@article{f8310ef810924dd58841d15e00da89f8,
title = "Drivers underpinning the malignant transformation of giant cell tumour of bone",
abstract = "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.",
keywords = "bone, cyclin D1, drivers, epigenetic, genomics, giant cell tumour, histone, methylation, osteoblast, osteoclast, sarcoma, transformation",
author = "Fittall, {Matthew W.} and Iben Lyskj{\ae}r and Peter Ellery and Patrick Lombard and Jannat Ijaz and Strobl, {Anna Christina} and Dahmane Oukrif and Maxime Tarabichi and Martin Sill and Christian Koelsche and Gunhild Mechtersheimer and Jonas Demeulemeester and Roberto Tirabosco and Fernanda Amary and Campbell, {Peter J.} and Pfister, {Stefan M.} and Jones, {David T.W.} and Nischalan Pillay and {Van Loo}, Peter and Sam Behjati and Flanagan, {Adrienne M.}",
note = "Funding Information: This work was supported by funding from The Tom Prince Cancer Trust, a UK Medical Research Council grant (MR/M00094X/1), The Wellcome Trust, Skeletal Cancer Action Trust UK, the Royal National Orthopaedic Hospital NHS Trust R&D Department, the Rosetrees and Stoneygate Trusts (M46‐F1), the Pathological Society of Great Britain and Ireland (PL), and the Bone Cancer Research Trust. AMF is an NIHR senior investigator. AMF and NP were supported by the National Institute for Health Research, UCLH Biomedical Research Centre, and the UCL Experimental Cancer Centre. MWF, JD, MT, and PVL are supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001202), the UK Medical Research Council (FC001202), and the Wellcome Trust (FC001202). Personal fellowships have been granted to SB (Wellcome Trust Intermediate Clinical Research Fellowship, St Baldrick's Foundation Robert J Arceci International Innovation Award), IL (Lundbeck Foundation, award 2018‐3018), PJC (Wellcome Trust Senior Clinical Research Fellowship), NP (CRUK Clinician Scientist Fellowship (grant number 18387) and EM (CRUK Career Development Fellow), MWF (from a CRUK accelerator award C422/A21434), and JD (Research Foundation – Flanders, FWO Postdoctoral Fellowship; European Union's Horizon 2020 Research and Innovation programme, MSCA 703594‐DECODE), MT (European Union's Horizon 2020 Research and Innovation programme postdoctoral fellowship, MSCA 747852‐SIOMICS). PVL is a Winton Group Leader in recognition of the Winton Charitable Foundation's support towards the establishment of The Francis Crick Institute. This project was enabled through access to the MRC eMedLab Medical Bioinformatics infrastructure, supported by the Medical Research Council (grant number MR/L016311/1). We are grateful to the RNOH Musculoskeletal Pathology Biobank team for consenting patients and accessing samples. We thank all the patients for participating in our research and the clinical teams involved in their care. Funding Information: This work was supported by funding from The Tom Prince Cancer Trust, a UK Medical Research Council grant (MR/M00094X/1), The Wellcome Trust, Skeletal Cancer Action Trust UK, the Royal National Orthopaedic Hospital NHS Trust R&D Department, the Rosetrees and Stoneygate Trusts (M46-F1), The Pathological Society of Great Britain and Ireland (PL), and the Bone Cancer Research Trust. AMF is an NIHR senior investigator. AMF and NP were supported by the National Institute for Health Research, UCLH Biomedical Research Centre, and the UCL Experimental Cancer Centre. MWF, JD, MT, and PVL are supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001202), the UK Medical Research Council (FC001202), and the Wellcome Trust (FC001202). Personal fellowships have been granted to SB (Wellcome Trust Intermediate Clinical Research Fellowship, St Baldrick's Foundation Robert J Arceci International Innovation Award), IL (Lundbeck Foundation, award 2018-3018), PJC (Wellcome Trust Senior Clinical Research Fellowship), NP (CRUK Clinician Scientist Fellowship (grant number 18387) and EM (CRUK Career Development Fellow), MWF (from a CRUK accelerator award C422/A21434), and JD (Research Foundation ? Flanders, FWO Postdoctoral Fellowship; European Union's Horizon 2020 Research and Innovation programme, MSCA 703594-DECODE), MT (European Union's Horizon 2020 Research and Innovation programme postdoctoral fellowship, MSCA 747852-SIOMICS). PVL is a Winton Group Leader in recognition of the Winton Charitable Foundation's support towards the establishment of The Francis Crick Institute. This project was enabled through access to the MRC eMedLab Medical Bioinformatics infrastructure, supported by the Medical Research Council (grant number MR/L016311/1). We are grateful to the RNOH Musculoskeletal Pathology Biobank team for consenting patients and accessing samples. We thank all the patients for participating in our research and the clinical teams involved in their care. Publisher Copyright: {\textcopyright} 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.",
year = "2020",
month = dec,
doi = "10.1002/path.5537",
language = "English (US)",
volume = "252",
pages = "433--440",
journal = "Journal of Pathology",
issn = "0022-3417",
publisher = "John Wiley and Sons Ltd",
number = "4",
}