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A negative genetic interaction map in isogenic cancer cell lines reveals cancer cell vulnerabilities |
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| Authors: | Frederick S Vizeacoumar Megha Chandrashekhar Alla Buzina Jordan T F Young Julian H M Kwan Azin Sayad Patricia Mero Steffen Lawo Hiromasa Tanaka Kevin R Brown Anastasia Baryshnikova Anthony B Mak Yaroslav Fedyshyn Yadong Wang Glauber C Brito Dahlia Kasimer Taras Makhnevych Troy Ketela Alessandro Datti Mohan Babu Andrew Emili Laurence Pelletier Jeff Wrana Zev Wainberg Philip M Kim Robert Rottapel Catherine A O'Brien Brenda Andrews Charles Boone Jason Moffat |
| Institution: | 1. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, , Toronto, Ontario, Canada;2. Donnelly Centre and Banting and Best Department of Medical Research, University of Toronto, , Toronto, Ontario, Canada;3. Department of Molecular Genetics, University of Toronto, , Toronto, Ontario, Canada;4. Campbell Family Institute, Ontario Cancer Institute, Princess Margaret Hospital, University Health Network, , Toronto, Ontario, Canada;5. Department of Biochemistry, Research and Innovation Centre, University of Regina, , Regina, Saskatchewan, Canada;6. Jonnson Comprehensive Cancer Center, Geffen School of Medicine, University of California at Los Angeles, , Los Angeles, California, USA;7. Department of Computer Science, University of Toronto, , Toronto, Ontario, Canada;8. Department of Medical Biophysics, University of Toronto, , Toronto, Ontario, Canada;9. Division of Rheumatology, Department of Medicine, St. Michael's Hospital, , Toronto, Ontario, Canada;10. Department of Laboratory Medicine and Pathology, and Department of Surgery, University of Toronto, , Toronto, Ontario, Canada;11. Department of Surgery, University Health Network, , Toronto, Ontario, Canada |
| Abstract: | Improved efforts are necessary to define the functional product of cancer mutations currently being revealed through large‐scale sequencing efforts. Using genome‐scale pooled shRNA screening technology, we mapped negative genetic interactions across a set of isogenic cancer cell lines and confirmed hundreds of these interactions in orthogonal co‐culture competition assays to generate a high‐confidence genetic interaction network of differentially essential or differential essentiality (DiE) genes. The network uncovered examples of conserved genetic interactions, densely connected functional modules derived from comparative genomics with model systems data, functions for uncharacterized genes in the human genome and targetable vulnerabilities. Finally, we demonstrate a general applicability of DiE gene signatures in determining genetic dependencies of other non‐isogenic cancer cell lines. For example, the PTEN?/? DiE genes reveal a signature that can preferentially classify PTEN‐dependent genotypes across a series of non‐isogenic cell lines derived from the breast, pancreas and ovarian cancers. Our reference network suggests that many cancer vulnerabilities remain to be discovered through systematic derivation of a network of differentially essential genes in an isogenic cancer cell model. |
| Keywords: | genetic interaction genome stability mitotic stress pooled shRNA screening |