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

文献类型：期刊论文

作者Pang, Yuzhi1; Xie, Feifei1; Liu, Xiaoxiao1; Lu, Xiaojing1; Li, Ke1; Jia, Xiaona1; Li, Zhang1; Zheng, Xufen1; Wang, Simin1; Wang, Yuexiang1
刊名PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
出版日期2019
卷号116期号:45页码:22746-22753
关键词sarcoma GIST KIT tyrosine kinase inhibitors DEPDC5
ISSN号0027-8424
DOI10.1073/pnas.1914542116
文献子类Article
英文摘要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.
学科主题Gastroenterology & Hepatology
WOS关键词FAMILIAL FOCAL EPILEPSY ; CELL-CYCLE PROGRESSION ; C-KIT ; COMPLEX ; MANAGEMENT ; CANCER ; COMMON ; SUPPRESSOR ; EVEROLIMUS ; DYSTROPHIN
语种英语
CSCD记录号CSCD:31636198
WOS记录号WOS:000494457400052
出版者NATL ACAD SCIENCES
版本出版稿
源URL[http://202.127.25.144/handle/331004/1185]  
专题中国科学院上海生命科学研究院营养科学研究所
作者单位1.Chinese Acad Sci, Univ Chinese Acad Sci,Inst Translat Med,Key Lab T, Mil Med Univ 2,Shanghai Inst Biol Sci,Shanghai In, Changzheng Hosp,Changzheng Hosp Joint Ctr Transla, Shanghai 200031, Peoples R China;
2.Shanghai Jiao Tong Univ, Ren Ji Hosp, Sch Med, Dept Gastrointestinal Surg, Shanghai 200127, Peoples R China;
3.Fudan Univ, Shanghai Canc Ctr, Dept Bone & Soft Tissue Sarcomas, Shanghai 200032, Peoples R China;
4.Fudan Univ, Shanghai Med Coll, Dept Oncol, Shanghai 200032, Peoples R China;
5.Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA;
6.Harvard Med Sch, Boston, MA 02115 USA;
7.Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai Inst Nutr & Hlth, Shanghai Informat Ctr Life Sci, Shanghai 200031, Peoples R China;
8.Shanghai Jiao Tong Univ, Ren Ji Hosp, Sch Med, Dept Pathol, Shanghai 200127, Peoples R China;
9.1 Hosp Jiaxing, Dept Urol, Jiaxing 314000, Peoples R China;
10.Second Mil Med Univ, Changzheng Hosp, Dept Urol, Shanghai 200003, Peoples R China,
推荐引用方式
GB/T 7714		 Pang, Yuzhi,Xie, Feifei,Liu, Xiaoxiao,et al. Mutational inactivation of mTORC1 repressor gene DEPDC5 in human gastrointestinal stromal tumors[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2019,116(45):22746-22753.
APA Pang, Yuzhi.,Xie, Feifei.,Liu, Xiaoxiao.,Lu, Xiaojing.,Li, Ke.,...&,.(2019).Mutational inactivation of mTORC1 repressor gene DEPDC5 in human gastrointestinal stromal tumors.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,116(45),22746-22753.
MLA Pang, Yuzhi,et al."Mutational inactivation of mTORC1 repressor gene DEPDC5 in human gastrointestinal stromal tumors".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 116.45(2019):22746-22753.

入库方式： OAI收割

来源：上海营养与健康研究所

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