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Аннотация
Наследственные опухоли молочной железы и яичника относятся к наиболее распространенным разновидностям семейного рака. Полагают, что не менее 10 % случаев рака молочной железы (РМЖ) и около 20–30 % случаев рака яичника (РЯ) вызваны наследственными дефектами генома. Наиболее изученными высокопенетрантными генами, связанными с РМЖ и РЯ, являются BRCA1 и BRCA2 — ключевые компоненты системы репарации двунитевых разрывов ДНК. У некоторых пациенток возникновение РМЖ или РЯ можно объяснить мутациями в других генах, отвечающих за стабильность генома: PALB2, CHEK2, BLM, FANCM, RECQL, MRE11, RAD51C, RAD51D, ATM, NBN, CDH1, TP53 и др. Примечательно, что около половины случаев РМЖ и РЯ с признаками наследственной этиологии до сих пор не имеют генетического объяснения. Развитие неоплазм у гетерозиготных носителей патогенных мутаций, как правило, происходит по двухударному механизму (two-hit), то есть сопровождается соматической инактивацией «нормальной» копии гена. Альтернативным вариантом патогенеза является конститутивное подавление функции пораженного гена (гаплонедостаточность), на фоне которой злокачественная трансформация становится более вероятной. Изначально исследования семейных случаев РМЖ и РЯ были нацелены преимущественно на раннюю диагностику и профилактику возникновения неоплазм. К настоящему времени накоплено множество данных о том, что наследственные раки зачастую имеют молекулярные мишени для таргетного терапевтического воздействия. Так, присутствие наследственных дефектов BRCA1/2 ассоциировано с чувствительностью опухолей к ингибиторам PARP и ДНК-повреждающим платиносодержащим препаратам. В данном обзоре представлены современные сведения о генетических механизмах предрасположенности к РМЖ и РЯ, а также изложены основные подходы к диагностике и лечению данной категории заболеваний.
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