IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours

Abstract

Somatic mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 occur in gliomas and acute myeloid leukaemia (AML). Since patients with multiple enchondromas have occasionally been reported to have these conditions, we hypothesized that the same mutations would occur in cartilaginous neoplasms. Approximately 1200 mesenchymal tumours, including 220 cartilaginous tumours, 222 osteosarcomas and another ∼750 bone and soft tissue tumours, were screened for IDH1 R132 mutations, using Sequenom(®) mass spectrometry. Cartilaginous tumours and chondroblastic osteosarcomas, wild-type for IDH1 R132, were analysed for IDH2 (R172, R140) mutations. Validation was performed by capillary sequencing and restriction enzyme digestion. Heterozygous somatic IDH1/IDH2 mutations, which result in the production of a potential oncometabolite, 2-hydroxyglutarate, were only detected in central and periosteal cartilaginous tumours, and were found in at least 56% of these, ∼40% of which were represented by R132C. IDH1 R132H mutations were confirmed by immunoreactivity for this mutant allele. The ratio of IDH1:IDH2 mutation was 10.6 : 1. No IDH2 R140 mutations were detected. Mutations were detected in enchondromas through to conventional central and dedifferentiated chondrosarcomas, in patients with both solitary and multiple neoplasms. No germline mutations were detected. No mutations were detected in peripheral chondrosarcomas and osteochondromas. In conclusion, IDH1 and IDH2 mutations represent the first common genetic abnormalities to be identified in conventional central and periosteal cartilaginous tumours. As in gliomas and AML, the mutations appear to occur early in tumourigenesis. We speculate that a mosaic pattern of IDH-mutation-bearing cells explains the reports of diverse tumours (gliomas, AML, multiple cartilaginous neoplasms, haemangiomas) occurring in the same patient.

Succinate dehydrogenase deficiency is associated with decreased 5-hydroxymethylcytosine production in gastrointestinal stromal tumors: implications for mechanisms of tumorigenesis

“…Mutations in a number of different epigenetic modifier proteins have been described in myeloid malignancies, including mutations in TET2, which are seen in 10-20% of cases of acute myeloid leukemia. 33 In addition, TET activity is thought to be inhibited in the context of mutations in isocitrate dehydrogenase 1 or 2 (IDH1/2), which are present in 15-30% of acute myeloid leukemias, 33 as well as in 470% of low-grade gliomas, 34 450% of enchondromas and chondrosarcomas, 32,35 and approximately 25% of cholangiocarcinomas. 36 Our findings suggest that alterations in SDH should be added to the growing list of mutations that lead to altered epigenetic regulation within tumor cells.…”

Epiphyseal growth plate and secondary peripheral chondrosarcoma: the neighbours matter

“…It has been shown that, while homozygous mutations in EXT1/EXT2 are crucial for the formation of an osteochondroma, genetic alteration(s) in other gene(s) than EXT1/EXT2 is(are) the causing event(s) of a subset of secondary peripheral chondrosarcoma [67]. Additionally, IDH1/IDH2 mutations are shown not to be involved in secondary peripheral chondrosarcomas formation [76]. Malignant progression of secondary peripheral chondrosarcomas is characterized by a high percentage of loss of heterozygosity (ie CDKN2A/p16, TP53, RB1 ) and ploidy ranging from half to twice the normal DNA content [77][78][79].…”

New chondrosarcoma cell lines and mouse models to study the link between chondrogenesis and chemoresistance

“…Sequencing of IDH1 and IDH2 identified point mutations at characteristic CS hot spots 6,7 in the two conventional central CH34 and CH56 CS cells, CH34 cells also harboring a referenced silent IDH1 polymorphism. 35 The dedifferentiated CS cell line CH03 did not show any IDH1 or IDH2 mutations, but presented a deletion in TP53-coding sequence (Figure 2b).…”

“…5 However, specific point mutations in IDH1-and/or IDH2-encoding isocitrate dehydrogenases were recently identified in 50-90% of enchondroma, conventional central, secondary central and dedifferentiated CS. 6,7 These somatic mosaic mutations lead to the accumulation of metabolites with potent stabilization of HIF1a and activation of the hypoxia response pathway. They can be considered as an early event in all cartilaginous tumors with secondary genetic alterations that lead to multiple chromosomal rearrangements.…”