title: Diagnostic value of H3F3A mutations in giant cell tumour of bone compared to osteoclast-rich mimics.
abstract: Driver mutations in the two histone 3.3 (H3.3) genes, H3F3A and H3F3B, were recently identified by whole genome sequencing in 95% of chondroblastoma (CB) and by targeted gene sequencing in 92% of giant cell tumour of bone (GCT). Given the high prevalence of these driver mutations, it may be possible to utilise these alterations as diagnostic adjuncts in clinical practice. Here, we explored the spectrum of H3.3 mutations in a wide range and large number of bone tumours (n = 412) to determine if these alterations could be used to distinguish GCT from other osteoclast-rich tumours such as aneurysmal bone cyst, nonossifying fibroma, giant cell granuloma, and osteoclast-rich malignant bone tumours and others. In addition, we explored the driver landscape of GCT through whole genome, exome and targeted sequencing (14 gene panel). We found that H3.3 mutations, namely mutations of glycine 34 in H3F3A, occur in 96% of GCT. We did not find additional driver mutations in GCT, including mutations in IDH1, IDH2, USP6, TP53. The genomes of GCT exhibited few somatic mutations, akin to the picture seen in CB. Overall our observations suggest that the presence of H3F3A p.Gly34 mutations does not entirely exclude malignancy in osteoclast-rich tumours. However, H3F3A p.Gly34 mutations appear to be an almost essential feature of GCT that will aid pathological evaluation of bone tumours, especially when confronted with small needle core biopsies. In the absence of H3F3A p.Gly34 mutations, a diagnosis of GCT should be made with caution.
authors: UCL Cancer Institute, University College LondonHuntley StreetLondonUK; Sarah Cannon-University College London Advanced Diagnostics Molecular Profiling Research LaboratoriesUCL Cancer Institute, UCLLondonUK; Present address: Department of Biomedical SciencesFaculty of Science and TechnologyUniversity of WestminsterW1W 6UWUK.
authors: Nadège
authors: N
authors: Presneau
authors: Bone Tumour Reference Centre at the Institute of Pathology University Hospital Basel Basel Switzerland.
authors: Daniel
authors: D
authors: Baumhoer
authors: Cancer Genome Project Wellcome Trust Sanger Institute Wellcome Trust Genome Campus Cambridgeshire UK.
authors: Sam
authors: S
authors: Behjati
authors: Department of Histopathology Royal National Orthopaedic Hospital NHS Trust Middlesex UK.
authors: Nischalan
authors: N
authors: Pillay
authors: Cancer Genome Project Wellcome Trust Sanger Institute Wellcome Trust Genome Campus Cambridgeshire UK.
authors: Patrick
authors: P
authors: Tarpey
authors: Cancer Genome Project Wellcome Trust Sanger Institute Wellcome Trust Genome Campus Cambridgeshire UK.
authors: Peter J
authors: PJ
authors: Campbell
authors: Bone Tumour Reference Centre at the Institute of Pathology University Hospital Basel Basel Switzerland.
authors: Gernot
authors: G
authors: Jundt
authors: UCL Cancer Institute, University College LondonHuntley StreetLondonUK; Sarah Cannon-University College London Advanced Diagnostics Molecular Profiling Research LaboratoriesUCL Cancer Institute, UCLLondonUK; Present address: Division of Surgery and Interventional ScienceUniversity College LondonW1W 7EJUK.
authors: Rifat
authors: R
authors: Hamoudi
authors: Cancer Genome Project Wellcome Trust Sanger Institute Wellcome Trust Genome Campus Cambridgeshire UK.
authors: David C
authors: DC
authors: Wedge
authors: Cancer Genome ProjectWellcome Trust Sanger InstituteWellcome Trust Genome CampusCambridgeshireUK; Department of Human GeneticsUniversity of LeuvenLeuvenBelgium.
authors: Peter Van
authors: PV
authors: Loo
authors: CR-UK Tumour Growth Group Oxford Molecular Pathology Institute Sir William Dunn School of Pathology University of Oxford Oxford UK.
authors: A Bassim
authors: AB
authors: Hassan
authors: Department of Histopathology Royal National Orthopaedic Hospital NHS Trust Middlesex UK.
authors: Bhavisha
authors: B
authors: Khatri
authors: Department of Histopathology Royal National Orthopaedic Hospital NHS Trust Middlesex UK.
authors: Hongtao
authors: H
authors: Ye
authors: Department of Histopathology Royal National Orthopaedic Hospital NHS Trust Middlesex UK.
authors: Roberto
authors: R
authors: Tirabosco
authors: Department of Histopathology Royal National Orthopaedic Hospital NHS Trust Middlesex UK.
authors: M Fernanda
authors: MF
authors: Amary
authors: UCL Cancer Institute, University College LondonHuntley StreetLondonUK; Sarah Cannon-University College London Advanced Diagnostics Molecular Profiling Research LaboratoriesUCL Cancer Institute, UCLLondonUK; Department of HistopathologyRoyal National Orthopaedic Hospital NHS TrustMiddlesexUK.
authors: Adrienne M
authors: AM
authors: Flanagan
keywords: H3F3A; H3F3B; USP6; giant cell granuloma; giant cell tumour of bone; malignant giant cell tumour of bone; solid variant of aneurysmal bone cyst