The dissertation is dedicated to the resolution of an actual problem - determination of the role of genetic factors in the development of benign tumors and cancers of female reproductive system organs (FRSO), and optimization of early diagnostics of malignant neoplasms (MNs) in females from families burdened with cancer.
To achieve this goal, a comprehensive analytical clinical-genealogical and molecular-genetic study was performed in 1313 females with benign tumors, MN, and conditionally healthy individuals. Determination of molecular-genetic criteria was provided in 210 females, from them 65 persons were verified with benign FRSO tumors, 90 - with malignant tumors, and 55 persons were used as conditional control..
The following research methods were implemented in the work: general clinical, morphological, cytological, histo- and cytochemical, immunohistochemical, clinical-genealogical, molecular-genetic, statistical. Molecular-genetic examinations of females from the studied groups involved the use of biological material, in particular - peripheral blood and tumor tissue.
Based on the results of clinical-genealogical analysis of pedigrees, it was found that the majority of relatives of probands with benign pathology and patients with thyroid cancer (62.3%) suffered from hormone-dependent tumors, namely: breast cancer (BC), endometrial cancer (EC), ovarian cancer (OC), and thyroid cancer. It was determined that BC has 23.0% of probands' relatives of І and ІІ degree of kindred, EC - 21.2%, OC -18.1%. In patients with benign and malignant pathology of FRSO, MNs were observed more often among relatives on a maternal line, than on a paternal line.
Forty-six of 90 patients with FRSO cancer were diagnosed with primary multiple tumors (PMTs), of which 7 (15.2%) at the time of onset were synchronous, and 39 (84.8%) - metachronous.
It was shown that in 18.2% of women with MNs of FRSO (BC and OC) and 15.2% of patients with PMTs of FRSO, one of which was BC or OC, a mutation of 5382 insC in the BRCA1 gene was identified in the tumor tissue, at that the age of the probands with PMT at the time of the first localization of a malignant neoplasm in the carriers of the mutation did not exceed 50 years.
For the first time, population features of the combination of levels of mutational changes in BRCA1/2 genes - BRCA1 185delAG, BRCA1 5382insC and BRCA2 6174delT, and polymorphic variants of CYP2D6, ESR1 genes were determined. For the first time, on the basis of a comprehensive clinical-genealogical and molecular-genetic study of patients with benign and malignant tumors of FRSO, who were residents of the Cherkasy region, polymorphic variants of genes CYP2D6, ESR1, associated with aggregation of malignant tumors in patients' pedigrees, were characterized.
For the first time, molecular-genetic prognostic models have been developed to predict the risk of benign pathology of FRSO, BC and OC in conditionally healthy members of families with a burdened family history of cancer. The best recognized prognostic molecular-genetic model for assessing the risk of benign pathology of FRSO was model 2 ** with reproducibility accuracy (71.68%) and confidence (p <0.001), which included polymorphic gene variants Т397ESR1/Cyp2D6*4.
For malignant tumors of FRSO, the most optimal models were, respectively, 1**/T397C and 2**, whose reliability in the development of malignant tumors was determined with a reproducibility accuracy of 68.23% and 66.11%, respectively.
Prognostic models of intergenic interaction have been developed that allow to optimize the diagnosis of benign tumors of FRSO, BC and OC and are associated with 5-year survival.
For the first time, it was found that in 27.3% of patients with OC the signs of tumor progression are observed within 1-3 years after completion of treatment and are associated with a prognostic molecular-genetic model 2** (Т397ESR1/Cyp2D6*4). At the same time, according to the results of 5-year survival in 84.8% of patients with BC, the optimal prognostic model of intergenic interaction should be considered 3 ** model (ERS1 T397C/A351G/Cyp2D6*4) that accommodate polymorphisms T397C/A351G of ESR1 gene and polymorphic variants of Cyp2D6*4 gene.
The possibility of using the results of clinical and genealogical research and identified molecular-genetic models to assess the risk of FRSO tumors in women with aggregation of malignant tumors in pedigrees and the prognosis of tumor progression in patients with BC and OC is substantiated.
