%0 Journal Article
%@ 2045-3329
%A Koelsche, Christian
%A Schrimpf, Daniel
%A Tharun, Lars
%A Roth, Eva
%A Sturm, Dominik
%A Jones, David T. W.
%A Renker, Eva-Kristin
%A Sill, Martin
%A Baude, Annika
%A Sahm, Felix
%A Capper, David
%A Bewerunge-Hudler, Melanie
%A Hartmann, Wolfgang
%A Kulozik, Andreas E.
%A Petersen, Iver
%A Flucke, Uta
%A Schreuder, Hendrik W. B.
%A Büttner, Reinhard
%A Weber, Marc-André
%A Schirmacher, Peter
%A Plass, Christoph
%A Pfister, Stefan M.
%A von Deimling, Andreas
%A Mechtersheimer, Gunhild
%C London
%D 2017
%F heidok:22923
%I BioMed Central
%J Clinical Sarcoma Research
%N 9
%P 1-11
%T Histone 3.3 hotspot mutations in conventional osteosarcomas: a comprehensive clinical and molecular characterization of six H3F3A mutated cases
%U https://archiv.ub.uni-heidelberg.de/volltextserver/22923/
%V 7
%X 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.