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Minina V.I.,Kemerovo State Medical Academy
European Journal of Cancer Prevention | Year: 2016

Lung cancer is one of the most common forms of cancer. The aim of this study was to validate chromosome aberrations in peripheral blood lymphocytes of lung cancer patients living in a region with high air pollution and increased background radon levels as a biomarker of cancer risk. A total of 417 lung cancer patients and 468 control participants were analysed using a chromosome aberration assay in peripheral blood lymphocytes. The results showed that chromatid-type aberrations (2.26±1.58 vs. 1.60±1.58) and chromosome-type aberrations (CSAs) (0.96±1.36 vs. 0.42±0.70) in lung cancer patients were increased significantly in comparison with the controls. The most significant two-fold increase was detected for CSAs (nonsmoking patients: 0.84±1.54 vs. 0.41±0.73%, smoking patients: 0.99±1.31 vs. 0.44±0.67%). The frequency of dicentric and ring chromosomes, double minutes and rogue cells was significantly higher (P=0.002, 0.00002, 0.01, 0.0007) in the lung cancer patients. As both analysed groups lived in the same environment, our results show that increased radon levels were not the only source for the detected genome damage. Using binomial logistic regression, the estimated odds ratios and 95% confidence intervals adjusted for the main confounders (smoking, occupational exposure, age) were 1.31 (1.20–1.40) for chromatid-type aberrations, 1.28 (1.17–1.33), and 1.68 (1.49–1.88) for CSAs. It may be suggested that lung cancer patients show a significant increase in genome damage that may be caused by an interplay between exposure and individual low capacity of DNA repair, leading to genome instability. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.


Kutikhin A.G.,Kemerovo State Medical Academy
Human Immunology | Year: 2011

Toll-like receptors (TLRs) constitute a family of receptors directly recognizing a wide spectrum of exogenous and endogenous ligands playing the key role in realization of innate and adaptive immune response, and participating in the processes of cell proliferation, survival, apoptosis, angiogenesis, tissue remodeling and repair. Polymorphisms in TLR genes may shift balance between pro- and anti-inflammatory cytokines, modulating the risk of infection, chronic inflammation and cancer. The short list of TLR polymorphisms perspective for oncogenomic investigations can include rs10008492, rs4833103, rs5743815, rs11466657, rs7696175 (TLR1-TLR6-TLR10 gene cluster); rs3804100, rs4696480, -196 - -174 del (Delta22), GT-microsatellite polymorphism (TLR2); 829A/C (TLR3); rs5743836, rs352140 (TLR9). The extended list can additionally include rs4833095 rs5743551, rs5743618 (TLR1); rs5743704, rs62323857, rs1219178642 (TLR2); rs5743305, rs3775291, rs121434431, rs5743316 (TLR3); rs5744168 (TLR5); rs179008 (TLR7); rs3764880, rs2407992 (TLR8); rs352139, rs187084, rs41308230, rs5743844 (TLR9); rs4129009 (TLR10). General reasons for discrepancies between studies are insufficiency of sample size, age/gender/BMI/ethnic/racial differences, differences in prevalence of infectious agent in case and control groups, differences in immune response caused by specific ligand, differences in stratification, methods of diagnostics of cancer or chronic inflammatory conditions, genotyping methods, and chance. Future well-designed studies on large samples should shed light on the significance of TLR polymorphisms for cancer prevention. © 2011 American Society for Histocompatibility and Immunogenetics.


Kutikhin A.G.,Kemerovo State Medical Academy | Yuzhalin A.E.,Kemerovo State Medical Academy
Cancer Management and Research | Year: 2012

The group of pattern recognition receptors includes families of Toll-like receptors, NOD-like receptors, C-type lectin receptors, and RIG-I-like receptors. They are key sensors for a number of infectious agents, some of which are carcinogenic, and they launch an immune response against them. Inherited structural variation in genes encoding these receptors and proteins of their signaling pathways may affect their function, modulating cancer risk and features of cancer progression. Relevant malignancies, valuable gene polymorphisms, prime questions about future directions, and answers to these questions are analyzed in this review. It is possible to suggest that polymorphisms of genes encoding pattern recognition receptors and proteins of their signaling pathways may be associated with almost all cancer types, particularly with those in which carcinogenic infectious agents are responsible for the substantial share of cases (namely gastric cancer, colorectal cancer, liver cancer, cervical cancer, and nasopharyngeal carcinoma). The concept of selection of polymorphisms for further oncogenomic investigation, based on a combination of results from basic and epidemiological studies, is proposed. © 2012 Kutikhin and Yuzhalin, publisher and licensee Dove Medical Press Ltd.


Yuzhalin A.E.,Kemerovo State Medical Academy | Kutikhin A.G.,Kemerovo State Medical Academy
Growth Factors | Year: 2012

The last decade has seen the emergence of immunomodulators as therapeutic agents in cancer treatment. Interleukins (ILs) are a category of small cell-signaling molecules that organize communication and interaction between immune cells and therefore they could be used as perfect immunomodulators. IL-12 is a promising candidate for cancer immunotherapy since it plays a major role in development of antitumor immune response. Numerous studies report that IL-12 promotes an effective destruction of cancer cells both in vivo and in vitro. In addition, IL-12 has anti-angiogenic activity and it is able to dramatically decrease tumor-supportive activities of tumor-associated macrophages. The first part of the review is devoted to immunobiology of IL-12. Signaling pathways of IL-12 as well as clinical trials of this cytokine are discussed. The second part of the review is concerned on the inherited variations in IL-12A and IL-12B genes that could modulate cancer susceptibility, and as a consequence, possess predictive, therapeutic, or prognostic significance. It is known that functional single nucleotide polymorphisms (SNPs) in IL-12A and IL-12B genes may dramatically affect on protein expression level, or alter its functions, which may lead to immune disorders, autoimmune diseases, and eventually contribute to cancer occurrence. The list of genetic polymorphisms for further investigations might include the following: IL-12B- + 1188A/C (rs3212227), IL-12A- + 277G/A (rs568408), IL-12A-798T/A (rs582054), IL-12A-504T/G (rs190533), IL-12A-1148T/C (rs2243123), and IL-12B- + 16974 A/C. Perhaps, some of these SNPs may become an attractive target for oncogenomics and possibly could be used in programs of early cancer diagnosis as well as cancer prevention in the nearest future. © 2012 Informa UK, Ltd.


Yuzhalin A.E.,Kemerovo State University | Kutikhin A.G.,Kemerovo State Medical Academy
Free Radical Research | Year: 2012

Antioxidant defence enzymes are essential protectors of living organisms against oxidative stress. These enzymes are involved in the detoxification and decomposition of harmful chemical compounds called reactive oxygen species (ROS), which are, first and foremost, a source of intracellular oxidative stress. ROS directly promote the oxidative damage of genes resulting in aberrant regulation of many vital cell processes. As a consequence, the presence of ROS can lead to genomic instability, deregulation of transcription, induction of mitogenic signal transduction pathways and replication errors, all of which may increase the risk of cancer development. Single nucleotide polymorphisms of antioxidant defence genes may significantly modify the functional activity of the encoded proteins; therefore, certain alleles can be established as risk factors for particular cancer types. In the future, these risk alleles may be utilized as genomic markers of cancer predisposition to allow for early prevention measures among carriers of these alleles. The review is devoted to common single nucleotide polymorphisms of the superoxide dismutase (SOD) and glutathione peroxidase (GPX) gene families and their impact on carcinogenesis. The predictive significance of several polymorphisms was determined, and these polymorphisms were recommended for further in-depth research. © 2012 Informa UK, Ltd.


Kutikhin A.G.,Kemerovo State Medical Academy | Yuzhalin A.E.,Kemerovo State Medical Academy
Cancer Management and Research | Year: 2012

The group of pattern recognition receptors includes families of Toll-like receptors, NOD-like receptors, C-type lectin receptors, and RIG-I-like receptors. They are key sensors for a number of infectious agents, some of which are oncogenic, and they launch an immune response against them, normally promoting their eradication. Inherited variations in genes encoding these receptors and proteins and their signaling pathways may affect their function, possibly modulating cancer risk and features of cancer progression. There are numerous studies investigating the association of single nucleotide polymorphisms within or near genes encoding Toll-like receptors and NOD-like receptors, cancer risk, and features of cancer progression. However, there is an almost total absence of articles analyzing the correlation between polymorphisms of genes encoding C-type lectin receptors and RIG-I-like receptors and cancer risk or progression. Nevertheless, there is some evidence supporting the hypothesis that inherited C-type lectin receptor and RIG-I-like receptor variants can be associated with increased cancer risk. Certain C-type lectin receptors and RIG-I-like receptors recognize pathogen-associated molecular patterns of potentially oncogenic infectious agents, and certain polymorphisms of genes encoding C-type lectin receptors and RIG-I-like receptors may have functional consequences at the molecular level that can lead to association of such single nucleotide polymorphisms with risk or progression of some diseases that may modulate cancer risk, so these gene polymorphisms may affect cancer risk indirectly. Polymorphisms of genes encoding C-type lectin receptors and RIG-I-like receptors thereby may be correlated with a risk of lung, oral, esophageal, gastric, colorectal, and liver cancer, as well as nasopharyngeal carcinoma, glioblastoma, multiple myeloma, and lymphoma. The list of the most promising polymorphisms for oncogenomic investigations may include rs1926736, rs2478577, rs2437257, rs691005, rs2287886, rs735239, rs4804803, rs16910526, rs36055726, rs11795404, and rs10813831. © 2012 Kutikhin and Yuzhalin, publisher and licensee Dove Medical Press Ltd.


Yuzhalin A.E.,Kemerovo State Medical Academy | Kutikhin A.G.,Kemerovo State Medical Academy
Journal of Environmental Science and Health - Part C Environmental Carcinogenesis and Ecotoxicology Reviews | Year: 2012

Modern approaches in health care are moving toward the model of personalized medicine. Today, current research in molecular biology and medicine is focused on developing genomic markers with predictive, therapeutic, and prognostic significance. One of the most widespread and significant genomic markers is the single nucleotide polymorphism (SNP), which represents a variation in DNA sequence when a single nucleotide differs between members of a biological species or paired chromosomes in an individual. Antioxidant defense enzymes break down dangerous reactive compounds, called reactive oxygen species, and prevent DNA strand from carcinogen-specific mutations. It is well known that inherited variations in genes that encode antioxidant defense enzymes may modulate individual susceptibility to cancer. In our previous study we have determined the predictive significance of several SNPs of superoxide dismutase (SOD) and glutathione peroxidase gene families in the context of cancer risk. The present review includes a summary and discussion of the current findings evaluating the role of SNPs of the myeloperoxidase (MPO) and paraoxanase (PON) genes in cancer occurrence and development. We suggest that rs2333227 (MPO-463G/A) and rs854560 polymorphisms have a great predictive significance; they could probably be utilized as cancer predictors in the future. Also, we recommend further in-depth research for rs11079344 (MPO), rs8178406 (MPO), rs2243828 (MPO), rs662 (PON1), rs705379 (PON1), and PON1-304A/G polymorphisms. These SNPs may become significant cancer-associated biomarkers. © 2012 Copyright Taylor and Francis Group, LLC.


Kutikhin A.G.,Kemerovo State Medical Academy
Human Immunology | Year: 2011

Toll-like receptor 4 (TLR4) is one of the key immune system effectors playing the main role in recognition of viruses and bacteria. Dysregulation of the TLR4 signaling owing to single nucleotide polymorphisms (SNPs) may alter the ligand binding and balance between pro- and anti-inflammatory cytokines, thereby modulating the risk of chronic inflammation and cancer. TLR4 polymorphisms may be associated with at least nine types of cancer. The most intensively investigating TLR4 polymorphisms are Asp299Gly (rs4986790) and Thr399Ile (rs4986791). It seems to be that Asp299Gly and Thr399Ile are related to increased risk of precancerous gastric lesions, and, possibly, gastric cancer. Thr399Ile also may be connected with gallbladder cancer, and both of these polymorphisms apparently have no impact on risk of prostate cancer. However, the data about many SNPs and their associations with different types of cancer are conflicting, and further large, well-designed, comprehensive studies in various populations are necessary for solution of this problem. The short list of TLR4 SNPs for further investigation may include TLR4_896A/G (Asp299Gly, rs4986790), TLR4_1196C/T (Thr399Ile, rs4986791), Thr135Ala, TLR4_1859 G/A (rs11536858), TLR4_2032T/C (rs10116253), TLR4_2437A/G (rs1927914), TLR4_2856T/C (rs10759932), TLR4_3725 G/C (rs11536889), TLR4_7764 G/A (rs1927911), TLR4_11350G/C, TLR4_11912 G/T (rs2149356), TLR4_16649G/C (rs7873784), and TLR4_17050T/C (rs11536891). © 2011 IBRO.


Kutikhin A.G.,Kemerovo State Medical Academy
Human Immunology | Year: 2011

NOD1/CARD4 and NOD2/CARD15 are members of Nod-like receptor family. They are located in cytosol, bind bacterial and viral ligands and play a key role in realization of innate and adaptive immune response, apoptosis, autophagy, and reactive oxygen species generation. Polymorphisms in NOD1/CARD4 and NOD2/CARD15 genes may shift balance between pro- and anti-inflammatory cytokines, modulating the risk of infection, chronic inflammation and cancer. NOD1/CARD4 and NOD2/CARD15 gene polymorphisms may be associated with altered risk of gastric, colorectal, breast, ovarian, prostate, testicular, lung, laryngeal, liver, gallbladder, biliary tract, pancreatic, small bowel, kidney, urinary bladder cancer, skin cancer, nonthyroid endocrine tumors, lymphoma and leukemia. The short list of such polymorphisms perspective for oncogenomic investigations may include rs2006847, rs2066845, rs2066844, rs2066842, ND(1)+32656, rs2075820 whereas rs104895493, rs104895476, rs104895475, rs104895474, rs104895473, rs104895472, rs104895462, rs104895461, rs104895460, rs104895438, rs5743291, rs5743260, rs2076756, rs2066843, Pro371Thr, Ala794Pro, Gln908His, rs72551113, rs72551107, rs6958571, rs2907749, rs2907748, rs2075822, rs2075819, rs2075818 may be added to the extended list. Reasons of discrepancies between different studies include confounding host genetic, bacterial, or environmental factors modulating penetrance of variant allele and affecting risk of condition increasing cancer risk, different bacterial impact in aetiology of such conditions, differences in sample size, clinicopathological characteristics, diagnostics, stratification, genotyping methods, and chance. © 2011 American Society for Histocompatibility and Immunogenetics.


Yuzhalin A.E.,Kemerovo State Medical Academy | Kutikhin A.G.,Kemerovo State Medical Academy
Asian Pacific Journal of Cancer Prevention | Year: 2012

Background: There is a large amount of evidence that the ABO blood group system may play a role in disease etiology. A relationship between ABO and Rhesus blood groups and cancer risk has been demonstrated in a number of studies. However, in relation to gynecological malignancies, these findings are inconsistent and contradictory. Aim: To perform a case-control study for analysis of the distribution of ABO and Rh blood antigens among women from South-East Siberia who suffered from ovarian, endometrial and cervical cancer, and to assess the potential role of these antigens in carcinogenesis. Design, Subjects and Methods: A total of 1,163 cases with ovarian cancer (n=551), endometrial cancer (n=440) and cervical cancer (n=172) were involved in the study. The control group was formed from 22,581 female blood donors. Blood groups were determined through patients medical records and blood donor records. Odds ratios (OR) with 95% confidence intervals (CI) were calculated. The blood group O was defined as the referent group, as it has the greatest frequency in the populations of Southern Siberia. P values less than 0.05 were regarded as statistically significant. Results: We found that carriage of non-O blood types increased the risk of ovarian cancer by 40-60%, and the magnitude of this relationship was strongest in women with the AB (IV) blood group. Carriage of the A (II) blood group strongly correlated with an increased risk of ovarian cancer in premenopausal, but not in postmenopausal women. No statistically significant correlations were obtained for endometrial cancer and cervical cancer. Additionally, we did not observe a relationship between Rhesus factor and cancer risk. Conclusion: We suggest that carriage of non-O blood groups may elevate risk of ovarian cancer and can play a role in its development.

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