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.

MALAT1 Long Non-coding RNA and Its Role in Breast Carcinogenesis.

Our genome consists not only of protein-coding DNA, but also of the non-coding part that plays a very important role in the regulation of all cellular processes. A part of the non-coding genome comes with non-coding RNAs (ncRNAs), and disruption of the functional activity of these RNAs may be associated with oncogenesis in various cancer types. There exist two types of ncRNAs: small and long non-coding RNAs, which are classified according to their transcript length. Long non-coding metastasis-associated lung adenocarcinoma transcript 1, MALAT1 RNA (NEAT2), is a long non-coding RNA of particular interest. The aforementioned transcript takes part in the regulation of numerous cellular processes and pathogenesis of different malignant tumors, including breast tumors. This review focuses on experimental and clinical studies into the role of MALAT1 in carcinogenesis and the progression of breast cancer.

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.

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.

[Viral co-infection with head and neck tumors]. / Virusnaya koinfektsiya pri opukholyakh golovy i shei.

The review is devoted to assessing the prevalence of human papillomavirus (HPV) in combination with other viral agents for head and neck tumors (HNT). HPV is recognized as an etiological factor in the development of cervical cancer, but there is evidence that it may be involved in carcinogenesis in other locations, in particular the upper respiratory tract. However, HPV is not the most important factor in tumor growth and progression. Recently, many researchers have reported the presence of concomitant co-infection, affecting tumor progression. Of all the studies analyzed, only 3 studies showed the absence or low rates of co-infection in HNT: from the Czech Republic (0%), China (0.6%) and Japan (3%). Most often, HPV infection was detected together with the Epstein-Barr virus (EBV) - from 12.5 to 34.1% of cases. In Russia, the prevailing combination of viral co-infection was a combination of EBV and cytomegalovirus (9.5%) and a combination of EBV and herpes simplex virus (6.7%). Thus, the degree of incidence of HPV in HNT varies greatly, and the mechanisms of coinfection are poorly understood, which raises the question of whether HPV and concomitant infection can be involved in tumor progression. This makes further research in this direction relevant and promising.

Changes in the genetic landscape during the malignization of high grade squamous intraepithelial lesion into cervical 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.

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.

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.