狭義のGISTの分子生物学的特徴

Molecular Characteristics of GISTs

要旨　gastrointestinal stromal tumor（GIST）の大多数には，c-kit遺伝子に機能獲得性突然変異が認められ，それがGIST発生に必須の役割を果たしていると考えられる．しかし，c-kit変異のみでGISTが発生しうるのかどうかは定かではない．GISTでは悪性度が増すほど，染色体レベルの異常が増えることが示されており，その発生，悪性化にc-kit以外の遺伝子異常の関与も疑われる．一部のc-kit遺伝子変異陰性GISTには血小板由来増殖因子受容体α（PDGFRα）遺伝子に機能獲得性突然変異が認められる．また，c-kit，PDGFRα遺伝子変異の乏しい神経線維腫症1型に合併する多発性GISTも報告されている．分子標的治療の適切な選択を行うためにも，さらなるGISTの発生，悪性化に関する分子メカニズムの解明が必要である．

　Most of gastrointestinal stromal tumors (GISTs) have gain-of-function mutations of the c-kit gene, suggesting that constitutive activation of KIT is a critical event in the development of GISTs. However, it is controversial whether KIT activation solely induces development of GISTs. Additional cytogenetic alterations involving genes other than c-kit, may participate in development and progression of GISTs. Moreover, a minority of GISTs lack c-kit gene mutations and such type of GISTs frequently have activating mutations of platelet-derived growth factor receptor (PDGFR) α gene. Multiple GISTs, which less frequently have mutations of c-kit and PDGFRα gene, develop in patients with neurofibromatosis1. Further studies clarifying molecular mechanisms of GISTs development and progression will be needed for rational selection of patients for molecular targeting therapy.

　1) Department of Pathology, Jichi Medical School, Tochigi, Japan