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

Koelsche, Christian; Roth, Eva; Kulozik, Andreas E; Büttner, Reinhard; Renker, Eva-Kristin; Bewerunge-Hudler, Melanie; Hartmann, Wolfgang; Pfister, Stefan; Petersen, Iver; Schirmacher, Peter; Sill, Martin; Capper, David; Tharun, Lars; Mechtersheimer, Gunhild; Schreuder, Hendrik W B; Flucke, Uta; Plass, Christoph; Jones, David; Schrimpf, Daniel; Sahm, Felix; von Deimling, Andreas; Sturm, Dominik; Weber, Marc-André; Baude, Annika

doi:10.1186/s13569-017-0075-5

Journal Article

DKFZ-2017-06124

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

Koelsche, C. (First author)DKFZ* ; Schrimpf, D. (First author)DKFZ* ; Tharun, L. ; Roth, E. ; Sturm, D.DKFZ* ; Jones, D.DKFZ* ; Renker, E.-K. ; Sill, M.DKFZ* ; Baude, A.DKFZ* ; Sahm, F.DKFZ* ; Capper, D.DKFZ* ; Bewerunge-Hudler, M.DKFZ* ; Hartmann, W. ; Kulozik, A. E. ; Petersen, I. ; Flucke, U. ; Schreuder, H. W. B. ; Büttner, R. ; Weber, M.-A. ; Schirmacher, P. ; Plass, C.DKFZ* ; Pfister, S.DKFZ* ; von Deimling, A. (Last author)DKFZ* ; Mechtersheimer, G.

2017
BioMed Central London

Clinical Sarcoma Research 7(1), 9 (2017) [10.1186/s13569-017-0075-5]

This record in other databases:

Please use a persistent id in citations: doi:10.1186/s13569-017-0075-5

Abstract: 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.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.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).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.

Classification: