Молекулярные особенности гастроинтестинальных стромальных опухолей «дикого типа» (KIT/PDGFRA WT)

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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