Polymorphic variants of the hOGG1, APEX1, XPD, SOD2, and CAT genes involved in DNA repair processes and antioxidant defense and their association with breast cancer risk.

Breast cancer is one of the leading causes of mortality among women. The most frequently encountered tumors are luminal tumors. Associations of polymorphisms in the hOGG1 (rs1052133), APEX1 (rs1130409), XPD (rs13181), SOD2 (rs4880), and CAT (rs1001179) genes were studied in 313 nonsmoking postmenopausal patients with luminal B subtype breast cancer. The control group consisted of 233 healthy nonsmoking postmenopausal women. Statistically significant associations of the XPD and APEX1 gene polymorphisms with the risk of developing luminal B Her2-negative subtype of breast cancer were observed in a log-additive inheritance model, while the CAT gene polymorphism showed an association in a dominant inheritance model (OR = 1.41; CI 95 %: 1.08-1.85; Padj.= 0.011; OR = 1.39; CI 95 %: 1.07-1.81; Padj = 0.013 и OR = 1.70; CI 95 %: 1.19-2.43; Padj = 0.004, respectively). In the group of elderly women (aged 60-74 years), an association of the CAT gene polymorphism with the risk of developing luminal B subtype of breast cancer was found in a log-additive inheritance model (OR = 1.87; 95 % CI: 1.22-2.85; Padj = 0.0024). Using MDR analysis, the most optimal statistically significant 3-locus model of gene-gene interactions in the development of luminal B Her2-negative subtype breast cancer was found. MDR analysis also showed a close interaction and mutual enhancement of effects between the APEX1 and SOD2 loci and the independence of the effects of these loci from the CAT locus in the formation of luminal B subtype breast cancer.

[Transcription of DNA-Methyltransferases in Endothelial Cells Exposed to Mitomycin C].

DNA-methyltransferases catalyze DNA methylation in the CpG sites, which play an important role in the maintenance of genome stability. The association between DNA methylation and genotoxic stress resulting in the action of various clastogens has been shown. Genotoxic stress is one of the triggers of endothelial dysfunction. In this study, the transcription of DNMT1, DNMT3A and DNMT3B genes in coronary (HCAEC) and internal thoracic (HITAEC) artery endothelial cells exposed to alkylating mutagen mitomycin C was studied using quantitative polymerase chain reaction. In HCAEC exposed to mitomycin C, DNMT1 transcription is 1.7-fold higher compared to the unexposed control. After elimination of the mutagen from the cultures followed by 24-hours of cultivation, a 2-fold increase of transcription of DNMT3B in HCAEC exposed to mitomycin C compared to the control was observed. At the same time, no changes in transcription of the studied DNA-methyltransferases were found in HITAEC exposed to the mutagen. Thus, increased transcription of DNA-methyltransferase may be a possible molecular mechanism underlying endothelial dysfunction in response to mutagenic load in an in vitro experiment.

Genetic damage in lymphocytes of lung cancer patients is correlated to the composition of the respiratory tract microbiome.

Recent findings indicate that the microbiome may have significant impact on the development of lung cancer by its effects on inflammation, dysbiosis or genome damage. The aim of this study was to compare the sputum microbiome of lung cancer (LC) patients with the chromosomal aberration (CA) and micronuclei (MN) frequency in peripheral blood lymphocytes. In the study, the taxonomic composition of the sputum microbiome of 66 men with untreated LC were compared with 62 control subjects with respect to CA and MN frequency and centromere fluorescence in situ hybridisation analysis. Results showed a significant increase in CA (4.11 ± 2.48% versus 2.08 ± 1.18%) and MN (1.53 ± 0.67% versus 0.87 ± 0.49%) frequencies, respectively, in LC patients as compared to control subjects. The higher frequency of centromeric positive MN of LC patients was mainly due to aneuploidy. A significant increase in Streptococcus, Bacillus, Gemella and Haemophilus in LC patients was detected, in comparison to the control subjects while 18 bacterial genera were significantly reduced, which indicates a decrease in the beta diversity in the microbiome of LC patients. Although, the CA frequency in LC patients is significantly associated with an increased presence of the genera Bacteroides, Lachnoanaerobaculum, Porphyromonas, Mycoplasma and Fusobacterium in their sputum, and a decrease for the genus Granulicatella after application of false discovery rate correction, significance was not any more present. The decrease of MN frequency of LC patients is significantly associated with an increase in Megasphaera genera and Selenomonas bovis. In conclusion, a significant difference in beta diversity of microbiome between LC and control subjects and association between the sputum microbiome composition and genome damage of LC patients was detected, thus supporting previous studies suggesting an etiological connection between the airway microbiome and LC.

Taxonomic diversity of sputum microbiome in lung cancer patients and its relationship with chromosomal aberrations in blood lymphocytes.

Here we report a pilot-sized study to compare the taxonomic composition of sputum microbiome in 17 newly-diagnosed lung cancer (LC) patients and 17 controls. Another object was to compare the representation of individual bacterial genera and species in sputum with the frequency of chromosomal aberrations in the blood lymphocytes of LC patients and in controls. Both groups were male; average age 56.1 ± 11.5 in patients and 55.7 ± 4.1 in controls. Differences in the species composition of bacterial communities in LC patients and controls were significant (pseudo-F = 1.94; p = 0.005). Increased prevalence in LC patients was detected for the genera Haemophilus and Bergeyella; whereas a decrease was observed for the genera Atopobium, Stomatobaculum, Treponema and Porphyromonas. Donors with high frequencies of chromosomal aberrations had a significant reduction in the microbiome of representatives of the genus Atopobium in the microbiome and a simultaneous increase in representatives of the species Alloprevotella compared to donors with a low level of chromosomal aberrations in lymphocytes. Thus, a comparison of the bacterial composition in the sputum of donors with cytogenetic damages in theirs lymphocytes, warrants further investigations on the potential role of microorganisms in the process of mutagenesis in somatic cells of the host body.

[Genotoxic effects of occupational environment in Kuzbass miners].

The authors studied chromosomal aberrations in blood lymphocytes of 100 miners in coal mines of Kuznetsk coal field, with underground length of service over 15 years. Reference data were collected by cytogenetic analysis in a group of workers with long length of service in Kemerovo thermal power plant, contacting coal dust (n = 104) and in healthy males of the same age group, residents of Kemerovo city, without occupational contact with mutagenes (n = 194). The miners appeared to have maximal frequency of structural chromosomal injuries--5.37%. In the workers of thermal power plant, this value was considerably lower than in the miners (4.23%; p < 0.01), but not exceeding the values obtained in the reference groups (1.07%; p < 0.0001). Analysis of qualitative spectrum of chromosomal structural changes revealed that the miners have higher frequency of both chromosomal and chromatid type aberrations. Differences in chromosomal aberrations frequency between the miners and the thermal power plant workers are mostly due to chromosomal type aberrations. This points to significant role of chemical and radiation factors contribution into chromosomal mutagenesis in miners.

[Cytogenetic effects in the population in agricultural regions of the Kemerovo region].

There was performed an analysis of chromosomal aberrations in peripheral blood lymphocytes of the inhabitants of 9 settlements from 6 agricultural regions of the Kemerovo region. 267 children-adolescents and 124 adults not involved in the industry were examined. The average level of chromosomal aberrations was 2.65% in children and 3.35% in adults. It can be regarded as a background regional level. There was no revealed the modifying ability of such factors as gender age, presence of harmful habits (smoking) on the formation of the frequency of cytogenetic abnormalities in residents of rural areas of the Kemerovo region.

[Association of the polymorphism of dna repair genes with chromosomal aberrations in lung cancer patients].

The results of the examination of association of polymorphisms of DNA repair genes and chromosomal aberrations in lung cancer patients are discussed. A significant positive association between the hOGG1 G/G genotypes, XPD G/G genotype and lung cancer was found. The hOGG1 C/C genotypes were significantly negatively associated with lung cancer. The patient chromosomal aberration frequencies were significantly higher than in control. Carriers of all APE1 and XPD genotypes, XRCC1 G/G genotype, ADPRT T/T genotype, hOGG1 C/C and Ser/Cys genotypes had statistically significant differences in the level of the chromosomal aberrations between patient and control groups. Statistically significant differences in the level of chromosomal aberrations between XPD T/T and G/G genotype of lung cancer patients were observed.

[Chromosomal aberrations and genetic polymorphism in genes of the xenobiotic detoxification and DNA repair enzymes in thermoelectric power plant employers].

The results of the investigation of the interrelationship between frequency of chromosomal aberrations and detoxification enzymes (GSTM1, GSTT1) and DNA repair (hOGG1, XPD) genes in the employees of fuel energy complex in Kemerovo are presented In the group of the workers frequency of metaphases with aberrations (3,9 +/- 0,2%: n = 288) was shown to be significantly higher than in the comparison group (2,1 0, 2%: n = +/- 141). In the group of workers and control donors statistically significant differences were revealed in the frequency of distribution of the GSTT1 and hOGG1 genes. The level of chromosomal aberrations was established to be higher in patients with GSTM1 genotype "0/0" in the group of control donors.

[Role of repair gene polymorphism in estimating the sensitivity of human genome to radon in concentrations exceeding maximum permissible level].

The paper gives the results of investigating chromosome aberrations in human peripheral blood lymphocytes due to DNA repair genes, such as hOGG1, ADPRT, APE1, XRCC1, XpG, XpC, XpD, and NBS1, upon long-term exposure to excess indoor radon concentrations. The frequency of chromosome aberrations was found to be significantly lower in the carriers of the genotype hOGG1 326 Ser/Ser (versus the variant Ser/Cys), APE1 148 Asp/Asp (versus Val/Ala and Ala/Ala). The study polymorphic systems were shown to be of value in giving rise to individual types of chromosome aberrations (single fragments and chromosome exchanges).

[Contribution of genetic polymorphism to the formation of individual genome sensitivity in workers engaged in heat and power industry].

The paper presents the results of investigating an association between the frequency of chromosome aberrations and the CYP1A1, CYP1A2*1F GSTM1, and GSTT1 genes involved in xenobiotic biotransformation in workers engaged in heat and power engineering. The group of workers is shown to have a significantly higher rate of metaphases with aberrations (4.03 +/- 0.17%; n = 231) than the control group (2.06 +/- 0.17%; n = 141). Cytogenetic disorders are not found to depend on gender, age, and length of service. The study indicated that the level of chromosome aberrations was significantly higher in carriers of the CTP1A1 C/C, GSTM1 0/0 and GSTT1 0/0 genotypes. In individuals with a combination of the GSTM1 0/0 and GSTT1 0/0 genotypes, the level of chromosome aberrations was ascertained to be significantly higher than that in those with the protective form of these genes.

[Spread of carcinogenic and mutagenic effects in the population of Gornaia Shoria].

Mutagenic and carcinogenic effects were studied in the population of Gornaya Shoria, Kemerovo Region. The carcinogenic effects were evaluated on the basis of the data given by the Kemerovo regional cancer registry over 1990-2008. The standardized cancer morbidity index in Gornaya Shoria (342 per 100,000 population) exceeded the average index in the Kemerovo Region (286 per 100,000) in the same period. The mutagenic effects were estimated on the basis of the monitoring data on the frequency and spectrum of chromosomal aberrations in the peripheral blood lymphocytes of the dwellers of Gornaya Shoria for the 1992-2009 period. The mean level of chromosomal aberrations (5.31%) in the residents of Gornaya Shoria was found to be greater than the regional background mutation rate (2.86%) (p < 0.001). The values of individual aberration types (chromatid and chromosomal breaks, as well as chromosome-type exchange aberrations) were significantly higher in the dwellers of Gornaya Shoria than those in the basic control group. The revealed high mutagenic load in the inhabitants of Tashtagol District, Kemerovo Region, allows this area to be assigned to high genetic risk ones.

[Genome sensitivity and genotoxic effects features in children-teenagers affected by radon radiation in living and educational environment].

The results of chromosomal aberration level and spectrum study in 48-hours peripheral blood lymphocytes cultures of 10-19 years old children-teenagers (n = 132, mean 14.2 +/- 0.16 years old) living in the south part of Kemerovskaya area Gornaya Shoria are presented. Mean metaphases with aberrations were 4.74 +/- 0.21% in studied group that is significantly higher (p < 0.01) than background level of this index in this region (Kemerovskaya area)- 2.62 +/- 0.29%. Aberrations frequencies of separate classes were 2.83 +/- 0.16 for single fragments; 1.89 +/- 0.14 for pair fragments; 0.05 +/- 0.02 for chromatide exchanges and 0.32 +/- 0.05 for chromosome type exchanges. Furthermore in 6 individuals (4.55%) were found Rogue cells that were contained polycentric, ring chromosomes and multiple pair dot fragments. The reasons of chromosomal aberrations frequency increasing in this mountain area inhabitants are discussed (ultrahigh radon radiation doses influence are included).

[Quantitative characteristics of chromosomal aberration frequency in the residents of the regions with different levels of cancer incidences].

We present the results of cytogenetic monitoring of the districts in Kemerovo region, which differ in standardized indices of cancer incidence. It has been shown that residents of the districts with high incidence of malignancies had higher average frequency of metaphases with chromosomal aberrations than the control group (4.06 +/- 0.12% and 2.76 +/- 0.13%, respectively). This difference is caused primarily by single or paired fragments. The increase in the frequency of aberrant metaphase incidence in the districts with elevated cancer frequency was observed both in the male and female groups as well as both in adults and children.

[Cytogenetic analysis of genotoxic effects in subjects employed in heat power industry].

Chromosomal aberration rate has been estimated in peripheral blood lymphocytes of subjects occupationally exposed to a set of hazardous factors (employees of the Kemerovo Heat Power Plant). The frequency of metaphases with aberrations in the workers (3.23 +/- 0.26%, N = 104) is significantly higher than in control subjects (2.11 +/- 0.28%, N = 70). The cytogenetic aberrations did not depend on the sex, age, duration of employment, or smoking.

[Polymorphisms in glutathione S-transferase M1 and T1 (GSTM1 and GSTT1) in the indigenous and the nonresident population of the Kemerovo region].

GSTM1 and GSTT1 gene polymorphisms were studied in Shorians, Teleuts, and Caucasians of the Kemerovo region. It has been shown that distribution of homozygous deletions in the examined groups is significantly heterogeneous. The frequency of deletion genotypes and combinations of deletion in these genes was lower in Shorians and, Teleuts than in Caucasians.

[A modification factor of spontaneous chromosomal aberrations in miner's towns and settlements].

The level and qualitative spectrum of spontaneous chromosomal aberrations (CA) were comparatively analyzed in the lymphocytes of 655 children and adolescents from the Kemerovo Region. The presented sample was divided into 3 groups according to the type of an inhabited locality: 1) small miner's towns; 2) large industrial towns; and 3) rural localities. The maximum frequency of CA (3.77 +/- 0.22%) was noted in a group of dwellers in the miner's towns; its minimum frequency (2.68 +/- 0.17%) among the rural inhabitants. The significant clastogenic effects (including the markers of radiation exposure) were detected in the miner's towns located in the southern part of the region, which represented mountain and submountain areas. At the same time, in the northern and western parts of the Kemerovo Region, the average frequencies of CA in children and adolescents did not exceed the control background values. Thus, the residence in the inhabited localities specializing in mining is not a factor of absolute toxicogenetic risk.

[Complex analysis of mutagenic and carcinogenic jeopardy of work conditions on JSC "Cox" in Kemerovo].

The authors present results of complex study concerning mutagenic and carcinogenic effects of work conditions in chemical-recovery industry. Oncologic morbidity and frequency of chromosomal aberrations in workers group is considerably higher than in controls. These effects appear to increase in males with longer length of service.

[Genomic dosages of active rRNA genes in coke-oven workers]. / genomnye dozy aktivnikh genov rRNK u rabochikh kaksokhimicheskogo proizvodstva.

Genomic dosage (copy number) of active ribosomal genes was evaluated using visual semi-quantitative method determining the sizes of Ag-NORs in acrocentric chromosomes after selective silver nitrate staining. A relationship between the length of service and the active ribosomal gene copy number was established: the highest numbers of active rRNA genes were observed in coke-oven workers with a length of service exceeding 20 years. An inverse relationship between the individual doses of active ribosomal genes and toxicogenetic susceptibility of the workers to the occupational factors was also revealed.

[Genotoxic effects in workers engaged in ore mining and processing]. / Genotoksicheskie éffekty u rabotnikov gorno-obogatitel'nogo proizvodstva.

The authors studied frequencies of chromosomal aberrations (CA) in 48 ore mining and processing workers exposed to occupational hazards complex. Finding is significantly increased frequency of CA, when compared to that in reference groups. Level of structural CA in the main group appeared not to depend on age, sex and bad habits (smoking). The study revealed indirect dependence between cytogenetic disorders frequency and length of service.

[Cytogenetic disorders in workers of coal-tar chemical industry]. / Tsitogeneticheskie narusheniia u rabochikh koksokhimicheskogo proizvodstva.

The authors studied frequencies of chromosomal aberration (CA) and sister chromatid exchanges (SCE) in workers of coal-tar chemical plant (34 individuals). The studies revealed significant increase of CA frequency (7.97 +/- 0.63%), when compared with reference groups 3.37 +/- 0.39% and 3.64 +/- 0.37%.