VALIDATION OF A PANEL OF BIOMARKERS ASSOCIATED WITH AGGRESSIVE PHENOTYPE OF ENDOMETRIOID CARCINOMA OF ENDOMETRIUM.

AIM: To evaluate the prognostic significance of a panel of biomarkers for the identification of a highly malignant molecular subtype of endometrioid carcinoma of the endometrium (ECE). MATERIALS AND METHODS: The expression of a number of markers (CD24, CD44, E2F1, FOXP3, Her2/neu, p21WAF1/CIP1, p53, ß-catenin, vimentin, Е-cadherin, с-Myc, cyclins D1 and Е1) was determined by the immunohistochemical method in the samples of resected tumors of 127 patients with ECE of I-II stage. The Kullback method and the PanelomiX web tool were used to assess the informativeness and identify the aggressive subtype of ECE. The associative relationships of the studied markers were determined using the STRING v11 database. RESULTS: The study of the prognostic significance of a number of biomarkers in ECE has revealed the informativeness, high specificity and sensitivity (> 95%) of the Ñ€53+FOXP3-c-Myc+ phenotype, which is associated with a more aggressive tumor process. Bioinformatics analysis confirmed the correlative relationships between p53, FOXP3 and c-Myc, which are significant prognostic markers associated with cancer progression in ECE patients. CONCLUSIONS: The identified molecular phenotype of ECE (р53+FOXP3-c-Myc+) has differential and prognostic significance and objectively reflects a highly malignant subtype of this form of cancer.

Molecular phenotype of high-grade endometrioid carcinoma of the endometrium.

BACKGROUND: Prognosis of the course of tumor progression is one of urgent problems of clinical oncology. A relevant specificity of endometrial cancer is its clinical polymorphism within the same histological type of the disease. The search for molecular-biological features associated with the aggressive phenotype of endometrioid carcinomas is indisputably urgent. AIM: To study molecular-biological features of endometrioid carcinoma of the endometrium (ECE) and to identify the molecular subtype of tumors with high potential of malignancy. MATERIALS AND METHODS: Surgical specimens of 127 patients with EC, stages I-II, aged 36-72 (the average age - 59.3 ± 3.2) were studied using morphological and immunohistochemical methods. The multivariant analysis with the Kullback's informative measure and PanelomiX were used to estimate the significance of the expression of specific biomarkers. RESULTS: The expression of a complex of multifunctional markers was evaluated in ECE cells of different malignancy stage: p53, FOXP3, p21WAF1/CIP1, р16INK4a, E2F1, cyclins Е and D1, Her2/neu, с-Myc, Е-cadherin, ß-catenin, vimentin, CD44, CD24. A triad of biomarkers with threshold expression levels was determined (р53 < 45%; FOXP3 > 14%; с-Myc < 10%). The high expression of oncogene c-Myc and oncosuppressor p53 along with the low level of FOXP3 in tumor cells of ECE was associated with high proliferative potential, low differentiation grade, and deep invasion of a tumor into the myometrium. CONCLUSIONS: The molecular phenotype of ECE, most informative in terms of specificity and sensitivity (95%) - р5highFOXP3lowc-Mychigh, was first characterized, which would help identify a high-grade subtype of this cancer form.

Overexpression of the mitochondrial ribosomal protein S18-2 in the invasive breast carcinomas.

BACKGROUND: Recent studies allow to consider the mitochondrial ribosomal protein S18-2 (MRPS18-2, S18-2) as a potential oncoprotein, which suggests the need for further characterization of its expression in tumors of different genesis including breast cancer (BC). The aim of the study was to analyze the expression of the S18-2 protein in BC of luminal A and basal subtypes. MATERIALS AND METHODS: Operational material of BC patients stage І-ІІ (luminal A subtype, n = 30, and basal subtype, n = 10) was studied with the use of morphological, immunohistochemical, statistical and bioinformatic methods. RESULTS: Using the immunohistochemical analysis, we found that the S18-2 protein showed the nuclear signal in 66.7% of luminal A subtype BC samples and 80.0% of basal subtype BC samples. The variability of the S18-2 expression in both the luminal A and basal subtypes of BC was revealed. Noteworthy, the number of cells expressing S18-2 in high-proliferating tumors of luminal A and basal subtype is significantly higher than in tumors with a low proliferative potential (p < 0.05). In 10 samples of luminal A subtype, the nuclear S18-2 signal was higher than median value. Moreover, the S18-2 protein was overexpressed in 4 out of such 10 samples. Metastases in the lymph nodes were found in 3 out of 4 patients with the stage II BC, low differentiation grade of the tumor and high proliferative activity. The bioinformatic analysis confirms our preliminary findings that the trend for increasing expression of the S18-2 protein in tumors correlates with the aggressiveness of malignant BC. CONCLUSION: The S18-2 protein may be a marker of cancer aggressiveness in BC patients.

Phenotypic features of endometrial tumors in patients with family history of cancer.

AIM: To determine the peculiarities of expression of a number of proteins-regulators of the cell cycle in endometrial cancer (EC) cells in patients with a family history of oncological pathologies. PATIENTS AND METHODS: 95 EC patients (stage І-ІІ) were included into the study. Clinical-genealogical analysis was performed. 54 patients (group I) had healthy relatives, and in families of 41 patients (group II) an aggregation of malignant tumors of different genesis (mainly tumors of the gastrointestinal tract and the female reproductive system) was recorded. p53, p21WAF1/CIP1, p16INK4a, and Ki-67 were assessed immunohistochemically in the surgical samples. RESULTS: In the majority of patients, both from group I and II, moderately differentiated tumors were observed (in 38.9 and 46.3% of cases, respectively), mainly with deep myometrium invasion (64.8 and 58.5% of cases, respectively). In EC patients from group II, a significantly higher number of p16INK4a-positive cells (17.7 ± 1.7%; p = 0.001) and lower number of p53-positive (30.9 ± 3.2%; p = 0.05) and Ki-67-positive (26.9 ± 2.7%; p = 0.048) cells was observed compared to those in tumors of patients from group I (12.0 ± 1.6; 37.7 ± 2.8 and 36.7 ± 3.4%, respectively). CONCLUSION: Phenotypic features of the EC in the patients with family history of cancer differ from those in tumors of patients without such aggregation. The biological heterogeneity of EC seems to relate to the oncogenealogical history of patients. Also this biological heterogeneity is linked to the molecular features of EC cells, which affects cancer aggressiveness and the course of the disease.

Comprehensive analysis of intratumoral lymphocytes and FOXP3 expression in tumor cells of endometrial cancer.

AIM: To study the tumor microenvironment (CD4(+), CD8(+) and FOXP3(+) lymphocytes) and FOXP3 expression by tumor cells and correlation of studied parameters with clinical and morphological characteristics of endometrial adenocarcinomas. MATERIALS AND METHODS: Tumor samples from 40 patients (mean age 56.9 ± 2.8) with endometrial cancer (EC), who did not receive special treatment before surgery (chemotherapy, radiation therapy and hormontherapy), were investigated. Morphological, immunohistochemical methods as well as methods of mathematical statistics were applied in the study. RESULTS: It has been determined that high quantity of FOXP3(+) tumor cells and intratumoral CD4(+) and CD8(+) Т-lymphocytes along with the low content of FOXP3(+)-lymphocytes is typical for the endometrial adenocarcinomas of high differentiation grade (G1). In poorly differentiated (G3) EC an increase of number of FOXP3(+)-lymphocytes and decrease of CD4(+) and CD8(+) lymphocytes in lymphocytic infiltrate have been observed. Moreover, decrease of the content of FOXP3(+) tumor cells has been determined. In EC patients correlation between the following parameters has been detected: proliferative activity and deep invasion of tumor in myometrium (R = 0.74); depth of invasion correlated with the number of the FOXP3(+) tumor cells (R = -0.63) and number of CD4(+) and CD8(+) lymphocytes (R = 0.68 and R = -0.55 respectively) in lymphocytic infiltrate. Thus, results of this study are the evidence of significance of the lymphocytic components of tumor microenvironment and content of FOXP3 expressing tumor cells in EC progression. CONCLUSION: Quantitative changes of tumor microenvironment, such as number of CD4(+), CD8(+) and FOXP3(+) lymphocytes and content of FOXP3(+) tumor cells correlate with biological characteristics of EC.

Risk assessment of cancer of the female reproductive system.

AIM: To create an information resource concerning multifactorial oncological diseases of the female reproductive system. MATERIALS AND METHODS: A comprehensive search of the literature in the PubMed and Ukrainian scientific sources published from 1995 to 2014 and the results of researches performed in R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, National Academy of Sciences of Ukraine. Development environment of information resource "Multifactorial oncological disease" was Borland Delphi. RESULTS: The information content of web page concerning cancers of the female reproductive system was posted in the information resource "Multifactorial oncological disease". The assessment algorithm of genetic contribution to cancers of the female reproductive system and recurrent risk of cancer development in families have been described. These algorithms can be used in assessment of contribution of genetic and environmental factors in the development of malignant tumors.