Genomic Profiling Identifies Association of <i>IDH1/IDH2</i> Mutation with Longer Relapse-Free and Metastasis-Free Survival in High-Grade Chondrosarcoma.

Abstract

Chondrosarcomas are the second most common primary malignant bone tumors. Although histologic grade is the most important factor predicting the clinical outcome of chondrosarcoma, it is subject to interobserver variability. Isocitrate dehydrogenase 1 (<i>IDH1</i>) and <i>IDH2</i> hotspot mutations were recently found to be frequently mutated in central chondrosarcomas. However, a few published articles have been controversial regarding the association between <i>IDH1/IDH2</i> mutation status and clinical outcomes in chondrosarcomas. We performed hotspot sequencing of <i>IDH1</i> and <i>IDH2</i> genes in 89 central chondrosarcomas and targeted next-generation sequencing in 54 of them, and then correlated the <i>IDH1/IDH2</i> mutation status with the patient's clinical outcome. Although no association was discovered between <i>IDH</i> mutation status and the patient's overall survival, <i>IDH1</i>/<i>IDH2</i> mutation was found to be associated with longer relapse-free and metastasis-free survival in high-grade chondrosarcomas. Genomic profiling reveals <i>TERT</i> gene amplification and <i>ATRX</i> mutation, for the first time, in addition to <i>TERT</i> promoter mutation in a subset (6/30, 20%) of high-grade and dedifferentiated chondrosarcomas. These abnormalities in telomere genes are concurrent with <i>IDH1</i>/<i>IDH2</i> mutation and with <i>CDKN2A/2B</i> deletion or <i>TP53</i> mutation, suggesting a possible association and synergy among these genes in chondrosarcoma progression. We found 21% of patients with chondrosarcoma also had histories of second malignancies unrelated to cartilaginous tumors, suggesting possible unknown genetic susceptibility to chondrosarcoma. <i>IDH1/IDH2</i> mutations are associated with longer relapse-free and metastasis-free survival in high-grade chondrosarcomas, and they tend to co-occur with <i>TERT</i> mutations and with <i>CDKN2A/2B</i> and <i>TP53</i> alterations in a subset of high-grade chondrosarcomas.