title: Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone.
abstract: It is recognized that some mutated cancer genes contribute to the development of many cancer types, whereas others are cancer type specific. For genes that are mutated in multiple cancer classes, mutations are usually similar in the different affected cancer types. Here, however, we report exquisite tumor type specificity for different histone H3.3 driver alterations. In 73 of 77 cases of chondroblastoma (95%), we found p.Lys36Met alterations predominantly encoded in H3F3B, which is one of two genes for histone H3.3. In contrast, in 92% (49/53) of giant cell tumors of bone, we found histone H3.3 alterations exclusively in H3F3A, leading to p.Gly34Trp or, in one case, p.Gly34Leu alterations. The mutations were restricted to the stromal cell population and were not detected in osteoclasts or their precursors. In the context of previously reported H3F3A mutations encoding p.Lys27Met and p.Gly34Arg or p.Gly34Val alterations in childhood brain tumors, a remarkable picture of tumor type specificity for histone H3.3 driver alterations emerges, indicating that histone H3.3 residues, mutations and genes have distinct functions.
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.|Department of Paediatrics, University of Cambridge, Hills Road, Cambridge, CB2 2XY.
authors.forename: Sam
authors.initials: S
authors.lastname: Behjati
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Tarpey
authors.affiliation: University College London Cancer Institute, Huntley Street, London, WC1E 6BT, UK.|Sarah Cannon / University College London Advanced Diagnostics Molecular Profiling Research Laboratories, Capper Street, London, WC1E 6JA, UK.
authors.forename: Nadège
authors.initials: N
authors.lastname: Presneau
authors.affiliation: University College London Cancer Institute, Huntley Street, London, WC1E 6BT, UK.|Universitätsklinik für Orthopädie und Orthopädische Chirurgie, Medizinische Universität, Graz, Austria.
authors.forename: Susanne
authors.initials: S
authors.lastname: Scheipl
authors.affiliation: University College London Cancer Institute, Huntley Street, London, WC1E 6BT, UK.|Histopathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex, HA7 4LP, UK.
authors.forename: Nischalan
authors.initials: N
authors.lastname: Pillay
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.|Human Genome Laboratory, Department of Human Genetics, VIB and KU Leuven, Herestraat 49 box 602, B-3000 Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Van Loo
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.
authors.forename: David C
authors.initials: DC
authors.lastname: Wedge
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.
authors.forename: Susanna L
authors.initials: SL
authors.lastname: Cooke
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.
authors.forename: Gunes
authors.initials: G
authors.lastname: Gundem
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Davies
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.
authors.forename: Serena
authors.initials: S
authors.lastname: Nik-Zainal
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.
authors.forename: Sancha
authors.initials: S
authors.lastname: Martin
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: McLaren
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.
authors.forename: Victoria
authors.initials: V
authors.lastname: Goodie
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.
authors.forename: Ben
authors.initials: B
authors.lastname: Robinson
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.
authors.forename: Adam
authors.initials: A
authors.lastname: Butler
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.
authors.forename: Jon W
authors.initials: JW
authors.lastname: Teague
authors.affiliation: Histopathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex, HA7 4LP, UK.
authors.forename: Dina
authors.initials: D
authors.lastname: Halai
authors.affiliation: Histopathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex, HA7 4LP, UK.
authors.forename: Bhavisha
authors.initials: B
authors.lastname: Khatri
authors.affiliation: Department of Tumour Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway.
authors.forename: Ola
authors.initials: O
authors.lastname: Myklebost
authors.affiliation: Bone Tumour Reference Centre, Institute of Pathology, University Hospital Basel, Basel, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Baumhoer
authors.affiliation: Bone Tumour Reference Centre, Institute of Pathology, University Hospital Basel, Basel, Switzerland.
authors.forename: Gernot
authors.initials: G
authors.lastname: Jundt
authors.affiliation: University College London Cancer Institute, Huntley Street, London, WC1E 6BT, UK.|Sarah Cannon / University College London Advanced Diagnostics Molecular Profiling Research Laboratories, Capper Street, London, WC1E 6JA, UK.
authors.forename: Rifat
authors.initials: R
authors.lastname: Hamoudi
authors.affiliation: Histopathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex, HA7 4LP, UK.
authors.forename: Roberto
authors.initials: R
authors.lastname: Tirabosco
authors.affiliation: Histopathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex, HA7 4LP, UK.
authors.forename: M Fernanda
authors.initials: MF
authors.lastname: Amary
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.
authors.forename: P Andrew
authors.initials: PA
authors.lastname: Futreal
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.|Department of Haematology, Addenbrooke's Hospital, Cambridge, UK.|Department of Haematology, University of Cambridge, Hills Road, Cambridge, CB2 2XY.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Campbell
authors.affiliation: University College London Cancer Institute, Huntley Street, London, WC1E 6BT, UK.|Sarah Cannon / University College London Advanced Diagnostics Molecular Profiling Research Laboratories, Capper Street, London, WC1E 6JA, UK.|Histopathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex, HA7 4LP, UK.
authors.forename: Adrienne M
authors.initials: AM
authors.lastname: Flanagan
mesh_terms: D000595:Amino Acid Sequence; D001859:Bone Neoplasms / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D002478:Cells, Cultured; D002648:Child; D002804:Chondroblastoma / Q000453:epidemiology / Q000235:genetics*; D005787:Gene Frequency; D018212:Giant Cell Tumor of Bone / Q000453:epidemiology / Q000235:genetics*; D006657:Histones / Q000235:genetics*; D006801:Humans; D009154:Mutation
chemical_list: D006657:Histones