Characteristics of immune-active and immune-silent phenotypes of early-stage cervical carcinoma as revealed by transcriptome sequencing

Molecular classification, immuneheterogeneity, and the existence of distinct immunophenotypes of virus-associated cervical cancer (CeCa) remain as-yet weakly explored issues, and this is particularly true of its earliest clinical stages and pre-invasive forms: cervical intraepithelial neoplastic (CIN) lesions. The goal of the study was to identify transcriptomic landscapes of invasive CeCa at its initial progression that differ substantially in their immune-related characteristics, patterns of signaling pathways and composition of the microenvironment. Transcriptome profiling was carried out using RNA-sequencing on Illumina platform. A panel of surgical-derived tissue samples comprised human papillomavirus-positive CIN grade 1-3, cancer of FIGO IA1-IIB stages, and morphologically normal epithelium. Transcriptomic profiles were analyzed with the use of bioinformatics tools, such as gene set enrichment (GAGE) for signaling pathways, xCell enrichment for cell composition identification, and PREDA positional analysis of genomic data. Hierarchical clustering revealed heterogeneity of transcriptomic profiles within the early-stage CeCa, namely, the existence of two clusters of tumor samples and three functional patterns of genes showing coordinately altered expression. Pathway enrichment analysis on genes differently expressed between the two clusters/groups of CeCa samples (‘A' and ‘B') and CIN (group ‘C') suggested that invasive tumor progression in groups ‘A' and ‘B' might rely on immunologically dissimilar mechanisms. xCell analysis confirmed heterogeneity of changes in the abundancies of cell populations when comparing CeCa sample groups and CIN, along with differences in immune and stromal scores. PREDA demonstrated that these transcriptomic differences could be linked to different chromosomal regions and co-localized with particular gene families and potentially the reported virus integration hotspots. Overall, the existence and detectability of different transcriptomic immune-based phenotypes of invasive CeCa at its initial stages of progression is shown, which may provide new options to broaden the knowledge and applicability of target and immune anti-cancer therapy

ANALYSIS OF APOPTOSIS FACTORS IN PATIENTS WITH PREINVASIVE AND INVASIVE CERVICAL CANCER

This article assesses the disturbance degree of apoptotic program in patients with preinvasive and invasive cervical cancer by investigating the expression level of genes of caspases-3, -6, -8 и -9 in mononuclear cells of periphery blood and in tumor tissue on the two regulating levels – on mRNA level (transcriptional) and proteolytic activity (post transcriptional). 75 patients with stage III of cervical intraepithelial neoplasias (CIN) III  (middle age of 32,9 ± 7,4),45 patients with stage IA (31,3 ± 6,0), 21 – with stage II (43,6 ± 13,2), 15 – with stage III–IV (46,9 ± 11,1) have been examined. The control group has been formed from 30 almost healthy donors without any cervical pathology and papilloma human virus (control 1) and 30 patients with a preinvasive and microinvasive cervical cancer (control 2). It has been found that in proportion of progress of cervix cancer, the membranous expression of CD95 increases in MPB – fraction (peripheral blood monocytes) when the a CIN and initial stages of cervix cancer, more than two times. Herewith number CD95+-lymphocytes is positively correlated with stage of cervical cancer (r = 0,91; R2  = 0,82; p << 0,01). It has been found out that the activity gain of caspase-8 (r = 0,92; R2  = 0,86; p << 0,01), caspase-6 (r = 0,77; R2 = 0,59; p << 0,01) and reduction activity of caspase-9 (r = –0,60;  R2 = 0,36; p < 0,01) in mononuclear cells of peripheral blood pointed out on the sensitivity increase to Fas-induced apoptosis. Opposite, in tumor tissue, beginning from CIN stage III, apoptosis-resistant phenotype is formed, it were defined by the expression of caspase-3 (r = –0,72; R2 = 0,52, p < 0,01), caspase-6 (r = –0,59; R2 = 0, 38; p < 0,01) и caspase-9 (r = –0,67; R2 = 0,45; p < 0,01) by mRNA level and proteolytic activity. It has been shown, that the cervical cancer development is accompanied by multilateral disturbances of apoptotic processes, which are realized in decreased function of caspases and multilateral resistance of tumor cells in against signals of apoptosis. The obtained results give an opportunity to examine the genes of caspase as a probable prospective biomarkers in complex diagnostic of a CIN and early diagnosis of a cervical cancer (in combination with morphological criteria and other molecular markers of viral origin

PREVENTION OF CANCER OF THE CERVIX UTERI AT AN ANTENATAL CLINIC

Cervical cancer (CC) morbidity is analyzed on the basis of the data of the Karelian cancer register over the period 1998-2007. During this period, 816 cases of CC were registered and 126 were found at an antenatal clinic (AC). Its early detection rate was ascertained to be 96% during screening at the AC. A comprehensive examination was made in 1742 women with various cervical diseases, of them 37.5% were infected with human papillomavirus (HPV). High-grade dysplasia and carcinoma in situ were diagnosed in 6.6% of the HPV-infected patients. Large-scale screening for HPV infection and pretumor disorders with their further treatment will aid in reduc- ing CC morbidity and mortality rates

Clinical efficiency of panavir in therapy of chronicle papillomavirus infections of cervix uteri

This research is devoted to determination of the clinical efficacy of Panavir in the combined therapy of the uterine cervix diseases associated with human papillomavirus (HPV). The article presents data of the complex examination of 59 patients. Patients with diagnosed 16th, 18th, 31st, 33rd types of HPV underwent destructive methods of treatment of the cervix followed by Panavir. The efficacy of Panavir was estimated by PCR in 3, 6 and 12 months from the beginning of treatment and it was 84,7%. Antiviral therapy permits to prevent recurrence of papillomavirus infection of the cervix uteri

THE ROLE OF CYTOLOGICAL AND VIROLOGICAL STUDIES IN SECONDARY PREVENTION OF CERVICAL CANCER

Abstract. This article is devoted to the role of cytological and virological screening in the secondary prevention of cervical cancer. Five hundred and fifty two cases of carcinoma in situ (of cervical cancer) and 1248 cases of invasive cervical cancer over a period of 15 years were analyzed. This period has separated into three stages: I — 1998–2002, II — 2003–2007, III — 2008–2012 years. Cervical cancer morbidity in Karelia is reported to increase tripled from 10.5 to 30.5 causes per 100 thousand women population. The excess incidence has identified among young women in reproductive age including an age group < 30 year. It has been noticed that the detection rate of carcinoma in situ was statistically significant increased from 24.34±9.2% in 1998–2002 to 62.8±20.9% in 2008–2012 years. There are three different level regional groups of early cervical cancer detection (0–I–II stage) in the Republic of Karelia. Despite of the fact, that the cervical cancer is increas-ing significantly, there are a good results of its early diagnostics, thanking to the cytological and virological screening in Karelia

THE CHANGES OF OF CELLULAR IMMUNITY PARAMETERS IN PATIENTS WITH PREINVASIVE AND MICROINVASIVE CERVICAL CANCER BEFORE AND AFTER TREATMENT

Abstract. The comparative study of immunocompetent cells’ phenotype was performed in patients with the preinvasive and microinvasive cervical cancer before and after the treatment. Besides, the study of importance of selected cellular immunity indices as a predicitive factors of effective surgical treatment in a combination with immunotherapy (the study group) in comparison with a surgical treatment only (the control group) have been conducted. The true numerical normalization of subpopulation composition of peripheral blood lymphocyte has been determined including the expression level of suppressor lymphocytes molecular markers (FOXP3 и TGF-β1) and the expression level of CD95-marker in a study group in comparison with a control group. Moreover, true decrease of HPV (human papillomavirus) — positive patients (1.7%) and the absence of E7 oncoprotein in the study group have been discovered

The body’s immune response in the induction and progression of cancer of the cervix uteri: possible mechanisms

Human papillomavirus (HPV) that is a main cause of cancer of the cervix uteri (CCU) has immunogenic properties, i.e. an abilityto activate antiviral immunity responses as adaptive HPV-specific and innate ones. For this reason, despite multiple mechanisms generated by HPV to avoid immunity responses, the human body can eliminate the infection in most cases. At the same time, CCU results from the combined influence of many factors of different nature, among which the factors that impair the normal course of an immune response are of vital importance.This review describes the major factors and mechanisms, which promote the establishment of persistent HPV infection and the progression of dysplasia to cancer, on the one hand, and allow the tumor cells in CCU to restrict the body’s immune reactions, on the other Immune disorders induced by the virus and/or tumor cells are considered at both local and systemic levels. Particular emphasis is placed on the molecular mechanisms that can change the population composition and functional activity of leukocytes and the cytokine profile of cells and can form the tumor suppressor microenvironment

Early response genes in the pathogenesis of cancer of the cervix uteri: a review

Early response genes are a group of proto-oncogenes that are the first to be activated in cell stimulation with different growth factors and to be involved in the regulation of cell proliferation and differentiation. Large amount of information supporting that altered expression of these genes is one of the central and earliest events of carcinogenesis has been accumulated. In this connection, it is promising to use early response genes as diagnostic and prognostic markers for the detection and combination therapy of cancer of the cervix uteri, one of the most common gynecological malignancies characterized by high mortality rates and difficulties in early diagnosis. The theoretical basis for these promises is the found mechanisms for the interaction of early response genes with human papillomavirus genome, the main cause of cervix uteri cancer