Mutational inactivation of mTORC1 repressor gene <i>DEPDC5</i> in human gastrointestinal stromal tumors.

Abstract

Gastrointestinal stromal tumors (GISTs) are the most common human sarcoma and are initiated by activating mutations in the <i>KIT</i> or <i>PDGFRA</i> receptor tyrosine kinases. Chromosome 22q deletions are well-recognized frequent abnormalities in GISTs, occurring in ∼50% of GISTs. These deletions are thought to contribute to the pathogenesis of this disease via currently unidentified tumor suppressor mechanisms. Using whole exome sequencing, we report recurrent genomic inactivated <i>DEPDC5</i> gene mutations in GISTs (16.4%, 9 of 55 patients). The demonstration of clonal <i>DEPDC5</i> inactivation mutations in longitudinal specimens and in multiple metastases from individual patients suggests that these mutations have tumorigenic roles in GIST progression. DEPDC5 inactivation promotes GIST tumor growth in vitro and in nude mice. DEPDC5 reduces cell proliferation through the mTORC1-signaling pathway and subsequently induces cell-cycle arrest. Furthermore, DEPDC5 modulates the sensitivity of GIST to KIT inhibitors, and the combination therapy with mTOR inhibitor and KIT inhibitor may work better in GIST patients with DEPDC5 inactivation. These findings of recurrent genomic alterations, together with functional data, validate the DEPDC5 as a bona fide tumor suppressor contributing to GIST progression and a biologically relevant target of the frequent chromosome 22q deletions.