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Human somatic cell mutagenesis creates genetically tractable sarcomas

Official URL:https://doi.org/10.1038/ng.3065
PubMed:View item in PubMed
Creators Name:Molyneux, S.D. and Waterhouse, P.D. and Shelton, D. and Shao, Y.W. and Watling, C.M. and Tang, Q.L. and Harris, I.S. and Dickson, B.C. and Tharmapalan, P. and Sandve, G.K. and Zhang, X. and Bailey, S.D. and Berman, H. and Wunder, J.S. and Izsvak, Z. and Lupien, M. and Mak, T.W. and Khokha, R.
Journal Title:Nature Genetics
Journal Abbreviation:Nat Genet
Volume:46
Number:9
Page Range:964-972
Date:September 2014
Keywords:Cell Line, DNA Transposable Elements, Genetic Vectors, HEK293 Cells, Human Genome, Insertional Mutagenesis, RNA-Binding Proteins, Retroviridae, Sarcoma
Abstract:Creating spontaneous yet genetically tractable human tumors from normal cells presents a fundamental challenge. Here we combined retroviral and transposon insertional mutagenesis to enable cancer gene discovery starting with human primary cells. We used lentiviruses to seed gain- and loss-of-function gene disruption elements, which were further deployed by Sleeping Beauty transposons throughout the genome of human bone explant mesenchymal cells. De novo tumors generated rapidly in this context were high-grade myxofibrosarcomas. Tumor insertion sites were enriched in recurrent somatic copy-number aberration regions from multiple cancer types and could be used to pinpoint new driver genes that sustain somatic alterations in patients. We identified HDLBP, which encodes the RNA-binding protein vigilin, as a candidate tumor suppressor deleted at 2q37.3 in greater than one out of ten tumors across multiple tissues of origin. Hybrid viral-transposon systems may accelerate the functional annotation of cancer genomes by enabling insertional mutagenesis screens in higher eukaryotes that are not amenable to germline transgenesis.
ISSN:1061-4036
Publisher:Nature Publishing Group (U.S.A.)
Item Type:Article

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