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  • 1
    Keywords: ENVIRONMENT ; CANCER ; COMBINATION ; SYSTEM ; DISEASE ; EPIDEMIOLOGY ; POPULATION ; RISK ; GENE ; GENES ; SAMPLE ; COMPLEX ; DNA ; GENETIC POLYMORPHISMS ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; SUSCEPTIBILITY ; ADENOMAS ; AGE ; REPAIR ; genetics ; colorectal cancer ; COLORECTAL-CANCER ; cancer risk ; DAMAGE ; COLON-CANCER ; NETHERLANDS ; SMOKERS ; heredity ; DNA repair ; case-control study ; individual susceptibility ; SINGLE-NUCLEOTIDE POLYMORPHISMS ; ALLELES ; analysis ; DNA repair genes ; BASE EXCISION-REPAIR ; POWER ; CANCER-RISK ; STRAND BREAKS ; microbiology ; biotechnology ; XRCC3 ; NUCLEOTIDE
    Abstract: Colorectal cancer represents a complex disease where susceptibility may be influenced by genetic polymorphisms in the DNA repair system. In the present study we investigated the role of nine single nucleotide polymorphisms in eight DNA repair genes on the risk of colorectal cancer in a hospital-based case-control population (532 cases and 532 sex- and age-matched controls). Data analysis showed that the variant allele homozygotes for the Asn148Glu polymorphism in the APE1 gene were at a statistically non-significant increased risk of colorectal cancer. The risk was more pronounced for colon cancer (odds ratio, OR: 1.50; 95% confidence interval, CI: 1.01-2.22;p = 0.05). The data stratification showed increased risk of colorectal cancer in the age group 64-86 years in both individuals heterozygous (OR: 1.79; 95% CI: 1.04-3.07; p = 0.04) and homozygous (OR: 2.57; 95% CI: 1.30-5.06; p = 0.007) for the variant allele of the APE1 Asn148Glu polymorphism. Smokers homozygous for the variant allele of the hOGG1 Ser326Cys polymorphism showed increased risk of colorectal cancer (OR: 4.17; 95% CI: 1.17-15.54; p = 0.03). The analysis of binary genotype combinations showed increased colorectal cancer risk in individuals simultaneously homozygous for the variant alleles of APE1 Asn148Glu and hOGG1 Ser326Cys (OR: 6.37; 95% CI: 1.40-29.02; p = 0.02). Considering the subtle effect of the DNA repair polymorphisms on the risk of colorectal cancer, exploration of gene-gene and gene-environmental interactions with a large sample size with sufficient statistical power are recommended. (C) 2007 Elsevier B.V. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 17991492
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  • 2
    Keywords: CANCER ; CELL ; COMMON ; LUNG-CANCER ; DISEASE ; POPULATION ; RISK ; RISKS ; GENE ; GENES ; GENOME ; GENETIC POLYMORPHISMS ; cell cycle ; CELL-CYCLE ; CYCLE ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; SUSCEPTIBILITY ; VARIANTS ; FREQUENCIES ; BREAST-CANCER ; genetics ; colorectal cancer ; COLORECTAL-CANCER ; CDKN2A ; ADENOCARCINOMAS ; TP53 ; RECTAL-CANCER ; VARIANT ; GENOTYPE ; HAPLOTYPES ; USA ; rectal cancer ; INCREASED RISK ; CANCERS ; Colorectal cancer susceptibility ; Haplotype analysis ; CRC ; CDKN1A ; P53 GENOTYPES ; WIDE ASSOCIATION SCAN
    Abstract: The Czech Republic has one of the highest incidences of colorectal cancer (CRC) in the world. To assess the role of genetic variants on the disease, we genotyped polymorphisms in the TP53 (rs17878362: A(1)〉A(2), rs1042522:G〉C, rs12947788: C〉T, and rs17884306:G〉A), CDKN1A (rs1801270: C〉A and rs1059234:C〉T), and CDKN2A (rs3731249:G〉A, rs11515:C〉G, and rs3088440: C〉T) genes in 614 hospital-based CRC cases and 614 matched controls from the country. Despite the tendency toward differential distribution of variant allele frequencies for some polymorphisms, none was significantly associated with CRC risk. We observed differential distribution of major haplotypes arising from four polymorphisms ill the TP53 gene between cases and controls (global P〈0.0001). The two most common haplotypes, A(1)GCG and A(2)CCG, were present in 81% of the cases compared to 71% of the controls. In comparison to the most common haplotype (A(1)GCG), the haplotype A2CCG was associated with an increased risk (odds ratio (OR], 1.40; 95% confidence interval [CI], 1.07-1.82), while the four other haplotypes A(1)CCG (OR, 0.60; 95% CI, 0.45-0.79), A(2)GCG (OR, 0.53; 95% CI, 0.35-0.81), A(1)GTG (OR, 0.31; 95% CI, 0.15-0.64), and A(1)GCA (OR, 0.19; 95% CI, 0.07-0.51) were associated with a decreased risk. The effect of haplotypes in the TP53 gene was similar in colon (global P 〈 0.000 1) and rectal cancers (P = 0.006). No association with the disease was observed with haplotypes of the CDKN1A and CDKN2A polymorphisms. The results from this study suggest that prevalent haplotypes within the TP53 gene may modulate CRC risks in the population. Hum Mutat 30, 661-668, 2009. (C) 2009 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 19224585
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  • 3
    Keywords: CANCER ; CELLS ; BLOOD ; CELL ; LUNG ; PROSTATE ; lung cancer ; LUNG-CANCER ; RISK ; PATIENT ; MARKER ; CARCINOGENESIS ; GENETIC POLYMORPHISMS ; FREQUENCY ; BREAST ; NEOPLASIA ; MALIGNANCIES ; NUMBER ; DNA-REPAIR ; ABERRATIONS ; MARKERS ; DAMAGE ; LYMPHOCYTES ; INSTABILITY ; STABILITY ; CANCER-PATIENTS ; CANCER PATIENTS ; PERIPHERAL-BLOOD ; micronuclei ; ONCOLOGY ; REGRESSION ; HUMAN CANCER ; methods ; prospective ; CANCERS ; ANEUPLOIDY ; CYTOGENETIC BIOMARKERS ; Type ; LUNG CANCERS ; INTERMEDIATE END-POINTS
    Abstract: Background: The majority of human cancers arise from cells unable to maintain genomic stability. Recent prospective studies indicated that enhanced chromosomal aberrations (CAs) frequencies are predictive of gastrointestinal and lung cancers. However, studies on incident cancer patients are lacking; thus, we investigated chromosomal damage in newly diagnosed cancer patients and healthy individuals. Methods: We analyzed chromosomal damage in peripheral blood lymphocytes in a group of 300 incident cancer patients (with different malignancies) in comparison with 300 healthy controls. Results and Conclusions: The frequencies of aberrant cells (ACs) and CAs were significantly higher in patients (2.38 +/- 1.56 and 2.53 +/- 1.69, respectively) as compared with controls (1.81 +/- 1.31 and 1.94 +/- 1.47, respectively, P 〈 0.01). The percentual difference in chromatid-type aberrations (CTAs) between patients and controls was moderately significant (1.37 +/- 1.20 and 1.11 +/- 0.99, respectively, P 〈 0.05), whereas the difference in chromosome-type aberrations (CSAs) was stronger (1.16 +/- 1.24 versus 0.83 +/- 1.12, P 〈 0.01). Using binomial logistic regression, the estimated odds ratios and 95% confidence interval for ACs were 1.33 (1.18-1.49), P 〈 0.01; for CAs, 1.27 (1.14-1.41), P 〈 0.01; for CTA 1.24 (1.07-1.44), P 〈 0.01 and for CSA, 1.27 (1.10-1.47), P 〈 0.01. By stratifying patients for distinct neoplasia, markers of chromosomal damage were significantly enhanced in patients with breast, prostate and head/neck cancers, whereas no effect was recorded in patients affected by gastrointestinal cancers. The present study shows for the first time evidence of increased chromosomal damage in lymphocytes of incident cancer patients compared with healthy controls. The effects were observed in different cancer types but as the number of patients was relatively small, further studies are warranted
    Type of Publication: Journal article published
    PubMed ID: 20215138
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  • 4
    Keywords: COMET ASSAY ; OXIDATIVE STRESS ; DNA-REPAIR GENES ; PERIPHERAL-BLOOD LYMPHOCYTES ; RISK-ASSESSMENT ; OPERATING-ROOM PERSONNEL ; INHALED ANESTHETICS ; MICRONUCLEUS ASSAY ; DERMAL EXPOSURE ; NITROUS-OXIDE
    Abstract: Objectives Structural chromosomal aberrations in blood lymphocytes represent a biomarker for cellular damage caused by genotoxic carcinogens and are an indicator of increased cancer risk. We evaluated the association between frequencies of total chromosomal aberrations, chromatid- and chromosome-type aberrations, and occupational exposures to volatile anesthetics, antineoplastic agents, and formaldehyde among 601 medical professionals. Methods Chromosomal damage among exposed individuals and unexposed controls was determined by conventional cytogenetic analysis. We used binary logistic regression to evaluate the effects of workplace exposures and major confounders on chromosomal damage. Results Significantly higher frequencies of total chromosomal, chromatid-type and chromosome-type aberrations were observed among subjects occupationally exposed to volatile anesthetics, antineoplastic agents, and formaldehyde compared to age- and sex-matched controls (P〈0.0001). The risk of an increased frequency of chromosomal aberrations was associated with exposure to anesthetics [odds ratio (OR) 3.9, 95% confidence interval (95% CI) 2.7-5.8], cytostatics (OR 2.7, 95% CI 1.9-3.9), and formaldehyde (OR 1.7, 95% CI 1.1-2.7). No other covariate contributed significantly to the model. Chromatid- and chromosome-type aberrations were associated with exposure to anesthetics and cytostatics without any contribution of other variables. Stratified data analysis showed the risk of increased chromosomal aberrations among non-smoking female nurses and physicians exposed to anesthetics, cytostatics and, partially, formaldehyde. Chromatid and chromosome exchanges were significantly higher in the exposed groups than among controls. Conclusion Our findings indicate that the presence of genotoxic compounds in operating rooms, oncological units, and pathological departments results in a significant increase of chromosomal damage (impair of chromosomal integrity) among medical workers employed in these facilities.
    Type of Publication: Journal article published
    PubMed ID: 23525098
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  • 5
    Keywords: CANCER ; RISK ; polymorphism ; DAMAGE ; LYMPHOCYTES ; MULTIPLE-MYELOMA ; TRANSLOCATIONS
    Type of Publication: Journal article published
    PubMed ID: 24270739
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  • 6
    Keywords: CANCER ; EXPOSURE ; RISK ; POLYMORPHISMS ; SUSCEPTIBILITY ; REPAIR ; MARKERS ; LYMPHOCYTES ; DNA-DAMAGE ; GSTT1
    Abstract: Nonspecific chromosomal aberrations (CAs) are found in about 1% of lymphocytes drawn from healthy individuals. They include chromosome-type aberrations (CSAs), which are increased in exposure to ionizing radiation, and chromatid-type aberrations (CTAs) which in experimental systems are formed by DNA binding carcinogens and mutagens. The frequency of CAs is associated with the risk of cancer, but the causes of CAs in general population are unknown. Here, we want to test whether variants in metabolic genes associate with CAs in healthy volunteers. Cases were considered those whose total CA (CAtot) frequency was 〉2% and for CSA and CTA the limit was 〉1%. Controls had lower frequencies of CAs. Functional polymorphisms in seven genes were selected for analysis: cytochrome P450 1B1 (CYP1B1), epoxide hydrolase 1 (EPHX1), NAD(P)H:quinone oxidoreductase 1 (NQO1), each coding for phase 1 enzymes, and glutathione S-transferase P1 (GSTP1), glutathione S-transferases M1 (GSTM1) and T1 (GSTT1), coding for enzymes which conjugate reactive metabolites, that is, phase 2 enzymes. The number of volunteers genotyped for each gene varied from 550 to 1,500. Only EPHX1 was individually associated with CAtot; high activity genotypes decreased CAtot. A total of six significant (P 〈 0.01) pair-wise interactions were observed, most including a GST variant as one of the pair. In all genotype combinations with significant odds ratios for CAs a GST variant was involved. The present data provide evidence that variants in genes coding for metabolic enzymes, which individually have small effects, interact and are associated with CA frequencies in peripheral lymphocytes of healthy volunteers. (c) 2015 Wiley Periodicals, Inc.
    Type of Publication: Journal article published
    PubMed ID: 25622915
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  • 7
    Keywords: BIOMARKERS ; ASSOCIATION ; FREQUENCY ; POLYMORPHISMS ; DAMAGE ; INSTABILITY ; CARCINOGENS ; DNA-REPAIR GENES ; PERIPHERAL-BLOOD LYMPHOCYTES ; HEALTHY HUMANS
    Abstract: Epidemiological prospective studies have shown that increased chromosomal aberrations (CAs) in peripheral blood lymphocytes may predict cancer risk. Here, we report CAs in newly diagnosed 101 colorectal, 87 lung and 158 breast cancer patients and corresponding healthy controls. Strong differences in distributions of aberrant cells (ACs), CAs, chromatid-type aberrations (CTAs) and chromosome-type aberrations (CSAs) were observed in lung and breast cancer patients as compared to healthy controls. In colorectal cancer (CRC) patients, only CTAs were significantly elevated. Binary logistic regression, adjusted for main confounders, indicates that all the analysed cytogenetic parameters along with smoking were significantly associated with breast and lung cancer risks. Significant differences in terminal deletions between breast cancer patients and corresponding female controls were recorded (0.39 vs. 0.18; P 〈= 0.05). We did not find any association of CAs with TNM (tumor nodus metastasis) stages or histopathological grade in either cancer type. CAs were neither associated with additional tumor characteristics-invasivity, ductal and lobular character, estrogene/progesterone receptors in breast tumors nor with non-small/small cell and bronchogenic/pulmonary types of lung tumors. Our study demonstrates that CAs serve as a predictive marker for breast and lung cancer, whereas only CTAs were elevated in incident CRC patients.
    Type of Publication: Journal article published
    PubMed ID: 25800034
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  • 8
    Keywords: PATHWAY ; PATHWAYS ; EXPOSURE ; ENZYMES ; GENE ; GENES ; DNA ; GENETIC POLYMORPHISMS ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; DIFFERENCE ; REPAIR ; genetics ; smoking ; MODULATION ; DAMAGE ; LYMPHOCYTES ; NETHERLANDS ; SMOKERS ; heredity ; DNA repair ; EXCISION-REPAIR ; glutathione-S-transferase ; SISTER-CHROMATID EXCHANGES ; REGRESSION ; SINGLE NUCLEOTIDE POLYMORPHISMS ; CULTURED HUMAN-LYMPHOCYTES ; HUMAN SENSITIVITY ; MICROSOMAL EPOXIDE HYDROLASE ; HEMOGLOBIN ADDUCTS ; analysis ; DNA repair genes ; EXTENT ; CANCER-RISK ; microbiology ; 1,3-butadiene ; comparison ; MEDIA ; biotechnology ; chromosomal aberrations ; 1,3-BUTADIENE-EXPOSED WORKERS ; xenobiotic-metabolizing genes
    Abstract: We evaluated chromosomal aberrations in lymphocytes of 177 workers exposed to xenobiotics in a tire plant and in 172 controls, in relation to their genetic background. Nine polymorphisms in genes encoding biotransformation enzymes and nine polymorphisms in genes involved in main DNA repair pathways were investigated for possible modulation of chromosomal damage. Chromosomal aberration frequencies were the highest among exposed smokers and the lowest in non-smoking unexposed individuals (2.5 +/- 1.8% vs. 1.7 +/- 1.2%, respectively). The differences between groups (ANOVA) were borderline significant (F = 2.6, P = 0.055). Chromosomal aberrations were higher in subjects with GSTF1-null (2.4 +/- 1.7%) than in those with GSTF1-plus genotype (1.8 +/- 1.4%; F = 7.2, P = 0.008). Considering individual groups, this association was significant in smoking exposed workers (F = 4.4, P = 0.040). Individuals with low activity EPHX1 genotype exhibited significantly higher chromosomal aberrations (2.3 +/- 1.6%) in comparison with those bearing medium (1.7 1.2%) and high activity genotype (1.5 +/- 1.2%; F = 4.7, P = 0.010). Both chromatid- and chromosome-type aberration frequencies were mainly affected by exposure and smoking status. Binary logistic regression analysis revealed that frequencies of chromatid-type aberrations were modulated by NBS1 Glu185Gln (OR 4.26, 95%CI 1.38-13.14, P = 0.012), and to a moderate extent, by XPD Lys751Gln (OR 0.16, 95%CI 0.02-1.25, P = 0.081) polymorphisms. Chromosome-type aberrations were lowest in individuals bearing the EPHX1 genotype conferring the high activity (OR 0.38, 95%CI 0.15-0.98, P = 0.045). Present results show that exposed individuals in the tire production, who smoke, exhibit higher chromosomal aberrations frequencies, and the extent of chromosomal damage may additionally be modified by relevant polymorphisms. (C) 2008 Elsevier B.V. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 18394656
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  • 9
    Abstract: We studied the relationship between DNA damage, DNA repair rates and mRNA expression levels of cell cycle genes TP53, p21(CDKN1A), BCL2 and BAX in a group of 71 styrene-exposed workers and 51 control individuals. The exposure was assessed by measuring the concentration of styrene at workplace and in blood. Parameters of DNA damage (measured as single-strand breaks and endonuclease III-sensitive sites), y-irradiation-specific DNA repair rates and mRNA levels of studied genes were analyzed in peripheral blood lymphocytes. The workers were divided into low (below 50 mg/m3) and high (above 50 mg/m3) styrene exposure groups. We found negative correlations between mRNA expression of TP53, BCL2, BAX, and styrene exposure (p〈0.001 for all parameters). In contrast, p21(CDKN1A) mRNA expression significantly increased with increasing styrene exposure (p=0.001). Single-strand breaks and endonuclease III-sensitive sites increased with increasing mRNA levels of TP53 (p〈0.001 for both) and BCL2 (p=0.038, p=0.002, respectively); while the same parameters decreased with increasing mRNA levels of p21(CDKN1A) (p〈0.001, p=0.007, respectively). y-irradiation-specific DNA repair rates increased with p21(CDKN1A) mRNA levels up to the low exposure level (p=0.044). Our study suggests a possible relationship between styrene exposure, DNA damage and transcript levels of key cell cycle genes.
    Type of Publication: Journal article published
    PubMed ID: 20966084
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  • 10
    Abstract: Decreased levels of single-strand breaks in DNA (SSBs), reflecting DNA damage, have previously been observed with increased styrene exposure in contrast to a dose-dependent increase in the base-excision repair capacity. To clarify further the above aspects, we have investigated the associations between SSBs, micronuclei, DNA repair capacity and mRNA expression in XRCC1, hOGG1 and XPC genes on 71 styrene-exposed and 51 control individuals. Styrene concentrations at workplace and in blood characterized occupational exposure. The workers were divided into low (below 50 mg/m3) and high (above 50 mg/m3)) styrene exposure groups. DNA damage and DNA repair capacity were analyzed in peripheral blood lymphocytes by Comet assay. The mRNA expression levels were determined by qPCR. A significant negative correlation was observed between SSBs and styrene concentration at workplace (R=-0.38, p=0.001); SSBs were also significantly higher in men (p=0.001). The capacity to repair irradiation-induced DNA damage was the highest in the low exposure group (1.34+-1.00 SSB/10(9) Da), followed by high exposure group (0.72+-0.81 SSB/10(9) Da) and controls (0.65+-0.82 SSB/10(9) Da). The mRNA expression levels of XRCC1, hOGG1 and XPC negatively correlated with styrene concentrations in blood and at workplace (p〈0.001) and positively with SSBs (p〈0.001). Micronuclei were not affected by styrene exposure, but were higher in older persons and in women (p〈0.001). In this study, we did not confirm previous findings on an increased DNA repair response to styrene-induced genotoxicity. However, negative correlations of SSBs and mRNA expression levels of XRCC1, hOGG1 and XPC with styrene exposure warrant further highly-targeted study.
    Type of Publication: Journal article published
    PubMed ID: 20692273
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