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Conference Paper: CRISPR/Cas9 somatic multiplex-mutagenesis for high-Throughput functional cancer genomics in mice

TitleCRISPR/Cas9 somatic multiplex-mutagenesis for high-Throughput functional cancer genomics in mice
Authors
Issue Date2015
Citation
Proceedings of the National Academy of Sciences of the United States of America, 2015, v. 112, n. 45, p. 13982-13987 How to Cite?
AbstractHere, we show CRISPR/Cas9-based targeted somatic multiplexmutagenesis and its application for high-Throughput analysis of gene function in mice. Using hepatic single guide RNA (sgRNA) delivery, we targeted large gene sets to induce hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). We observed Darwinian selection of target genes, which suppress tumorigenesis in the respective cellular/tissue context, such as Pten or Cdkn2a, and conversely found low frequency of Brca1/2 alterations, explaining mutational spectra in human ICC/HCC. Our studies show that multiplexed CRISPR/Cas9 can be used for recessive genetic screening or high-Throughput cancer gene validation in mice. The analysis of CRISPR/Cas9-induced tumors provided support for a major role of chromatin modifiers in hepatobiliary tumorigenesis, including that of ARID family proteins, which have recently been reported to be mutated in ICC/HCC. We have also comprehensively characterized the frequency and size of chromosomal alterations induced by combinatorial sgRNA delivery and describe related limitations of CRISPR/Cas9 multiplexing, as well as opportunities for chromosome engineering in the context of hepatobiliary tumorigenesis. Our study describes novel approaches to model and study cancer in a high-Throughput multiplexed format that will facilitate the functional annotation of cancer genomes.
Persistent Identifierhttp://hdl.handle.net/10722/249110
ISSN
2017 Impact Factor: 9.504
2015 SCImago Journal Rankings: 6.883

 

DC FieldValueLanguage
dc.contributor.authorWeber, Julia-
dc.contributor.authorÖllinger, Rupert-
dc.contributor.authorFriedrich, Mathias-
dc.contributor.authorEhmer, Ursula-
dc.contributor.authorBarenboim, Maxim-
dc.contributor.authorSteiger, Katja-
dc.contributor.authorHeid, Irina-
dc.contributor.authorMueller, Sebastian-
dc.contributor.authorMaresch, Roman-
dc.contributor.authorEngleitner, Thomas-
dc.contributor.authorGross, Nina-
dc.contributor.authorGeumann, Ulf-
dc.contributor.authorFu, Beiyuan-
dc.contributor.authorSegler, Angela-
dc.contributor.authorYuan, Detian-
dc.contributor.authorLange, Sebastian-
dc.contributor.authorStrong, Alexander-
dc.contributor.authorRosa, Jorge De La-
dc.contributor.authorEsposito, Irene-
dc.contributor.authorLiu, Pentao-
dc.contributor.authorCadiñanos, Juan-
dc.contributor.authorVassiliou, George S.-
dc.contributor.authorSchmid, Roland M.-
dc.contributor.authorSchneider, Gönter-
dc.contributor.authorUnger, Kristian-
dc.contributor.authorYang, Fengtang-
dc.contributor.authorBraren, Rickmer-
dc.contributor.authorHeikenwälder, Mathias-
dc.contributor.authorVarela, Ignacio-
dc.contributor.authorSaur, Dieter-
dc.contributor.authorBradley, Allan-
dc.contributor.authorRad, Roland-
dc.date.accessioned2017-10-27T05:59:08Z-
dc.date.available2017-10-27T05:59:08Z-
dc.date.issued2015-
dc.identifier.citationProceedings of the National Academy of Sciences of the United States of America, 2015, v. 112, n. 45, p. 13982-13987-
dc.identifier.issn0027-8424-
dc.identifier.urihttp://hdl.handle.net/10722/249110-
dc.description.abstractHere, we show CRISPR/Cas9-based targeted somatic multiplexmutagenesis and its application for high-Throughput analysis of gene function in mice. Using hepatic single guide RNA (sgRNA) delivery, we targeted large gene sets to induce hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). We observed Darwinian selection of target genes, which suppress tumorigenesis in the respective cellular/tissue context, such as Pten or Cdkn2a, and conversely found low frequency of Brca1/2 alterations, explaining mutational spectra in human ICC/HCC. Our studies show that multiplexed CRISPR/Cas9 can be used for recessive genetic screening or high-Throughput cancer gene validation in mice. The analysis of CRISPR/Cas9-induced tumors provided support for a major role of chromatin modifiers in hepatobiliary tumorigenesis, including that of ARID family proteins, which have recently been reported to be mutated in ICC/HCC. We have also comprehensively characterized the frequency and size of chromosomal alterations induced by combinatorial sgRNA delivery and describe related limitations of CRISPR/Cas9 multiplexing, as well as opportunities for chromosome engineering in the context of hepatobiliary tumorigenesis. Our study describes novel approaches to model and study cancer in a high-Throughput multiplexed format that will facilitate the functional annotation of cancer genomes.-
dc.languageeng-
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of America-
dc.titleCRISPR/Cas9 somatic multiplex-mutagenesis for high-Throughput functional cancer genomics in mice-
dc.typeConference_Paper-
dc.description.natureLink_to_subscribed_fulltext-
dc.identifier.doi10.1073/pnas.1512392112/-/DCSupplemental-
dc.identifier.pmid26508638-
dc.identifier.scopuseid_2-s2.0-84946771643-
dc.identifier.volume112-
dc.identifier.issue45-
dc.identifier.spage13982-
dc.identifier.epage13987-
dc.identifier.eissn1091-6490-

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