Τίτλος:
IDH1 or -2 mutations do not predict outcome and do not cause loss of
5-hydroxymethylcytosine or altered histone modifications in central
chondrosarcomas
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Background: Mutations in isocitrate dehydrogenase (IDH)1 or -2 are found
in similar to 50% of conventional central chondrosarcomas and in up to
87% of their assumed benign precursors enchondromas. The mutant enzyme
acquires the activity to convert a-ketoglutarate into the oncometabolite
d-2-hydroxyglutarate (d-2-HG), which competitively inhibits
a-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.
Συγγραφείς:
Cleven, Arjen H. G.
Suijker, Johnny
Agrogiannis, Georgios and
Briaire-de Bruijn, Inge H.
Frizzell, Norma
Hoekstra, Attje S.
and Wijers-Koster, Pauline M.
Cleton-Jansen, Anne-Marie
Bovee,
Judith V. M. G.
Περιοδικό:
Clinical Sarcoma Research
Λέξεις-κλειδιά:
5-Hydroxymethylcytosine; 5-Methylcytosine; Histone methylation;
Chondrosarcoma; Isocitrate dehydrogenase; Bone tumour; Enchondroma
DOI:
10.1186/s13569-017-0074-6
