TY  - JOUR
AU  - Fittall, Matthew W
AU  - Lyskjaer, Iben
AU  - Ellery, Peter
AU  - Lombard, Patrick
AU  - Ijaz, Jannat
AU  - Strobl, Anna-Christina
AU  - Oukrif, Dahmane
AU  - Tarabichi, Maxime
AU  - Sill, Martin
AU  - Koelsche, Christian
AU  - Mechtersheimer, Gunhild
AU  - Demeulemeester, Jonas
AU  - Tirabosco, Roberto
AU  - Amary, Fernanda
AU  - Campbell, Peter J
AU  - Pfister, Stefan
AU  - Jones, David T W
AU  - Pillay, Nischalan
AU  - Van Loo, Peter
AU  - Behjati, Sam
AU  - Flanagan, Adrienne M
TI  - Drivers underpinning the malignant transformation of giant cell tumour of bone.
JO  - The journal of pathology
VL  - 252
IS  - 4
SN  - 1096-9896
CY  - Bognor Regis [u.a.]
PB  - Wiley
M1  - DKFZ-2020-01785
SP  - 433-440
PY  - 2020
N1  - 2020 Dec;252(4):433-440
AB  - The 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:32866294
DO  - DOI:10.1002/path.5537
UR  - https://inrepo02.dkfz.de/record/157748
ER  -