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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 .    Electronic supplementary material  The online version of this article (doi:10.1186/s13569-017-0075-5) contains supplementary material, which is available to authorized users.

Histone 3.3 hotspot mutations in conventional osteosarcomas: a comprehensive clinical and molecular characterization of six H3F3A mutated cases