eprintid: 22923
rev_number: 16
eprint_status: archive
userid: 1589
dir: disk0/00/02/29/23
datestamp: 2017-05-10 07:31:36
lastmod: 2024-03-10 13:20:19
status_changed: 2017-05-10 07:31:36
type: article
metadata_visibility: show
creators_name: Koelsche, Christian
creators_name: Schrimpf, Daniel
creators_name: Tharun, Lars
creators_name: Roth, Eva
creators_name: Sturm, Dominik
creators_name: Jones, David T. W.
creators_name: Renker, Eva-Kristin
creators_name: Sill, Martin
creators_name: Baude, Annika
creators_name: Sahm, Felix
creators_name: Capper, David
creators_name: Bewerunge-Hudler, Melanie
creators_name: Hartmann, Wolfgang
creators_name: Kulozik, Andreas E.
creators_name: Petersen, Iver
creators_name: Flucke, Uta
creators_name: Schreuder, Hendrik W. B.
creators_name: Büttner, Reinhard
creators_name: Weber, Marc-André
creators_name: Schirmacher, Peter
creators_name: Plass, Christoph
creators_name: Pfister, Stefan M.
creators_name: von Deimling, Andreas
creators_name: Mechtersheimer, Gunhild
title: Histone 3.3 hotspot mutations in conventional osteosarcomas: a comprehensive clinical and molecular characterization of six H3F3A mutated cases
subjects: 610
divisions: 712000
divisions: 718000
divisions: 850300
divisions: 910500
divisions: 911400
divisions: 912000
abstract: Background: Histone 3.3 (H3.3) hotspot mutations in bone tumors occur in the vast majority of giant cell tumors of bone (GCTBs; 96%), chondroblastomas (95%) and in a few cases of osteosarcomas. However, clinical presentation, histopathological features, and additional molecular characteristics of H3.3 mutant osteosarcomas are largely unknown.   Methods: In this multicentre, retrospective study, a total of 106 conventional high-grade osteosarcomas, across all age groups were re-examined for hotspot mutations in the H3.3 coding genes H3F3A and H3F3B. H3.3 mutant osteosarcomas were re-evaluated in a multidisciplinary manner and analyzed for genome-wide DNA-methylation patterns and DNA copy number aberrations alongside H3.3 wild-type osteosarcomas and H3F3A G34W/L mutant GCTBs.   Results: Six osteosarcomas (6/106) carried H3F3A hotspot mutations. No mutations were found in H3F3B. All patients with H3F3A mutant osteosarcoma were older than 30 years with a median age of 65 years. Copy number aberrations that are commonly encountered in high-grade osteosarcomas also occurred in H3F3A mutant osteosarcomas. Unlike a single osteosarcoma with a H3F3A K27M mutation, the DNA methylation profiles of H3F3A G34W/R mutant osteosarcomas were clearly different from H3.3 wild-type osteosarcomas, but more closely related to GCTBs. The most differentially methylated promoters between H3F3A G34W/R mutant and H3.3 wild-type osteosarcomas were in KLLN/PTEN (p < 0.00005) and HIST1H2BB (p < 0.0005).   Conclusions: H3.3 mutations in osteosarcomas may occur in H3F3A at mutational hotspots. They are overall rare, but become more frequent in osteosarcoma patients older than 30 years. Osteosarcomas carrying H3F3A G34W/R mutations are associated with epigenetic dysregulation of KLLN/PTEN and HIST1H2BB.
date: 2017
publisher: BioMed Central
id_scheme: DOI
ppn_swb: 1659043689
own_urn: urn:nbn:de:bsz:16-heidok-229236
language: eng
bibsort: KOELSCHECHHISTONE33H2017
full_text_status: public
publication: Clinical Sarcoma Research
volume: 7
number: 9
place_of_pub: London
pagerange: 1-11
issn: 2045-3329
citation:   Koelsche, Christian ; Schrimpf, Daniel ; Tharun, Lars ; Roth, Eva ; Sturm, Dominik ; Jones, David T. W. ; Renker, Eva-Kristin ; Sill, Martin ; Baude, Annika ; Sahm, Felix ; Capper, David ; Bewerunge-Hudler, Melanie ; Hartmann, Wolfgang ; Kulozik, Andreas E. ; Petersen, Iver ; Flucke, Uta ; Schreuder, Hendrik W. B. ; Büttner, Reinhard ; Weber, Marc-André ; Schirmacher, Peter ; Plass, Christoph ; Pfister, Stefan M. ; von Deimling, Andreas ; Mechtersheimer, Gunhild  (2017) Histone 3.3 hotspot mutations in conventional osteosarcomas: a comprehensive clinical and molecular characterization of six H3F3A mutated cases.  Clinical Sarcoma Research, 7 (9).  pp. 1-11.  ISSN 2045-3329     
document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/22923/1/13569_2017_Article_75.pdf