Journal
CELL
Volume 173, Issue 2, Pages 499-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2018.02.037
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Funding
- Alex's Lemonade Stand Foundation-Center of Excellence
- Damon Runyon fellowship
- NIH
- DOD Breast Cancer Research Program
- Ludwig grant
- CPRIT [RP120583]
- NIH/NCI [1R01CA178039-01, NCI-P30CA125123]
- DOD Breast Cancer Research Program [BC120604]
- Adrienne Helis Melvin Medical Research Foundation
- [1K99CA212621-01]
- CDMRP [BC120604, 542284] Funding Source: Federal RePORTER
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Genomics has provided a detailed structural description of the cancer genome. Identifying oncogenic drivers that work primarily through dosage changes is a current challenge. Unrestrained proliferation is a critical hallmark of cancer. We constructed modular, barcoded libraries of human open reading frames (ORFs) and performed screens for proliferation regulators in multiple cell types. Approximately 10% of genes regulate proliferation, with most performing in an unexpectedly highly tissue-specific manner. Proliferation drivers in a given cell type showed specific enrichment in somatic copy number changes (SCNAs) from cognate tumors and helped predict aneuploidy patterns in those tumors, implying that tissue-type-specific genetic network architectures underlie SCNA and driver selection in different cancers. In vivo screening confirmed these results. We report a substantial contribution to the catalog of SCNA-associated cancer drivers, identifying 147 amplified and 107 deleted genes as potential drivers, and derive insights about the genetic network architecture of aneuploidy in tumors.
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