Document Detail


Human somatic cell mutagenesis creates genetically tractable sarcomas.
MedLine Citation:
PMID:  25129143     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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.
Authors:
Sam D Molyneux; Paul D Waterhouse; Dawne Shelton; Yang W Shao; Christopher M Watling; Qing-Lian Tang; Isaac S Harris; Brendan C Dickson; Pirashaanthy Tharmapalan; Geir K Sandve; Xiaoyang Zhang; Swneke D Bailey; Hal Berman; Jay S Wunder; Zsuzsanna Iszvak; Mathieu Lupien; Tak W Mak; Rama Khokha
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-8-17
Journal Detail:
Title:  Nature genetics     Volume:  -     ISSN:  1546-1718     ISO Abbreviation:  Nat. Genet.     Publication Date:  2014 Aug 
Date Detail:
Created Date:  2014-8-17     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9216904     Medline TA:  Nat Genet     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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