Advances in Molecular OncologyAdvances in Molecular OncologyУспехи молекулярной онкологии2313-805X2413-3787Publishing House ABV Press61010.17650/2313-805X-2023-10-4-61-75REVIEWОБЗОРНАЯ СТАТЬЯMolecular features of gastrointestinal stromal tumors “wild-type” (KIT/PDGFRA WT)Молекулярные особенности гастроинтестинальных стромальных опухолей «дикого типа» (KIT/PDGFRA WT)https://orcid.org/0000-0003-4767-6983MazurenkoN. N.МазуренкоН. Н.
Russian Federation

Natalia N. Mazurenko.

24 Kashirskoye Shosse, Moscow 115522

Мазуренко Наталья Николаевна.

115522 Москва, Каширское шоссе, 24

nnmazurenko@mail.ruhttps://orcid.org/0000-0001-6169-2723YugayV. V.ЮгайВ. В.
Russian Federation

24 Kashirskoye Shosse, Moscow 115522

115522 Москва, Каширское шоссе, 24

https://orcid.org/0000-0002-3388-7547TsyganovaI. V.ЦыгановаИ. В.
Russian Federation

24 Kashirskoye Shosse, Moscow 115522

115522 Москва, Каширское шоссе, 24

N.N. Blokhin National Medical Russian Research Center of Oncology, Ministry of Health of RussiaФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава России1512202310461752609202315122023Copyright ©; 2023, Mazurenko N.N., Yugay V.V., Tsyganova I.V.Copyright ©; 2023, Мазуренко Н.Н., Югай В.В., Цыганова И.В.2023Mazurenko N.N., Yugay V.V., Tsyganova I.V.Мазуренко Н.Н., Югай В.В., Цыганова И.В.https://creativecommons.org/licenses/by/4.0https://umo.abvpress.ru/jour/article/view/610

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Their main features are the expression of CD117 (KIT) and mutations of KIT or PDGFRA in 85 % of patients. however, 10–15 % of adult GIST and 85 % of pediatric GIST do not have KIT/PDGFRA mutations (KIT/PDGFRA WT GIST or “wild-type” GIST). The prognosis and clinical course of these tumors and GIST with KIT/PDGFRA mutations differ. “Wild-type” GIST are quite heterogeneous group of tumors in terms of clinical phenotype, genetic etiology, and molecular pathways. Gastrointestinal stromal tumors are divided into SDH-deficient and SDH-competent based on the succinate dehydrogenase (SDH) complex. SDH-deficient GIST occur predominantly in children and young patients  with Carney–Stratakis syndrome and Carney triad; there are also sporadic tumors. More than half of SDH-deficient GIST contain mutations in SDHA, SDHB, SDHD or SDHC, while the rest are caused by hypermethylation of the SDHC promoter. SDH-competent “wild-type” GIST include tumors with BRAF, RAS, or NF1 mutations that activate the RAS-RAF-MAPK pathway and KIT/PDGFRA/SDH/RAS-P WT GIST subtype or “quadruple wild type” GIST. The genomic profiles of these tumors and GIST with KIT/PDGFRA mutation or SDH deficiency differ significantly. One of the features of “quadruple wild type” GIST is activation of the FGFR (fibroblast growth factor receptors) signaling pathway due to chimeric FGFR, FGFR mutations, or overexpression of FGF (fibroblast growth factor). Another feature is chimeric genes containing fragments of NTRK, BRAF, FGFR and other genes that behave as oncogene drivers. In “quadruple wild-type” GIST the somatic mutations in TP53, MAX, MEN1, CTNND2, CHD4, ARIDIA and other genes were revealed as well as in the cell cycle genes RB1, CDK4, CDKN1B. There is no specific treatment for patients with “wild-type” GIST; the choice of drug is determined by the genetic disorder. There is a need to improve our understanding of the molecular mechanisms underlying the different GIST subtypes to develop more effective therapeutic approaches.

Гастроинтестинальные стромальные опухоли (ГИСО) – наиболее распространенные мезенхимальные опухоли желудочно-кишечного тракта. Их основными признаками являются экспрессия cD117 (KIT) и мутации в генах KIT или PDGFRA у 85 % пациентов. Однако 10–15 % ГИСО взрослых и 85 % ГИСО детей не имеют мутаций KIT/PDGFRA (ГИСО KIT/PDGFRA WT, или ГИСО «дикого типа»). Прогноз и клиническое течение этих опухолей и ГИСО с мутациями KIT/PDGFRA различаются. Гастроинтестинальные стромальные опухоли «дикого типа» довольно гетерогенная группа опухолей по клиническому фенотипу, генетической этиологии и по молекулярным путям. Гастроинтестинальные стромальные опухоли разделяют на SDH-дефицитные и SDH-компетентные по комплексу сукцинатдегидрогеназы (SDH). SDH-дефицитные ГИСО встречаются преимущественно у детей и молодых пациентов с синдромом Карни–Стратакиса и триадой Карни, есть и спорадические опухоли. Более 50 % SDH-дефицитных ГИСО содержат мутации в генах SDHA, SDHB, SDHD, SDHC, а остальные вызваны гиперметилированием промотора SDHC. SDH-компетентные ГИСО «дикого типа» включают опухоли с мутациями  BRAF, RAS или NF1, которые активируют RAS-RAF-MAPK-путь и подтип ГИСО KIT/PDGFRA/SDH/RAS-P WT, или ГИСО «четырежды дикого типа». Профили генома этих опухолей и ГИСО с мутацией KIT/PDGFRA или дефицитом SDH значительно различаются. Одной из особенностей ГИСО «четырежды дикого типа» является активация  FGFR-сигнального пути (FGFR – рецепторы фактора роста фибробластов) из-за химерных генов FGFR, мутаций FGFR или гиперэкспрессии фактора роста фибробластов (FGF). Еще одной особенностью являются химерные гены, содержащие фрагменты генов NTRK, BRAF,  FGFR и других, которые ведут себя как онкогены-драйверы. В ГИСО «четырежды дикого типа» выявлены соматические мутации генов TP53, MAX, MEN1, CTNND2, CHD4, ARIDIA  и других, а также генов клеточного цикла RB1, CDK4, CDKN1B. Специфического лечения для пациентов с ГИСО «дикого типа» не существует, выбор препарата обусловлен генетическим нарушением. Необходимо совершенствовать понимание молекулярных механизмов, лежащих в основе различных подтипов ГИСО, для разработки более эффективных терапевтических подходов.

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