In vivo multiplexed interrogation of amplified genes identifies GAB2 as an ovarian cancer oncogene

被引：35

作者：

Dunn, Gavin P. ^{[1
,2
,4
,6
]}

Cheung, Hiu Wing ^{[2
,6
]}

Agarwalla, Pankaj K. ^{[1
,2
,4
,7
]}

Thomas, Sapana ^{[6
]}

Zektser, Yulia ^{[6
]}

Karst, Alison M. ^{[2
,5
]}

Boehm, Jesse S. ^{[6
]}

Weir, Barbara A. ^{[6
]}

Berlin, Aaron M. ^{[6
]}

Zou, Lihua ^{[6
]}

Getz, Gad ^{[6
]}

Liu, Joyce F. ^{[2
,7
]}

Hirsch, Michelle ^{[8
,9
]}

Vazquez, Francisca ^{[6
]}

Root, David E. ^{[6
]}

Beroukhim, Rameen ^{[2
,3
,4
,6
,7
]}

Drapkin, Ronny ^{[2
,5
,8
,9
]}

Hahn, William C. ^{[2
,3
,6
,7
]}

机构：

[1] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA

[2] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

[3] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02215 USA

[4] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02215 USA

[5] Harvard Univ, Sch Med, Ctr Mol Oncol Pathol, Boston, MA 02215 USA

[6] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA

[7] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA

[8] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[9] Harvard Univ, Sch Med, Boston, MA 02115 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2014年 / 111卷 / 03期

基金：

加拿大健康研究院;

关键词：

functional genomics; open reading frame; ORF; BREAST-CANCER; LIVER-CANCER; AMPLIFICATION; TRANSFORMATION; SENSITIVITY; METASTASIS; COMPLEXITY; EXPRESSION; CARCINOMA; SUBTYPES;

D O I：

10.1073/pnas.1311909111

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

High-grade serous ovarian cancers are characterized by widespread recurrent copy number alterations. Although some regions of copy number change harbor known oncogenes and tumor suppressor genes, the genes targeted by the majority of amplified or deleted regions in ovarian cancer remain undefined. Here we systematically tested amplified genes for their ability to promote tumor formation using an in vivo multiplexed transformation assay. We identified the GRB2-associated binding protein 2 (GAB2) as a recurrently amplified gene that potently transforms immortalized ovarian and fallopian tube secretory epithelial cells. Cancer cell lines overexpressing GAB2 require GAB2 for survival and show evidence of phosphatidylinositol 3-kinase (PI3K) pathway activation, which was required for GAB2-induced transformation. Cell lines overexpressing GAB2 were as sensitive to PI3K inhibition as cell lines harboring mutant PIK3CA. Together, these observations nominate GAB2 as an ovarian cancer oncogene, identify an alternative mechanism to activate PI3K signaling, and underscore the importance of PI3K signaling in this cancer

引用

页码：1102 / 1107

页数：6

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