Mutational inactivation of mTORC1 repressor gene DEPDC5 in human gastrointestinal stromal tumors
Mutational inactivation of mTORC1 repressor gene DEPDC5 in human gastrointestinal stromal tumors
复制标题
人胃肠道间质瘤中 mTORC1 阻遏基因 DEPDC5 的突变失活
DOI：
10.1073/pnas.1914542116
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发表时间：
2019-11-05
影响因子：
11.1
通讯作者：
Wang, Yuexiang
中科院分区：
文献类型：
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作者：
Pang, Yuzhi;Xie, Feifei;Wang, Yuexiang
胃肠道间质瘤（GIST）是最常见的人类肉瘤，由激活KIT或PDGFRA受体酪氨酸激酶突变引发。染色体22 q缺失是公认的GIST中常见的异常，发生在约50%的GIST中。这些缺失被认为是通过目前尚未确定的肿瘤抑制机制促成这种疾病的发病机制。使用全外显子组测序，我们报告复发性基因组失活DEPDC5基因突变的GIST（16.4%，55例患者中的9例）。在纵向标本和来自个体患者的多个转移灶中克隆DEPDC5失活突变的证明表明这些突变在GIST进展中具有致瘤作用。DEPDC5失活促进体外和裸鼠中GIST肿瘤生长。DEPDC5通过mTORC1信号通路减少细胞增殖，随后诱导细胞周期停滞。此外，DEPDC5调节GIST对KIT抑制剂的敏感性，并且mTOR抑制剂和KIT抑制剂的联合治疗可能在DEPDC5失活的GIST患者中更好地起作用。这些复发性基因组改变的发现，以及功能数据，验证了DEPDC 5作为一个真正的肿瘤抑制因子，有助于GIST的进展和频繁的染色体22 q缺失的生物学相关的目标。
Gastrointestinal stromal tumors (GISTs) are the most common human sarcoma and are initiated by activating mutations in the KIT or PDGFRA receptor tyrosine kinases. Chromosome 22q deletions are well-recognized frequent abnormalities in GISTs, occurring in similar to 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 DEPDC5 gene mutations in GISTs (16.4%, 9 of 55 patients). The demonstration of clonal DEPDC5 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.