TY  - JOUR
Y1  - 2017///
IS  - 9
SN  - 2045-3329
A1  - Koelsche, Christian
A1  - Schrimpf, Daniel
A1  - Tharun, Lars
A1  - Roth, Eva
A1  - Sturm, Dominik
A1  - Jones, David T. W.
A1  - Renker, Eva-Kristin
A1  - Sill, Martin
A1  - Baude, Annika
A1  - Sahm, Felix
A1  - Capper, David
A1  - Bewerunge-Hudler, Melanie
A1  - Hartmann, Wolfgang
A1  - Kulozik, Andreas E.
A1  - Petersen, Iver
A1  - Flucke, Uta
A1  - Schreuder, Hendrik W. B.
A1  - Büttner, Reinhard
A1  - Weber, Marc-André
A1  - Schirmacher, Peter
A1  - Plass, Christoph
A1  - Pfister, Stefan M.
A1  - von Deimling, Andreas
A1  - Mechtersheimer, Gunhild
CY  - London
N2  - 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.
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/22923/
TI  - Histone 3.3 hotspot mutations in conventional osteosarcomas: a comprehensive clinical and molecular characterization of six H3F3A mutated cases
SP  - 1
JF  - Clinical Sarcoma Research
AV  - public
ID  - heidok22923
VL  - 7
EP  - 11
PB  - BioMed Central
ER  -