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In addition, CRISPR\/Cas9 is widely used to define the significance of cancer oncogenes and genetic dependencies in loss\u2010of\u2010function studies. However, how CRISPR\/Cas9 influences gain\u2010of\u2010function oncogenic mutations is elusive. Here, we demonstrate that single guide RNA targeting exon 3 of\n                    <jats:italic>Ctnnb1<\/jats:italic>\n                    (encoding \u03b2\u2010catenin) results in exon skipping and generates gain\u2010of\u2010function isoforms\n                    <jats:italic>in vivo<\/jats:italic>\n                    . CRISPR\/Cas9\u2010mediated exon skipping of\n                    <jats:italic>Ctnnb1<\/jats:italic>\n                    induces liver tumor formation in synergy with YAP\n                    <jats:sup>S127A<\/jats:sup>\n                    in mice. We define two distinct exon skipping\u2010induced tumor subtypes with different histological and transcriptional features. Notably, ectopic expression of two exon\u2010skipped \u03b2\u2010catenin transcript isoforms together with YAP\n                    <jats:sup>S127A<\/jats:sup>\n                    phenocopies the two distinct subtypes of liver cancer. Moreover, we identify similar\n                    <jats:italic>CTNNB1<\/jats:italic>\n                    exon\u2010skipping events in patients with hepatocellular carcinoma. Collectively, our findings advance our understanding of \u03b2\u2010catenin\u2010related tumorigenesis and reveal that CRISPR\/Cas9 can be repurposed,\n                    <jats:italic>in vivo<\/jats:italic>\n                    , to study gain\u2010of\u2010function mutations of oncogenes in cancer. \u00a9 2023 The Authors.\n                    <jats:italic>The Journal of Pathology<\/jats:italic>\n                    published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.6054","type":"journal-article","created":{"date-parts":[[2023,1,15]],"date-time":"2023-01-15T10:02:21Z","timestamp":1673776941000},"page":"415-427","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["<scp>CRISPR<\/scp>\n                    \u2010induced exon skipping of \u03b2\u2010catenin reveals tumorigenic mutants driving distinct subtypes of 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