IDH1/2 Mutations Predict Shorter Survival in Chondrosarcoma

Abstract

Background. Recent studies have shown that isocitrate dehydrogenase 1/2 (IDH1/2)- activating mutations occur in a variety of cancers, including acute myeloid leukaemia, gliomas, and chondrosarcomas (CHS)s. The effect of IDH1/2 mutation on overall survival (OS) has not been reported in CHS. The aim of our study was to assess the prevalence of known cancer-related gene mutations in CHS, as well as their prognostic role in patient survival.Methods. DNA from FFPE samples of 80 patients (F:M- 1:1.3; mean age: 58 years; range 27-86) with histologically confirmed CHS (G1:29; G2:34; G3:17) was subjected to library preparation with the Ion AmpliSeq Cancer Hotspot Panel v2 and sequenced on the PGM Ion Torrent.Results. Among the clinical features only histological grade influenced OS. Deep sequencing identified 1784 single nucleotide variants. Of them, 426 were considered to be pathogenic or probably pathogenic. Activating IDH1/2 mutations were found in 27 patients (34%) including 17 R132 IDH1 (21%), 10 R172 IDH2 (13%) and 3 R140 IDH2 variants (4%). Three patients had concurrent IDH1 and IDH2 mutations. The R140 IDH2 mutant has not been reported to date in CHS patients. OS for CHS patients with IDH1/2 mutations was significantly lower than in patients without mutations (93% vs 64%; p<0.001). No other genetic feature of the Cancer Hotspot Panel had an impact on OS.Conclusions. In CHS, IDH1/2-mutation status and the histological aggressiveness of the CHS are important predictors for OS. The R140 IDH2 may also be a novel target for the treatment of CHS patients.

Differential Diagnosis of Cartilaginous Lesions of Bone

“…Genetically, chondrosarcomas of primary and secondary types are characterized by mutations in the isocitrate dehydrogenase isoforms IDH1 and IDH2, which have been detected in approximately 50% to 60% of primary and secondary central chondrosarcomas. 71,72 Peripheral chondrosarcomas appear to show similar EXT1 and EXT2 aberrations to solitary and hereditary osteochondromas. 73 The genetic underpinnings mediating the transformation from benign cartilaginous lesions to malignant lesions are not entirely elucidated; however, complex karyotypic abnormalities, mutations in TP53, and defects in the RB1 pathway have been described in these lesions as they transform into higher-grade chondrosarcomas.…”

Is the IDH Mutation a Good Target for Chondrosarcoma Treatment?

“…Long-term outcomes did not differ in a series of patients with chondrosarcomas harbouring IDH mutations when compared to IDH wild-type chondrosarcoma [65]. In contrast, IDH1 and IDH2 mutant chondrosarcoma had worse outcomes relative to IDH wild-type chondrosarcoma in another study reported by Lugowksa et al [66]. The authors of both studies performed correlation with the tumour grade; however, the histological subtype was not investigated.…”

Genomics and Therapeutic Vulnerabilities of Primary Bone Tumors

“…Hotspot mutations are present at the IDH1 p.Arg132 and the IDH2 p.Arg172 positions, the former being the most frequent. Mutations at the IDH1 p.Arg140 position have also been reported [67]. Grade 2 and 3 central chondrosarcomas are intermediate-and high-grade malignant tumors, respectively.…”

“…Grade 2 and 3 central chondrosarcomas, including dedifferentiated chondrosarcomas are also characterized by complex karyotypes with aneuploidy [39,71]. Other genetic alterations described in the literature are alterations of the RB1 pathway (86% of cases) with a loss of p16 and an overexpression and/or amplification of CDK4, a mutation of TP53 (in up to 59% of the cases) [72] and mutations in COL2A1 (in 45% of cases) [73,74], and also mutations in YEATS2 (12%), EGFR (19%), NRAS (12%), and IHH signaling (18%) [67,74,75]. In about 75% of cases, CDKN2A copy number variations are present.…”