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

Gavin P. Dunn, Hiu Wing Cheung, Pankaj K. Agarwalla, Sapana Thomas, Yulia Zektser, Alison M. Karst, Jesse S. Boehm, Barbara A. Weir, Aaron M. Berlin, Lihua Zou, Gad Getz, Joyce F. Liu, Michelle Hirsch, Francisca Vazquez, David E. Root, Rameen Beroukhim, Ronny Drapkin, William C. Hahn*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1102-1107
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number3
DOIs
StatePublished - Jan 21 2014

Keywords

  • Functional genomics
  • ORF
  • Open reading frame

ASJC Scopus subject areas

  • General

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