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dc.contributor.authorWang, Guangchuan
dc.contributor.authorChow, Ryan D.
dc.contributor.authorYe, Lupeng
dc.contributor.authorGuzman, Christopher D.
dc.contributor.authorDai, Xiaoyun
dc.contributor.authorDong, Matthew B.
dc.contributor.authorZhang, Feng
dc.contributor.authorPlatt, Randall Jeffrey
dc.contributor.authorChen, Sidi
dc.contributor.authorSharp, Phillip A.
dc.date.accessioned2018-10-11T14:38:33Z
dc.date.available2018-10-11T14:38:33Z
dc.date.issued2018-02
dc.date.submitted2017-08
dc.identifier.issn2375-2548
dc.identifier.urihttp://hdl.handle.net/1721.1/118426
dc.description.abstractCancer genomics consortia have charted the landscapes of numerous human cancers. Whereas somemutations were found in classical oncogenes and tumor suppressors, others have not yet been functionally studied in vivo. To date, a comprehensive assessment of how these genes influence oncogenesis is lacking. We performed direct highthroughput in vivo mapping of functional variants in an autochthonous mouse model of cancer. Using adenoassociated viruses (AAVs) carrying a single-guide RNA (sgRNA) library targeting putative tumor suppressor genes significantly mutated in human cancers, we directly pool-mutagenized the livers of Cre-inducible CRISPR (clustered regularly interspaced short palindromic repeats)-associated protein 9 (Cas9) mice. All mice that received the AAV-mTSG library developed liver cancer and diedwithin 4 months.We usedmolecular inversion probe sequencing of the sgRNA target sites to chart the mutational landscape of these tumors, revealing the functional consequence of multiple variants in driving liver tumorigenesis in immunocompetent mice. AAV-mediated autochthonous CRISPR screens provide a powerful means for mapping a provisional functional cancer genome atlas of tumor suppressors in vivo.en_US
dc.description.sponsorshipDamon Runyon Cancer Research Foundation (DRG-2117-12; DFS-13-15)en_US
dc.description.sponsorshipMelanoma Research Foundation (412806, 16-003524)en_US
dc.description.sponsorshipSt. Baldrick’s Foundation (426685)en_US
dc.description.sponsorshipAmerican Cancer Society (IRG 58-012-54)en_US
dc.description.sponsorshipCancer Research Institute (New York, N.Y.)en_US
dc.description.sponsorshipBreast Cancer Allianceen_US
dc.description.sponsorshipCancer Research Institute (New York, N.Y.) (Clinic and Laboratory Integration Program)en_US
dc.description.sponsorshipAmerican Association for Cancer Research (499395)en_US
dc.description.sponsorshipUnited States. Department of Defense (W81XWH-17-1-0235)en_US
dc.description.sponsorshipNational Cancer Institute (U.S.) (1U54CA209992)en_US
dc.description.sponsorshipNational Cancer Institute (U.S.) (5P50CA196530-A10805)en_US
dc.description.sponsorshipNational Cancer Institute (U.S.) (4P50CA121974-A08306)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (R01-CA133404)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (R01-GM034277)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (CCNE)en_US
dc.description.sponsorshipSkolkovo Foundationen_US
dc.description.sponsorshipCasimir-Lambert Funden_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (grant 1R01-HG009761)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (grant R01-MH110049)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (grant DP1-HL141201)en_US
dc.description.sponsorshipHoward Hughes Medical Instituteen_US
dc.description.sponsorshipNew York Stem Cell Foundationen_US
dc.description.sponsorshipSimons, Paul G. Allen Familyen_US
dc.description.sponsorshipVallee Foundationsen_US
dc.description.sponsorshipPoitras Center for Affective Disorders Research at MITen_US
dc.description.sponsorshipHock E. Tan and K. Lisa Yang Center for Autism Research at MITen_US
dc.publisherAmerican Association for the Advancement of Science (AAAS)en_US
dc.relation.isversionofhttp://dx.doi.org/10.1126/SCIADV.AAO5508en_US
dc.rightsCreative Commons Attribution-NonCommercial 4.0 Internationalen_US
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/en_US
dc.sourceScience Advancesen_US
dc.titleMapping a functional cancer genome atlas of tumor suppressors in mouse liver using AAV-CRISPR–mediated direct in vivo screeningen_US
dc.typeArticleen_US
dc.identifier.citationWang, Guangchuan, Ryan D. Chow, Lupeng Ye, Christopher D. Guzman, Xiaoyun Dai, Matthew B. Dong, Feng Zhang, Phillip A. Sharp, Randall J. Platt, and Sidi Chen. “Mapping a Functional Cancer Genome Atlas of Tumor Suppressors in Mouse Liver Using AAV-CRISPR–mediated Direct in Vivo Screening.” Science Advances 4, no. 2 (February 2018): eaao5508.en_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biological Engineeringen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biologyen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Brain and Cognitive Sciencesen_US
dc.contributor.departmentMcGovern Institute for Brain Research at MITen_US
dc.contributor.departmentKoch Institute for Integrative Cancer Research at MITen_US
dc.contributor.mitauthorZhang, Feng
dc.contributor.mitauthorSharp, Phillip A
dc.contributor.mitauthorPlatt, Randall Jeffrey
dc.contributor.mitauthorChen, Sidi
dc.relation.journalScience Advancesen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dc.date.updated2018-10-10T16:12:45Z
dspace.orderedauthorsWang, Guangchuan; Chow, Ryan D.; Ye, Lupeng; Guzman, Christopher D.; Dai, Xiaoyun; Dong, Matthew B.; Zhang, Feng; Sharp, Phillip A.; Platt, Randall J.; Chen, Sidien_US
dspace.embargo.termsNen_US
dc.identifier.orcidhttps://orcid.org/0000-0003-2782-2509
dc.identifier.orcidhttps://orcid.org/0000-0003-1465-1691
mit.licensePUBLISHER_CCen_US


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