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  • POLYMORPHISMS  (16)
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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: 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 ; 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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  • 4
    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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  • 5
    Keywords: APOPTOSIS ; CANCER ; IONIZING-RADIATION ; radiotherapy ; Germany ; IN-VIVO ; TOXICITY ; RISK ; RISKS ; GENE ; GENES ; HYBRIDIZATION ; SURGERY ; radiation ; PATIENT ; GENETIC POLYMORPHISMS ; SKIN ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; SUSCEPTIBILITY ; VARIANTS ; BREAST ; breast cancer ; BREAST-CANCER ; AGE ; WOMEN ; REPAIR ; p53 ; PCR ; DNA-DAMAGE ; Jun ; CANCER-PATIENTS ; BODY ; p21 ; CANCER PATIENTS ; TP53 ; MASS INDEX ; RE ; VARIANT ; WEIGHT ; OVERWEIGHT ; prospective ; prospective study ; INCREASED RISK ; acute toxicity ; female breast cancer ; CODON-31 ; REPOPULATION
    Abstract: p53 and p21 play an important role in G1/S checkpoint control in response to ionizing radiation. Yet the genetic polymorphisms in these genes have not been investigated with respect to radiation toxicity in patients. We therefore assessed the association between TP53 Arg72Pro, p53PIN3 and p21 Ser31Arg polymorphisms and the risk of acute skin toxicity after radiotherapy in a prospective study of 446 female breast cancer patients (average age 60.3 +/- 9.0 years) receiving radiotherapy after breast conserving surgery. The p53PIN3 polymorphism was determined by standard PCR, and TP53 Arg72Pro and p21 Ser31Arg polymorphisms using melting point analysis of sequence-specific hybridization probes. The development of acute skin toxicity (moist desquamation) was modelled using Cox proportional hazards, accounting for cumulative biologically effective radiation dose. Overall, the development of acute skin toxicity, which presented in 77 patients, was not significantly associated with the polymorphisms studied. Risks were however differential by body mass index. Compared to non-carriers, TP53 72Pro carriers had a non-significantly decreased risk of acute skin toxicity in normal weight women (hazard ratio 0.46, 95% CI, 0.18-1.18) but not in overweight patients (hazard ratio 1.07, 95% CI, 0.61-1.89) (p(interaction) =0.14). Haplotype analysis for the TP53 polymorphisms suggested that effect modification by TP53 72Pro may differ according to the p53PIN3 allele (p(interaction)=0.06). Furthermore, in TP53 72Pro carriers with p21 Ser/Ser genotype, the occurrence of acute toxicity was reduced in normal weight but not overweight patients. In conclusion, the TP53 72Pro variant may be associated with the development of acute skin toxicity after radiotherapy in patients with normal weight. Large clinical studies are needed to clearly confirm this association
    Type of Publication: Journal article published
    PubMed ID: 16331344
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  • 6
    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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  • 7
    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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  • 8
    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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  • 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: 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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