{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T15:34:00Z","timestamp":1785598440478,"version":"3.56.0"},"reference-count":37,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2022,6,7]],"date-time":"2022-06-07T00:00:00Z","timestamp":1654560000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2022,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Giant cell tumour of bone (GCTB) comprises the eponymous osteoclastic multinucleated giant cells eliciting bone lysis, an <jats:italic>H3F3A<\/jats:italic>\u2010mutated neoplastic mononucleated fibroblast\u2010like cell population, and <jats:italic>H3F3A<\/jats:italic> wild\u2010type mononucleated stromal cells. In this study, we characterised four new cell lines from GCTB. Furthermore, we compared the genome\u2010wide DNA methylation profile of 13 such tumours and three further cell lines with giant cell\u2010rich lesions comprising three <jats:italic>H3F3B<\/jats:italic>\u2010mutated chondroblastomas, three <jats:italic>USP6\u2010<\/jats:italic>rearranged aneurysmal bone cysts, three non\u2010ossifying fibromas, two hyperparathyroidism\u2010associated brown tumours as well as mesenchymal stem cells, osteoblasts, and osteoclasts. In an unsupervised analysis, we delineated GCTB and chondroblastomas from the other analysed tumour entities. Using comparative methylation analysis, we demonstrated that the methylation pattern of the cell lines approximately equals that of <jats:italic>H3F3A<\/jats:italic>\u2010mutated stromal cells in tissue. These patterns more resemble that of osteoblasts than that of mesenchymal stem cells, which argues for the osteoblast as the cell of origin of giant cell tumours of bone. Using enrichment analysis, we detected distinct hypermethylated clusters containing histone and collagen genes as well as target genes of the tumour suppressor p53. We found that the promotor regions of <jats:italic>CDKN1A<\/jats:italic>, <jats:italic>CDKN2A<\/jats:italic>, and <jats:italic>IGFBP3<\/jats:italic> are methylated more strongly in GCTB than in the other giant cell\u2010containing lesions, mesenchymal stem cells, osteoblasts, and osteoclasts (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001). This hypermethylation correlates with the lower gene expression at the mRNA level for these three genes in the cell lines, the lack of p16 and p21 in these cell lines, and the lower expression of p16 and p21 in GCTB. Overall, our analysis reveals characteristic DNA methylation patterns of giant cell tumours of bone and chondroblastomas and shows that cell lines of giant cell tumours of bone are a valid model for further analysis of <jats:italic>H3F3A<\/jats:italic>\u2010mutated tumour cells. \u00a9 2022 The Authors. <jats:italic>The Journal of Pathology<\/jats:italic> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.5925","type":"journal-article","created":{"date-parts":[[2022,5,6]],"date-time":"2022-05-06T12:47:39Z","timestamp":1651841259000},"page":"687-696","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Epigenetic lockdown of <scp><i>CDKN1A<\/i><\/scp> (p21) and <scp><i>CDKN2A<\/i><\/scp> (p16) characterises the neoplastic spindle cell component of giant cell tumours of 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