oncotomskСибирский онкологический журналSiberian journal of oncology1814-48612312-3168Tomsk National Research Medical Сепtеr of the Russian Academy of Sciences10.21294/1814-4861-2024-23-1-130-141oncotomsk-2957Research ArticleОБЗОРЫREVIEWSРоль молекулярно-генетической диагностики в выборе терапии при опухолях билиарного трактаThe role of molecular diagnostics in the choice of therapy for biliary tract cancershttps://orcid.org/0000-0002-0179-3191МитюшкинаН. В.MitiushkinaN. V.

Митюшкина Наталья Владимировна - кандидат биологических наук, научный сотрудник научной лаборатории молекулярной онкологии.

197758, Санкт-Петербург, пос. Песочный, ул. Ленинградская, 68

Researcher ID (WOS): N-4855-2016; Author ID (Scopus): 8639200300

Natalia V. Mitiushkina - PhD, Researcher, Laboratory of Molecular Oncology, N.N. Petrov National Medical Oncology Research Center of the Ministry of Health of Russia.

68, Leningradskaya St., Saint Petersburg, Pesochny village, 197758

Researcher ID (WOS): N-4855-2016; Author ID (Scopus): 8639200300

nmmail@inbox.ruhttps://orcid.org/0000-0003-4529-7891ИмянитовЕ. Н.ImyanitovE. N.

Имянитов Евгений Наумович - доктор медицинских наук, профессор, член-корреспондент РАН, руководитель научного отдела.

197758, Санкт-Петербург, пос. Песочный, ул. Ленинградская, 68

Evgeny N. Imyanitov - MD, Professor, Corresponding Member of the Russian Academy of Sciences, Head of the Department of Tumor Biology, N.N. Petrov National Medical Oncology Research Center of the Ministry of Health of Russia.

68, Leningradskaya St., Saint Petersburg, Pesochny village, 197758

ФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Петрова» Минздрава РоссииРоссияN.N. Petrov National Medical Oncology Research Center of the Ministry of Health of RussiaRussian Federation202421032024231130141Copyright © Митюшкина Н.В., Имянитов Е.Н., 20242024Митюшкина Н.В., Имянитов Е.Н.Mitiushkina N.V., Imyanitov E.N.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.siboncoj.ru/jour/article/view/2957

Цель исследования – оценить частоту и клиническое значение различных молекулярно-генетических нарушений при опухолях билиарного тракта и определить оптимальные методы их тестирования. Материал и методы. Проведен поиск литературных источников, содержащих сведения о предиктивных молекулярных маркерах, имеющих значение для выбора терапии при опухолях билиарного тракта, в базах данных PubMed и eLibrary за период с 2010 по 2023 г. В обзор включены данные 60 исследований. Результаты. Опухоли билиарного тракта отличаются плохим прогнозом и низкой чувствительностью к основным видам системной терапии. Тем не менее появление новых таргетных препаратов и назначение терапии на основе результатов молекулярно-генетического анализа могут увеличить продолжительность и улучшить качество жизни значительной части пациентов. К наиболее часто выявляемым во всех опухолях билиарного тракта клинически значимым нарушениям относятся амплификация/гиперэкспрессия гена HER2 (5–20 % случаев), микросателлитная нестабильность (1–2 % случаев), мутация онкогена BRAF V600E (1–2 % случаев) и мутация онкогена KRAS G12C (около 1 % случаев). К специфическим таргетируемым нарушениям, характерным только для холангиокарцином внутрипеченочной локализации, относятся аберрации гена, кодирующего рецептор фактора роста фибробластов 2, FGFR2 (10–20 % случаев) и мутации в гене, кодирующем фермент изоцитратдегидрогеназу 1, IDH1 (5–30 % случаев). К очень редким для опухолей билиарного тракта клинически значимым молекулярным маркерам относятся транслокации с участием генов рецепторных тирозинкиназ NTRK1-3, RET, ALK и ROS1. Также потенциально значимыми для выбора терапии являются мутации в генах системы репарации двунитевых разрывов ДНК по механизму гомологичной рекомбинации. Прежде всего, это гены BRCA1/2, наследственные мутации в которых, по данным двух исследований, характерны для 5–7 % пациентов с билиарным раком. Хотя значительная часть вышеперечисленных нарушений может быть выявлена при помощи традиционных молекулярно-биологических подходов, таких как ПЦР, ИГХ, FISH и секвенирование методом Сэнгера, комплексный анализ всех молекулярных маркеров, имеющих предиктивное значение при опухолях билиарного тракта, сложно осуществить без помощи секвенирования нового поколения (NGS). Заключение. Для улучшения результатов лечения пациентов с распространенным и метастатическим раком билиарного тракта путем индивидуализации лекарственной терапии необходимо проводить комплексный молекулярно-генетический анализ опухолевой ткани.

The aim of the study was to assess the frequency and clinical significance of various molecular genetic aberrations in biliary tract tumors and to determine the optimal methods of their testing. Material and Methods. We searched the literature sources containing information on predictive molecular markers relevant for the choice of therapy in biliary tract tumors in PubMed and eLibrary databases for the period from 2010 to 2023. data from 60 studies were included in this review. Results. Biliary tract tumors are characterized by poor prognosis and low sensitivity to major systemic therapies. Nevertheless, the emergence of new targeting drugs and prescription of therapy based on the results of molecular genetic analysis can increase the life expectancy and improve the quality of life of a significant proportion of patients. The most frequently detected clinically significant abnormalities in all biliary tract tumors include HER2 gene amplification/hyperexpression (5–20 % of cases), microsatellite instability (1–2 % of cases), BRAF V600E oncogene mutation (1–2 % of cases) and KRAS G12C oncogene mutation (about 1 % of cases). Specific targetable abnormalities unique to intrahepatic cholangiocarcinomas include aberrations in the gene encoding fibroblast growth factor receptor 2, FGFR2 (10–20 % of cases) and mutations in the gene encoding the enzyme isocitrate dehydrogenase 1, IDH1 (5–30 % of cases). Very rare clinically significant molecular markers for biliary tract tumors include translocations involving the receptor tyrosine kinase genes NTRK1-3, RET, ALK and ROS1. Mutations in the genes of the dNA double-strand break repair system by the mechanism of homologous recombination are also potentially significant for the choice of therapy. First of all, these are BRCA1/2 genes, hereditary mutations in which, according to two studies, are characteristic of 5–7 % of patients with biliary cancer. Although a significant part of the above-mentioned disorders can be detected by traditional molecular biological approaches such as PCR, IHC, FISH and Sanger sequencing, a comprehensive analysis of all molecular markers of predictive value in biliary tract tumors is difficult to perform without the help of next-generation sequencing (NGS). Conclusion. To improve treatment outcomes of patients with advanced and metastatic biliary tract cancer by individualizing drug therapy, it is necessary to perform comprehensive molecular genetic analysis of tumour tissue.

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The authors declare that there are no conflicts of interest present.