In: Clinical Sarcoma Research, 7 (2017), Nr. 9. pp. 1-11. ISSN 2045-3329

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PDF, English Download (1MB) | Lizenz: Histone 3.3 hotspot mutations in conventional osteosarcomas: a comprehensive clinical and molecular characterization of six H3F3A mutated cases by 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 underlies the terms of Creative Commons Attribution 3.0 Germany

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.