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

Clin Sarcoma Res 2017 4;7. Epub 2017 May 4.

Department of General Pathology, Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany.

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 and . 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 G34W/L mutant GCTBs.

Results: Six osteosarcomas (6/106) carried hotspot mutations. No mutations were found in . All patients with 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 mutant osteosarcomas. Unlike a single osteosarcoma with a K27M mutation, the DNA methylation profiles of 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 G34W/R mutant and H3.3 wild-type osteosarcomas were in (p < 0.00005) and (p < 0.0005).

Conclusions: H3.3 mutations in osteosarcomas may occur in at mutational hotspots. They are overall rare, but become more frequent in osteosarcoma patients older than 30 years. Osteosarcomas carrying G34W/R mutations are associated with epigenetic dysregulation of and .

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http://dx.doi.org/10.1186/s13569-017-0075-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5418758PMC
May 2017
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