Universität zu Köln

Koelsche, Christian ORCID: 0000-0001-8763-8864, Schrimpf, Daniel, Tharun, Lars, Roth, Eva, Sturm, Dominik ORCID: 0000-0003-0250-1696, Jones, David T. W., Renker, Eva-Kristin, Sill, Martin, Baude, Annika, Sahm, Felix ORCID: 0000-0001-5441-1962, Capper, David ORCID: 0000-0003-1945-497X, Bewerunge-Hudler, Melanie, Hartmann, Wolfgang ORCID: 0000-0002-7609-5021, Kulozik, Andreas E., Petersen, Iver, Flucke, Uta, Schreuder, Hendrik W. B., Buettner, Reinhard, Weber, Marc-Andre, Schirmacher, Peter, Plass, Christoph, Pfister, Stefan M., von Deimling, Andreas ORCID: 0000-0002-5863-540X and Mechtersheimer, Gunhild (2017). Histone 3.3 hotspot mutations in conventional osteosarcomas: a comprehensive clinical and molecular characterization of six H3F3A mutated cases. Clin. Sarcoma Res., 7. LONDON: BMC. ISSN 2045-3329

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Koelsche, Christian UNSPECIFIED orcid.org/0000-0001-8763-8864 UNSPECIFIED Schrimpf, Daniel UNSPECIFIED UNSPECIFIED UNSPECIFIED Tharun, Lars UNSPECIFIED UNSPECIFIED UNSPECIFIED Roth, Eva UNSPECIFIED UNSPECIFIED UNSPECIFIED Sturm, Dominik UNSPECIFIED orcid.org/0000-0003-0250-1696 UNSPECIFIED Jones, David T. W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Renker, Eva-Kristin UNSPECIFIED UNSPECIFIED UNSPECIFIED Sill, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Baude, Annika UNSPECIFIED UNSPECIFIED UNSPECIFIED Sahm, Felix UNSPECIFIED orcid.org/0000-0001-5441-1962 UNSPECIFIED Capper, David UNSPECIFIED orcid.org/0000-0003-1945-497X UNSPECIFIED Bewerunge-Hudler, Melanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Hartmann, Wolfgang UNSPECIFIED orcid.org/0000-0002-7609-5021 UNSPECIFIED Kulozik, Andreas E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Petersen, Iver UNSPECIFIED UNSPECIFIED UNSPECIFIED Flucke, Uta UNSPECIFIED UNSPECIFIED UNSPECIFIED Schreuder, Hendrik W. B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Buettner, Reinhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Weber, Marc-Andre UNSPECIFIED UNSPECIFIED UNSPECIFIED Schirmacher, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Plass, Christoph UNSPECIFIED UNSPECIFIED UNSPECIFIED Pfister, Stefan M. UNSPECIFIED UNSPECIFIED UNSPECIFIED von Deimling, Andreas UNSPECIFIED orcid.org/0000-0002-5863-540X UNSPECIFIED Mechtersheimer, Gunhild UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-231345
DOI:	10.1186/s13569-017-0075-5
Journal or Publication Title:	Clin. Sarcoma Res.
Volume:	7
Date:	2017
Publisher:	BMC
Place of Publication:	LONDON
ISSN:	2045-3329
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GIANT-CELL TUMOR; PEDIATRIC GLIOBLASTOMA; DNA HYPOMETHYLATION; DRIVER MUTATIONS; ATRX EXPRESSION; BONE; TELOMERES; SARCOMAS; GENE; CHONDROBLASTOMA Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/23134