title: In vivo multiplexed interrogation of amplified genes identifies GAB2 as an ovarian cancer oncogene.
abstract: 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.
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.
authors.forename: Gavin P
authors.initials: GP
authors.lastname: Dunn
authors.forename: Hiu Wing
authors.initials: HW
authors.lastname: Cheung
authors.forename: Pankaj K
authors.initials: PK
authors.lastname: Agarwalla
authors.forename: Sapana
authors.initials: S
authors.lastname: Thomas
authors.forename: Yulia
authors.initials: Y
authors.lastname: Zektser
authors.forename: Alison M
authors.initials: AM
authors.lastname: Karst
authors.forename: Jesse S
authors.initials: JS
authors.lastname: Boehm
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Weir
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Berlin
authors.forename: Lihua
authors.initials: L
authors.lastname: Zou
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.forename: Joyce F
authors.initials: JF
authors.lastname: Liu
authors.forename: Michelle
authors.initials: M
authors.lastname: Hirsch
authors.forename: Francisca
authors.initials: F
authors.lastname: Vazquez
authors.forename: David E
authors.initials: DE
authors.lastname: Root
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.forename: Ronny
authors.initials: R
authors.lastname: Drapkin
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D016366:Open Reading Frames; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C490895:GAB2 protein, human; D019869:Phosphatidylinositol 3-Kinases
keywords: ORF; functional genomics; open reading frame