CNA Landscape of HER2-Negative Breast Cancer in Anthracycline-Based Neoadjuvant Chemotherapy Regimens.

Critical evaluation of how and when to include anthracyclines in preoperative chemotherapy is becoming more relevant in an era when the molecular genetic approach not only allows for the development of biologically targeted therapeutics, but also implies the ability to select the patients likely to benefit from certain cytotoxic agents. Changes in the copy number aberration (CNA) landscape of luminal B HER2- negative (HER2-) breast cancer (BC) during anthracycline-based neoadjuvant chemotherapy (NAC) regimens were studied in order to identify groups of potential CNA markers of objective response and CNA markers for predicting the development of hematogenous metastasis. Comparison of CNA frequencies depending on the response to NAC showed that objective response was observed in a larger number of deletions in the 11q22.3 and 11q23.1 loci (p = 0.004). Comparison of CNA frequencies in groups of patients after treatment showed that hematogenous metastasis was observed with a greater number of amplifications in the 9p22.2 locus (p = 0.003) and with a greater number of deletions in the 9p21.3 locus (p = 0.03). Potential predictive CNA markers of objective response and prognostic CNA markers of hematogenous metastasis in anthracycline- based NAC regimens have been identified.

Human papillomavirus and ovarian cancer (review of literature and meta-analysis).

Many factors are involved in carcinogenesis of the ovary, such human genetic and physiological characteristics as lifestyle, existing diseases of the reproductive system, and, as suggested, the human papillomavirus (HPV). It is well known that the human papillomavirus virus of high carcinogenic risk (HCR) plays a crucial role in the onset and development of cervical cancer, as well as cases of HPV positive breast cancer and endometrial cancer. The data on the presence of HPV in ovarian cancer are ambiguous: the researchers claim that there is no complete effect of the virus on the development of this type of cancer, and the detection of HPV in 60-80% of tumors. In this regard, there is a need to systematize the currently available research results on this controversial issue and conduct a meta-analysis of the association of HPV infection with the risk of ovarian cancer.

Methylation of Promoters of Apoptosis-Related Genes in Blood Lymphocytes of Workers Exposed to Occupational External Irradiation.

We studied the effect of technogenic radiation on the degree of promoter methylation in genes involved in apoptosis in blood lymphocytes of workers exposed to long-term γ-radiation during their professional activities. Blood samples for the analysis were obtained from 11 conventionally healthy men aged from 54 to 71 years (mean 66 years), workers of the Siberian Group of Chemical Enterprises working experience from 27 to 40 years (mean 30 years); the external exposure dose was 175.88 mSv (158.20-207.81 mSv). In all examined subjects, the degree of methylation of the promoters of apoptosis-related genes ranged from 0.22 to 50.00%. A correlation was found between the degree of methylation of BCLAF1 promoters (p=0.035) with the age of workers, BAX promoters (p=0.0289) with high content of aberrant cells, and APAF1 promoters (p=0.0152) with increased number of dicentric chromosomes. A relationship was found between the dose of external irradiation and the degree of methylation of gene promoters of BAD (p=0.0388), BID (р=0.0426), and HRK (р=0.0101) genes.

In vitro modeling of tumor interclonal interactions using breast cancer cell lines.

AIM: To study the peculiarities of ecological relationships of breast cancer (BC) cell lines MCF-7, BT-474 and MDA-MD-231 under co-culturing conditions. MATERIALS AND METHODS: Three BC cell lines: luminal A - MCF-7, luminal B - BT-474 and triple-negative - MDA-MD-231 were co-cultured pairwise. Immunocytochemistry was used to differentiate the cell lines in the wells. The effect of the cell-free culture medium on the growth rate of the alternate cell line in the pair was also evaluated. RESULTS: It was shown that when BT-474 cells were co-cultured with MCF-7 and BT-474 cells were co-cultured with MDA-MD-231, two types of ecological interactions could be observed: commensalism and amensalism, respectively. While the cells do not interact with each other in contact, the supernatants of single cultures of MCF-7 and MDA-MD-231 exert the same effect on BT-474 as co-cultivation of BT-474 with these cells. CONCLUSIONS: The paracrine mechanism of intercellular interaction between different human BC cell lines has been demonstrated. The models used in population ecology can be applicable to identify the types of interaction between cell lines.

NF-kB as a potential prognostic marker and a candidate for targeted therapy of cancer.

The NF-kB1 gene belongs to the family of transcription factors that are involved in the regulation of a wide range of biological reactions. It has been established that NF-kB1 plays an important role in the regulation of immune responses, but more and more studies indicate that this gene is involved in the processes of oncogenesis and DNA repair. The product of this gene regulates the expression of genes involved in the development and progression of cancer. In recent years, numerous studies have been aimed at elucidating the functional consequences of the activation of NF-kB1, as well as its signaling mechanisms. In this regard, NF-kB1 is an interesting therapeutic target for a possible personalized approach in the treatment of cancer. This article provides an overview of modern clinical studies of the NF-kB1 gene, which acts as a predictive and prognostic marker in the treatment of cancer.

Breast tumour cell subpopulations with expression of the MYC and OCT4 proteins.

The MYC and OCT4 genes are known factors associated with maintaining pluripotency and are linked with a more aggressive course, progression, and resistance to therapy in cancer. Determining the subpopulations of tumour cells expressing the Myc and Oct4 proteins will provide an opportunity to understand which tumour cell subpopulations expressing MYC and OCT4 are associated with metastasis and resistance and which subpopulations can be targeted by anti-MYC and anti-OCT4 therapy. The study included paraffin-embedded tissue from tumours from 27 patients with luminal B breast cancer obtained after neoadjuvant chemotherapy (NACT). Immunofluorescence staining was used to identify subpopulations of tumour cells expressing Myc, Oct4 and Snai2 (Opal™ 7-Color Kit (PerkinElmer, Hopkinton, MA). The following tumour cell subpopulations were identified with the Myc and Oct4 proteins and the Snai2 EMT marker: stem/progenitor tumour cells with/without Myc, Oct4 or Snai2 expression; differentiated tumour cells with/without Myc, Oct4 or Snai2 expression; and other nontumour cells (CK7-EpCAM-CD44+/-Myc+/-(Oct4, Snai2)+/-) within the inflammatory infiltrate in the tumour parenchyma and stroma. The circulating tumour cell subpopulations with Oct4 protein expression in the bloodstream were studied by flow cytometry. It was found that in patients with partial regression (PR) in response to NACT, the frequency of tumour stem cells was 3.6-fold increased (p = 0.038) in the non-EMT state (CK7+EpCam+CD44+Snai2-). In patients with metastases, there was a statistically significant 2.5-fold increase in the frequency of differentiated tumour cells with Myc expression (CK7+EpCam+CD44-Myc+) and a 2.7-fold increase in the frequency of cells with Oct4 expression (CK7+EpCam+CD44-OCT4+). In the next stage, the frequencies of subpopulations with expression of the Oct4 protein and signs of EMT among circulating tumour cells (CTCs) were determined. In patients with metastases, the frequency of tumour stem cells in the EMT state (CD326+CD44+CD24-CD325+) (p = 0.015) was more than fourfold increased, and the frequency of progenitor tumour cells with expression of the Oct4 stem protein (CD326+CD44+CD24+Oct4+) (p = 0.016) was almost sixfold higher than that in patients without metastases. Nonstem (differentiated) tumour cells with expression of the stemness proteins Myc and Oct4 were present in the breast tumour. Their content was significantly higher in residual tumours after NACT in patients who subsequently developed metastases compared with that in patients without metastases. Such cells are a new in situ marker of metastasis.

Human papillomavirus and lung cancer: an overview and a meta-analysis.

PURPOSE: This review is devoted to assessing the prevalence of human papillomavirus (HPV) in lung cancer (LC) in the world. HPV is recognized as the etiological factor of cervical cancer, however, there is widespread evidence that this virus is detected not only in gynecological carcinomas, but also in tumors of other organs, in particular the upper respiratory tract and digestive tract. MATERIALS AND METHODS:  A search was conducted to a depth of 29 years in the PubMed, Web of Science, Scopus, databases. The review includes 95 articles. RESULTS: Of all the analyzed studies (9195 patients), 12 works showed a complete absence of HPV in the biological material in patients with LC. The absence of a virus among lung cancer patients has been established for Canada, the Netherlands and Singapore. The highest average percent of occurrence of this virus is shown for such countries as: Brazil, Korea, Greece and Taiwan (more than 40%). But the highest percentage of HPV occurrence by region is observed in Latin America (33.5%), followed by the Asian countries (31%), in European countries the frequency is 18%. Interestingly, the highest occurrence of high oncogenic types (16 and 18) is observed in Asia (40.3%), then in Latin America (33.6%), Europe (25.6%) and North America (15.4%). Low-oncogenic types (6 and 11) are also predominantly observed in Asia (39.9%), while in Europe and North America 30% and 12.8%, respectively. A meta-analysis of the prevalence of HPV was conducted using Comprehensive Meta-Analysis 3.0. Program, which included 26 studies, the results of which revealed: the prevalence of HPV infection in tumor lung tissue was compared with normal lung tissue OR (95% CI) = 5.38 (3.21-9.00) p < 0.0001, significance was also found for Chinese studies OR = 6.3, 95% CI 3.42-11.53, p < 0.0001, I2 = 71.8% and for nine studies in Europe OR = 6.3, 95% CI 1.8-22.18, p = 0.004, I2 = 51.0%. However, given the fact that the frequency of occurrence of HPV in lung tumor tissue varies greatly, a question may arise about the real role of HPV in LC carcinogenesis, which makes further research relevant and promising.

Intratumoral Morphological Heterogeneity of Breast Cancer As an Indicator of the Metastatic Potential and Tumor Chemosensitivity.

Breast cancer (BC) demonstrates considerable intratumoral morphological heterogeneity. The aim of this work was to evaluate the relationship among different morphological structures, the rate of metastasis, and efficacy of neoadjuvant chemotherapy (NAC) in NAC-treated (n = 427) and NAC-naïve (n = 249) BC patients. We also studied the involvement of an epithelial-mesenchymal transition (EMT) in the development of the intratumoral morphological heterogeneity of BC. We found a significant association between the intratumoral morphological heterogeneity and the rate of BC metastasis and response to NAC, which, in most cases, correlated with the presence of alveolar and trabecular structures. In particular, the rate of lymph node metastasis in tumors containing alveolar and trabecular structures was higher compared to that in tumors lacking such structures. NAC-treated patients with alveolar and trabecular structures had a high distant metastasis rate and a low metastasis-free survival rate. Furthermore, alveolar and trabecular structures were found to be associated with a lack of response to NAC. Interestingly, the association between alveolar structures and a high distant metastasis rate was found only in NAC-unresponsive patients, whereas the association between trabecular structures and an increased distant metastasis was revealed in responders. Alveolar structures were associated with chemoresistance only in patients with lymph node metastases, whereas trabecular structures were associated with chemoresistance only in patients without lymph node metastases. In general, increased intratumoral morphological diversity correlated with considerable chemoresistance and a high metastasis rate of BC. We found variable expressions of epithelial (EPCAM and CDH1) and mesenchymal (ITGA5, ITGB5, CDH2, CDH11, TGFb2, ZEB1, MMP2, DCN, MST1R) markers and, thus, different EMT manifestations in different morphological structures. Therefore, intratumoral morphological heterogeneity of BC may serve as an indicator of the metastatic potential and tumor chemosensitivity.

Circulating tumor cells in breast cancer: functional heterogeneity, pathogenetic and clinical aspects.

Each patient has a unique history of cancer ecosystem development, resulting in intratumor heterogeneity. In order to effectively kill the tumor cells by chemotherapy, dynamic monitoring of driver molecular alterations is necessary to detect the markers for acquired drug resistance and find the new therapeutic targets. To perform the therapeutic monitoring, frequent tumor biopsy is needed, but it is not always possible due to small tumor size or its regression during the therapy or tumor inaccessibility in advanced cancer patients. Liquid biopsy appears to be a promising approach to overcome this problem, providing the testing of circulating tumor cells (CTC) and/or tumor-specific circulating nucleic acids. Their genomic characteristics make it possible to assess the clonal dynamics of tumors, comparing it with the clinical course and identification of driver mutation that confer resistance to therapy. The main attention in this review is paid to CTC. The biological behavior of the tumor is determined by specific cancer-promoting molecular and genetic alterations of tumor cells, and by the peculiarities of their interactions with the microenvironment that can result in the presence of wide spectrum of circulating tumor clones with various properties and potentialities to contribute to tumor progression and response to chemotherapy and prognostic value. Indeed, data on prognostic or predictive value of CTC are rather contradictory, because there is still no standard method of CTC identification, represented by different populations manifesting various biological behavior as well as different potency to metastasis. Circulating clasters of CTC appear to have essentially greater ability to metastasize in comparison with single CTC, as well as strong association with worse prognosis and chemoresistance in breast cancer patients. The Food and Drug Administration (USA) has approved the CTC-based prognostic test for clinical application in patients with advanced breast cancer. Prospective clinical trials have demonstrated that measuring changes in CTC numbers during treatment is useful for monitoring therapy response in breast cancer patients. Molecular and genetic analysis of CTC gives the opportunity to have timely information on emergence of resistant tumor clones and may shed light on the new targets for pathogenetic antitumor therapy.

Natural and Chemotherapy-Induced Clonal Evolution of Tumors.

Evolution and natural selection of tumoral clones in the process of transformation and the following carcinogenesis can be called natural clonal evolution. Its main driving factors are internal: genetic instability initiated by driver mutations and microenvironment, which enables selective pressure while forming the environment for cell transformation and their survival. We present our overview of contemporary research dealing with mechanisms of carcinogenesis in different localizations from precancerous pathologies to metastasis and relapse. It shows that natural clonal evolution establishes intratumoral heterogeneity and enables tumor progression. Tumors of monoclonal origin are of low-level intratumoral heterogeneity in the initial stages, and this increases with the size of the tumor. Tumors of polyclonal origin are of extremely high-level intratumoral heterogeneity in the initial stages and become more homogeneous when larger due to clonal expansion. In cases of chemotherapy-induced clonal evolution of a tumor, chemotherapy becomes the leading factor in treatment. The latest research shows that the impact of chemotherapy can radically increase the speed of clonal evolution and lead to new malignant and resistant clones that cause tumor metastasis. Another option of chemotherapy-induced clonal evolution is formation of a new dominant clone from a clone that was minor in the initial tumor and obtained free space due to elimination of sensitive clones by chemotherapy. As a result, in ~20% of cases, chemotherapy can stimulate metastasis and relapse of tumors due to clonal evolution. The conclusion of the overview formulates approaches to tumor treatment based on clonal evolution: in particular, precision therapy, prediction of metastasis stimulation in patients treated with chemotherapy, methods of genetic evaluation of chemotherapy efficiency and clonal-oriented treatment, and approaches to manipulating the clonal evolution of tumors are presented.

Genome-wide association study of loss of heterozygosity and metastasis-free survival in breast cancer patients.

One of the factors providing the diversity and heterogeneity of malignant tumors, particularly breast cancer, are genetic variations, due to gene polymorphism, and, especially, the phenomenon of loss of heterozygosity (LOH). It has been shown that LOH in some genes could be a good prognostic marker. AIM: To perform genome-wide study on LOH in association with metastasis-free survival in breast cancer. MATERIALS AND METHODS: The study involved 68 patients with breast cancer. LOH status was detected by microarray analysis, using a high density DNA-chip CytoScanTM HD Array (Affymetrix, USA). The Chromosome Analysis Suite 3.1 (Affymetrix, USA) software was used for result processing. RESULTS: 13,815 genes were examined, in order to detect LOH. The frequency of LOH varied from 0% to 63%. The association analysis identified four genes: EDA2R, PGK1, TAF9B and CYSLTR1 that demonstrated the presence of LOH associated with metastasis-free survival (log-rank test, p < 0.03). CONCLUSIONS: The presence of LOH in EDA2R, TAF9B, and CYSLTR1 genes is associated with metastasis-free survival in breast cancer patients, indicating their potential value as prognostic markers.

Comprehensive meta-analytical summary on human papillomavirus association with head and neck cancer.

An etiological role of high risk human papillomavirus (HPV) in the development of cervical cancer has been well established. Hence, attention of researchers has been focused on the role of HPV in pathogenesis of other malignancies, such as head and neck cancers. An analysis of epidemiological data on the prevalence of HPV infection among healthy people and patients with precancerous lesions and/or cancer is an important step in understanding the role of HPV in head and neck carcinogenesis. More and more data de-monstrate the impact of HPV infection on disease outcome. HPV-positive patients have been shown to have better responses to radiotherapy and better overall and disease-free survival than HPV-negative patients. This review presents data of the meta-analysis based on a large number of original studies on HPV prevalence in patients with precancerous lesions and in patients with oral, oropharyngeal and laryngeal cancers as well as findings on the impact of HPV infection on survival of these patients.

Integrative and episomal forms of genotype 16 of human papillomavirus in patients with cervical intraepithelial neoplasia and cervical cancer.

The study involved 500 patients with LSIL (low grade squamous intraepithelial lesion), HSIL (high grade squamous intraepithelial lesion), stage I-IV cervical cancer, infected with human papillomavirus (HPV), as well as 235 women without pathological changes in cervical mucosa. The comprehensive survey included colposcopy, cytological and histological analysis, detection and genotyping of high-risk human papillomavirus. Viral load and physical status of HPV16 DNA was evaluated in cases of mono-infection (n = 148). The prevalence of virus-positive cases among the patients with LSIL/NSIL, cervical cancer patients and healthy women was 69.2%, 76.7% and 51.9%, respectively. An association between the severity of disease and high viral load was revealed. The frequency of integrated DNA was strongly increased in patients with a high viral load. The frequency of episomal forms was either reduced or not detecteable in patients with high viral load as compared to patients with low viral load. It is reasonable to suggest that a high HPV16 viral load may cause an increase in the frequency of integration of virus DNA into the cellular/host genome. This suggests that a high HPV16 viral load may be considered as a risk factor for prognosis of cervical intraepithelial neoplasia and cervical cancer.

Genetic aspects of HPV infection detection in tumor and adjacent tissues of patients with laryngeal squamous cell carcinoma.

The article describes methods for the human papillomavirus (HPV) detection in tumor and adjacent (morphologically intact) tissues of patients with laryngeal squamous cell carcinoma (LSSC) in terms of viral pathogenesis. Comparative evaluation of the principles and techniques for HPV detection was performed. Advantages and disadvantages of the HPV detection methods are described. Approaches for DNA and HPV oncoproteins E6-E7 identification are substantiated. The results of our research into the qualitative and quantitative detection of HPV in the tumor and adjacent tissues of patients with Lssc are described. The research was conducted using commercial test systems Amplisens HPV HR screen-titre-FL and Amplisens HPV HR genotype-FL. Based on these results we developed the algorithm of HPV detection in samples of tumor tissue of patients with Lssc. The need for typing HPV-positive tissue samples with low concentration of HPV DNA was discussed.

Invasive and drug resistant expression profile of different morphological structures of breast tumors.

In order to understand invasive/adhesive and drug resistant properties of intratumor morphological heterogeneity of breast cancer, we compared the expression of genes responsible for the cell adhesion and for the drug resistance between distinct morphological structures of breast tumors. Tubular (hollow-like), alveolar (morula-like), trabecular, solid structures/patterns, and discrete (small) groups of tumor cells were isolated from invasive carcinoma of no special type (n=3) and invasive micropapillary carcinoma (n=1) of the breast using laser microdissection. The gene expression of cadherins, catenins, integrins, ABC transporters, GSTP1, and drug targets was analyzed using qRT-PCR. Expression of catenin genes was identified in almost all structures. In contrast, the expression of cadherin and integrin genes significantly varied depending on the morphological variant. Cadherin expression declined in the row: solid - alveolar and trabecular structures - discrete groups of tumor cells. Expression of integrins declined in the row: solid and alveolar - trabecular structures - discrete groups of tumor cells. For drug resistance genes, trabecular structures more often demonstrated activity of genes coding for ABC transporters compared to other morphological variants. These results indicate that intratumoral morphological heterogeneity in breast cancer correlates with expression profile of adhesion and drug resistance genes reflecting different patterns of invasive growth and responsiveness to chemotherapy.

The phenomenon of multi-drug resistance in the treatment of malignant tumors.

Multi-drug resistance (MDR) is a condition when there is broad cross-resistance of cells to various agents which are different in structure and effect. Modern perceptions on mechanisms of MDR development in malignant tumors have been considered, in particular, in tre-ating breast cancer. Physiological functions and contribution to MDR development of ABC-transporter protein families have been described. The role of activation of glutathione system enzymes and apoptosis-regulating proteins in MDR formation has been shown.

[The frequency and spectrum of cytogenetic anomalies in employees of Siberian Group of Chemical Enterprises].

The results of the study of frequency and spectrum of cytogenetic anomalies in 657 healthy employees of the main facilities of the Siberian Group of Chemical Enterprises exposed to external, internal and combined irradiation are presented. No dependence between age and chromosome aberrations frequency was revealed. Chronic external exposure appeared to be the main factor of induction of chromosome aberrations. The frequency of aberrant cells, chromosome type aberrations, paired fragments and rings was statistically significantly higher in employees exposed to external irradiation as compared to persons exposed to combined irradiation. A nonlinear dependence the dose of irradiation and frequency of chromosome aberrations was revealed. A statistically significant decrease of prevalence of aberrant cells, aberration of chromatid and chromosome type was established in employees exposed to irradiation at a dose range of > 0-10 mSv compared to the control group. This agrees with the phenomenon of radiation hormesis. A significant increase of the frequency of chromosome aberrations was not observed at doses below > 40 mSv. In employees exposed to irradiation at a dose range > 40-100 mSv, a statistically significant increase of frequencies of aberrant metaphases, aberrations of chromatid and chromosome types was established. Same was found for dicentrics at dose range of >100-200 mSv. This supports a well known linear threshold model. Dose-effect curve has a plateau at doses ranged from 100 to 500 mSv.

[Correlation of metastasis-free survival in patients with breast cancer and changes in the direction of expression of multidrug resistance genes during neoadjuvant chemotherapy].

Previously, we showed the association of neoadjuvant chemotherapy (NAC) response with changing the expression vector (increase or decrease) of multidrug resistance genes (MDR) in breast tumors during chemotherapy. The aim of the present study was to evaluate the relation between changes in the expression vector of MDR genes and distant metastasis-free survival. Patients (n = 120) with breast cancer (T1-4N0-3M0) treated by 2-4 cycles of NAC (CAX, FAC, and taxane regimes) and 4 cycles of adjuvant chemotherapy (FAC) were included. TaqMan-based quantitative reverse transcriptase PCR (qRT-PCR) was used to estimate the expression of the following MDR genes: ABCB1, ABCC1, ABCC2, ABCC5, ABCG1, ABCG2, GSTP1, and MVP--in biopsies before NAC and in tumor samples after chemotherapy. Comparing the corresponding expression levels allowed us to identify the vector of expression change during NAC. The results showed that 5-year distant metastasis-free survival was 73-78% in patients with a decrease in ABCB1, ABCC2, and ABCG1 expression. The up-regulation of these genes during NAC was related to a significant decrease (up to 50-55%) in metastasis-free survival (Kaplan-Meier analysis: log-rank p value = 0.006-0.03). The association of changing the expression vector of MDR genes with metastasis-free survival did not depend on tumor size, lymph node involvement, histological form, receptor status, molecular subtype, and others clinicopathological parameters of breast cancer. The obtained data suggest that changing the expression vector of MDR genes in breast tumors during NAC may be used as a new potential prognostic marker of breast cancer. An increase in tumor expression of ABCB1, ABCC2, and ABCG1 during chemotherapy is a factor of poor prognosis, whereas down-regulation of these genes--a favorable prognostic marker.

[The estimate of association between gene polymorphisms and the frequency and spectrum of cytogenetic abnormalities in the cohort of Siberian Group of Chemical Enterprises employees exposed to professional irradiation (microarray studies)].

The results from the research into the association between polymorphisms of genes-candidates for individual radiosensitivity and the frequency and spectrum of cytogenetic abnormalities are analyzed. The study was conducted among Siberian Group of Chemical Enterprises healthy employees exposed to professional irradiation in a dose range of 100-300 mSv. Genotyping of DNA samples from 96 employees was carried out by oligonucleotide microarray: "Cancer_SNP_Panel GT-17-211" ("Illumina") containing 1, 421 SNP-markers (Single Nucleotide Polymorphisms) of 406 genes. The standard cytogenetic analysis was performed in the entire examined group. We have also analyzed the association of these SNP with the frequencies of aberrant cells and following chromosomal aberrations: single chromatid fragments, chromatid exchanges, paired fragments, dicentric, ring and frequencies, translocations. We have found that 40 SNP (rs1800389, rs1051690, rs2392221, rs1041163, rs2114443, rs6083, rs1760904, rs4986894, rs488133, rs7462102, rs11249938, rs34206126, rs33945943, rs34324628, rs5742694, rs978458, rs5742667, rs2373721, rs2162679, rs889162, rs2233679, rs2010457, rs2873950, rs1574154, rs10934500, rs4688046, rs10934503, rs4624596, rs2288729, rs4227, rs1367696, rs751087, rs1269486, rs1149901, rs1800404, rs887477, rs696405, rs751087, rs81 92284, rs312016) are associated with the frequency of different types of chromosomal abnormalities (p-value with FDR of Benjamini-Hochberg--equal less than 0.05). 24 SNP (underlined) are associated with more than one type of chromosome abnormalities. In the future, we are going to confirm the results in further studies on the cohort of more than 600 persons.

Intratumor heterogeneity: nature and biological significance.

Intratumor heterogeneity inherent in the majority of human cancers is a major obstacle for a highly efficient diagnosis and successful prognosis and treatment of these diseases. Being a result of clonal diversity within the same tumor, intratumor heterogeneity can be manifested in variability of genetic and epigenetic status, gene and protein expression, morphological structure, and other features of the tumor. It is most likely that the appearance of this diversity is a source for the adaptation of the tumor to changes in microenvironmental conditions and/or a tool for changing its malignant potential. In any case, both processes result in the appearance of cell clones with different undetermined sets of hallmarks. In this review, we describe the heterogeneity of molecular disorders in various human tumors and consider modern viewpoints of its development including genetic and non-genetic factors of heterogeneity origin and the role of cancer stem cells and clonal evolution. We also systematize data on the contribution of tumor diversity to progression of various tumors and the efficiency of their treatment. The main problems are indicated in the diagnosis and therapy of malignant tumors caused by intratumor heterogeneity and possible pathways for their solution. Moreover, we also suggest the key goals whose achievement promises to minimize the problem of intratumor heterogeneity and to identify new prognostic, predictive, and target markers for adequate and effective treatment of cancer.