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Clinical Sarcoma Research
Published in: Clinical Sarcoma Research 1/2017

Open Access 01-12-2017 | Research

IDH1 or -2 mutations do not predict outcome and do not cause loss of 5-hydroxymethylcytosine or altered histone modifications in central chondrosarcomas

Authors: Arjen H. G. Cleven, Johnny Suijker, Georgios Agrogiannis, Inge H. Briaire-de Bruijn, Norma Frizzell, Attje S. Hoekstra, Pauline M. Wijers-Koster, Anne-Marie Cleton-Jansen, Judith V. M. G. Bovée

Published in: Clinical Sarcoma Research | Issue 1/2017

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Abstract

Background

Mutations in isocitrate dehydrogenase (IDH)1 or -2 are found in ~50% of conventional central chondrosarcomas and in up to 87% of their assumed benign precursors enchondromas. The mutant enzyme acquires the activity to convert α-ketoglutarate into the oncometabolite d-2-hydroxyglutarate (d-2-HG), which competitively inhibits α-ketoglutarate dependent enzymes such as histone- and DNA demethylases.

Methods

We therefore evaluated the effect of IDH1 or -2 mutations on histone modifications (H3K4me3, H3K9me3 and H3K27me3), chromatin remodeler ATRX expression, DNA modifications (5-hmC and 5-mC), and TET1 subcellular localization in a genotyped cohort (IDH, succinate dehydrogenase (SDH) and fumarate hydratase (FH)) of enchondromas and central chondrosarcomas (n = 101) using immunohistochemistry.

Results

IDH1 or -2 mutations were found in 60.8% of the central cartilaginous tumours, while mutations in FH and SDH were absent. The mutation status did not correlate with outcome. Chondrosarcomas are strongly positive for the histone modifications H3K4me3, H3K9me3 and H3K27me3, which was independent of the IDH1 or -2 mutation status. Two out of 36 chondrosarcomas (5.6%) show complete loss of ATRX. Levels of 5-hmC and 5-mC are highly variable in central cartilaginous tumours and are not associated with mutation status. In tumours with loss of 5-hmC, expression of TET1 was more prominent in the cytoplasm than the nucleus (p = 0.0001).

Conclusions

In summary, in central chondrosarcoma IDH1 or -2 mutations do not affect immunohistochemical levels of 5-hmC, 5mC, trimethylation of H3K4, -K9 and K27 and outcome, as compared to wildtype.
Appendix
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Metadata
Title
IDH1 or -2 mutations do not predict outcome and do not cause loss of 5-hydroxymethylcytosine or altered histone modifications in central chondrosarcomas
Authors
Arjen H. G. Cleven
Johnny Suijker
Georgios Agrogiannis
Inge H. Briaire-de Bruijn
Norma Frizzell
Attje S. Hoekstra
Pauline M. Wijers-Koster
Anne-Marie Cleton-Jansen
Judith V. M. G. Bovée
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Clinical Sarcoma Research / Issue 1/2017
Electronic ISSN: 2045-3329
DOI
https://doi.org/10.1186/s13569-017-0074-6

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