The increasing application of gene panels for familial cancer susceptibility disorders will probably lead to an increased proposal of susceptibility gene candidates. Using ERCC2 DNA repair gene as an example, we show that proof of a possible role in cancer susceptibility requires a detailed dissection and characterization of the underlying mutations for genes with diverse cellular functions (in this case mainly DNA repair and basic cellular transcription). In case of ERCC2, panel sequencing of 1345 index cases from 587 German, 405 Lithuanian and 353 Czech families with breast and ovarian cancer (BC/OC) predisposition revealed 25 mutations (3 frameshift, 2 splice-affecting, 20 missense), all absent or very rare in the ExAC database. While 16 mutations were unique, 9 mutations showed up repeatedly with population-specific appearance. Ten out of eleven mutations that were tested exemplarily in cell-based functional assays exert diminished excision repair efficiency and/or decreased transcriptional activation capability. In order to provide evidence for BC/OC predisposition, we performed familial segregation analyses and screened ethnically matching controls. However, unlike the recently published RECQL example, none of our recurrent ERCC2 mutations showed convincing co-segregation with BC/OC or significant overrepresentation in the BC/OC cohort. Interestingly, we detected that some deleterious founder mutations had an unexpectedly high frequency of > 1% in the corresponding populations, suggesting that either homozygous carriers are not clinically recognized or homozygosity for these mutations is embryonically lethal. In conclusion, we provide a useful resource on the mutational landscape of ERCC2 mutations in hereditary BC/OC patients and, as our key finding, we demonstrate the complexity of correct interpretation for the discovery of "bonafide" breast cancer susceptibility genes.

• MeSH
• genetická predispozice k nemoci * MeSH
• heterozygot MeSH
• lidé MeSH
• missense mutace MeSH
• nádory prsu genetika   patologie   MeSH
• nádory vaječníků genetika   patologie   MeSH
• oprava DNA genetika   MeSH
• xeroderma pigmentosum - protein skupiny D chemie   genetika   MeSH
• zárodečné mutace MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

DNA integrity was investigated in the lymphocytes of 50 bus drivers, 20 garagemen and 50 controls using the comet assay with excision repair enzymes. In parallel, 8-oxo-7,8-dihydro-2'-deoxyguanosine and 15-F(2t)-isoprostane levels in the urine and protein carbonyl levels in the plasma were assessed as markers of oxidative damage to DNA, lipids and proteins. Exposure to carcinogenic polycyclic aromatic hydrocarbons (cPAHs) and volatile compounds was measured by personal samplers for 48 and 24h, respectively, before the collection of biological specimens. Both exposed groups exhibited a higher levels of DNA instability and oxidative damage to biological macromolecules than the controls. The incidence of oxidized lesions in lymphocyte DNA, but not the urinary levels of 8-oxodG, correlated with exposure to benzene and triglycerides increased this damage. Oxidative damage to lipids and proteins was associated with exposure to cPAHs and the lipid peroxidation levels positively correlated with age and LDL cholesterol, and negatively with vitamin C. The carriers of at least one variant hOGG1 (Cys) allele tended to higher oxidative damage to lymphocyte DNA than those with the wild genotype, while XPD23 (Gln/Gln) homozygotes were more susceptible to the induction of DNA strand breaks. In contrast, GSTM1 null variant seemed to protect DNA integrity.

• MeSH
• dinoprost analogy a deriváty   moč   MeSH
• DNA-glykosylasy genetika   metabolismus   MeSH
• DNA účinky léků   MeSH
• genetická predispozice k nemoci MeSH
• glutathiontransferasa genetika   MeSH
• guanin analogy a deriváty   moč   MeSH
• karbonylace proteinů účinky léků   MeSH
• kometový test MeSH
• látky znečišťující vzduch v pracovním prostředí toxicita   MeSH
• lidé MeSH
• lymfocyty chemie   účinky léků   MeSH
• oxidační stres účinky léků   MeSH
• peroxidace lipidů účinky léků   MeSH
• polycyklické aromatické uhlovodíky analýza   toxicita   MeSH
• polymorfismus genetický MeSH
• poškození DNA MeSH
• těkavé organické sloučeniny analýza   toxicita   MeSH
• vazokonstriktory moč   MeSH
• výfukové emise vozidel toxicita   MeSH
• xeroderma pigmentosum - protein skupiny D genetika   MeSH
• znečištění ovzduší MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The purpose of the present study was to investigate the impact of carcinogenic polycyclic aromatic hydrocarbons and volatile organic compounds on sperm quality in a group of city policemen in Prague during a period of increased concentrations of ambient air-pollutants (winter season) compared to a period of low exposure (spring). Polymorphisms in metabolic genes (CYP1A1, EPHX1, GSTM1, GSTP1, GSTT1), folic acid metabolism genes (MTR, MTHFR) and DNA repair genes (XRCC1, XPD6, XPD23, hOGG1) were evaluated in these men as potential modifiers of associations between air pollution exposure and changes in sperm quality. The study population was a group of 47 policemen working in the center of the city. Seasonal differences in exposure were verified by ambient and personal monitoring. Markers of sperm injury included semen volume, sperm concentration, sperm morphology, sperm motility, and sperm DNA damage measured with the sperm chromatin structure assay The sperm chromatin structure assay (SCSA) includes a measure of DNA damage called DNA Fragmentation Index (DFI). The % of cells with detectable DFI (detDFI) by this assay includes sperm with either medium or high DNA damage; the term hDFI is used to define the % of sperm with only high DNA damage. The assay also detects immature sperm defined by high density staining (HDS). No significant differences were found in any of the standard semen parameters between the sampling periods except for vitality of sperms. Both DFI and HDS were significantly higher in winter than in spring samples for all men and for non-smokers. At the bivariate level, significant associations between hDFI or detDFI and polymorphisms of the repair genes XRCC1, XPD6 and XPD23 were observed. In multivariate models, polymorphisms of the genes XPD6, XPD23 and CYP1A1MspI were associated with hDFI and HDS. Moreover, HDS was significantly associated with polymorphisms in GSTM1 gene.

• MeSH
• chromatin genetika   MeSH
• cytochrom P-450 CYP1A1 genetika   metabolismus   MeSH
• dospělí MeSH
• enzymy opravy DNA genetika   metabolismus   MeSH
• fragmentace DNA účinky léků   MeSH
• genotyp MeSH
• glutathiontransferasa genetika   metabolismus   MeSH
• kotinin moč   MeSH
• kouření MeSH
• kyselina listová metabolismus   MeSH
• látky znečišťující vzduch v pracovním prostředí škodlivé účinky   MeSH
• lidé MeSH
• policie MeSH
• polymerázová řetězová reakce MeSH
• polymorfismus délky restrikčních fragmentů MeSH
• polymorfismus genetický MeSH
• poškození DNA genetika   MeSH
• spermie účinky léků   MeSH
• xeroderma pigmentosum - protein skupiny D genetika   metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• práce podpořená grantem MeSH

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 GSTT1-null (2.4+/-1.7%) than in those with GSTT1-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.

• MeSH
• automobily MeSH
• biotransformace MeSH
• chemický průmysl MeSH
• chromozomální aberace * chemicky indukované   MeSH
• dospělí MeSH
• enzymy opravy DNA * genetika   MeSH
• epoxid hydrolasy genetika   MeSH
• genotyp MeSH
• glutathiontransferasa genetika   MeSH
• guma * MeSH
• jednonukleotidový polymorfismus * genetika   MeSH
• lidé MeSH
• lymfocyty MeSH
• oprava DNA * genetika   MeSH
• polymerázová řetězová reakce MeSH
• polymorfismus délky restrikčních fragmentů MeSH
• poškození DNA genetika   MeSH
• pracovní expozice * MeSH
• studie případů a kontrol MeSH
• xenobiotika MeSH
• xeroderma pigmentosum - protein skupiny D genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• práce podpořená grantem MeSH
• srovnávací studie MeSH

In the context of a molecular epidemiology study dealing with the effects of individual genetic susceptibility on childhood respiratory morbidity, DNA repair genotypes for the XPD/ERCC2 gene in exon 6 (Arg156Arg) and exon 23 (Lys751Gln) have been analyzed by PCR/RFLP assays in DNA samples isolated from the fetal parts of placentas. The study was performed using a cohort of 729 children born in 1994-1998 in two districts of the Czech Republic. On the basis of these data, we tested the association between the two genotypes. The principal finding of this study is that the exon 6 and exon 23 polymorphisms in the XPD/ERCC2 gene are tightly associated, with persons who are homozygous CC in exon 23 being mostly (81%) homozygous CC in exon 6, and persons homozygous AA in exon 6 mostly (88%) homozygous AA in exon 23. This strong association may have serious consequences for the interpretation of cancer susceptibility and other molecular epidemiology studies dealing with the XPD6 and XPD23 genotypes, since the observed effects of the silent XPD6 polymorphism might be, in fact, the result of XPD23 polymorphism, which is connected with an amino acid substitution in the resulting XPD protein.

• MeSH
• dítě MeSH
• exony MeSH
• financování organizované MeSH
• frekvence genu MeSH
• genetické poradenství MeSH
• heterozygot MeSH
• hodnocení rizik MeSH
• homozygot MeSH
• kohortové studie MeSH
• lidé MeSH
• mladiství MeSH
• nádory MeSH
• nemoci dýchací soustavy genetika   MeSH
• polymorfismus délky restrikčních fragmentů MeSH
• regulace genové exprese u nádorů MeSH
• rizikové faktory MeSH
• xeroderma pigmentosum - protein skupiny D genetika   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• multicentrická studie MeSH
• Geografické názvy
• Česká republika MeSH