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Significance Activating mutations ofKIT orPDGFRA are initiating events in most gastrointestinal stromal tumors (GISTs) and indeed are present in micro-GISTs, which are asymptomatic subcentimeter lesions found in one-third of the general population. The biological underpinnings of GIST progression are poorly understood. Chromosome 22q deletions are well-recognized abnormalities in GISTs. However, the crucial gene has been unknown. We report recurrent genomic inactivatedDEPDC5 mutations in GISTs. TheDEPDC5 inactivated mutations are prognostic in that they are associated with aggressive GISTs in which they promote GIST progression and reduce sensitivity to KIT inhibitors.

Mutational inactivation of mTORC1 repressor gene DEPDC5 in human gastrointestinal stromal tumors