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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2017-12

AUTHORS

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

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. More... »

PAGES

9

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/s13569-017-0075-5

DOI

http://dx.doi.org/10.1186/s13569-017-0075-5

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1085132838

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/28484590


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