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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., (Copyright © 2020. Published by Elsevier Inc.)

The total chymotrypsin-like activity of proteasornes, the activity of 20S- and 26S-proteasome pools and calpains, and the expression of metalloproteinase PAPP-A in primary tumors and metastasized tissues were studied in 13 patients with epithelial ovarian cancer. It was shown that initiation of the process of tumor dissemination occurs against the background of active proteolytic processes; A decrease in activity of 26S-proteasomes and total calpain activity and increased expression ofmetalloproteinase PAPP-A in the primary tu mors were found in patients with ascites as compared with patients without ascites. The disease progression after treatment and achieved stabilization were found in patients with decreased activity of intracellular proteases and a high content of PAPP-A in the primary tumors.

Insulin-like growth factors (IGFs), vascular endothelial growth factor (VEGF), hypoxia-inducible factor-1 (HIF-1), and nuclear factor kappa-B (NF-κB) are known to play an important role in endometrial cancer pathogenesis. However, the proteolytic regulation of these factors is still poorly understood. We studied the correlation between chymotrypsin-like activity of proteasomes and IGF-I, IGF-II, VEGF, HIF-1, and NF-κB levels in endometrial cancer tissues. It was shown that the total activity of proteasomes and the activity of the 20S and 26S proteasomes in malignant tumors were significantly higher than those observed in the normal endometrium. Negative relationships between the proteasome activity and IGF-I, HIF-1, and NF-κB p50 expressions were found. High 20S proteasome activity was associated with increase of HIF-1 level. Positive relationships between IGF-I expression and two classic forms of NF-κB p50 and p65 in endometrial cancer were revealed. The data obtained indicate the possible proteasomal regulation of growth and transcription factors. The major pool of IGF-I is located in the extracellular space, and it is likely that extracellular proteasomes also take part in the regulation of the IGF-I content. The present data show the evidence of proteasome regulation of growth and nuclear factors that can play an important role in cancer pathogenesis.