Cancer Proliferation Gene Discovery Through Functional Genomics

doi:10.1126/science.1149200

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Cancer Proliferation Gene Discovery Through Functional Genomics

Michael R. Schlabach,¹^* Ji Luo,¹^* Nicole L. Solimini,¹^* Guang Hu,¹^* Qikai Xu,¹ Mamie Z. Li,¹ Zhenming Zhao,¹ Agata Smogorzewska,¹^,2 Mathew E. Sowa,³ Xiaolu L. Ang,³ Thomas F. Westbrook,¹ Anthony C. Liang,¹ Kenneth Chang,⁴ Jennifer A. Hackett,¹ J. Wade Harper,³ Gregory J. Hannon,⁴ Stephen J. Elledge¹

Abstract: Retroviral short hairpin RNA (shRNA)–mediated geneticscreens in mammalian cells are powerful tools for discoveringloss-of-function phenotypes. We describe a highly parallel multiplexmethodology for screening large pools of shRNAs using half-hairpinbarcodes for microarray deconvolution. We carried out dropoutscreens for shRNAs that affect cell proliferation and viabilityin cancer cells and normal cells. We identified many shRNAsto be antiproliferative that target core cellular processes,such as the cell cycle and protein translation, in all cellsexamined. Moreover, we identified genes that are selectivelyrequired for proliferation and survival in different cell lines.Our platform enables rapid and cost-effective genome-wide screensto identify cancer proliferation and survival genes for targetdiscovery. Such efforts are complementary to the Cancer GenomeAtlas and provide an alternative functional view of cancer cells.

¹ Howard Hughes Medical Institute and Department of Genetics, Center for Genetics and Genomics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
² Department of Pathology, Massachusetts General Hospital (MGH), Boston, MA 02114, USA.
³ Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
⁴ Watson School of Biological Sciences, Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.

^* These authors contributed equally to this work.

To whom correspondence should be addressed. E-mail: selledge{at}genetics.med.harvard.edu

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