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000157748 0247_ $$2ISSN$$a1555-2039
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000157748 1001_ $$00000-0002-5172-4100$$aFittall, Matthew W$$b0
000157748 245__ $$aDrivers underpinning the malignant transformation of giant cell tumour of bone.
000157748 260__ $$aBognor Regis [u.a.]$$bWiley$$c2020
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000157748 500__ $$a2020 Dec;252(4):433-440
000157748 520__ $$aThe rare benign giant cell tumour of bone (GCTB) is defined by an almost unique mutation in the H3.3 family of histone genes H3-3A or H3-3B, however the same mutation is occasionally found in primary malignant bone tumours which share many features with the benign variant. Moreover, lung metastases can occur despite the absence of malignant histological features in either the primary or metastatic lesions. Herein we investigated the genetic events of 17 GCTBs including benign and malignant variants and the methylation profiles of 122 bone tumour samples including GCTBs. Benign GCTBs possessed few somatic alterations and no other known drivers besides the H3.3 mutation, whereas all malignant tumours harboured at least one additional driver mutation and exhibited genomic features resembling osteosarcomas, including high mutational burden, additional driver event(s) and a high degree of aneuploidy. The H3.3 mutation was found to predate the development of aneuploidy. In contrast to osteosarcomas, malignant H3.3-mutated tumours were enriched for a variety of alterations involving TERT, other than amplification, suggesting telomere dysfunction in the transformation of benign to malignant GCTB. DNA sequencing of the benign metastasising GCTB revealed no additional driver alterations; polyclonal seeding in the lung was identified, implying that the metastatic lesions represent an embolic event. Unsupervised clustering of DNA methylation profiles revealed that malignant H3.3- mutated tumours are distinct from their benign counterpart, and other bone tumours. Differential methylation analysis identified CCND1, encoding cyclin D1, as a plausible cancer driver gene in these tumours because hypermethylation of the CCND1 promoter was specific for GCTBs. We report here the genomic and methylation patterns underlying the rare clinical phenomena of benign metastasising and malignant transformation of GCTB and show how the combination of genomic and epigenomic findings could potentially distinguish benign from malignant GCTBs, thereby predicting aggressive behaviour in challenging diagnostic cases. This article is protected by copyright. All rights reserved.
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000157748 7001_ $$00000-0003-3446-1182$$aLyskjaer, Iben$$b1
000157748 7001_ $$aEllery, Peter$$b2
000157748 7001_ $$aLombard, Patrick$$b3
000157748 7001_ $$aIjaz, Jannat$$b4
000157748 7001_ $$aStrobl, Anna-Christina$$b5
000157748 7001_ $$aOukrif, Dahmane$$b6
000157748 7001_ $$aTarabichi, Maxime$$b7
000157748 7001_ $$0P:(DE-He78)45440b44791309bd4b7dbb4f73333f9b$$aSill, Martin$$b8
000157748 7001_ $$0P:(DE-HGF)0$$aKoelsche, Christian$$b9
000157748 7001_ $$aMechtersheimer, Gunhild$$b10
000157748 7001_ $$aDemeulemeester, Jonas$$b11
000157748 7001_ $$aTirabosco, Roberto$$b12
000157748 7001_ $$aAmary, Fernanda$$b13
000157748 7001_ $$aCampbell, Peter J$$b14
000157748 7001_ $$0P:(DE-He78)f746aa965c4e1af518b016de3aaff5d9$$aPfister, Stefan$$b15
000157748 7001_ $$0P:(DE-He78)551bb92841f634070997aa168d818492$$aJones, David T W$$b16
000157748 7001_ $$aPillay, Nischalan$$b17
000157748 7001_ $$aVan Loo, Peter$$b18
000157748 7001_ $$aBehjati, Sam$$b19
000157748 7001_ $$00000-0002-2832-1303$$aFlanagan, Adrienne M$$b20
000157748 773__ $$0PERI:(DE-600)1475280-3$$a10.1002/path.5537$$gp. path.5537$$n4$$p433-440$$tThe journal of pathology$$v252$$x1096-9896$$y2020
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