: The development of gene therapy using genome editing tools recently became relevant. With the invention of programmable nucleases, it became possible to treat hereditary diseases due to introducing targeted double strand break in the genome followed by homology directed repair (HDR) or non-homologous end-joining (NHEJ) reparation. CRISPR-Cas9 is more efficient and easier to use in comparison with other programmable nucleases. To improve the efficiency and safety of this gene editing tool, various modifications CRISPR-Cas9 basis were created in recent years, such as prime editing – in this system, Cas9 nickase is fused with reverse transcriptase and guide RNA, which contains a desired correction. Prime editing demonstrates equal or higher correction efficiency as HDR-mediated editing and much less off-target effect due to inducing nick. There are several studies in which prime editing is used to correct mutations in which researchers reported little or no evidence of off-target effects. The system can also be used to functionally characterize disease variants. However, prime editing still has several limitations that could be further improved. The effectiveness of the method is not yet high enough to apply it in clinical trials. Delivery of prime editors is also a big challenge due to their size. In the present article, we observe the development of the platform, and discuss the candidate proteins for efficiency enhancing, main delivery methods and current applications of prime editing.

Purpose of the study. Evaluation of the therapy optimization for patients with solid tumors using comprehensive genomic profiling (CGP). Patients and methods. The article presents the results of a study involving patients from the Yamalo-Nenets Autonomous Okrug with malignant neoplasms of various localizations: breast cancer (n = 4), colorectal cancer (n = 3), gastric cancer (n = 1), cervical cancer (n = 1), ovarian cancer (n = 1), and prostate cancer (n = 1). Molecular genetic testing was performed using the Sentis™ Cancer+Discovery Panel (BGI). Biological material included FFPE tumor tissue sections containing >20 % tumor cells. Next-generation sequencing (NGS) parameters were as follows: sequencing depth > 900× for tumor samples and >300× for matched control samples (venous blood); insertion size ~140–210 bp; Q30 > 80 %; target coverage > 90 %. The analysis included 689 genes, microsatellite instability (MSI), tumor mutational burden (TMB), and germline pathogenic variants. Results. Clinically significant somatic biomarkers were identified in 8 of 11 cases (72.7 %), enabling optimization of treatment strategies toward the most effective therapeutic approaches. In 5 of these 8 cases (62.5 %), treatment plan modification included the potential use of off-label therapy following approval by a multidisciplinary tumor board. Germline (inherited) variants were detected in 4 of 11 cases (36.4 %), indicating the need for genetic counseling and evaluation of relatives. Conclusion. The implementation of CGP in clinical practice expands the possibilities for a personalized approach to the treatment of patients with metastatic and progressive malignant neoplasms through the identification of additional potential biomarkers of sensitivity or resistance to targeted anticancer agents and immunotherapy. Further evaluation of CGP effectiveness in a larger patient cohort appears warranted.

Introduction. In 20–25 % of cases of patients with hereditary forms of breast cancer (BC), pathogenic variants of the BRCA1 and BRCA2 genes predisposing to BC and ovarian cancer can be identified. Based on the results of previous Russian studies, a simple and inexpensive testing system using real-time polymerase chain reaction consisting of the 8 most frequently identified variants (mutations) in the BRCA1 and BRCA2 genes was developed. The use of targeted panels for high-throughput sequencing and whole genome sequencing for diagnosis of hereditary BC led to identification of a number of genes with pathological variants causing this pathology in patients and their relatives. Aim. To evaluate the profile and frequency of pathological variants in genes associated with tumor development in Russian patients with BC. Materials and methods. Analysis of the results of whole genome sequencing of samples from 1514 patients with BC and 5163 individuals without oncological diseases (control group) was performed. Results. A spectrum of mutations in the BRCA1 and BRCA2 genes, as well as pathogenic variants in other genes, were identified. Based on the results of whole genome sequencing a new panel was developed consisting of 10 most common mutations in the BRCA1, BRCA2, АТМ and PALB2 genes. Additionally, significant associations between pathogenic variants in the ATM gene with estrogen-positive luminal BC (р = 0.034) and pathogenic variants in the BRCA1 gene with triple negative BC (p 0.001) were found. Conclusion. In accordance with the obtained data, the new panel of the most common pathogenic variants includes BRCA1 (rs28897672, rs80357522, rs80357906, rs41293455, rs80358094), BRCA2 (rs28897756, rs80359604), АТМ (rs587782652) and PALB2 (rs180177143, rs515726123). Implementation of the new extended panel for identification of frequent mutations in Russian patients with BC in clinical practice will allow to identify up to 7.7 % of germline variants in a random sample.

Introduction : Hereditary cancer syndromes (HCS) represent a group of genetically determined diseases where the risk of developing various types of tumors is significantly higher compared to the general population. Iden tifying germline pathogenic variants (PVs) associated with an increased risk of tumor formation is crucial for prevention, diagnosis, and treatment of patients. Scientific studies conducted on Russian patients with malignant neoplasms (MNs) will help to identify genetic markers of HCS that are specific to different ethnic groups and patient samples. Aim : To analyze the results of whole-genome sequencing (WGS) of 500 patients with MNs from the Yamalo-Nenets Autonomous Okrug (YNAO) and to identify germline variants associated with the development of HCS in oncology patients, along with a description of the structure and frequency of the genetic variants obtained. Methods : Since 2021, unique scientific projects aimed at identifying genetic variants associated with HCS have been implemented in YNAO using WGS. This study included 500 patients with MNs meeting at least one of the following criteria: 1) early age at onset of MN; 2) multiple primary MNs; 3) certain histological and immunohisto chemical characteristics of MNs; 4) a significant family cancer history. Whole-genome sequencing of DNA isolated from peripheral blood lymphocytes was performed. Results : WGS results demonstrated that 83 out of 500 patients with MNs were found to have PVs in genes associ ated with carcinogenesis, accounting for 16.6 %. This article presents the structure of the identified PVs in groups of patients with breast and ovarian cancers, patients with colorectal cancer and endometrial cancer, as well as in a heterogeneous group of patients with various tumor types. Conclusion : We have published the WGS results from YNAO for the first time and analyzed the structure of the obtained genetic variants in oncology patients. Research on the genetic characteristics of the patients from YNAO not only helps to identify patients at increased risk of developing cancer, providing them with preventive measures and effective treatment but also generates unique scientific information necessary for the development and adap tation of molecular genetic tests considering the sample’s peculiarities and international experience.

While pathogenic germline CHEK2 variants are known to increase cancer risk, there is currently insufficient evidence regarding the precise risk of developing malignant neoplasms associated with specific missense variants or variants of uncertain significance. As a result, no clear clinical guidelines exist regarding consultation, monitoring and specific treatment options for those patients. For the first time in Russia, clinical data and whole-genome sequencing (WGS) results were analyzed for 3150 patients with cancer and suspected hereditary cancer syndromes (HCS) and 5163 healthy individuals. This dataset formed the basis for assessing the role of germline CHEK2 variants in the development of different cancer types. The chromosomal coordinates and coding sequence coordinates are given in accordance with the GRCh38 (hg38) genome assembly and the NM_007194.4 transcript. Pathogenic (P) and likely pathogenic (LP) variants of CHEK2 significantly increased the risk of breast cancer (OR = 2.015 [95% CI: 1.27–3.21]; p = 0.0031), but the association with colorectal cancer was not statistically significant (OR = 1.354 [95% CI: 0.42–4.42]; p = 0.616). A moderate increase in cancer risk was identified for the c.1100del variant (OR = 2.263 [95% CI: 1.19–4.32]; p = 0.0132) and for the common P/LP variants c.1100del, c.444+1G>A and c.433C>T (OR = 2.219 [95% CI: 1.40–3.51]; p = 0.0007). Notably, our study confirmed that CHEK2 c.470T>C (p.Ile157Thr) is the most common variant in the patient group, identified in 3.8% of cases (120/3150), compared with 3.0% in the control group (155/5163). Although the association between the most common CHEK2 variant c.470T>C and cancer risk reached nominal statistical significance (OR = 1.279 [95% CI: 1.00–1.63]; p = 0.0463), the effect size was minimal, suggesting that the contribution of this variant to hereditary cancer risk in the Russian population is modest. Additional studies are required before this variant can be definitively excluded from clinical interpretation.

Introduction. The blood coagulation factor XII (FXII) is involved in opposing processes of hemostasis: contact activation of the intrinsic pathway of blood coagulation and fibrinolysis. What might the clinical picture of FXII deficiency present with: bleeding, thromboses or be asymptomatic? The issue remains debatable. Aim: To present the clinical and laboratory characteristics of patients with congenital FXII deficiency in the Russian population. Materials and methods . A retrospective study included 29 of 212 patients with FXII deficiency who underwent genetic analysis, confirming the hereditary nature of the disease. Results. The mean APTT in the study group was 187 seconds (control 29–38 sec.). The mean FXII activity was 20%. The most common mutation of F12 in the Russian population was the nucleotide substitution c.1681 –1 G>A. The reasons for contacting a hematologist and conducting diagnostics of the disease were: preoperative examination in 9 (31%) patients; abnormalities in the coagulogram during examination prior to pregnancy planning or during examination for a chronic disease in 8 (28%) patients; bleeding — in 7 (24%) patients; abnormalities in the coagulogram during screening in pregnancy in 2 (7%); family examination in 2 (7%) patients. In 21 (72%) of 29 patients, the clinical picture was represented by hemorrhagic manifestations. Thrombotic events were noted in 2 (7%) of 29 patients. Among 16 (80%) women with a history of pregnancy, miscarriages occurred in 6 (38%). Conclusion. The diagnosis of hereditary FXII deficiency is most often established during preoperative examination. However, 24% of patients consulted a hematologist with complaints of hemorrhagic manifestations, mostly mild or moderate. Surgical bleeding was noted in 21% of patients. The obstetric history of more than a third of women was complicated by miscarriages. In patients with hereditary FXII deficiency, it is necessary to be wary of mild spontaneous bleeding, surgical bleeding, miscarriage and, to a lesser extent, thromboses.