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Weber, J.* ; Öllinger, R.* ; Friedrich, M.* ; Ehmer, U.* ; Barenboim, M.* ; Steiger, K.* ; Heid, I.M.* ; Mueller, S.* ; Maresch, R.* ; Engleitner, T.* ; Gross, N.* ; Geumann, U.* ; Fu, B.* ; Segler, A.* ; Yuan, D.T. ; Lange, S.* ; Strong, A.* ; de la Rosa, J.* ; Esposito, I.* ; Liu, P.* ; Cadiñanos, J.* ; Vassiliou, G.S.* ; Schmid, R.M.* ; Schneider, G.* ; Unger, K. ; Yang, F.* ; Braren, R.* ; Heikenwälder, M. ; Varela, I.* ; Saur, D.* ; Bradley, A.* ; Rad, R.*

CRISPR/Cas9 somatic multiplex-mutagenesis for high-throughput functional cancer genomics in mice.

Proc. Natl. Acad. Sci. U.S.A. 112, 13982-13987 (2015)

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Here, we show CRISPR/Cas9-based targeted somatic multiplex-mutagenesis 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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Chromosome Engineering ; Hepatocellular Carcinoma ; In Vivo Crispr/cas9 ; Intrahepatic Cholangiocarcinoma ; Somatic Multiplex-mutagenesis

ISSN (print) / ISBN 0027-8424

e-ISSN 1091-6490

Journal Proceedings of the National Academy of Sciences of the United States of America

Quellenangaben Volume: 112, Issue: 45, Pages: 13982-13987

Publisher National Academy of Sciences

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Virology (VIRO)
Translational Metabolic Oncology (TMO)