The analysis of 50 patients with a clinical diagnosis of MUTYH-associated polyposis (more than 20 colorectal polyps) with genetic confirmation was conducted. Twenty-six different pathogenic/likely pathogenic variants were detected in the MUTYH gene, including four new ones. A predominance of four variants was demonstrated: c.1103G>A (p.Gly368Asp), c.650G>A (p.Arg217His), c.452A>G (p.Tyr151Cys), c.464G>A (p.Gly155Asp), that together account for 68

AIM: to identify the genotype-phenotype correlation in children with familial adenomatous polyposis (FAP) and to assess the risk of surgery. PATIENTS AND METODS: a retrospective study included children with FAP from January 2000 to December 2023. For analysis they were divided in two groups (“severe” and “non-severe” genotype) according to the results of the genetics. RESULTS: forty-two patients from 36 families with FAP were included in the study. Statistical analysis revealed that the mean age at the time of surgery was significantly different and was 13 ± 4 years in the “severe” genotype group vs. 16 ± 1 in the “non-severe” group (p = 0.04). The age of first colonoscopy (OR: 0.74, 95 % CI: 0.53–0.94, р = 0.03) and the carpeting of polyps (OR: 8.06, 95 % CI: 1.71–81.1, р = 0.04) were significantly associated with severe genotype. CONCLUSION: the “severe” genotype is characterized by earlier onset of the disease and age of colonoscopy, of polyps carpeting.

Colorectal cancer (CRC) is the third in prevalence among oncological diseases worldwide and second in the structure of oncological mortality. Genetic assessment of CRC is a necessary stage during selecting further treatment for patients. Many studies demonstrate a diverse distribution of mutations in the KRAS, NRAS, and BRAF genes in CRC. A critical literature review was conducted in order to systematize data on the mutational profile and genetic heterogeneity of these driver mutations in Russian patients with CRC. Articles were searched for in open databases. Totally 17 Russian studies and 3 English meta-analyses were analyzed for comparison with Russian data. Mutations in the KRAS, NRAS, and BRAF genes, according to Russian and international studies, are found in 40 %, 4 %, and 7 % in CRC patients, respectively. The frequency and specific localization of mutations may depend on the geographical location and nationality of the cohort. High intertumoral and intratumoral heterogeneity in CRC, especially in KRAS gene mutations, significantly influences the choice of further therapy and underscores the need for more detailed study of the mutational profile of the primary tumor, affected lymph nodes, and distant metastases. In Russia, several molecular genetic methods are used to determine somatic mutations in CRC with different sensitivity and specificity, the most common is real-time PCR. More accurate diagnostic methods include digital droplet PCR, Sanger sequencing, and next-generation sequencing, but each method has its limitations that must be considered when planning diagnostics and research. The promising directions in personalized oncology is the study of gene copy number variations, which may contribute to the development of new methods for treating CRC in the future. Despite the large number of studies, some aspects of the mutational profile of CRC in Russian studies remain poorly understood, which is why further research is needed on patients with colorectal cancer in Russia.

To determine the molecular genetic cause of the disease in a patient with colon oligopolyposis, whole exome sequencing was performed. The c.333+5G/C variant was detected in the BMPR1A gene. The functional significance of the found variant was elucidated, which demonstrated exon elongation at the mRNA level. This made it possible to confirm the diagnosis of juvenile polyposis in the patient.

А im: to reveal the rate of large rearrangements in the genes responsible for familial adenomatous polyposis, MUTYH -associated polyposis and Peutz–Jeghers syndrome. Materials and methods. The MLPA method was used for identification of large rearrangements. A total number of 135 patients was included in the study: 83 patients with a clinical diagnosis of “familial adenomatous polyposis”, 18 — with suspected MUTYH -associated polyposis, and 34 — with a clinical diagnosis of “Peutz–Jeghers syndrome”. Results. Seven large deletions and one large duplication in the APC gene were identified in 83 patients with classic familial adenomatous polyposis, with rate of large rearrangements 9.6 % (8/83). In 18 patients with suspected MUTYH -associated polyposis, no large rearrangements were found in the MUTYH gene. Four large deletions in the STK11 gene (12 %, 4/34) were detected in 34 patients with Peutz–Jeghers syndrome. Conclusion. For the first time, the expediency of including the method of detecting large rearrangements in routine DNA test list for Russian patients with various hereditary polyposis syndromes is demonstrated. Routine use of MLPA method makes it possible to increase the total frequency of detection of pathogenic variants in the APC and STK11 genes above 90 %. At the same time, the need for searching of large rearrangements in the MUTYH gene were not justified.

Introduction: local treatment of metastases is an integral part of colon cancer treatment. However, there is not enough data on the efficacy of surgical resection of metastases in patients with a BRAF gene mutation to recom‑mend this approach in routine practice. We initiated a retrospective multicenter study to assess the incidence of BRAF gene mutations in patients with metastatic colon cancer and to study the efficacy of metastasectomy in this group of patients.Materials and methods: we selected all patients who underwent surgical resection of metastases in various sites from the database of patients with BRAF gene mutations created as a result of a multicenter retrospective study with participation of 7 clinics in the Russian Federation. All 57 patients with RAS gene mutations and 43 patients with wild‑type RAS and BRAF genes who also underwent surgical resection of metastases at any stage of treatment were selected from the register of the Chemotherapy Department No. 2 of the NMRC of Oncology named after N. N. Blokhin for comparative analysis. Disease‑free survival and overall survival were used as primary efficacy criteria.Results: we found 26 patients with BRAF gene mutations who underwent surgical resection of metastases. When comparing disease‑free survival, the worst median was achieved in the group of patients with BRAF gene mutations: 7 months versus 14 months in patients with RAS gene mutations (HR 0.4, 94 % CI 0.23–0.7, P = 0.006); median disease‑free survival was not achieved in the wild‑type RAS and BRAF group (HR 0.2, 95 % CI 0.11–0.45, P <0.001).The median overall survival in the BRAF gene mutation group was 26 months versus 38 months in the RAS gene mutations group (HR 0.8, 95 % CI 0.33–1.98, P = 0.6) and 49 months in the wtRAS/wtBRAF group (RR 0.46, 95 % CI 0.17–1.24, P = 0.1). Resection of recurrent tumors in patients with metastases in retroperitoneal lymph nodes was associated with extremely low disease‑free survival (2 months); at the same time, disease‑free survival was 7 months after resection of isolated metastases in the liver and 8 months for metastases in the peritoneum.Conclusion: prognosis of patients with a BRAF gene mutation after surgical resection of metastases is worse than in patients with a different mutation phenotype. Nevertheless, literature data, as well as the results of our study, confirm the possibility of performing metastasectomy with careful selection of patients.

Introduction. mBRAF mCRC has the aggressive phenotype. The incidence of such mutation in Europe and the USA is around 8–14%, in Asian countries – 4–8%. The purpose of this population-based study was to determine the incidence and identifying prognostic factors in pts with mBRAF mCRC in Russia. Materials and methods. A multicenter retrospective analysis of clinical data and treatment results of pts with mBRAF mCRC was performed. The main method for determining mutations was a PCR. The main efficacy endpoint was progression free survival (PFS) at the 1 st line. Multivariate analysis was performed using Cox regression model. Results and discussion. 437 out of 8648 pts (5.17%) with a known mutational status had mBRAF (V600). Clinical data were collected from 131/437 (30%): the right-sided primary tumor – in 58,6%, left-sided – in 19%, rectum – in 21,4%. ORR in pts with mBRAF was 31%, median PFS was 6 months. We didn’t revealed any differences between FOLFOXIRI and doublets (XELOX/ FOLFOX or XELIRI/FOLFIRI) in terms of PFS (HR 0.9, 95% CI 0.49–1.52, р = 0.6) and OS (HR 1.5, 95% CI 0.61–4.1, р = 0.35) in pts with mBRAF. Conclusions . The incidence of mBRAF gene in the population of pts with mCRC in the Russia is low and we found a high incidence of localization of the primary tumor in the rectum. We didn’t reveal any differences between the usual duplets and standard regimen for such mutation - FOLFOXIRI in term of 1 st line PFS.

With the aim to find the genetic cause of adenomatous polyposis, DNA samples from six members of the same family (three affected patients, two healthy individuals, and one individual with unknown disease status) were examined via whole exome sequencing and segregation analysis. Previously, no APC/MutYH mutations were found in one patient by Sanger sequencing despite all the symptoms of adenomatous polyposis syndrome. As a result of bioinformatic analysis of data obtained from four blood relatives (three affected patients and one individual with unknown disease status), the mutation in the NSUN7 gene was observed, which was not previously associated with the development of adenomatous polyposis. However, subsequently, the population frequency of this genetic variant in Russia appeared to be significantly higher than the incidence of adenomatous polyposis itself. Additional bioinformatic analysis of copy number variation (CNV) revealed previously undescribed large heterozygous deletion in three patients, which included exons 2–16 of the APC gene and regions of the SRP19 and REEP5 genes, which was subsequently confirmed by Multiplex Ligation-dependent Probe Amplification (MLPA). The conducted molecular-genetic study demonstrated the need to develop and constantly update the national database with variants detected under high-throughput sequencing. In addition, the necessity to search for large deletions in the APC gene in Russian patients with adenomatous polyposis has also been established.

AIM: to evaluate the genetic and clinical characteristics of Russian patients with Lynch syndrome.PATIENTS AND METHODS: in the period from 2012 to 2019, patients with suspected Lynch syndrome were studied, according to the selection recommendations (Amsterdam II and original criteria). All patients underwent a microsatellite instability test in the tumor, and if it was detected, for germline mutations in the genes of MMR system. All patients underwent standard clinical procedures (colonoscopy, gastroscopy, CT, MRI, etc.).RESULTS: Lynch syndrome was genetically confirmed in 60 unrelated patients (included 30 women and 30 men, ranging in age from 24 to 68 years). Germline mutations were found in the following genes: MLH1 — 30, MSH2 — 26, MSH6 — 2, PMS1 — 1, PMS2 — 1. For the first time in the world, 12 novel mutations have been described. Clinical features of Russian patients with Lynch syndrome include: the early average age of development of the first cancer — 39.0 years; frequent 45% localization in the left colon; high (55%) incidence of poorly differentiated adenocarcinomas. A total of 234 tumors were diagnosed in Russian patients with Lynch syndrome and their relatives. It is also important to note that the stomach cancer is the third most common cancer after colon cancer.CONCLUSION: Russian patients with Lynch syndrome showed clinical and genetic and features, that distinguish them from European and North American population and should be taken into account when treating.

Adenomatous polyposis syndromes are severe hereditary diseases, characterized by the development of tens and hundreds colonic polyps and an extremely high risk of colorectal cancer without timely surgical treatment. Two hundred and forty Russian patients with more than 20 adenomatous colonic polyps were included in genetic study. Hereditary heterozygous mutations in the APC gene were detected in 157 patients, and biallelic mutations in the MutYH gene - in 14 patients. According to our results, patients with more than 100 polyps should undergo colectomy before 25 y.o.

Аденоматозные полипозные синдромы являются тяжелыми наследственными заболеваниями, которые характеризуются развитием десятков и сотен полипов в толстой кишке пациента и высоким риском возникновения колоректального рака на их фоне при отсутствии своевременного хирургического лечения. Было проведено молекулярно-генетическое обследование 240 российских пациентов с количеством аденоматозных полипов от 20 до нескольких сотен. Герминальные мутации в гетерозиготном состоянии в гене APC выявлены у 157 человек, а биаллельные мутации в гене MutYH - у 14 больных. Для пациентов с количеством полипов более 100 был определен возраст выполнения операции по удалению толстой кишки - до 25 лет. Adenomatous polyposis syndromes are severe hereditary diseases, characterized by the development of tens and hundreds colonic polyps and an extremely high risk of colorectal cancer without timely surgical treatment. Two hundred and forty Russian patients with more than 20 adenomatous colonic polyps were included in genetic study. Hereditary heterozygous mutations in the APC gene were detected in 157 patients, and biallelic mutations in the MutYH gene - in 14 patients. According to our results, patients with more than 100 polyps should undergo colectomy before 25 y.o.

Purpose: to evaluate the effect of somatic mutations of the KRAS, NRAS, BRAF genes and the status of microsatellite instability on the overall and disease-free survival of patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.Material and Methods. From 2012 to 2018, the study included 45 patients who underwent surgery for synchronous peritoneal carcinomatosis with colorectal cancer. In all patients, mutations of the KRAS, NRAS, BRAF genes and MSI status of the tumor and peritoneum metastases were determined using Sanger sequencing, fragment analysis and digital droplet polymerase chain reaction. The effect of mutations on patient survival was evaluated.Results. The prevalence of somatic mutations was 69 % of patients. The discordance between the tumor and peritoneum metastases was 9 %. All tumors and peritoneum metastases were microsatellite stable. KRAS, NRAS, BRAF mutations did not affect the overall and disease-free survival (p=0.87 and p=0.85, respectively).Conclusion. Somatic mutations in the KRAS, NRAS, or BRAF genes are not a prognostic factor affecting the overall and relapse-free survival of colorectal cancer patients with peritoneal carcinomatosis. The molecular status of primary tumor may differ from the status of peritoneal metastasis. It should be taken into account when prescribing targeted drugs.

AIM: to analyze the literature on the molecular genetic characteristics in patients with peritoneal carcinomatosis and liver metastases of colorectal cancer. PATIENTS AND METHODS: RSCI, Google Scoolar, PubMed, Web of Science databases were used for review. Over 200 literature sources on the given subject were analyzed, of which 67 were included in this review. RESULTS: in the review, the data on molecular genetic changes occurring during peritoneal carcinomatosis and liver metastases in patients with colorectal cancer were presented. The key points for treatment patients with metastatic colorectal cancer were identified. CONCLUSION: the presented data summarizes molecular genetic studies, which in turn enable clinical oncologists, surgeons and chemotherapists to determine treatment modality. CONFLICTS OF INTERESTS: The authors declare no conflicts of interest.

MutYH-associated polyposis (MAP) is hereditary syndrome with autosomal recessive inheritance, caused by biallelic mutation in MutYH gene and characterized by presence of multiple (20 and more) polyps in the bowel and increased life-time risk of colorectal cancer. At the same time finding 2 heterozygous mutations in MutYH gene (by Sanger method) doesn`t mean the diagnosis of MAP because of need to confirm their biallelic location. This case-report demonstrates difficulties in diagnostic of MAP caused by inability to investigate parent DNA samples and our options for solution of this problem.

AIM: to analyze the literature on the molecular genetic characteristics in patients with peritoneal carcinomatosis and liver metastases of colorectal cancer. PATIENTS AND METHODS : RSCI, Google Scoolar, PubMed, Web of Science databases were used for review. Over 200 literature sources on the given subject were analyzed, of which 67 were included in this review. RESULTS: in the review, the data on molecular genetic changes occurring during peritoneal carcinomatosis and liver metastases in patients with colorectal cancer were presented. The key points for treatment patients with metastatic colorectal cancer were identified.  CONCLUSION: the presented data summarizes molecular genetic studies, which in turn enable clinical oncologists, surgeons and chemotherapists to determine treatment modality.

Familial adenomatous polyposis (FAP) is a hereditary syndrome characterized by the presence of multiple adenomatous polyps in the colon.The main cause of the disease is a germline mutation in the APC gene.Here we report 4 unrelated FAP patients with different large deletions in the APC gene detected by Multiplex Ligation-dependent Probe Amplification (MLPA) method: deletion of exons 7-15, deletion of promoters B, A, and 5'-UTR region and deletion of promoter B (in 2 patients).The deletion of promoters B, A, and 5'-UTR was not described in the literature earlier, so we report it for the first time.In 2 families with promoter B deletion, we could identify the tendency for decreasing the age of disease manifestation in each next generation, in contrast to the previous one.The incidence of large deletions in APC among Russian patients with FAP reached 4.8% and our finding suggests the need to study this gene by MLPA in "no mutation patients" after Sanger's sequencing.

Aim. In this research, we aim to develop a criterion for differentiating MutYH-associated polyposis from sporadic colon polyps.Materials and methods. A search for mutations in the MutYH gene was carried out using the PCR, electrophoresis and direct sequencing methods among the following groups of people: 18 patients under 45 years old with more than 100 polyps diagnosed in the large intestine; 86 patients over 45 years old with 4–100 polyps; 150 people of the control group.Results. Mutations in the MutYH gene were detected in 2 out of 18 patients having more than 100 polyps. Among 86 patients with 4–100 polyps, mutations were found in 10 people having more than 20 polyps. Mutations in the MutYH gene were not detected in patients with 4–19 polyps (p <0.05). The pathogenic significance of the disease development was established not only for biallelic, but also for monoallelic mutations.Conclusion. For the first time, the lower limit of the polyp number has been established, allowing the MutYH-associated polyposis to be differentiated from sporadic polyps.

The aim of the research was to study the expression of marker genes for the epithelial-mesenchymal transition in the ductal adenocarcinoma of the pancreas.Material and methods. Surgical material from 44 patients with ductal adenocarcinoma of the pancreas was subjected to morphological analysis with molecular genetic research. Total RNA was detected in the detected sections of the anaplastic component using the RNeasy Mini Kit (Qiagen, Germany). 5 marker genes were used for molecular genetic studies of the epithelial-mesenchymal transition (EMT): ZEB1, ZEB2, CDH1, VIM, SNAIL1 (SLUG). Gene expression was measured in triplicate using an EvaGreen intercalating dye. On serial paraffin sections using tissue microarrays technology, immunohistochemical detection of p63, smooth muscle actin, total cytokeratin, cytokeratin 7, vimentin, E-cadherin (Ventana) was performed.Results. As a result of the study, a positive reaction with mesenchymal markers (vimentin, p63, smooth muscle actin) was detected in the cells of the anaplastic component, in contrast to the glandular component. In a molecular study of the anaplastic component, changes in gene expression were characterized as EMT-positive.Conclusion. The heterogeneity of ductal cancer is manifested in the appearance of an anaplastic (sarcomalike) component, in which the ability of epithelial tumor cells to acquire the property of mesenchymal cells that do not require stroma and have aggressive malignant potential that affects the survival of patients is traced.