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Drivers underpinning the malignant transformation of giant cell tumour of bone
Author(s) -
Fittall Matthew W,
Lyskjær Iben,
Ellery Peter,
Lombard Patrick,
Ijaz Jannat,
Strobl AnnaChristina,
Oukrif Dahmane,
Tarabichi Maxime,
Sill Martin,
Koelsche Christian,
Mechtersheimer Gunhild,
Demeulemeester Jonas,
Tirabosco Roberto,
Amary Fernanda,
Campbell Peter J,
Pfister Stefan M,
Jones David TW,
Pillay Nischalan,
Van Loo Peter,
Behjati Sam,
Flanagan Adrienne M
Publication year - 2020
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.5537
Subject(s) - malignant transformation , biology , pathology , cancer research , mutation , lung cancer , dna methylation , osteosarcoma , medicine , gene , genetics , gene expression
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. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.