Genomic profiling identifies association of IDH1/IDH2 mutation with longer relapse-free and metastasis-free survival in high-grade chondrosarcoma Journal Article
| Authors: | Zhu, G. G.; Nafa, K.; Agaram, N.; Zehir, A.; Benayed, R.; Sadowska, J.; Borsu, L.; Kelly, C.; Tap, W. D.; Fabbri, N.; Athanasian, E.; Boland, P. J.; Healey, J. H.; Berger, M. F.; Ladanyi, M.; Hameed, M. |
| Article Title: | Genomic profiling identifies association of IDH1/IDH2 mutation with longer relapse-free and metastasis-free survival in high-grade chondrosarcoma |
| Abstract: | Purpose: 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 (IDH1) and IDH2 hotspot mutations were recently found to be frequently mutated in central chondrosarcomas. However, a few published articles have been controversial regarding the association between IDH1/IDH2 mutation status and clinical outcomes in chondrosarcomas. Experimental Design: We performed hotspot sequencing of IDH1 and IDH2 genes in 89 central chondrosarcomas and targeted next-generation sequencing in 54 of them, and then correlated the IDH1/IDH2 mutation status with the patient's clinical outcome. Results: Although no association was discovered between IDH mutation status and the patient's overall survival, IDH1/IDH2 mutation was found to be associated with longer relapse-free and metastasis-free survival in high-grade chondrosarcomas. Genomic profiling reveals TERT gene amplification and ATRX mutation, for the first time, in addition to TERT promoter mutation in a subset (6/30, 20%) of high-grade and dedifferentiated chondrosarcomas. These abnormalities in telomere genes are concurrent with IDH1/ IDH2 mutation and with CDKN2A/2B deletion or TP53 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. Conclusions: IDH1/IDH2 mutations are associated with longer relapse-free and metastasis-free survival in high-grade chondrosarcomas, and they tend to co-occur with TERT mutations and with CDKN2A/2B and TP53 alterations in a subset of high-grade chondrosarcomas. © 2019 American Association for Cancer Research. |
| Keywords: | adolescent; adult; cancer survival; child; controlled study; aged; major clinical study; overall survival; promoter region; gene deletion; cancer growth; outcome assessment; cancer grading; telomere; genetic association; genetic susceptibility; gene identification; dna sequence; chondrosarcoma; recurrence free survival; isocitrate dehydrogenase 1; idh1 gene; idh2 gene; cdkn2a gene; next generation sequencing; isocitrate dehydrogenase 2; atrx gene; metastasis free survival; tert gene; human; male; female; priority journal; article; dedifferentiated chondrosarcoma; cdkn2b gene; tumor-related gene |
| Journal Title: | Clinical Cancer Research |
| Volume: | 26 |
| Issue: | 2 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2020-01-15 |
| Start Page: | 419 |
| End Page: | 427 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-18-4212 |
| PUBMED: | 31615936 |
| PROVIDER: | scopus |
| PMCID: | PMC6980683 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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