years) with squamous-cell carcinoma (OR, 2.80 in patients homozygous for 72Pro; CI, 1.19-6.58), but not in tight smokers (〈= 20 pack-years). The results for the p21 Ser31Arg polymorphism suggested that 31Ser is a moderate-risk allele for squamous-cell carcinoma. Analysis of the combined effects of the two polymorphisms revealed a higher OR for TP53 72Pro carriers homozygous for p21 31Ser than for 72Pro carriers in general; this effect being most pronounced in heavy smokers with squamous-cell carcinoma (OR, 3.84; CI, 1.46-10.1). Our data indicate that the TP53 Arg72Pro polymorphism increases the risk for squamous-cell carcinoma mainly in heavy smokers. The observed interaction with smoking is biologically plausible as, for the 72Pro p53 variant, decreased apoptosis and extended G1 cell cycle arrest is reported after carcinogen exposure. Nevertheless, confirmation by further molecular and epidemiological studies is warranted. (c) 2006 Elsevier Ireland Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 17059853
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  • 9
    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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  • 10
    Keywords: CANCER ; CELLS ; EXPRESSION ; IN-VITRO ; IRRADIATION ; radiotherapy ; Germany ; THERAPY ; NEW-YORK ; RISK ; SURGERY ; radiation ; PATIENT ; DNA ; DONOR ; RISK-FACTORS ; INDUCTION ; SKIN ; fibroblasts ; SUSCEPTIBILITY ; BREAST ; breast cancer ; BREAST-CANCER ; RADIATION-THERAPY ; ASSAY ; DNA-REPAIR ; REPAIR ; REPRODUCIBILITY ; risk factors ; cancer risk ; COMET ASSAY ; DAMAGE ; LYMPHOCYTES ; DNA repair ; radiation sensitivity ; alkaline single-cell microgel electrophoresis assay ; CELLULAR RADIOSENSITIVITY ; CHROMOSOMAL RADIOSENSITIVITY ; DNA repair capacity ; DOUBLE-STRAND BREAKS ; IN-VITRO RADIOSENSITIVITY ; NORMAL-TISSUE RADIOSENSITIVITY ; PERIPHERAL-BLOOD LYMPHOCYTES ; radiation effects ; radiosensitivity ; TELANGIECTASIA
    Abstract: Purpose: Repair of radiation-induced DNA damage plays a critical role for both the susceptibility of patients to side effects after radiotherapy and their subsequent cancer risk. The study objective was to evaluate whether DNA repair data determined in vitro are correlated with the occurrence of acute side effects during radiotherapy. Methods and Materials: Breast cancer patients receiving radiation therapy after a breast- conserving surgery were recruited in a prospective epidemiologic study. As an indicator for clinical radiosensitivity, adverse reactions of the skin were recorded. Cryo-preserved lymphocytes from 113 study participants were gamma-irradiated with 5 Gy in vitro and analyzed using the alkaline comet assay. Reproducibility of the assay was determined by repeated analysis (n = 26) of cells from a healthy donor. A coefficient of variation of 0.3 was calculated. Results: The various parameters determined to characterize the individual DNA repair capacity showed large differences between patients. Eleven patients were identified with considerably enhanced DNA damage induction, and 7 patients exhibited severely reduced DNA repair capacity after 15 and 30 min. Six patients were considered as clinically radiosensitive, indicated by moist desquamation of the skin after a total radiation dose of about 50 Gy. Conclusions: Using the alkaline comet assay as described here, breast cancer patients were identified showing abnormal cellular radiation effects, but this repair deficiency corresponded only at a very limited extent to the acute radiation sensitivity of the skin. Because impaired DNA repair could be involved in the development of late irradiation effects, individuals exhibiting severely reduced DNA repair capacity should be followed for the development of late clinical symptoms. (C) 2003 Elsevier Science Inc
    Type of Publication: Journal article published
    PubMed ID: 12654430
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