BACKGROUND: to find predictive value of KRAS gene’s copy number variation (CNV_KRAS) to anti-EGFR therapy.PATIENTS AND METHODS: a prospective cohort single-center study included 150 patients, 103 patients with colorectal cancer (CRC) and wild-type RAS/BRAF, 39 patients with colorectal cancer with somatic mutations in the KRAS gene, as well as 8 non-oncological patients (as normal controls). CNV_KRAS was determined using digital droplet PCR.RESULTS: the clinically significant CNV_KRAS level of ≥ 9 copies established for a refusal of targeted anti-EGFR therapy. The incidence of clinically significant CNV_KRAS level in patients with wild-type RAS/BRAF was 17% (the first group of patients). Incidence of clinically significant CNV_KRAS level in patients with mutations in the KRAS gene was 3% (the second group of patients). At the I stage of CRC clinically significant CNV_KRAS was not detected in either the first or second group; at the stage II of CRC in the first group — in 14% of patients (3/22), and in the second group — not detected; at the stage III of CRC in the first group — in 21% of patients (8/39), and in the second group of patients — not detected; at the stage IV of CRC in the first group — in 17% (6/35) of patients, and in the second group of patients — in 5% (1/20). Tumor DNA was analyzed in 10 patients with the stage IV CRC from the first group who received anti-EGFR therapy to find out the clinically significant level of CNV_KRAS. Disease control was achieved in 7 out of 10 patients. The median CNV_KRAS score in the remaining three patients was higher than in the disease control group, 9.2 (9.05, 10.10) and 5.38 (4.77, 7.35) (p = 0.017).CONCLUSIONS: detection of CNV_KRAS level of ≥ 9 copies in a malignant colon tumor is a contraindication to targeted therapy. This phenomenon occurs significantly more often in patients without somatic mutations in the RAS genes (KRAS, NRAS) and BRAF, than in patients with point mutations in the KRAS gene (p = 0.02).

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.

Aim: based on literature data and our own experience, to demonstrate the need for a meticulous family history harvesting in patients with suspected hereditary polyposis syndrome, as well as the importance of conducting a complex molecular genetic study. Materials and methods: the most known among hereditary polyposis syndromes is familial adenomatous polyposis (FAP).At the same time, according to the literature, one of the hamartomatous polyposis syndromes- juvenile polyposis - may mimic endoscopic picture of adenomatous polyposis. The article presents a clinical observation of a family whose members have been suspected of having FAP for several years, and only whole-exome sequencing helped to establish the diagnosis of juvenile polyposis syndrome. Results: based on the family history, as well as the clinical picture of the disease, which was somewhat unusual for FAP, the patient underwent whole-exome sequencing, which revealed a previously undescribed pathogenic variant in the SMAD4 gene - c.705dupA (p.Gly236ArgfsTer28). The presence of a similar mutation was also confirmed in 3 close relatives of the patient. Conclusion: taking into account the wide phenotypic variability of manifestations of juvenile polyposis, molecular genetic study of the SMAD4 and BMPR1A genes is of particular importancein patients with a clinic of adenomatous polyposis syndrome and the absence of mutations in the APC and MutYH genes.

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.

Purpose: to study the etiological structure and incidence rate of various genesis optical neuropathies (ON) according to the own observation data. Material and methods. The study is based on the data analysis from a survey of 658 patients (982 eyes) with ON. The results of routine physical examination of all patients were analyzed to determine the genesis of ON. Results. The most common cases of ON were ischemic ON (31.2 % of all cases), as well as optic neuritis (18.3 % of cases). The anterior optic pathway tumor or infiltrative lesions were detected in 9.9 %, dysthyroid ON was found in 7.2 %. Acute and chronic ON with the optic nerve drusen accounted for 12.4 % of all cases of ON, was found in 60.5 % of all patients with the optic nerve drusen. Hereditary ON was found in 10 % of all cases of ON, toxic - in 4,3 % as a result of acute and chronic alcohol intoxication, chronic narcotic poisoning, drug poisoning. Traumatic ON was found in 6.7 % of all cases of ON. Conclusions. The causes of ON are diverse, vary from innate changes to diseases of the optic nerve as a result of serious therapeutic and neurosurgical pathology, which threaten not only the ophthalmologic, but also the life prediction. The patient thorough clinical study is required to determine the disease genesis at the time of ON symptoms identifying.