Abstract
To determine whether IDH1 mutations are present in primary and relapsed (local and distal) conventional central chondrosarcomas; and secondly, to assess if loss of p16/CDKN2A is associated with tumour grade progression, 102 tumour samples from 37 patients, including material from presenting and relapse events, were assessed. All wild-type cases for IDH1 R132 substitutions were also tested for IDH2 R172 and R140 alterations. The primary tumour and the most recent relapse sample were tested for p16/CDKN2A by interphase fluorescence in situ hybridisation. An additional 120 central cartilaginous tumours from different patients were also tested for p16/CDKN2A copy number. The study shows that if an IDH1 mutation were detected in a primary central chondrosarcoma, it is always detected at the time of presentation, and the same mutation is detected in local recurrences and metastatic events. We show that p16/CDKN2A copy number variation occurs subsequent to the IDH1 mutation, and confirm that p16/CDKN2A copy number variation occurs in 75 % of high grade central chondrosarcomas, and not in low grade cartilaginous tumours. Finally, p16/CDKN2A copy number variation is seen in both the IDH1 wild-type and mutant cartilaginous central tumours.
Highlights
Isocitrate dehydrogenase 1 (IDH1), and IDH2 mutations were originally reported as frequent events in gliomas and acute myeloid leukaemia
We confirm the data published in our previous report showing that IDH1 mutations occur in ∼50 % of solitary conventional central chondrosarcomas, that the IDH1 mutations are found in all grades of this subtype of chondrosarcoma, that the R132C mutation is the most common genetic alteration in this gene, that IDH2 mutations are significantly less common than IDH1 mutations and that to date an IDH2 R140 mutation, which is seen in acute myeloid leukaemia, is not found in cartilaginous tumours [1]
We show that when an IDH1 mutation is present in a solitary primary central conventional chondrosarcoma, the same mutation is always detected in local recurrences and metastatic events
Summary
Isocitrate dehydrogenase 1 (IDH1), and IDH2 mutations were originally reported as frequent events in gliomas and acute myeloid leukaemia. The mutations are present in enchondromas, the benign central cartilaginous tumour considered to represent the precursor of central chondrosarcoma, and occur as early post-zygotic events in the common forms of multiple enchondromas, namely Ollier disease and Maffucci syndrome [3, 9]. These findings make a case for IDH1/2 mutations occurring early in the development of the nonsyndromic disease and that the mutations represent driver mutations, to which the tumours are addicted for survival. This is an important question if drugs, which may be developed against the mutant protein, are to be effective [10]
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