The molecular-genetic profile of lung cancer is highly diverse, complicating the formation of a unified patient portrait and necessitating the incorporation of specific genetic testing into diagnosis. There are key mechanisms for the activation of oncogenes, including point mutations, copy number changes (amplifications), and fusions, which are observed in non-small cell lung cancer (NSCLC). Modern molecular-targeted therapy for patients with NSCLC increases the duration of disease control and, in some cases, can transform a once-fatal disease into a chronic condition. Currently, the standard testing panel includes the identification of mutations in the EGFR gene (exons 18–21), ALK translocations, ROS1 translocations, and BRAF V600E mutations. However, less common alterations such as RET and NTRK translocations also occur. The use of next-generation sequencing (NGS) allows for the identification of rarer genetic alterations. NTRK gene fusions are considered oncogenic factors for various solid tumors in both adults and children. The prevalence of NTRK gene alterations varies by tumor type. However, in lung cancer, this type of genetic alteration is rare, with an overall prevalence of less than 3%, and typically the occurrence rate is less than 1%. Currently, three drugs have been included in international clinical guidelines as potential treatment options for NTRK translocations, demonstrating their effectiveness. Several other drugs are at various stages of clinical trials. In this review, we will highlight the existing data for a better understanding of the patient profile with NTRK and present a clinical case.

Introduction. Next-generation sequencing (NGS) is a molecular approach that can provide clinicians with comprehensive information about a patient’s molecular profile, which is an important aspect of the effective application of targeted therapy.Aim. To assess the frequency of tumor somatic mutations in non-small cell lung cancer (NSCLC) in a cohort of Russian patients to subsequently optimize diagnostics and personalize treatment strategies.Materials and methods. The study included the results of NGS testing from a cohort of 1.400 NSCLC patients between March 17, 2023, and July 22, 2024. Several other clinics across the country participated in this multicenter study. Panels with various options for identifying potential genetic alterations were used. An analysis of the frequency of various alterations was conducted based on the panel used, clinical characteristics of the patients, considering the geographical and ethnographic diversity of the regions in the country.Results. Mutations were most frequently found in the KRAS (17.9%) and EGFR (15.8%) genes, particularly among never-smoker women. The frequency of rare mutations such as RET, MET, and NTRK corresponds to literature data and underscores the need to expand the group of patients being tested for these alterations. However, deletions in exon 19 of EGFR (12.7%) and KRAS G12C (16.4%) were also found among smokers. The results highlight the inadequate scope of existing testing, partly due to the lack of co-mutation assessment and primary resistance mutations, while also demonstrating possible differences when using various diagnostic panels.Conclusion. The implementation of NGS in public health systems allows for a more personalized approach to selecting treatment strategies for patients. The data obtained can be used in predictive models to optimize drug distribution.

Lung cancer remains one of the most dangerous and most common cancers, requiring constant improvement of diagnostic and treatment methods. The genetic heterogeneity of lung cancer forces us to search for new therapeutic targets in an attempt to achieve greater effectiveness for certain groups of patients. The purpose of the study was to update current knowledge about lung adenocarcinoma with a mutation in the KRAS gene, to consider new opportunities for personalized treatment of KRAS-mutated NSCLC and to form an image of a Russian patient who is potentially indicated for targeted therapy. Material and methods. A search of available literature sources published in the Pubmed, Cochrane Library, Elibrary database was carried out, publications covering the period from 2008 to 2023 were included. Results. The article discussed molecular genetic testing, including NGS next generation sequencing, and its role in determining the presence of KRAS gene mutations in patients with lung cancer. the effectiveness of targeted drugs, such as Sotorasib and Adagrasib was also discussed. The mechanism of action is aimed at suppressing the activity of the mutant KRAS G12C protein, which can significantly improve patient survival prognosis. We obtained data on the results of testing 935 patients with non-squamous non-small cell lung cancer from various medical centers in Russia. The KRAS gene mutation was identified in 160 (17.1 %) patients, of whom 96 (10.3 %) had KRAS G12C variant. The KRAS mutation was determined by PCR in 44 patients and by NGS (including on the FoundationOne platform) in 111 patients. Clinical characteristics, such as gender, age, smoking status, PD-L1 expression level, presence of co-mutations (TP53, STK11, KEAP1, were largely similar between patients from real-world clinical practice and patients included in the CodeBreak100 study. Conclusion. The research results confirm the high effectiveness of Sotorasib and Adagrasib for patients with the KRAS G12C mutation and open up new prospects in the treatment of lung cancer. The clinical data obtained from Russian patients demonstrate consistency with the patient profile from registration studies of these drugs. This once again demonstrates the need to expand the range of molecular genetic testing for timely identification of this group of patients and prescribing the most effective treatment for them.

651 Background: The objective of this work was to evaluate the molecular and genetic features of the NET gastrointestinal tract. Genomic sequencing of 30 tumor samples of the latest generation was carried out and the data obtained were evaluated. Methods: In total, 30 tumor blocks of patients with gastrointestinal NET were tested by the new generation sequencing (NGS) method. The following genes were analyzed: ATM, ATR, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CDK12, CHEK1, CHEK2, EPCAM, FANCL, MLH1, MSH2, NBN, NF1, PALB2, PMS2, RAD51B, RAD51C, RAD51D, RAD54L, STK11, TP53, POLE, KRAS, NRAS, BRAF, EGFR, ERBB2, PIK3CA, MET ex14, BAT25, BAT26, NR21, NR24, MONO27, KIT, PDGFRA, Pi3Ca. Preparation of libraries for sequencing was carried out using NimblGen SepCapEZ Choice. Sequencing was performed on the Illumina MiSeq device. Results: In the study cohort of patients whose tumor blocks were sent for examination by the NGS method, there were more women – 19 (63.3%) than men – 11 (36.7%). When analyzing the age of patients, it should be noted that among all age groups, elderly patients predominated (60-74 years according to the WHO classification, 2016) – 12 (40%). In the majority of patients – 10 (33.3%) – the primary tumor focus was localized in the pancreas, in 6 (20%) patients it was primarily affected stomach, 7 (23.3%) – small intestine. Other parts of the gastrointestinal tract were affected much less frequently: the colon – in 1 (3.3%) patients. According to the division according to the degree of differentiation of gastrointestinal NET10 tumors had a degree of differentiation G1 (33.3%), 16 -G3 (54.3%), 4– G3 (13.3%). In the tumor sample of a patient with gastric NET G1 (Ki 67 = 2%), POLE mutations were found: c.2276G > A, p.R759H and CHEK2: c.470T > C, p.I157T. Also, mutations MLH1: c.199G > A, p.G67R BRCA1: c.1881 were found in the tumor sample of another patient with gastric NET G2 (Ki 67 = 7%). Conclusions: To improve the survival rates of patients, it is worth paying special attention to the molecular genetic study of the NET gastrointestinal tract. It is molecular genetic profiling that can become the basis for building more individualized algorithms for treating patients. The results of this study allow us to count on the fact that when conducting a study on a larger cohort of patients with gastrointestinal NET, it is possible to obtain results that will expand our knowledge of this nosology and allow us to supplement the already available information about prognosis factors and predictors of response to treatment.

Purpose: to study the molecular genetic landscape of the Russian cohort of patients with stage I–IIIA non-small cell lung cancer, to identify correlations between molecular genetic and clinical and morphological parameters of the tumor. Materials and methods: routine pathological examination and targeted sequencing of tumor material (and paired material of normal lung tissue) in 90 patients diagnosed with non-small cell lung cancer. Collection of clinical information. Statistical processing of the obtained material using the SPSS Statistics 23.0 program, based on the collected database. Descriptive statistics methods were used to analyze the socio-demographic and clinical characteristics of patients. Results: data were obtained on the frequency of occurrence of somatic mutations included in the study panel among patients of the Russian population, the correlation between clinical and morphological (stage, gender, age, histological subtype) and genetic parameters of the tumor was studied. Conclusion: An in-depth study of the genetic profile in patients with localized NSCLC using the Next generation sequencing (NGS) method allows us to determine the mutational landscape of this group of patients in more detail. More detailed, per-exon sequencing makes it possible to more accurately determine the clinical significance of the identified mutations, which improves diagnosis and makes subsequent treatment tactics more precise.

Hereditary form of prostate cancer is often caused by pathogenic variants in genes associated with the DNA repair system. Identification of genetic aberrations allows to stratify patients into groups for personalization and improvement of therapy effectiveness. With this approach, it is important to take into account that the frequency of pathogenic variants can vary significantly in different ethnic populations. The article presents a case of metastatic castration-resistant prostate cancer in a carrier of hereditary pathogenic variant in the BRCA2 gene c.6341del (р.Pro2114fs). The results support the need for genetic testing using up-to-date methods capable of detecting rare genetic variants.

Circulating tumor DNA (ctDNA) refers to small fragments of nucleic acid (approximately 166 base pairs) that are not associated with cells or cell fragments and circulate in the bloodstream. Circulating tumor DNA has been proven to be a marker of minimal residual disease (MRD), a tumor process that cannot be detected using routine investigations. Circulating tumor DNA can be used as a marker of MRD because tumor cells secrete their DNA into the blood during necrosis, apoptosis, and functioning (with extracellular vesicles, etc.); therefore, it is possible to detect it and identify MRD. Circulating tumor DNA accounts for 0,01 % to several percent of all circulating extracellular DNA depending on the size of the tumor, its vascularization and biological properties. Currently, much attention is paid to the detection of minimal residual disease after radical surgery for non‑small cell lung cancer (NSCLC), since a number of large studies have shown postoperative plasma ctDNA to be a negative prognostic sign. For example, Chaudhuri et al. showed that 36‑month relapse‑free survival (RFS) in patients with and without postoperative plasma ctDNA was nearly 0 % and 90–99 %, respectively. The status of MRD determined by postoperative plasma ctDNA levels may be potentially used for adjuvant treatment selection in the postoperative period. In the DYNAMIC study, MRD‑positive patients (with postoperative plasma ctDNA) who received adjuvant therapy had an RFS of 22,4 months while those who did not receive adjuvant treatment had an RFS of 9,3 months. Thus, the status of MRD based on the plasma ctDNA level after radical surgery may allow a personalized treatment approach for patients undergoing radical surgery for non‑small cell lung cancer (NSCLC).

169 Background: The HRRm detection is used to prescribe PARP inhibitors in mCRPC patients. The frequency of HRR alterations has been investigated in several clinical studies, but the prevalence of HRRm in real clinical practice remains unclear. We conducted the first study to evaluate prevalence of HRRm in mCRPC patients in Russia. This interim analysis is aimed to provide HRRm rate in real practice in Russian population. Methods: Patients with mCRPC and available tumor tissue samples (FFPEs) were enrolled from October 2020 till May 2021. Samples were analyzed in 3 labs. Target enrichment using multiplex PCR and library preparation of genes involved in HRR (BRCA2, BRCA1, RAD54L, FANCL, BARD1, ATM, CHEK1, RAD51B, PALB2, RAD51D, CDK12, RAD51C, BRIP1, CHEK2) was performed using three different techniques: GeneReader NGS System (QIAGEN), KAPA HyperPlus and SeqCap EZ Choice (Roche) and in-house targeted NGS-panel. For last 2 sequencing was performed using MiSeq (Illumina). Results: In this interim analysis we included 331 mCRPC patients from 20 sites with median age 67 years, 86,7% caucasian. Family or personal history of oncological diseases had 66 (20%) of pts 300 FFPEs were analyzed by NGS, 31 (9%) were not valid (poor quality/not enough DNA). HRRm rate is 19,7% (59/300). Most frequently mutated genes ( > 1%) listed in the table below. Other mutations (RAD51B, RAD51C, BARD1, FANCL, RAD51D, RAD54L) were detected in 1-2 cases per gene. Conclusions: This first systematic analysis of HRRm in Russian population of mCRPC patients showed general consistency with previously reported HRRm data (19,7% in our trial in comparison with 27.9% in PROfound trial). Lab approach using different techniques in real practice has to be established.[Table: see text]

Рост заболеваемости нейроэндокринными опухолями увеличивает интерес к изучению генетического ландшафта новообразований. В большей степени нейроэндокринные опухоли (НЭО) исследованы в контексте наследственных генетических синдромов, включая гены, такие как MEN1 , VHL , TSC1 / TSC2 , NF1 и CDKN1B . Взаимосвязь между наследственными (генеративными) мутациями в генах системы репараций ДНК и нейроэндокринными опухолями на сегодня практически не изучена. В условиях ГАУЗ «Республиканский клинический онкологический диспансер Министерства здравоохранения Республики Татарстан имени профессора М. З. Сигала» был изучен молекулярный профиль пациентов с диагнозом «нейроэндокринная опухоль» в зависимости от наследственного анамнеза. В проведенном исследовании у каждого четвертого пациента обнаруживались патогенные мутации. У 33 % пациентов при наличии наследственного анамнеза выявлены патогенные, либо условно-патогенные мутации

The article describes a clinical case of colorectal cancer with a positive family history. In the course of a molecular genetic study by NGS sequencing, a germinal c.1607delC mutation was detected in exon 15 of the CHEK2 gene (NM_007194.4). According to ClinVar, this option has uncertain clinical significance. The article provides literature data on cases of carriage of CHEK2 gene mutations. More careful monitoring of carriers of pathogenic variants in the CHEK2 gene from families with multiple manifestations of colorectal cancer is now recommended.

The formation of primary multiple malignant neoplasms, such as breast cancer and prostate cancer, in one patient is a rather rare combination. Treatment and diagnostic strategies in such cases require a multidisciplinary approach. Currently, there are no approved recommendations for the management of patients with a combination of these diseases. This manuscript presents a clinical case of diagnosis and treatment of breast and prostate cancer in one patient.

Genome instability-the increased tendency of acquiring mutations in the genome and ability of a cell to tolerate high mutation burden-is one of the drivers of cancer. Genome instability results from many causes including defects in DNA repair systems. Previously, it has been shown that germline pathogenic mutations in DNA Mismatch Repair (MMR) pathway cause cancer-predisposing Lynch Syndrome. We proposed that Lynch Syndrome-related germline mutations (LS-mutations) are associated with breast cancer (BC). In this study, we performed Targeted Next-Generation Sequencing of MMR pathway genes MLH1, MSH2, MSH6, EPCAM, and PMS2 in a cohort of 711 patients with hereditary BC, 60 patients with sporadic BC, and 492 healthy donors. Sixty-nine patients (9.7%) with hereditary BC harbored at least one germline mutation in the MMR pathway genes, of them 32 patients (4.5%) harbored mutations in MMR pathway genes which we define as pathogenic or likely pathogenic, and of them 26 patients (3.6%) did not have any pathogenic mutations in DDR pathway genes, compared to two mutations in MMR pathway genes (0.4%) detected in a group of 492 healthy donors [p = 0.00013, OR = 8.9 (CI 95% 2.2-78.4)]. Our study demonstrates that LS-mutations are present in patients with hereditary BC more frequently than in healthy donors, and that there is an association of hereditary BC and mutations c.1321G>A in MLH1, c.260C>G and c.2178G>C in MSH2, c.3217C>T in MSH6, c.1268C>G and c.86G>C in PMS2 genes. This finding provides a rationale for including pathogenic LS-mutations into genetic counseling tests for patients with hereditary BC.

Neuroendocrine tumors (NETs) are one of the most poorly studied neoplasms today. At the same time, the interrelation between hereditary mutations in genes of the repair system of DNA and NETs is not well-studied. Our aim was to carry out an analysis of the occurrence of mutations in genes of the repair system of DNA in patients with NETs. 37 patients with a diagnosis of NETs with the burdened hereditary anamnesis observed in 2018 were analysed. The diagnosis of NETs, early age of a demonstration (up to 60 years), hereditary anamnesis at relatives of 1st, and 2nd line of relationship were criteria of inclusion. 10 (27%) patients had pathogenic and presumably pathogenic mutations in DNA repair system genes. The average age of patients was 51.3 years. In the group with opportunistic options mutations in genes of POLE, APC, FANCL, SLX4, CDH1, MSH2, PALB2, 6 patients were revealed. Pathogenic variants were observed in 4 patients (RAD51B, BRCA2, MLH3, CHEK2). In the control group, without hereditary anamnesis, only 2 patients had PALB2 and BRCA2 mutations. Patient with MSH2 mutation showed rapid progression against the background of target therapy (3 months). Patients with mutations of BRCA2, MLH3, CHEK2, PALB2 were radically operated on for localized NETs and no progression was observed for 2-4 years. There were no pathogenic mutations found in 27 patients, of which 19 patients had heritable anamnesis. Patients with NETs with hereditary anamnesis can have mutations in the genes of DNA repair systems and need genetic consultation. The conducted research showed the high relevance of studying a hereditary genetic component in NETs and the project will be continued with more numerous selection of patients.

With the increased rate of stable remission after gonadotoxic cancer treatment, new methods of fertility preservation are required in order to provide the best possible care for oncological patients. Here, we report an original case of euploid blastocyst cryopreservation after in vitro maturation of ovarian tissue oocytes (OTO IVM). Thirty-three oocytes were obtained from the ovarian tissue after ovariectomy in the breast cancer patient. Six out of 12 matured oocytes fertilized successfully and 3 blastocysts were formed. Genetic investigation for mutations associated with this type of malignancy found that the patient is not a carrier. Preimplantation genetic testing was performed only for aneuploidies and found all 3 blastocysts to be euploid and suitable for embryo transfer. Our study showed that the ovarian tissue oocytes matured in vitro have the potential for euploid blastocyst formation after ICSI which could be screened for aneuploidies and inherited mutations and then be vitrified in order to provide the best fertility preservation strategy for women with cancer.

Non-small cell lung cancer (NSCLC) is a heterogeneous group of diseases with a wide range of possible targeted activating mutations. In this regard, a lot of attention is paid to such treatment of patients with NSCLC as adjuvant targeted therapy after radical surgical treatment, nowadays. The active interest in this option is associated with several reasons: sufficient low efficacy of adjuvant chemotherapy, increased capabilities of molecular genetic methods to determine the activating mutations, extensive introduction of liquid biopsy into the clinical practice, as well as the results of the trials associated with the use of targeted therapy both in the treatment of advanced forms of NSCLC and in an adjuvant regimen. The results of such trials as SELECT, ADJUVANT/CTONG1104, ADAURA have shown the benefit of adjuvant targeted therapy in comparison with chemotherapy, placebo or historical control. The ability to identify circulating tumor DNA as a marker of minimal residual disease after surgical treatment, as well as the determination of the mutation profile using the minimally invasive method such as the fluid biopsy will allow achieving an even more personalized approach to the appointment of adjuvant therapy. All this makes the use of adjuvant targeted therapy a promising and effective treatment option.

Background. The development of hereditary cancer syndromes is caused by genetic disorders in the DNA repair system, which consists of more than 100 genes. However, at present, in the majority of medical centers in Russia, the diagnosis of hereditary OC and BC is limited to the determination of the most frequent mutations (8 points) in BRCA1 and BRCA2 genes using PCR methods. However, the given mutations are frequent for Slavic population while in other populations of Russia they occur less often or do not occur at all. Aim. To reveal the landscape of hereditary pathogenic variants in the genes of the reparation system and develop methods for a fast analysis of the NGS data. Methods. A panel of 34 genes of the reparation system was analyzed by next generation sequencing (NGS) in 1644 samples of patients with inherited cancer syndromes. Results. The NGS analysis revealed 119 pathogenic mutations of BRCA1/BRCA2 genes in 374 patients, with a marked difference in mutation frequencies between different ethnic groups Slavs, Tatars, Bashkirs and Chuvash. A public database of the frequencies of mutations and polymorphisms of the genes of the DNA reparation system in different ethnoses was created at https://oncobrca.ru. Methods were created for automatic parallel processing of any number of samples from the raw data to the final report. Conclusions. The NGS method has created a possibility to identify rare mutations characteristic of different ethnic groups, which makes it possible to prescribe optimal chemotherapy and develop diagnostic methods of population screening for carrying gene mutations of the DNA repair system. The modern approaches to the analysis of genome sequencing data allowed reducing the time of obtaining the result to several hours after the analysis.

Обоснование . Развитие наследственных онкологических синдромов обусловлено генетическими нарушениями в системе репарации ДНК, состоящей более чем из 100 генов. Однако в настоящее время в большинстве медицинских центров России диагностика наследственных заболеваний раком яичника и раком молочной железы сводится к определению наиболее частых мутаций (8 точек) в генах BRCA1 и BRCA2 с помощью методов полимеразной цепной реакции. При этом данные мутации являются частыми для славянской популяции, в то время как в остальных популяциях России они встречаются реже или не встречаются вообще. Цель исследования — получить представление о ландшафте наследственных патогенных вариантов в генах системы репарации; разработать методы быстрого анализа данных полногеномного секвенирования. Методы. Методом секвенирования нового поколения (Next Generation Sequencing, NGS) была проанализирована панель из 34 генов системы репарации в 1644 образцах биоматериала пациентов с наследственными онкологическими синдромами. Результаты. Выявлены 119 патогенных мутаций генов BRCA1/BRCA2 у 374 пациентов, при этом обнаружена выраженная разница в частоте встречаемости мутаций между различными этносами — славянами, татарами, башкирами и чувашами. Созданы публичная база данных частоты мутаций и полиморфизмов генов системы репарации ДНК в различных этносах ( https://oncobrca.ru ), а также методы для автоматической параллельной обработки любого количества образцов от сырых данных до готового отчета. Заключение. С помощью метода NGS появилась возможность выявления редких мутаций, характерных для различных этносов, что дает возможность назначать оптимальную химиотерапию и разрабатывать диагностические методы популяционного скрининга носительства мутаций генов системы репарации ДНК. Современные подходы к анализу данных полногеномного секвенирования позволили сократить время получения результата до нескольких часов после проведения анализа.