Denis K. Chernevskiy

Hepatitides of unspecified etiology in children may be caused by genetic disorders. Its early detection can improve the patient management with understanding the pathogenesis, more accurately predicting the course, preventive examinations and prescribing specialized pathogenetic therapy in selected cases. However, currently there are no guidelines for the optimal diagnosis of such cases. The purpose of this research was to develop an algorithm for the differential diagnosis of hepatitides of unspecified etiology in children based on the identified clinical and genetic features of hereditary liver diseases. Materials and methods used: a single-center cohort retrospective study of 179 children with hepatitides of unspecified etiology aged 0 to 18 y/o was conducted. All patients had undergone genetic examination, based on the results of which the two groups were formed as follows: with and without genetic liver disease. Statistical analysis of the patients’ clinical, laboratory and instrumental examinations was aimed at identifying key markers for common hereditary liver diseases in different age groups as well as statistically significant differences in rare genetic reasons for hepatitis. Results: 27 different genetic liver diseases were identified in 101 (56.4%) with hepatitis of unspecified etiology. The most frequently detected diseases were Wilson's disease (41 or 40.6%), alpha-1 antitrypsin deficiency (A1AD or AATD) (9 or 8.9%) and Alagille syndrome (ALGS) (8 or 7.9%). Other hereditary pathologies occurred in isolated cases though its total incidence was nearly half of all cases (43 or 42.6%). In order to identify such cases, it is advisable to perform exome sequencing. In order to determine the indications for genetic examination, Authors have developed the mathematical model for assessing the risk of hereditary liver disease (ROC-AUC 0.787 with 95% CI: 0.696-0.877, sensitivity 69.8% with 95% CI: 57.7%-81.3%, specificity 79.2% with 95% CI: 72.3%-84.8%). Conclusion: Authors offer the suggested algorithm for differential diagnosis of hepatitides of unspecified etiology in children that includes, on the first place, the exclusion of the most common genetic liver diseases followed by exome sequencing in high-risk cases that in its turn is calculated using the developed mathematical model.

Wilson’s disease is severe autosomal recessive disease manifested primarily by hepatic, neurological, and psychiatric disorders due to excessive copper deposition in organs and tissues. Clinical case description. The variant with uncertain clinical value of the ATP7B gene, c.2111C>T (p.T704I, chr13:52534294G>A (HG19)), was described in the family where parents are cousins. The eldest daughter out of four children died at the age of 11 due to liver cirrhosis. Wilson’s disease was genetically confirmed in two children (clinically — abdominal form). The younger son was diagnosed heterozygous state of the disease (without any clinical manifestations). The revealed variant of the ATP7B gene was previously identified in 3 more patients with Wilson’s disease, however, in a compound heterozygous state with known pathogenic genetic variant. Conclusion. c.2111C>T (p.T704I) variant of the ATP7B gene can be considered as probably pathogenic. Further research is required to evaluate its functional significance in Wilson’s disease pathogenesis.

With the development of modern next generation sequencing based DNA diagnostic methods, it has become possible to study hereditary predisposition to oncohematological diseases. Germline variants (mutations) of RUNX1, CEBPA, GATA2, ANKRD26, DDX41, FANC- (Fanconi anemia), etc. genes, associated with the development of hereditary hematological malignancies, have been identified. Timely diagnosis of such diseases will allow for medical genetic counseling and testing of the patient’s relatives to identify or exclude the risk of developing the disease, select a donor for the patient (it is undesirable to use a mutation carrier relative as a donor), and personalize the choice of chemotherapy regimens (for example, patients with Fanconi anemia may experience increased sensitivity to chemotherapy). The aim of this review is to present a modern view of the genetic predisposition to the development of hematological malignancies.

Сегодня результаты развития геномных технологий меняют подход к диагностике и лечению онкологических заболеваний. Так, клинические подходы к профилактике, диагностике и лечению рака молочной железы сместились в сторону использования молекулярно-генетической и иммуногистохимической информации. Целью настоящего обзора является описание возможностей применения различных молекулярно-генетических исследований опухолевой ткани с целью повышения эффективности лечения рака молочной железы. В обзоре обсуждаются результаты применения современных молекулярных (The Cancer Genome Atlas) и иммуногистохимических (суррогатных) маркеров, обеспечивающих разделение РМЖ по молекулярным подтипам, приведены преимущества и недостатки такого разделения. Представлены основные характеристики современных экспрессионных прогностических тестов, обсуждается целесообразность и сложности применения высокопроизводительного секвенирования, в том числе расширенных мультигенных NGS-панелей в клинической практике. Обзор предназначен для ординаторов и аспирантов, врачей-генетиков и врачей-онкологов, использующих в своей работе результаты современных молекулярно-генетических тестов.

Russia and other countries report an increase in the incidence of malignant neoplasms, and approximately 10 % of all oncological cases have hereditary background. Molecular genetic testing in patients with diagnosed malignant neoplasms and a suspected hereditary factor will help to select effective modern methods of treatment and prevention of the development of neoplasms of other localizations. According to the study, 12,6 % of patients had hereditary cancer syndrome, which allowed to administer molecular genetic tests to patients’ relatives. Consequently, it becomes possible to detect hereditary cancer risk factors, improve the efficiency of clinical examination, elaborate and implement programs for prevention and early detection of the disease.

More than 275 million people in the world are carriers of a heterozygous mutation of the CFTR gene, associated with cystic fibrosis, the most common autosomal recessive disease among Caucasians. Some recent studies assessed the association between carriers of CFTR variants and some pathologies, including cancer risk. The aim of this study is to analyze the landscape of germline pathogenic heterozygous CFTR variants in patients with diagnosed malignant neoplasms. For the first time in Russia, we evaluated the frequency of CFTR pathogenic variants by whole-genome sequencing in 1800 patients with cancer and compared this with frequencies of CFTR variants in the control group (1825 people) adjusted for age and 10,000 healthy individuals. In the issue, 47 out of 1800 patients (2.6%) were carriers of CFTR pathogenic genetic variants: 0.028 (42/1525) (2.8%) among breast cancer patients, 0.017 (3/181) (1.7%) among colorectal cancer patients and 0.021 (2/94) (2.1%) among ovarian cancer patients. Pathogenic CFTR variants were found in 52/1825 cases (2.85%) in the control group and 221 (2.21%) in 10,000 healthy individuals. Based on the results of the comparison, there was no significant difference in the frequency and distribution of pathogenic variants of the CFTR gene, which is probably due to the study limitations. Obviously, additional studies are needed to assess the clinical significance of the heterozygous carriage of CFTR pathogenic variants in the development of various pathologies in the future, particularly cancer.

Significance. Malignant neoplasms can be associated with genetic predisposition. Identification of clinically significant mutations enables to determine the risk of neoplasms of other localizations in patients and their relatives. Besides, diagnosis of oncological diseases at an early stage increases the treatment success. One of the objectives of the genetic diagnostics is to reduce the malignant neoplasms associated incidence and mortality in families with a high hereditary risk, thus reducing financial burden of patients and the state. The purpose of the study is to develop a model for assessing medical efficacy and cost effectiveness of early diagnosis of malignant neoplasms based on whole-genome and targeted testing. Material and Methods. To develop a model for assessing medical efficacy and cost effectiveness, the authors used data of the study "Development of a personalized approach in providing medical care to persons with hereditary forms of malignant neoplasms in the Yamalo-Nenets Autonomous Okrug" as well as official data of the Federal State Statistics Service, Pension Fund of Russia, Territorial Compulsory Health Insurance Fund of the Yamalo-Nenets Autonomous Okrug and the Ministry of Economic Development of the Russian Federation. To assess medical efficacy and cost effectiveness, a standard method of cost-benefit analysis was applied to compare social costs in case of genetic testing (whole genome and targeted sequencing) of patients and their relatives and social costs without genetic testing. Results. The use of whole genome and targeted genetic testing in the sample of 200 patients with diagnosed malignant neoplasms, provided the survival of the study participants and their relatives up to retirement age with due regard to demographic indicators, makes it possible to save 1 billion rubles (the cumulative social effect over a 20–year period with the average age of 40 years for patients with pathogenic genetic variants), primarily by reducing mortality. Conclusions. Despite high initial costs of genetic testing, it allows to detect malignant neoplasms at an early stage, which is especially effective for relatives of patients. In the long term, the expenses are more than covered by both saving costs associated with cancer treatment at a late stage, social payments, and other disability benefits, and preserving human capital, especially the labor function of patients.

ЦЕЛЬ ИССЛЕДОВАНИЯ Описание структуры патогенных герминальных вариантов при колоректальном раке в выборке пациентов Москвы. МАТЕРИАЛ И МЕТОДЫ Проведена оценка результатов полногеномного секвенирования ДНК пациентов с колоректальным раком с подозрением на наследственный опухолевый синдром. Все выявленные генетические варианты валидированы с помощью секвенирования по Сэнгеру. РЕЗУЛЬТАТЫ В исследование включены 238 пациентов с диагностированным колоректальным раком, из них у 41 (17,2%) выявлены патогенные герминальные варианты, ассоциированные с наследственными опухолевыми синдромами или повышенным риском развития злокачественных новообразований, из них на синдром Линча приходится 8% всех случаев колоректального рака в исследуемой выборке (19/238), а на аденоматозный полипозный синдром — 1,7% (4/238). Впервые описано 5 новых генетических вариантов в российской выборке пациентов: MLH1 c.1921dup (p.Leu641fs), APC c.2929C>T (p.Gln977Ter), PMS2 c.327del (p.Ala110LeufsTer2), MSH2 c.1857dup (p.Val620CysfsTer24), ATM c.895G>T (p.Glu299Ter). У 197 из 238 пациентов не обнаружено клинически значимых вариантов или выявлены варианты с неопределенной клинической значимостью. ЗАКЛЮЧЕНИЕ По результатам исследования отмечена более ранняя манифестация злокачественного новообразования и более частая встречаемость карцином высокой степени злокачественности при наличии патогенных герминальных мутаций по сравнению с группой пациентов без клинически значимых мутаций, при этом в группе с выявленными мутациями частота регионарного и отдаленного метастазирования не повышена.

The correlation between the risk of death from COVID-19 and the patient's ethnogeographic origin has been previously detected. LZTFL1 gene was identified as a potential marker of a two times higher risk of severe COVID-19. The study was aimed to assess spatial variation in the LZTFL1 SNP markers in indigenous populations of Russia and the world. Spatial variation in the LZTFL1 polymorphic markers was analyzed in 28 metapopulations (97 ethnic groups) of North Eurasia (n = 1980) and 34 world's metapopulations (n = 3637) by bioinformatics, statistical and cartographic methods. In North Eurasia, the major geographic variation vectors, North–South and West–East, are generally in line with the Caucasoid–Mongoloid anthropological vector. Global variation also corresponds to anthropological features: each cluster of indigenous populations includes only those from the place where it originates: Africa, Asia, or America. Indo-European cluster integrates Caucasoid populations of Europe and Asia. All four clusters of the world's indigenous population are separated from each other. The huge genetic diversity of Russia peoples and neighboring countries forms a bridge between three continents: Europe, Asia and America. Cartographic atlas for spatial variation in 11 LZTFL1 markers in the populations has been created. The following major patterns have been revealed: а) the world's extrema fall on the indigenous populations of Africa and America; 2) Eurasia constitutes a transition zone between these two extrema, but has its own patterns and shows enormous scale of variation shows enormous variation on a global scale; 3) the genetic landscape of Russia tends to be seamlessly integrated into the Eurasian landscape.