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Cell ; 173(2): 499-514.e23, 2018 04 05.
Article in English | MEDLINE | ID: mdl-29576454

ABSTRACT

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.


Subject(s)
Aneuploidy , Neoplasms/pathology , Animals , Cell Line, Tumor , Cell Proliferation , Chromosome Mapping , Chromosomes/genetics , E2F1 Transcription Factor/antagonists & inhibitors , E2F1 Transcription Factor/genetics , E2F1 Transcription Factor/metabolism , Female , Gene Library , Genomics , Humans , Keratins/metabolism , Mice , Mice, Inbred NOD , Mice, SCID , Oncogenes , Open Reading Frames/genetics , RNA Interference , RNA, Small Interfering/metabolism
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