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The assessment of molecular genetic landscape changes during NAC and the relationship between molecular signatures in residual tumors are promising approaches for identifying effective markers of outcome in breast cancer. The majority of the data in the literature present the relationship between the molecular genetic landscape and the response to NAC or are simply descriptive. The present study aimed to determine changes in expression profiles during NAC and assess the relationship between gene expression and the outcome of patients with luminal B HER2 breast cancer depending on distant hematogenous metastasis. The study included 39 patients with luminal B HER2-BC. The patients received 6–8 courses of NAC, and paired samples consisting of biopsy and surgical materials were analyzed. A full transcriptome microarray analysis was performed using the human Clariom™ S Assay platform (Affymetrix, 3450 Central Expy, Santa Clara, CA, 95051, USA). A comparison of the expression profiles of patients with breast cancer before and after NAC, depending on the status of hematogenous metastasis, was conducted. It was shown that the amount of DEGs in the tumor was reduced by more than six times after NAC. The top 10 signaling pathways were also found, the activity of which varied depending on the status of hematogenous metastasis before and after NAC. In addition, the association of DEGs with hematogenous metastasis in patients with breast cancer was evaluated: MFS was assessed depending on the expression level of 21 genes. It was shown that MFS was significantly associated with the expression level and pattern of nine genes. The expression levels of nine DEGs in the tumors of patients with breast cancer after NAC were significantly correlated with MFS when the status of hematogenous metastasis was taken into account.

Objectives: A growing body of evidence suggests the important role of chemosensitive gene expression in the prognosis of patients with lung cancer. However, studies on combined gene expression assessments for personalized prescriptions of chemotherapy regimens in patients have not yet been conducted. The aim of this work was to conduct a prospective study on the appointment of personalized chemotherapy in patients with non-small-cell lung cancer. Materials and methods: The present study analyzed 85 patients with lung cancer (stage IIB-IIIB). Within this group, 48 patients received individualized chemotherapy, and 37 patients received classical chemotherapy. In the individualized chemotherapy group, the mRNA expression levels of ERCC1, RRM1, TUBB3, TYMS, TOP1, TOP2α, BRCA1, and GSTP1 in lung tissues were measured by quantitative real-time PCR (qPCR), and an individual chemotherapy regimen was developed for each patient according to the results. Patients in the classical chemotherapy group received the vinorelbine/carboplatin regimen. Survival analyses were performed using the Kaplan–Meier method. Prognostic factors of metastasis-free survival (MFS) and overall survival (OS) of patients were identified via Cox’s proportional hazards regression model. Results: MFS and OS were significantly better in the personalized chemotherapy group compared to the classic chemotherapy group (MFS, 46.22 vs. 22.9 months, p = 0.05; OS, 58.6 vs. 26.9 months, p < 0.0001). Importantly, the best metastasis-free survival rates in the group with personalized ACT were achieved in patients treated with the paclitaxel/carboplatin regimen. Based on an assessment of chemosensitivity gene expression in the tumors, the classical chemotherapy strategy also increased the risk of death (HR = 14.82; 95% CI: 3.33–65.86; p < 0.000) but not metastasis (HR = 1.95; 95% CI: 0.96–3.98; p = 0.06) compared to the group of patients with chemotherapy. Conclusions: The use of combined ERCC1, RRM1, TUBB3, TYMS, TOP1, TOP2α, BRCA1, and GSTP1 gene expression results for personalized chemotherapy can improve treatment efficacy and reduce unnecessary toxicity.

Background Amplification of chromosome 8q with locus 8q24 is the most common copy number aberration, and is associated with tumour progression and chemoresistance. Materials and methods The study used paired samples of biopsy and surgical material from 60 patients with breast cancer. The amplification status of 8q was determined using a CytoScan HD Array microarray; complete transcriptomic analysis was performed using a Human Clariom S Assays microarray (Affymetrix, USA). Results It was shown that in 65% of cases, amplification of 8q was preserved in the tumour after neoadjuvant chemotherapy (NAC). NAC significantly enhanced the heterogeneity of the transcriptome between tumours with and without amplification of 8q. Compared with a good response, a poor response to NAC also led to increased heterogeneity of the transcriptome of residual tumours. Eight differentially expressed genes of patients with different amplification status of 8q before and after NAC overlapped. Conclusion Amplification of 8q leads to a significant shift in the level of transcription of a large number of genes after exposure to chemotherapy.

Background: In this study, we examined the CNA-genetic landscape (CNA – copy number aberration) of breast cancer prior to and following neoadjuvant chemotherapy (NAC) and correlated changes in the tumor landscape with chemotherapy efficiency as well as metastasis-free survival. Objective: Breast cancer patients (n = 30) with luminal B molecular subtypes were treated with anthracycline- based therapy. Methods: To study CNAs in breast tumors, microarray analysis was performed. Results: Three effects of NAC on tumor CNA landscape were identified: 1 – the number of CNA-bearing tumor clones decreased following NAC; 2 – there were no alterations in the number of CNA-containing clones after NAC; 3 – the treatment with NAC increased the number of CNA-bearing clones (new clones appeared). All NAC-treated patients who had new tumor clones with amplification (20%) had a 100% likelihood of metastasis formation. In these cases, NAC contributed to the emergence of potential metastatic clones. Our study identified the following loci – 5p, 6p, 7q, 8q, 9p, 10p, 10q22.1, 13q, 16p, 18Chr and 19p – that were amplified during the treatment with NAC and may be the markers of potential metastatic clones. In other patients who showed total or partial elimination of CNA-bearing cell clones, no new amplification clones were observed after NAC, and no evidence of metastases was found with follow-up for 5 years (р = 0.00000). Conclusion: Our data suggest that the main therapeutic result from NAC is the elimination of potential metastatic clones present in the tumor before treatment. The results showed the necessity of an intelligent approach to NAC to avoid metastasis stimulation.

Despite the advantages of neoadjuvant chemotherapy (NACT), associated toxicity is a serious complication that renders monitoring of the patients’ response to NACT highly important. Thus, prediction of tumor response to treatment is imperative to avoid exposure of potential non-responders to deleterious complications. We have performed genome-wide analysis of DNA methylation by XmaI-RRBS and selected CpG dinucleotides differential methylation of which discriminates luminal B breast cancer samples with different sensitivity to NACT. With this data, we have developed multiplex methylation sensitive restriction enzyme PCR (MSRE-PCR) protocol for determining the methylation status of 10 genes (SLC9A3, C1QL2, DPYS, IRF4, ADCY8, KCNQ2, TERT, SYNDIG1, SKOR2 and GRIK1) that distinguish BC samples with different NACT response. Analysis of these 10 markers by MSRE-PCR in biopsy samples allowed us to reveal three top informative combinations of markers, (1) IRF4 and C1QL2; (2) IRF4, C1QL2, and ADCY8; (3) IRF4, C1QL2, and DPYS, with the areas under ROC curves (AUCs) of 0.75, 0.78 and 0.74, respectively. A classifier based on IRF4 and C1QL2 better meets the diagnostic panel simplicity requirements, as it consists of only two markers. Diagnostic accuracy of the panel of these two markers is 0.75, with the sensitivity of 75% and specificity of 75%.

Despite advances in the diagnosis and treatment of breast cancer (BC), the main cause of deaths is resistance to existing therapies. An approach to improve the effectiveness of therapy in patients with aggressive BC subtypes is neoadjuvant chemotherapy (NACT). Yet, the response to NACT for aggressive subtypes is less than 65% according to large clinical trials. An obvious fact is the lack of biomarkers predicting the therapeutic effect of NACT. In a search for epigenetic markers, we performed genome-wide differential methylation screening by XmaI-RRBS in cohorts of NACT responders and nonresponders, for triple-negative (TN) and luminal B tumors. The predictive potential of the most discriminative loci was further assessed in independent cohorts by methylation-sensitive restriction enzyme quantitative PCR (MSRE-qPCR), a promising method for the implementation of DNA methylation markers in diagnostic laboratories. The selected most informative individual markers were combined into panels demonstrating cvAUC = 0.83 (TMEM132D and MYO15B markers panel) for TN tumors and cvAUC = 0.76 (TTC34, LTBR and CLEC14A) for luminal B tumors. The combination of methylation markers with clinical features that correlate with NACT effect (clinical stage for TN and lymph node status for luminal B tumors) produces better classifiers, with cvAUC = 0.87 for TN tumors and cvAUC = 0.83 for luminal B tumors. Thus, clinical characteristics predictive of NACT response are independently additive to the epigenetic classifier and in combination improve prediction.

This review is devoted to a rare in clinical practice, but promising phenomenon of regression distant non-irradiated metastases in combination therapy of cancer patients. R. H. Mole in 1953 suggested introducing the term “abscopal effect” to denote the effect of ionizing radiation “at a distance from the irradiated volume but within the same organism.” Currently, it is a hypothesis in the treatment of metastatic cancer, when there is a regression of untreated areas simultaneously with a decrease in the tumor. After the discovery of immune checkpoint cases were increase with patients treated with check-point blockade (especially lymphocyte associated protein 4, programmed cell death 1/programmed cell death 1 ligand 1) and which have an abscopal effect. This review systematizes works covering the time period from 1969 to 2019, which give cases of the abscopal effect at different localizations. However, abscopal effect is a poorly understood phenomenon. In this review, the authors tried to collect all information about the possible mechanisms of the abscopal effect, possible role in antitumor response and frequency abscopal effect at radio/immunotherapy or combined both.

Increasingly, many researchers are focusing on the sensitivity in breast tumors (BC) to certain chemotherapy drugs and have personalized their research based on the assessment of this sensitivity. One such personalized approach is to assess the chemotherapy's gene expression, as well as aberrations in the number of DNA copies-deletions and amplifications with the ability to have a significant effect on the gene's activity. Thus, the aim of this work was to study the predictive and prognostic significance of the expression and chromosomal aberrations of eight chemosensitivity genes in breast cancer patients.The study involved 97 patients with luminal B breast cancer IIB-IIIB stages. DNA and RNA were isolated from samples of tumor tissue before and after treatment. Microarray analysis was performed for all samples on high-density microarrays (DNA chips) of Affymetrix (USA) CytoScanTM HD Array and Clariom™ S Assay, human. Detection of expression level of seven chemosensitivity genes-The expression of theThus, a complex assessment of the chemotherapy's gene expression is important not only for understanding the heterogeneity and molecular biology of breast cancer but also to obtain a more accurate disease prognosis.

Simple Summary Breast cancer is a genetically heterogeneous disease with different molecular biological and clinical characteristics. The available knowledge about the genetic heterogeneity of the most aggressive molecular subtype of breast cancer—triple-negative—has led to discoveries in drug treatment. Identification of the molecular-genetic phenotype of breast cancer is an important prognostic factor of the disease and allows personalization of the patient’s treatment. Abstract Understanding of the genetic mechanisms and identification of the biological markers of tumor progression that form the individual molecular phenotype of transformed cells can characterize the degree of tumor malignancy, the ability to metastasize, the hormonal sensitivity, and the effectiveness of chemotherapy, etc. Breast cancer (BC) is a genetically heterogeneous disease with different molecular biological and clinical characteristics. The available knowledge about the genetic heterogeneity of the most aggressive molecular subtype of breast cancer—triple-negative (TN)—has led to discoveries in drug treatment, including the use of DNA damaging agents (platinum and PARP inhibitors) for these tumors, as well as the use of immunotherapy. Most importantly, the ability to prescribe optimal drug treatment regimens for patients with TNBC based on knowledge of the molecular-genetic characteristics of this subtype of BC will allow the achievement of high rates of overall and disease-free survival. Thus, identification of the molecular-genetic phenotype of breast cancer is an important prognostic factor of the disease and allows personalization of the patient’s treatment.

Aim: To provide a breast cancer (BC) methylotype classification by genome-wide CpG islands bisulfite DNA sequencing. Materials & methods: XmaI-reduced representation bisulfite sequencing DNA methylation sequencing method was used to profile DNA methylation of 110 BC samples and 6 normal breast samples. Intrinsic DNA methylation BC subtypes were elicited by unsupervised hierarchical cluster analysis, and cluster-specific differentially methylated genes were identified. Results & conclusion: Overall, six distinct BC methylotypes were identified. BC cell lines constitute a separate group extremely highly methylated at the CpG islands. In turn, primary BC samples segregate into two major subtypes, highly and moderately methylated. Highly and moderately methylated superclusters, each incorporate three distinct epigenomic BC clusters with specific features, suggesting novel perspectives for personalized therapy.

We analyzed the results of treatment of 68 patients with NSCLC stage III, of which the main group included 36 patients with perioperative chemotherapy vinorelbin / carboplatin. The control group included 32 patients who underwent only surgical treatment. The correlation of monoresistance and multidrug resistance (MDR) genes expression with clinical and morphological parameters of tumor process and with the frequency of distant metastasis was studied. Results. The three - year relapse-free and overall survival in the study group was 60.0±13.8% and 80.0±8.5 %, in the control group-35.7±25.4% and 50.0±18.9%, respectively. The relationship between the expression genes of the studied MDR genes and monoresistance with the main clinical and morphological parameters of patients and the frequency of metastasis was established. Conclusion. The results of the study show a higher efficiency of combined treatment of NSCLC due to a significant reduction in the number of long-term metastases and local recurrences and, accordingly, improved overall and relapse-free survival. Monoresistance anMDR genes play an important role in NSCLC chemoresistance, so the study of the expression level of these genes is important for the planning of personalized treatment.

Funding Acknowledgements Type of funding sources: None. Introduction. Myocardial infarction (MI) and following heart failure (HF) have various clinical scenarios. However, despite the clinical heterogeneity, the management of MI lacks effective personalized approaches. The response to ischemic injury in the infarct zone and remote myocardium has a definite spatio-temporal sequence and underlies the mechanism of adverse cardiac remodeling. Understanding its myocardial biology remains unclear due to insufficiency of heart tissue molecular and genetic analysis. Although animal models play an important role in data accumulation, they failure to reflect all the compounds of response to ischemic injury and following HF syndrome. Purpose. The purpose of the study was to investigate myocardial expression profile in the infarct zone in comparison to remote myocardium in patients with MI. Methods. The study included 4 patients with fatal MI type 1. All patients died within 48 hours of MI. The post-mortem examination was performed according to country policy. In each case, we obtained myocardial samples from the infarct zone and remote myocardium. Genome-wide gene-level expression was assessed by microarray analysis. We used transcriptome analysis software to analyze and visualize global expression patterns of genes. The analysis included normalization process. Differentially expressed genes (DEGs) were defined as gene-level fold change 2 and adjusted P-value of Results. We studied expression of 21448 genes. A total of 1785 DEGs, including 1692 up-regulated genes and 93 down-regulated genes in the infarct zone, were identified (Figure 1). According to the fold change, the first 10 up-regulated genes were TNFSF10 (TRAIL), SUCLA2, NAE1, PDCL3, OSBPL5, FCGR2C, SELE, CEP63, ST3GAL3, C4orf3. Fold changes for TNFSF10 (TRAIL), SUCLA2, and NAE1 were 19.83 (p = 0.049), 10.68 (p = 0.048), and 10.24 (p = 0.008), respectively. These 3 up-regulated genes were enriched in apoptotic signaling pathways, immune response, angiogenesis, inflammation, tricarboxylic acid cycle, and protein binding. Conclusions. We performed myocardial transcriptomic analysis in patients with MI. DEG analysis clearly distinguishes the infarct zone and remote myocardium. Genes overexpressed in the infarct zone included TNFSF10 (TRAIL), SUCLA2, NAE1. TNFSF10 (TRAIL) regulates vasodilation, angiogenesis, and inflammation. TNFSF10 (TRAIL) regulated effects could be both protective and harmful in ischemic heart disease. The enzyme encoded by SUCLA2 is active in tissues that require a large amount of energy, such as those of the heart, brain, and muscle. Overexpression of NAE1 causes apoptosis through deregulation of NEDD8 conjugation. It is known that the protein encoded by NAE1 binds to the beta-amyloid precursor protein, and it is thought to play a role in the pathogenesis of Alzheimer"s disease. Thus, our pilot study emphasized the potential of translational approach and identified targets to consider for precision diagnostics and therapeutics. Abstract Figure. С1: infarct zone; C2: remote myocardium

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.

Currently, more researchers are attracted by the possibility of assessing the sensitivity of a lung tumor to certain chemotherapy drugs and their personalized choice based on an assessment of this sensitivity. The purpose of this study was to explore the prognostic significance of the level of 8 chemosensitivity genes' expression in patients with non-small cell lung cancer (NSCLC).The study included 59 patients with NSCLC IIB-IIIA stage. RNA was isolated from the surgical material of the tumor and normal lung tissue. The expression level of 8 chemosensitivity genes BRCA1, RRM1, ERCC1, TOP1, TOP2a, TUBB3, TYMS, GSTP1 was evaluated using RT-PCR.Cases with higher metastasis-free survival rates showed a significantly low level of expression of the ERCC1, BRCA1, GSTP1 genes (p=0.0004, p=0.01, p=0.01). In addition, analysis of the overall survival revealed that the highest rates were achieved in patients with overexpression of the ERCC1 gene. The overall survival in these patients was 86%, versus 55% in the other group and the differences were statistically significant (p=0.002). No statistically significant differences were found for the remaining genes.Thus, a comprehensive assessment of the chemosensitivity genes expression is important not only from the point of view of understanding the heterogeneity and complexity in the field of molecular biology of NSCLC, but also for a more accurate prognosis and course of the disease.

This review is devoted to assessing the world’s prevalence of human papillomavirus (HPV) in lung cancer (LC), which is recognized as the etiological factor of cervical cancer. However, data show that this virus is presents not only in gynecological carcinomas, but also in tumors of other organs, in particular, the upper respiratory tract and the digestive tract. The review includes 54 articles. Of all the studies analyzed, 10 of them showed a complete absence of HPV in the biological material in patients with LC. The highest percentage of HPV occurrence by region is observed in Australia, Latin America, followed by the Asian region. Interestingly, the highest occurrence of high oncogenic types (16 and 18) is observed in Asia (35.4%), then in Latin America (33.6%) and Europe (23.6%). Low oncogenic types (6 and 11) are mainly observed in Asia (40.0%). This review is the first such study in Russia. However, the frequency of occurrence of HPV in lung tumor tissue highly variety. This may raise the question of whether HPV really plays a role in the carcinogenesis of lung cancer, which makes further research in this area relevant and promising.

The study included 168 patients with precancerous cervical lesions 37 with low-grade squamous intraepithelial lesions (LSIL), 131 with high-grade squamous intraepithelial lesions (HSIL), and 150 women, who had not abnormal cervical cell changes. All patients underwent full colposcopy assessment, cytological/histological examination, molecular detection and genotyping of high-risk human papillomavirus. Viral load and physical status of HPV-16 DNA was evaluated in cases of mono-infection (n=208). The prevalence of virus-positive cases among the patients with LSIL/NSIL and healthy women was 78.5 and 50.7 %, respectively. The frequency of recurrence in patients with LSIL and HSIL was found to be determined by the physical status of HPV-16. A significant difference in episomal, mixed and integrated forms of HPV-16 between patients with LSIL/HSIL and patients without abnormal cervical cell changes was found (p=0.0002).

Objective: To study the long-term results of the combined treatment of non-small cell lung cancer (NSCLC) using pre-surgery chemotherapy, radical surgery and personalized adjuvant chemotherapy based on the level of monoresistance genes. Methods: Four-year results of treatment of 72 patients of NSCLC II-III stage were analyzed. All patients underwent 2 courses of neoadjuvant chemotherapy (vinorelbine/carboplatin) and surgical treatment. Personalized adjuvant chemotherapy based on the levels of expression of monoresistance genes АВСС5, RRM1, TYMS, TOP1, TOP2α, TUBB3, BRCA1, and ERCC1 was performed in the main group (n=35). Three courses of adjuvant chemotherapy (vinorelbine/carboplatin) were performed in the control group (n=37). Results: In the main group the progression of the disease was observed in 14 out of 35, and in the control group – in 21 out of 37 patients. Relapsefree survival (RFS) in the main group was 60.0% (95% CI: 43.6-74.5), in the control group – 43.2% (95% CI: 28.7-59.1); Log-Rank test χ2 =3,071, р=0,080; RR=1,808 (95% CI: 0.918-3.561). The median RFS in the control group was 27 months (95% CI: 5.7-48.3). The overall survival rate in the main group was 77.1% (95% CI: 61.0-87.9), in the control group – 54.1% (95% CI: 38.4-69.0); Log-Rank test χ2 =2,813, p=0.094; RR=2,024 (95% CI: 0,870-4,709). Conclusion: The developed method of personalized prescribing adjuvant chemotherapy to patients with NSCLC based on the molecular genetic characteristics of the tumor improves relapse-free and overall survival. Keywords: Non-small cell lung cancer , monoresistance genes , personalized chemotherapy.

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 metastasisfree 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.

We aimed to investigate the association between the polymorphism and expression patterns of multiple drug resistance genes (MDR) in breast cancer (BC). The MDR gene expression levels were measured in tumor tissues of 106 breast cancer patients using quantitative real-time PCR. Affymetrix CytoScan™ HD Array chips were used to assess genotypes. Pairwise correlation analysis for ABCB1, ABCC1, ABCC2 and ABCG2 gene expression levels was carried out to reveal co-expression clusters. Associations between SNPs of MDR genes and their preoperative expression levels were assessed using analysis of covariance adjusting for covariates. The SNPs associated with the expression of the ABCB1, ABCC1, ABCC2 and ABCG2 genes before NAC were detected. In addition, 21 SNPs associated with the expression of four ABC-transporter genes and involved in the expression regulation were identified. Validation in an independent sample confirmed the association between the MDR cluster genes and 11 SNPs. Four MDR genes: ABCB1, ABCC1, ABCC2 and ABCG2 were shown to form the functional expression cluster in breast tumor. Further studies are required to discover precise mechanisms of the cluster regulation, thereby providing new approaches and targets to combat the development of the MDR phenotype during chemotherapy.

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.

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.

In 5 patients, a change in the genetic landscape from HPV16 positive high-grade squamous intraepithelial lesion (HSIL) to squamous cervical cancer was traced, which occurred in these patients within the period from 7 months to 5 years after diagnosing HSIL. Materials and Methods: The DNA from paraffin blocks of dysplasia tissue and the tumor that emerged afterwards was used for the study, which was analyzed using the OncoScan FFPE microarray Assay Kit Affymetrix (USA) for genome-wide determination of gene abundance and 65 key somatic driver mutations of oncogenes and tumor suppressor genes. Results: In the study of HSIL material, somatic mutations were observed in 4/5 cases, 18 different somatic driver mutations of the NRAS, EGFR, BRAF, KRAS, IDH2 oncogenes and TP53 suppressor genes were found and almost no CNA-Copy Number Aberration was identified. HSIL malignization is associated with the appearance of secondary driver mutations in oncogenes and tumor suppressor genes and a large number of structural and numerical CNA, the frequency of which correlates with the time of dysplasia malignization into cancer with a very high correlation coefficient r = 0.98, P = 0.004. The trees of dysplasia evolution into tumor were constructed for each patient. Conclusion: According to the results of the work, it is assumed that the initiation of the development of mucosa dysplastic changes is due to primary driver mutations. The formation of secondary driver mutations and CNA are genetic mechanisms of malignant transformation, while the scenarios of the evolution of dysplasia into a tumor are individual and very diverse.

Introduction The phenomenon of non-CSC (cancer stem cell) to CSC plasticity has been previously described in multiple studies and occurs during the ectopic expression of stemness genes such as OCT3, SOX2, KLF4, MYC, NOTCH1, and NANOG. In our opinion, acquiring the ability to ectopically express stemness genes, selected by bioinformatics analysis and, accordingly, non-CSC to CSC plasticity, is due to amplification of genes at the following locations: 3q, 5p, 6p, 7q, 8q, 13q, 9p, 9q, 10p, 10q21.1, 16p, 18chr, 19p. This paper demonstrates the significance of stemness gene amplifications leading to metastasis and stem-like cancer cell activity. Materials and methods In our studies, stemness gene amplifications were determined using the CytoScan HD Array. We studied the association of changes in stemness gene amplifications in tumors with metastasis treated with neoadjuvant chemotherapy (NAC) in 50 patients with breast cancer. We used qPCR to evaluate the expression of 13 stemness genes in tumors before and after NAC in 98 patients with breast cancer. Using primary cultures from the breast tumor of patient St23784/17 with stemness gene amplifications (SOX2, MYC, KLF4, NOTCH1, NODAL) and patient Ti41749/17 without stemness gene amplifications in the tumor, we studied the expression of stemness genes, proliferative tumor stem-cell activity, mammosphere formation, and expression of the CD44 tumor stem cell marker. Results The occurrence of amplifications at regions of stemness gene localization during NAC (22% cases) in residual tumors was associated with a very high metastasis rate (91% cases). Eliminating tumor clones with stemness gene amplifications using NAC (42% cases) led to 100% metastasis-free survival. In patients who developed hematogenic metastases after treatment, the expression of 7/13 stemness genes in the residual tumor after NAC was statistically higher than in patients without metastases. Primary cultures of EpCam+ tumor cells from patients with stemness gene amplifications revealed high proliferative activity. After the 3rd passage, the number of tumor cells increased 30-fold. Due to IL-6, this cell population showed a 2.5-fold increase in the EpCam+CD44hiCD24-/low and 2-fold decrease in the EpCam+CD44lowCD24- subpopulations of tumor stem cells; the formation of mammospheres was also observed. Primary cultures of EpCam+ tumor cells from the patient with no stemness gene amplifications had relatively low proliferative activity. IL-6 caused a 2.3-fold increase in the EpCam+CD44lowCD24- and 2-fold decrease in the EpCam+CD44hiCD24-/low subpopulations of tumor stem cells with no induction of mammospheres. Conclusions The results of this study show that stemness gene amplifications in tumor cells are associated with metastasis and determine their potential stem property activation and non-CSC to CSC plasticity with the formation of EpCam+CD44hiCD24-/low cells, active proliferation, mammosphere formation, and metastasis.

In this prospective study, a new strategy for the prescription of neoadjuvant chemotherapy (NAC) was prospectively tested and depended on the presence of stemness gene amplifications in the tumor before treatment, which in our early studies showed a connection with metastasis. The study included 92 patients with grade IIA–IIIB luminal B breast cancer. Patients underwent a biopsy before treatment, and with the use of a CytoScan HD Array microarray (Affymetrix, Santa Clara, CA, USA), the presence of stemness gene amplifications (3q, 5p, 6p, 7q, 8q, 13q, 9p, 9q, 10p, 10q21.1, 16p, 18chr, 19p) in the tumor was determined. In group 1 (n = 41), in the presence of two or more amplifications, patients were prescribed a personalized NAC regimen. In group 2 (n = 21), if there was no amplification of stemness genes in the tumor, then patients were not prescribed NAC, and treatment began with surgery. Group 3 (n = 30) served as a historical control. The frequency of an objective response to NAC in groups 1 and 3 was 79%. Nonmetastatic survival was found in 100% of patients in group 2, who did not undergo NAC. In patients in group 1, the frequency of metastasis was 10% (4/41). At the same time, in patients in group 3, who received NAC, the rate of metastasis was 47% (14/30). The differences between group 1 and group 3 and between group 2 and group 3 were statistically significant, both by Fisher’s criterion and a log-rank test. The appointment of NAC was most feasible in patients with clones with stemness gene amplifications in the primary tumor, while in the absence of amplifications, preoperative chemotherapy led to a sharp decrease in metastasis-free survival. This strategy of NAC prescription allowed us to achieve 93% metastatic survival in patients with breast cancer.

A significant role in the development of lung tumor resistance to drug therapy play so called mono resistance genes that determine resistance/sensitivity of tumor cells to distinct chemotherapeutic agents, they include BRCA1, RRM1, ERCC1, TOP1, TOP2a, TUBB3, TYMS, ABCC5 genes. It is shown that the use of these biomarkers as a criteria to appoint the adequate postoperative chemotherapy is associated with the forecast. However in the course of neoadjuvant chemotherapy change the expression profile of these genes can occur, which can lead to misinterpretation of results. In this regard perspective is the development of new relevant prognostic factors, which take into account occurred molecular genetic alterations in lung tumors after preoperative therapy. We presented the results of the combined treatment of 52 patients with NSCLC IIA - IIIB stage, based on the analysis of chemotherapy resistance/sensitivity gene expression for appointment the suitable drugs. It was found that the lack of expression of ERCC1 gene in lung tumor derived after neoadjuvant chemotherapy is associated with high rates of disease-free survival (P. = 0,00913). Low level expression of RRM1 gene (less than 0.5) is also associated with high rates of patient's survival (log-rank test P. = 0,01808), while a high level is a marker of poor prognosis. It is found that the combination of enhanced expression (>0.5) of any two or three genes: RRM1, ABCC5, TYMS, are the indicators of poor disease-free survival. We have shown that expression of ERCC1 gene is the independent prognostic factor. At zero ERCC1 expression in lung tumors, regardless of high or low level of expression of RRM1, ABCC5, TYMS genes, a high recurrence-free survival is observed. Thus, the data suggest the prognostic significance of the expression of ERCC1, TUBB3, RRM1, ABCC5 and TYMS genes in the lung tumor after neoadjuvant chemotherapy.

Our previous studies have shown that BRCA1 gene deficiency caused by changes in the tumor such as low expression, deletion, loss of heterozygosity, etc., can be associated with the effectiveness of chemotherapy and the disease prognosis. However, even in the absence of these factors, the effectiveness of taxotere therapy was variable. This may be due to the availability of another BRCA1 gene somatic changes in the tumor tissue and their determination will help to define the personalize treatment strategy for each breast cancer patient. Here we investigated the entire spectrum germline and somatic mutation of coding region of the BRCA1 gene in tumor tissue. We obtained that absence of BRCA1 somatic mutation was associated with objective response on taxotere in the preoperative period. Germline mutations BRCA1: c.4837A>G (p.Ser1613Gly), c.999T>C (p.Ser333=), c.3548A>G (p.Lys1183Arg), c.3113A>G (p.Glu1038Gly), c.2612C>T (p.Pro871Leu), c.2311T>C (p.Leu771=), c.2082C>T (p.Ser694=) were associated with non-objective response on neoadjuvant chemotherapy (NAC), furthermore effect of chemotherapy was more than 80% without of these mutations. During chemotherapy, 13% of patients showed the appearance of 5 new BRCA1 mutations in the tumor and this is associated with a non-objective response to NAC by taxotere. Overall, our results suggest that it makes sense to take into account not only identified germline mutations, but also somatic changes in the BRCA1 gene when appointment taxotere.

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. A search was conducted to a depth of 29 years in the PubMed, Web of Science, Scopus, databases. The review includes 95 articles. 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

Background According to our previous studies, the presence of amplifications of stem genes can lead to their ectopic expression and this is associated with an increased activity of tumor stem cells in these patients. This leads to a high aggressiveness of the tumor and the development of metastatic disease. The aim was to evaluate the prognostic significance of the presence of amplifications of stem genes and their expression in patients with early breast cancer (BC). Methods The study included 28 patients with T1NxM0 BC. We used surgical specimens, including formalin-fixed paraffin-embedded archive materials, for 8 patients. A microarray analysis was performed on high-density DNA chips from CytoScanHDArray to assess the status of copy number aberration (CNA) of stem genes locus. Gene expression was assessed using RT-qPCR. Results CNA analysis of the studied tumors of patients without chemotherapy showed that 17/18 patients without metastases did not have two or more amplifications of chromosomal regions. Ten patients had visceral metastases. In 9/10 of these patients in the primary tumor there were two or more amplifications of the stem genes locus. Two or more amplifications of stem genes locus were found in 12 patients with stage I. Hematogenous metastases did not develop in all patients. Comparison of metastasis-free survival rates in groups of patients with 1 or without amplifications and with two or more amplifications showed statistically significant differences (P = 0.01). Conclusion Our studies have shown that the presence of clones with two or more amplifications of stem gene in patients with BC T1NxM0 has a significant prognostic value and determines an unfavorable prognosis for distant metastasis., Graphical Abstract

The involvement of human papillomavirus in carcinogenesis of colorectal cancer is a contentious issue. The presented meta-analysis was performed to systematize the currently available research results on the matter. The analysis was based on the data from 19 studies to assess the association of HPV infection with colorectal cancer. According to the obtained data, researchers determined the statistically significant level of HPV infection in tumor tissue of CRC and the resulting relative risk of developing CRC with HPV infection to be RR (95% CI) = 2.97 (1.42–6.22) with p = 0.0039.

In breast cancer, the tumor microenvironment plays a critical role in the tumor progression and responses to therapy. Tumor-associated macrophages (TAMs) are major innate immune cells in tumor microenvironment that regulate intratumoral immunity and angiogenesis by secretion of cytokines, growth factors as well as chitinase-like proteins (CLPs), that combine properties of cytokines and growth factors. YKL-39 is a chitinase-like protein found in human and absent in rodents, and its expression in TAMs and role in breast cancer progression was not studied to date. Here for the first time we demonstrate that YKL-39 is expressed on TAMs, predominantly positive for stabilin-1, but not by malignant cells or other stromal cells in human breast cancer. TGF-beta in combination with IL-4, but not IL-4 alone was responsible of the stimulation of the production of YKL-39 in human primary macrophages. Mechanistically, stabilin-1 directly interacted with YKL-39 and acted as sorting receptor for targeting YKL-39 into the secretory pathway. Functionally, purified YKL-39 acted as a strong chemotactic factor for primary human monocytes, and induced angiogenesis in vitro. Elevated levels of YKL-39 expression in tumors after neoadjuvant chemotherapy (NAC) were predictive for increased risk of distant metastasis and for poor response to NAC in patients with nonspecific invasive breast carcinoma. Our findings suggest YKL-39 as a novel therapeutic target, and blocking of its activity can be combined with NAC in order to reduce the risk of metastasis in breast cancer patients.

Neoadjuvant chemotherapy (NAC) is intensively used for the treatment of primary breast cancer. In our previous studies, we reported that clinical tumor response to NAC is associated with the change of multidrug resistance (MDR) gene expression in tumors after chemotherapy. In this study we performed a combined analysis of MDR gene locus deletions in tumor DNA, MDR gene expression and clinical response to NAC in 73 BC patients. Copy number variations (CNVs) in biopsy specimens were tested using high-density microarray platform CytoScanTM HD Array (Affymetrix, USA). 75%-100% persons having deletions of MDR gene loci demonstrated the down-regulation of MDR gene expression. Expression of MDR genes was 2-8 times lower in patients with deletion than in patients having no deletion only in post-NAC tumors samples but not in tumor tissue before chemotherapy. All patients with deletions of ABCB1 ABCB 3 ABCC5 gene loci--7q21.1, 6p21.32, 3q27 correspondingly, and most patients having deletions in ABCC1 (16p13.1), ABCC2 (10q24), ABCG1 (21q22.3), ABCG2 (4q22.1), responded favorably to NAC. The analysis of all CNVs, including both amplification and deletion showed that the frequency of 13q14.2 deletion was 85% among patients bearing tumor with the deletion at least in one MDR gene locus versus 9% in patients with no deletions. Differences in the frequency of 13q14.2 deletions between the two groups were statistically significant (p = 2.03 × 10(-11), Fisher test, Bonferroni-adjusted p = 1.73 × 10(-8)). In conclusion, our study for the first time demonstrates that deletion MDR gene loci can be used as predictive marker for tumor response to NAC.

High activity of enzyme TOP2a in tumor cells is known to be associated with sensitivity to anthracycline chemotherapy, but 20% of such patients do not show clinical response. Tumor microenvironment, including tumor-associated macrophages (TAM), is an essential factor defining the efficiency of chemotherapy. In the present study, we analyzed the expression of M2 macrophage markers, YKL-39 and CCL18, in tumors of breast cancer patients received anthracycline-based NAC. Patients were divided into two groups according to the level of doxorubicin sensitivity marker TOP2a: DOX-Sense and DOX-Res groups. Expression levels of TOR2a, CD68, YKL-39 and CCL18 genes were analyzed by qPCR, the amplification of TOR2a gene locus was assessed by the microarray assay. Clinical and pathological responses to neoadjuvant chemotherapy were assessed. We found that the average level of TOP2a expression in patients of DOX-Sense group was almost 10 times higher than in patients of DOX-Res group, and the expression of CD68 was 3 times higher in the DOX-Sense group compared to DOX-Res group. We demonstrated that expression levels of M2-derived cytokines but not the amount of TAM is indicative for clinical and pathological chemotherapy efficacy in breast cancer patients. Out of 8 patients from DOX-Sense group who did not respond to neoadjuvant chemotherapy (NAC), 7 patients had M2+ macrophage phenotype (YKL-39+CCL18− or YKL-39−CCL18+) and only one patient had M2− macrophage phenotype (YKL-39−CCL18−). In DOX-Res group, out of 14 patients who clinically responded to NAC 9 patients had M2− phenotype and only 5 patients had M2+ macrophage phenotype. Among pathological non-responders in DOX-Sense group, 19 (82%) patients had M2+ tumor phenotype and only 4 (18%) patients had M2− phenotype. In DOX-Res group, all 5 patients who pathologically responded to NAC had M2 phenotype (YKL-39−CCL18−). Unlike the clinical response to NAC, the differences in the frequency of M2+ and M2− phenotypes between pathologically responding and non-responding patients within DOX-Sense and DOX-Res groups were statistically significant. Thus, we showed that in patients with breast cancer who received anthracycline-containing NAC the absence of clinical response is associated with the presence of M2+ macrophage phenotype (YKL-39-CCL18 + or YKL-39 + CCL18-) based on TOP2a overexpression data.

To evaluate the relapse-free and overall survival of HPV-positive patients with regard to the physical status of type 16 HPV and of HPV-negative patients with primary CC. As a main result of the study the predictive value of the physical status of type 16 HPV was determined for relapse-free and overall survival of patients with CC. Episomal form of the virus is a favorable predictive factor. Integrated form of the virus is a severely unfavorable predictive factor and survival of such patients is significantly lower, than for HPV- patients and patients with mixed form of the virus. The results of the research are data on survival of patients with CC depending on the physical status of the virus (for HPV+ patients) and of patients with HPV-negative cancer.

e14655 Background: Neoadjuvant chemotherapy (NAС) is one of the treatment options for breast cancer (BC). However, chemotherapy is known can cause intratumoral changes that increase the risk of metastasis. We have previously found that the appearance of new amplifications in the chromosomal regions harboring stemness genes (3q, 5p, 6p, 7q, 8q, 9p, 9q, 10p, 10q21.1, 13q, 16p, 18Chr, 19p) is associated with the development of hematogenous metastases in 100% of cases. In our study, we evaluated the prognostic significance of amplifications stemness genes in primary BC depending on the NAC response. Methods: The study included 104 patients with stage II-III luminal B (Her2Neu -) breast cancer. All patients received 4-8 courses of NAС followed by surgery and hormone therapy. The follow-up period was 4-10 years. Amplifications in primary tumor DNA were determined using Affymetrix high density microarrays. Metastasis-free survival was estimated using the Kaplan-Meier method. Results: Zero or only 1 amplification was identified in tumor tissue of 42 patients (41%) (group 1). Two or more amplifications were identified in tumor tissue of 60 patients (59%) (group 2). We evaluated metastasis-free survival separately in each group, depending on the NAС response. It was found that in group 1, the median survival time was 122 months in cases with partial or complete regression (PR + pCR, and 63 months in cases with stable disease or disease progression (S + P), p > 0.05. In group 2, the median survival of patients with PR + pCR was not reached, and it was 63 months in patients with S + P, p = 0.025. Conclusions: Achievement of partial or complete regression in breast cancer patients, whose primary tumors displayed 2 or more amplifications of stemness genes, was associated with the increased rates of metastasis-free survival and can be considered as a positive prognostic criterion. However, the response to NAC did not impact survival of patients with 0-1 amplification of stemness genes.

Most current research is limited by only germinal mutations of the BRCA1 gene (more often 5382insC) and the number of studies, which characterize various somatic alterations of the BRCA1 gene in a tumor, namely the expression of this gene and its correlation with the efficiency of chemotherapy, which is scarce. Taking into account the data on the connection between the genetic mutation of BRCA1 with the high efficiency of the platinum medication one may suggest that the expression of the BRCA1 gene is also associated with the high sensitivity of the tumor to the platinum medication. Aim: to evaluate the correlation between the expression of the BRCA1 gene in a breast tumor with the neoadjuvant chemotherapy (NACT) efficiency. The research included 86 patients with BC. We evaluated the expression of BRCA1 in the tumor material before and after NACT. We established that objective response to NACT is connected with a high level of BRCA1 in the general group of patients (p = 0.01) and in case of docetaxel mono...

The research involved 80 patients diagnosed with breast cancer (BC). Each patient had their tumor biopsy material sampled before their treatment. We studied the tumor tissue using the CytoScan HD Array (Affymetrix, USA) microarray to evaluate the CNA landscape. We studied the frequency of segmental and numerical CNA occurrence, their association with the efficiency of neoadjuvant chemotherapy (NAC). We found that the biggest number of amplifications (with frequency over 60%) were found on in the following locuses; 1q32.1 1q32.3, 1q42.13, 1q42.2, 1q43. The biggest frequency of deletions (more than in 58% of the patients) was found in these locuses: 16q21, 16q23.2, 16q23.3, 17p12, 17p13.1. However, we found the locuses with full absence of segmental chromosome anomalies. We observed trisomy most frequently in the 7, 8, 12, and 17 chromosomes, and monosomy in the 3, 4, 9, 11, 18, and X-chromosomes. We demonstrated the connection between the high frequency of cytobands with CNA in the patients’ tumors and the efficiency of NAC. We also identified the cytobands, whose CNA are linked to the response to NAC.

In this experiment we studied oncologic safety of model implants created using the solution blow spinning method with the use of the PURASORB PL-38 polylactic acid polymer and organic mineral filler which was obtained via laser ablation of a solid target made of dibasic calcium phosphate dihydrate. For this purpose the implant was introduced into the area of Wistar rats’ iliums, and on day 17 after the surgery the Walker sarcoma was transplanted into the area of the implant. We evaluated the implant’s influence on the primary tumor growth, hematogenous and lymphogenous metastasis of the Walker sarcoma. In comparison with sham operated animals the implant group demonstrated significant inhibition of hematogenous metastasis on day 34 after the surgery. The metastasis inhibition index (MII) equaled 94% and the metastases growth inhibition index (MGII) equaled 83%. The metastasis frequency of the Walker sarcoma in para aortic lymph nodes in the implant group was not statistically different from the control frequency; there was also no influence of the implant on the primary tumor growth noted. In case of the Walker sarcoma transplantation into the calf and the palmar pad of the ipsilateral limb to the one with the implant in the ilium, we could not note any attraction of tumor cells to the implant area, i.e. stimulation of the Walker sarcoma relapse by the implant. Thus, the research concluded that the studied implant meets the requirements of oncologic safety.

Background There are numerous evidences suggesting that tumor evolution follows the laws of Darwinian evolution, whereby individual tumor cell clones have private genetic aberrations, including chromosomal abnormalities. The combined effect of genetic instability and differential selective pressures of the microenvironment and chemotherapy can result in the creation of new tumor clones (Navin et al., 2011; Ng et al., 2012). The aim of this study is to show breast tumor clonal evolution during neoadjuvant chemotherapy (NAC) using microarray analysis. Material and methods Breast cancer patients ( n = 26) with stage IIA to IIIC (T1-4N0-3M0), were treated with NAC (FAC or CAX regimens). DNA was extracted from 26 samples of tumor tissue derived before or after NAC using QIAamp DNA mini Kit (Qiagen, Germany). Copy Number Aberrations (CNA, deletions and amplifications, or Loss and Gain, respectively) and number of mutant clones were detected in pre- and post-NAC tumor samples using the high density microarray platform Affymetrix (USA) CytoScanTM HD Array. This study was approved by Tomsk Cancer Research Institute review board. Results We have revealed that 19% (5/26) of patients during the NAC showed the decrease in the number of mutant clones and CNA frequency right up to their complete elimination (genetic regression) at one case. In 7 (27%) cases chemotherapy had no any effect on number of mutant clones and the frequency of CNA in tumor. In the tumors of 10 patients the elimination of some mutant clones as well as the formation of new clones with deleted genetic material occurred under the influence of chemotherapy. 6 patients have demonstrated the appearance of new tumor clones with gene amplifications which were associated with the development of metastases in 83% of cases (5/6). All other patients ( n = 21) who has not acquired the new tumor clones with Gain function mutation after NAC did not manifest distant metastasis in 5-year follow-up (Kaplan–Meier, p = 0.00001 Log-rank test). Conclusion The first time evidence is presented that the formation of new tumor clones may occur during the NAC. Metastasis of breast cancer is associated with the appearance of new clones with DNA amplifications. Detection of these clones allow getting new prognostic factor in breast cancer. The study was supported by the Russian Foundation for Basic Research – Russia (Project 15-04-03091).

Our previous research establishes that changes of expression of the ATP-binding cassette genes family is connected with the neoadjuvant chemotherapy effect. However, the mechanism of regulation of resistance gene expression remains unclear. As many researchers believe, single nucleotide polymorphisms can be involved in this process. Thereupon, microarray analysis is used to study polymorphisms in ATP-binding cassette genes. It is thus found that MDR gene expression is connected with 5 polymorphisms, i.e. rs241432, rs241429, rs241430, rs3784867, rs59409230, which participate in the regulation of expression of own genes.

The real-time PCR method is used to study scrapings of cervical epithelium and outer portion of the cervix in 116 patients aged 24–79 years with stage I–IV primary cervical cancer. The comprehensive survey included colposcopy, cytological and histological analysis, detection and genotyping of high-risk human papillomavirus. In 84 patients (72.4%) the presence of human papillomavirus (HPV) of high carcinogenic risk (HCR) is found, in 32 patients (27.6%) the presence of the virus has not been inspected in the tumor. A significant decrease in the survival rate as well as the prevalence of the worst prognosis for patients with HPV-negative cervical cancer are shown.