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Article: Human somatic cell mutagenesis creates genetically tractable sarcomas

TitleHuman somatic cell mutagenesis creates genetically tractable sarcomas
Authors
Issue Date2014
Citation
Nature Genetics, 2014, v. 46, n. 9, p. 964-972 How to Cite?
Abstract© 2014 Nature America, Inc. All rights reserved. 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.
Persistent Identifierhttp://hdl.handle.net/10722/292866
ISSN
2023 Impact Factor: 31.7
2023 SCImago Journal Rankings: 17.300
ISI Accession Number ID
Errata

 

DC FieldValueLanguage
dc.contributor.authorMolyneux, Sam D.-
dc.contributor.authorWaterhouse, Paul D.-
dc.contributor.authorShelton, Dawne-
dc.contributor.authorShao, Yang W.-
dc.contributor.authorWatling, Christopher M.-
dc.contributor.authorTang, Qing Lian-
dc.contributor.authorHarris, Isaac S.-
dc.contributor.authorDickson, Brendan C.-
dc.contributor.authorTharmapalan, Pirashaanthy-
dc.contributor.authorSandve, Geir K.-
dc.contributor.authorZhang, Xiaoyang-
dc.contributor.authorBailey, Swneke D.-
dc.contributor.authorBerman, Hal-
dc.contributor.authorWunder, Jay S.-
dc.contributor.authorIzsvák, Zsuzsanna-
dc.contributor.authorLupien, Mathieu-
dc.contributor.authorMak, Tak W.-
dc.contributor.authorKhokha, Rama-
dc.date.accessioned2020-11-17T14:57:23Z-
dc.date.available2020-11-17T14:57:23Z-
dc.date.issued2014-
dc.identifier.citationNature Genetics, 2014, v. 46, n. 9, p. 964-972-
dc.identifier.issn1061-4036-
dc.identifier.urihttp://hdl.handle.net/10722/292866-
dc.description.abstract© 2014 Nature America, Inc. All rights reserved. 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.-
dc.languageeng-
dc.relation.ispartofNature Genetics-
dc.titleHuman somatic cell mutagenesis creates genetically tractable sarcomas-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1038/ng.3065-
dc.identifier.pmid25129143-
dc.identifier.scopuseid_2-s2.0-84922393391-
dc.identifier.volume46-
dc.identifier.issue9-
dc.identifier.spage964-
dc.identifier.epage972-
dc.identifier.eissn1546-1718-
dc.identifier.isiWOS:000341579400010-
dc.relation.erratumdoi:10.1038/ng1214-1372-
dc.relation.erratumeid:eid_2-s2.0-84927556204-
dc.relation.erratumdoi:10.1038/s41588-020-0589-2-
dc.relation.erratumeid:eid_2-s2.0-85079777315-
dc.identifier.issnl1061-4036-

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