Profound Tissue Specificity in Proliferation Control Underlies Cancer Drivers and Aneuploidy Patterns
2018
Sack, Laura Magill | Davoli, Teresa | Li, Mamie Z. | Li, Yuyang | Xu, Qikai | Naxerova, Kamila | Wooten, Eric C. | Bernardi, Ronald J. | Martin, Timothy D. | Chen, Ting | Leng, Yumei | Liang, Anthony C. | Scorsone, Kathleen A. | Westbrook, Thomas F. | Wong, Kwok-Kin | Elledge, Stephen J.
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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