Defining a Cancer Dependency Map

Aviad Tsherniak; Francisca Vazquez; Phil G Montgomery; Barbara A Weir; Gregory Kryukov; Glenn S Cowley; Stanley Gill; William F Harrington; Sasha Pantel; John M Krill-Burger; Robin M Meyers; Levi Ali; Amy Goodale; Yenarae Lee; Guozhi Jiang; Jessica Hsiao; William F J Gerath; Sara Howell; Erin Merkel; Mahmoud Ghandi; Levi A Garraway; David E Root; Todd R Golub; Jesse S Boehm; William C Hahn

doi:10.1016/j.cell.2017.06.010

Defining a Cancer Dependency Map

Cell. 2017 Jul 27;170(3):564-576.e16. doi: 10.1016/j.cell.2017.06.010.

Authors

Aviad Tsherniak¹, Francisca Vazquez², Phil G Montgomery¹, Barbara A Weir², Gregory Kryukov², Glenn S Cowley¹, Stanley Gill², William F Harrington¹, Sasha Pantel¹, John M Krill-Burger¹, Robin M Meyers¹, Levi Ali¹, Amy Goodale¹, Yenarae Lee¹, Guozhi Jiang¹, Jessica Hsiao¹, William F J Gerath¹, Sara Howell¹, Erin Merkel¹, Mahmoud Ghandi¹, Levi A Garraway³, David E Root¹, Todd R Golub⁴, Jesse S Boehm¹, William C Hahn⁵

Affiliations

¹ Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, MA, USA.
² Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, MA, USA; Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, USA.
³ Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, MA, USA; Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, USA; Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, USA; Harvard Medical School, 25 Shattuck Street, Boston, MA, USA; Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, MD, USA.
⁴ Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, MA, USA; Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, USA; Harvard Medical School, 25 Shattuck Street, Boston, MA, USA; Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, MD, USA.
⁵ Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, MA, USA; Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, USA; Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, USA; Harvard Medical School, 25 Shattuck Street, Boston, MA, USA. Electronic address: william_hahn@dfci.harvard.edu.

Abstract

Most human epithelial tumors harbor numerous alterations, making it difficult to predict which genes are required for tumor survival. To systematically identify cancer dependencies, we analyzed 501 genome-scale loss-of-function screens performed in diverse human cancer cell lines. We developed DEMETER, an analytical framework that segregates on- from off-target effects of RNAi. 769 genes were differentially required in subsets of these cell lines at a threshold of six SDs from the mean. We found predictive models for 426 dependencies (55%) by nonlinear regression modeling considering 66,646 molecular features. Many dependencies fall into a limited number of classes, and unexpectedly, in 82% of models, the top biomarkers were expression based. We demonstrated the basis behind one such predictive model linking hypermethylation of the UBB ubiquitin gene to a dependency on UBC. Together, these observations provide a foundation for a cancer dependency map that facilitates the prioritization of therapeutic targets.

Keywords: RNAi screens; cancer dependencies; cancer targets; genetic vulnerabilities; genomic biomarkers; precision medicine; predictive modeling; seed effects; shRNA.

MeSH terms

Cell Line, Tumor
Humans
Neoplasms / genetics*
Neoplasms / pathology*
RNA Interference
Software
Ubiquitin / genetics

Substances

Ubiquitin

Abstract

MeSH terms

Substances

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