Irina Yu. Efimova

Research Centre for Medical Genetics

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Andrey V. Marakhonov

Research Centre for Medical Genetics

S.V. Voronin

Research Centre for Medical Genetics

Sergey I. Kutsev

Research Centre for Medical Genetics

Anna Mukhinа

Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology

Anna Shcherbina

Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology

РА

Р. А. Зинченко

Research Centre for Medical Genetics

Oleg I. Kit

Rostov Research Institute of Oncology

Natalia Balinova

Research Centre for Medical Genetics

Dmitry Pershin

Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology

D. I. Vodolazhsky

Research Institute of Agriculture of Crimea

Cooperative Institutions

Ministry of Health of the Russian Federation

Research Centre for Medical Genetics

Rostov Research Institute of Oncology

Russian Academy of Sciences

Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology

Research Institute of Medical Genetics of Russian Academy of Medical Sciences

Academy of Medical Sciences

Pirogov Russian National Research Medical University

Sechenov University

Moscow Clinical Scientific Center

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Epidemiology of Spinal Muscular Atrophy Based on the Results of a Large-Scale Pilot Project on 202,908 Newborns

Pediatric Neurology (2024)

Irina Yu. Efimova Р. А. Зинченко Andrey V. Marakhonov Natalia Balinova Kristina Mikhalchuk

10.1016/j.pediatrneurol.2024.04.015

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Advanced neonatal screening for hereditary diseases in Russia: first results and future prospects

PEDIATRIA Journal named after G N SPERANSKY (2024)

S.V. Voronin Ekaterina Zakharova Galina Baydakova Andrey V. Marakhonov Olga Shchagina

Under the implementation of the “Advanced neonatal screening” Federal Program and the Ministry of Healthcare of Russia Order No. 274n “On approval of the Procedure for providing medical care to patients with congenital and/or hereditary diseases” that started jointly on Jan. 01, 2023 overall Russia, the examination of all newborns for the 29 nosologies of exchange disorders by tandem mass spectrometry as well as spinal muscular atrophy and primary immunodeficiencies by polymerase chain reaction had begun. Circa 1 million and 230 thousand newborns were examined in 85 Russia regions during 2023 with the level of births coverage exceeding 98%. As a result, a risk group that amounted to 1.86% of all examined was formed with confirming diagnostics performed for 8712 neonatal patients at risk, of which 676 have had their deceases confirmed including 379 hereditary metabolic diseases, 117 spinal muscular atrophies and 180 primary immunodeficiencies. Effective treatment and dispensary follow-up methods have been developed so far for all the screened nosologies. Thus, the introduction of the neonatal screening made it possible to initiate therapy for most of the identified patients at preclinical stages reducing the overall infant mortality and improving the quality of life for such patients and their caretakers.

Christian ministry

10.24110/0031-403x-2024-103-1-16-29

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CPG-METHYLATION OF THE PROMOTER APC, CDH13, MLH1, MGMT, P16, RASSF1A GENES IN COLORECTAL CANCER PATIENTS

Natalia A. Petrusenko Nadezhda V. Nikolaeva Natalya N. Timoshkina Д. В. Бурцев D. I. Vodolazhsky

Aim - quantitative analysis of CpG-methylation of oncosuppressor gene APC, CDH13, MLH1, MGMT, P16 and RASSF1A in bi-opsies of normal and tumor tissue and the identification of activating SNP mutations in KRAS, NRAS, BRAF genes in colorectal cancer. Methods. The level of methylation (Met, %) of 65 CpG-sites was determined in tumors and conditionally normal tissue of 50 pa-tients (median age 60.5 years) with sporadic colorectal cancer (CRC) using the method of bisulphite pyrosequencing. Mutations in the KRAS and NRAS genes were determined by direct Sanger sequencing, the V600E mutation in the BRAF were by the Real-Time-PCR method. Results. Samples of tumors with significantly increased methylation level of promoter sites of all the investigated genes were detect-ed in the sample (3–5 times for p <0.01). The hypermethylation status of APC, CDH13, MGMT, P16 and RASSF1A was revealed with the formation of metastases (χ2 = 7.3, p = 0.007). The mutation BRAF V600E was not identified. 7 types of mutations in the KRAS gene and one mutation in the NRAS gene were identified in 19 patients (38 %). The majority of activating mutations in the KRAS gene were identified in tumors with metastases to regional lymph nodes (58 %). CpG-hypermethylation for at least one gene and the presence of an activating mutation in the KRAS gene increases the risk of metastasis by 2.6 times (OR-2.63; CI 95 %: 1.15–6.09, p <0.05). Conclusions. Using the pyrosequencing method, it was possible to demonstrate a statistically significant increase in the level of methylation of the promoter sites of the gene APC, CDH13, MGMT, MLH1, P16, RASSF1A in adenocarcinomas (G2-3) compared to samples of conventionally normal colon tissue in 32, 34, 55, 28, 4, 26 and 8 % of the cases, respectively. Aberrant methylation of the proposed gene pattern is significantly more frequent in colon malignant tumors with regional and dis-tant metastases (χ2 = 7.3, p = 0.007). The presence of hypermethylation of one or more loci (APC, CDH13, MGMT, MLH1, P16, RASSF1A) in medium and low grade CRC-tumors bearing an SNP-activating mutation in the KRAS gene significantly increases the risk of metastasis (p <0.05) .

MLH1

CpG site

Bisulfite sequencing

10.23683/0321-3005-2017-3-2-111-117

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ABERRANT METHYLATION OF THE PROMOTER OF APC, CDH13 AND MGMT GENES IN COLORECTAL CANCER PATIENTS

Siberian Journal of Oncology (2016)

Oleg I. Kit D.I. Vodolazhskiy К. В. Двадненко Irina Yu. Efimova Elena Oleynikova

Aberrant methylation of gene promoter regions is the main epigenetic change characterizing colorectal cancer. Methylation levels of 42 CpG-sites of promoter regions of the MGMT, APC and CDH13 genes in colorectal cancer were studied in comparison with methylation levels of the adjacent normal tissue in 25 patients. Pyrosequencing showed an increase in methylation levels of promoter regions of the MGMT, APC and CDH13 genes in tumor samples by 3 to 5 times. These tumor samples were screened for activating SNP-mutations in the KRAS (40 %), NRAS (0 %) and BRAF (0 %) oncogenes. SNP-mutations in the KRAS gene were accompanied by hypermethylation of one or more promoters of the studied genes. Association of this epigenetic index with tumor metastasis was proved. The data on an increase in methylation of the promoter regions of oncosupressor genes can be used as sensitive prognostic markers of progression and metastasis of colorectal cancer.

CpG site

10.21294/1814-4861-2016-15-2-48-55

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Newborn screening for primary immunodeficiencies as a way to detect syndromal disorders in neonates: a clinical case of 22q11.2DS syndrome

Pediatric Hematology/Oncology and Immunopathology (2022)

Irina Yu. Efimova Anna Mukhinа Natalia Balinova S. A. Matulevich Dmitry Pershin

One of the main goals of newborn screening is the early detection of a number of severe disorders for which effective treatment is available, and early diagnosis prevents serious consequences. Primary immunodeficiencies (PIDs) are a heterogeneous group of congenital immune disorders and are urgent immunological conditions requiring prompt diagnosis and treatment. Screening for primary immunodeficiencies using T-cell receptor excision circles (TREC) is used in many countries around the world. However, in addition to severe combined immunodeficiency, other forms of PIDs with T cell deficiency such as 22q11.2 deletion syndrome (22q11.2DS), CHARGE syndrome, trisomy 21, etc., can be detected during newborn screening. 22q11.2DS syndrome is one of the most common chromosomal microdeletion syndromes with an estimated prevalence of 1 in 3000–6000 births. The clinical manifestations of 22q11.2DS are quite variable. Neonatal diagnosis is traditionally based on the recognition of classic features and cytogenetic testing but many patients only come to medical attention after later symptoms have been identified. Still, the early diagnosis of 22q11.2DS ensures adequate treatment and the highest possible quality of life in such patients. Here, we report a clinical case of 22q11.2DS syndrome identified during a pilot project of newborn screening for primary immunodeficiencies in the Russian Federation in 2022. The patient’s parents gave their consent to the use of their child's data, including photographs, for research purposes and in publications.

Deletion syndrome

DiGeorge syndrome

Primary Immunodeficiency

Microdeletion syndrome

Trisomy

10.24287/1726-1708-2022-21-4-158-162

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Citations (1)

A Rare Case of TP63-Associated Lymphopenia Revealed by Newborn Screening Using TREC

International Journal of Molecular Sciences (2024)

Andrey V. Marakhonov Elena Serebryakova Anna Mukhinа Anastasia O. Vechkasova Nikolai S. Prokhorov

The expanded newborn screening (NBS) program in the Russian Federation was initiated in 2023, among which severe combined immunodeficiency (SCID) is screened using TREC/KREC assays. Here, we report a rare case of a

10.3390/ijms251910844

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Identification of a spectrum of germline mutations for hereditary diffuse gastric cancer in the Russian population by next-generation sequencing

Annals of Oncology (2019)

Irina Yu. Efimova E. Ignatova И И Быков Alexey I. Kalinkin А. С. Танас

Sanger sequencing

STK11

10.1093/annonc/mdz247.152

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Association between promoter hypermethylation of APC, CDH13, MLH1 and MGMT genes and colorectal cancer metastasis.

Journal of Clinical Oncology (2016)

Oleg I. Kit D. I. Vodolazhsky К. В. Двадненко Elena Oleynikova Denis D. Oleynikov

e15066 Background: Aberrant methylation of CpG sites within promoter regions of cancer-related genes is an important epigenetic event in carcinogenesis. The frequency of methylation changes of different genes in sporadic colorectal cancer (CRC), according to various estimates, varies from 15 to 80% which allows the use of this indicator for the development of new prognostic biomarkers of CRC. Methods: Methylation was quantified at 47 CpG-sites within promoter regions of four genes (MGMT, APC, CDH13 and MLH1) in colorectal tumors and normal colorectal tissue using bisulfite pyrosequencing. 25 patients (aged 50 to 81 years, median age 59) received surgery for sporadic colorectal cancer at Rostov Research Institute of Oncology. The sample of histologically confirmed CRC included G2-G3 adenocarcinoma with 10 T3N0M0 tumors, 15 tumors with metastases to regional lymph nodes and/or distant metastases (T3-4N1-2M0-1). Results: Methylation of the MGMT, APC and CDH13 promoter regions increased by 3-5 times in 40%, 40% and 58% of tumors, respectively. 20 (80%) CRC samples showed CpG-hypermethylation of at least one gene, 4 of them (16%) were hypermethylated in all three genes (the difference in methylation level between colorectal tumors and normal tissue was significant at p < 0.01). Association between methylation status of MGMT, APC and CDH13 and metastasis development was found (χ2 = 6.52, p = 0.017). At the same time, there was no correlation of age and sex of the patients with methylation level of the investigated CpG sites in normal tissue, as well as with frequency of CpG-hypermethylation in tumor tissue. Pyrosequencing showed only one case of CpG-hypermethylation (38%) of the MLH1 promoter. Conclusions: The data on increase in methylation of promoter regions of the three genes MGMT, APC and CDH13 can be used as sensitive predictive markers of CRC progression and metastasis.

MLH1

CpG site

Bisulfite sequencing

10.1200/jco.2016.34.15_suppl.e15066

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Routing improvement in the expanded neonatal screening system for primary immunodeficiencies diagnosis

PEDIATRIA Journal named after G N SPERANSKY (2024)

Andrey V. Marakhonov Anna Mukhinа Galina Baydakova Irina Yu. Efimova M.P. Petrik

Expanded neonatal screening (ENS) system is a crucial invention that was aimed at reducing infant mortality by enabling the early detection and treatment of severe and life-threatening conditions. Since its Russia-wide implementation in 2023 ENS had successfully identified hundreds of cases of newborns at risk allowing further timely medical intervention that often happened even at a pre-symptomatic stage. However, further optimization of patient routing algorithms within ENS is necessary in order to enhance the identification of newborns at risk and expedite their diagnosis and treatment. This manuscript focuses on optimizing of the routing algorithms specifically for newborns with suspected adenosine deaminase (ADA) deficiency, a severe form of primary immunodeficiency. Given the unique therapeutic and preventive measures required for these patients, the proposed guidelines expand the criteria for referring newborns for confirmatory diagnostics based on nucleoside metabolism data obtained from tandem mass spectrometry of dried blood spots. These improvements are aimed to the earliest detection and targeted treatment of newborns with ADA deficiency thereby enhancing the overall efficiency of primary immunodeficiency screening in Russia.

Primary (astronomy)

10.24110/0031-403x-2024-103-6-134-139

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Association between braf gene mutation status and clinical-morphological features of cutaneous melanoma

DOAJ (DOAJ: Directory of Open Access Journals) (2016)

Oleg I. Kit D. I. Vodolazhsky E. Yu. Zlatnik Irina Yu. Efimova Sergey Kochuev

Association (psychology)

10.25207/1608-6228-2016-3-67-71

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