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Its invasive, lobular growth despite low\u2010grade histology suggests a loss of chondrocyte polarity. The known genetics of osteochondromagenesis include mosaic loss of <jats:italic><jats:styled-content style=\"fixed-case\">EXT1<\/jats:styled-content><\/jats:italic> or <jats:italic><jats:styled-content style=\"fixed-case\">EXT2<\/jats:styled-content><\/jats:italic> in both hereditary and non\u2010hereditary cases. The most frequent genetic aberrations in human <jats:styled-content style=\"fixed-case\">PCS<\/jats:styled-content> also include disruptions of <jats:italic><jats:styled-content style=\"fixed-case\">CDKN2A<\/jats:styled-content><\/jats:italic> or <jats:italic><jats:styled-content style=\"fixed-case\">TP53<\/jats:styled-content><\/jats:italic>. In order to test the sufficiency of either of these to drive progression of an osteochondroma to <jats:styled-content style=\"fixed-case\">PCS<\/jats:styled-content>, we added conditional loss of <jats:italic>Trp53<\/jats:italic> or <jats:italic>Ink4a\/Arf<\/jats:italic> in an <jats:italic>Ext1<\/jats:italic>\u2010driven mouse model of osteochondromagenesis. Each additional tumour suppressor silencing efficiently drove the development of growths that mimic human <jats:styled-content style=\"fixed-case\">PCS<\/jats:styled-content>. As in humans, lobules developed from both <jats:italic>Ext1<\/jats:italic>\u2010null and <jats:italic>Ext1<\/jats:italic>\u2010functional clones within osteochondromas. Assessment of their orientation revealed an absence of primary cilia in the majority of mouse <jats:styled-content style=\"fixed-case\">PCS<\/jats:styled-content> chondrocytes, which was corroborated in human <jats:styled-content style=\"fixed-case\">PCSs<\/jats:styled-content>. Loss of primary cilia may be responsible for the lost polarity phenotype ascribed to <jats:styled-content style=\"fixed-case\">PCS<\/jats:styled-content>. Cilia deficiency blocks proliferation in physeal chondrocytes, but cell cycle deregulation is sufficient to rescue chondrocyte proliferation following deciliation. This provides a basis of selective pressure for the frequent cell\u2010cycle regulator silencing observed in peripheral chondrosarcomagenesis. Mosaic loss of <jats:italic>Ext1<\/jats:italic> combined with loss of cell cycle regulators promotes peripheral chondrosarcomagenesis in the mouse and reveals deficient ciliogenesis in both the model and the human disease, explaining biological behaviour including lobular and invasive growth. Copyright \u00a9 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.4510","type":"journal-article","created":{"date-parts":[[2015,1,30]],"date-time":"2015-01-30T03:23:47Z","timestamp":1422588227000},"page":"210-218","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Cell cycle deregulation and mosaic loss of <i>Ext1<\/i> drive peripheral chondrosarcomagenesis in the mouse and reveal an intrinsic cilia deficiency"],"prefix":"10.1002","volume":"236","author":[{"given":"Carlos E","family":"de Andrea","sequence":"first","affiliation":[{"name":"Department of Pathology Leiden University Medical Center  Leiden The Netherlands"},{"name":"Department of Histology and Pathology University of Navarra  Pamplona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ju\u2010Fen","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics University of Utah  Salt Lake City Utah 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