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There is very little information about the genetic alterations leading to tumourigenesis or malignant transformation. Distinguishing between UPSb and other malignant bone sarcomas, including dedifferentiated chondrosarcoma and osteosarcoma, can be challenging due to overlapping features. To explore the genomic and transcriptomic landscape of UPSb tumours, whole\u2010exome sequencing (WES) and RNA sequencing (RNA\u2010Seq) were performed on UPSb tumours. All tumours lacked hotspot mutations in <jats:italic>IDH1\/2 132<\/jats:italic> or 172 codons, thereby excluding the diagnosis of dedifferentiated chondrosarcoma. Recurrent somatic mutations in <jats:italic>TP53<\/jats:italic> were identified in four of 14 samples (29%). Moreover, recurrent mutations in histone chromatin remodelling genes, including <jats:italic>H3F3A<\/jats:italic>, <jats:italic>ATRX<\/jats:italic> and <jats:italic>DOT1L<\/jats:italic>, were identified in five of 14 samples (36%), highlighting the potential role of deregulated chromatin remodelling pathways in UPSb tumourigenesis. The majority of recurrent mutations in chromatin remodelling genes identified here are reported in COSMIC, including the <jats:italic>H3F3A<\/jats:italic> G34 and K36 hotspot residues. Copy number alteration analysis identified gains and losses in genes that have been previously altered in UPSb or UPS of soft tissue. Eight somatic gene fusions were identified by RNA\u2010Seq, two of which, <jats:italic>CLTC\u2010VMP1<\/jats:italic> and <jats:italic>FARP1\u2010STK24<\/jats:italic>, were reported previously in multiple cancers. Five gene fusions were genomically characterised. Hierarchical clustering analysis, using RNA\u2010Seq data, distinctly clustered UPSb tumours from osteosarcoma and other sarcomas, thus molecularly distinguishing UPSb from other sarcomas. RNA\u2010Seq expression profiling analysis and quantitative reverse transcription\u2010polymerase chain reaction showed an elevated expression in <jats:italic>FGF23<\/jats:italic>, which can be a potential molecular biomarker for UPSb. To our knowledge, this study represents the first comprehensive WES and RNA\u2010Seq analysis of UPSb tumours revealing novel protein\u2010coding recurrent gene mutations, gene fusions and identifying a potential UPSb molecular biomarker, thereby broadening the understanding of the pathogenic mechanisms and highlighting the possibility of developing novel targeted therapeutics. Copyright \u00a9 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.5176","type":"journal-article","created":{"date-parts":[[2018,10,5]],"date-time":"2018-10-05T10:32:03Z","timestamp":1538735523000},"page":"166-176","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Genomic and transcriptomic characterisation of undifferentiated pleomorphic sarcoma of bone"],"prefix":"10.1002","volume":"247","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7824-5169","authenticated-orcid":false,"given":"Naser M","family":"Ali","sequence":"first","affiliation":[{"name":"Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3655-9968","authenticated-orcid":false,"given":"Stefania","family":"Niada","sequence":"additional","affiliation":[{"name":"Laboratory of 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University of Wolverhampton  Wolverhampton UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdullah","family":"Alholle","sequence":"additional","affiliation":[{"name":"Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Huen","sequence":"additional","affiliation":[{"name":"Research Institute in Healthcare Science, Faculty of Science and Engineering, University of Wolverhampton  Wolverhampton UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina R","family":"Antonescu","sequence":"additional","affiliation":[{"name":"Department of Pathology Memorial Sloan Kettering Cancer Center  New York NY 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