dc.contributor.author | Wakimoto, H. | |
dc.contributor.author | Tanaka, S. | |
dc.contributor.author | Curry, W. T. | |
dc.contributor.author | Loebel, F. | |
dc.contributor.author | Zhao, D. | |
dc.contributor.author | Tateishi, K. | |
dc.contributor.author | Chen, J. | |
dc.contributor.author | Klofas, L. K. | |
dc.contributor.author | Lelic, N. | |
dc.contributor.author | Kim, J. C. | |
dc.contributor.author | Dias-Santagata, D. | |
dc.contributor.author | Ellisen, L. W. | |
dc.contributor.author | Borger, D. R. | |
dc.contributor.author | Fendt, Sarah-Maria | |
dc.contributor.author | Batchelor, Tracy T. | |
dc.contributor.author | Iafrate, A. John | |
dc.contributor.author | Cahill, D. P. | |
dc.contributor.author | Chi, A. S. | |
dc.contributor.author | Vander Heiden, Matthew G. | |
dc.date.accessioned | 2015-04-28T19:35:30Z | |
dc.date.available | 2015-04-28T19:35:30Z | |
dc.date.issued | 2014-04 | |
dc.date.submitted | 2014-03 | |
dc.identifier.issn | 1078-0432 | |
dc.identifier.issn | 1557-3265 | |
dc.identifier.uri | http://hdl.handle.net/1721.1/96830 | |
dc.description.abstract | Purpose: Isocitrate dehydrogenase (IDH) gene mutations occur in low-grade and high-grade gliomas. We sought to identify the genetic basis of malignant phenotype heterogeneity in IDH-mutant gliomas.
Methods: We prospectively implanted tumor specimens from 20 consecutive IDH1-mutant glioma resections into mouse brains and genotyped all resection specimens using a CLIA-certified molecular panel. Gliomas with cancer driver mutations were tested for sensitivity to targeted inhibitors in vitro. Associations between genomic alterations and outcomes were analyzed in patients.
Results: By 10 months, 8 of 20 IDH1-mutant gliomas developed intracerebral xenografts. All xenografts maintained mutant IDH1 and high levels of 2-hydroxyglutarate on serial transplantation. All xenograft-producing gliomas harbored “lineage-defining” mutations in CIC (oligodendroglioma) or TP53 (astrocytoma), and 6 of 8 additionally had activating mutations in PIK3CA or amplification of PDGFRA, MET, or N-MYC. Only IDH1 and CIC/TP53 mutations were detected in non–xenograft-forming gliomas (P = 0.0007). Targeted inhibition of the additional alterations decreased proliferation in vitro. Moreover, we detected alterations in known cancer driver genes in 13.4% of IDH-mutant glioma patients, including PIK3CA, KRAS, AKT, or PTEN mutation or PDGFRA, MET, or N-MYC amplification. IDH/CIC mutant tumors were associated with PIK3CA/KRAS mutations whereas IDH/TP53 tumors correlated with PDGFRA/MET amplification. Presence of driver alterations at progression was associated with shorter subsequent progression-free survival (median 9.0 vs. 36.1 months; P = 0.0011).
Conclusion: A subset of IDH-mutant gliomas with mutations in driver oncogenes has a more malignant phenotype in patients. Identification of these alterations may provide an opportunity for use of targeted therapies in these patients. | en_US |
dc.description.sponsorship | Koch Institute Dana Farber/Harvard Cancer Center Bridge Project | en_US |
dc.language.iso | en_US | |
dc.publisher | American Association for Cancer Research | en_US |
dc.relation.isversionof | http://dx.doi.org/10.1158/1078-0432.ccr-13-3052 | en_US |
dc.rights | Creative Commons Attribution-Noncommercial-Share Alike | en_US |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-sa/4.0/ | en_US |
dc.source | PMC | en_US |
dc.title | Targetable Signaling Pathway Mutations Are Associated with Malignant Phenotype in IDH-Mutant Gliomas | en_US |
dc.type | Article | en_US |
dc.identifier.citation | Wakimoto, H., S. Tanaka, W. T. Curry, F. Loebel, D. Zhao, K. Tateishi, J. Chen, et al. “Targetable Signaling Pathway Mutations Are Associated with Malignant Phenotype in IDH-Mutant Gliomas.” Clinical Cancer Research 20, no. 11 (April 8, 2014): 2898–2909. | en_US |
dc.contributor.department | Massachusetts Institute of Technology. Department of Biology | en_US |
dc.contributor.mitauthor | Vander Heiden, Matthew G. | en_US |
dc.relation.journal | Clinical Cancer Research | en_US |
dc.eprint.version | Author's final manuscript | en_US |
dc.type.uri | http://purl.org/eprint/type/JournalArticle | en_US |
eprint.status | http://purl.org/eprint/status/PeerReviewed | en_US |
dspace.orderedauthors | Wakimoto, H.; Tanaka, S.; Curry, W. T.; Loebel, F.; Zhao, D.; Tateishi, K.; Chen, J.; Klofas, L. K.; Lelic, N.; Kim, J. C.; Dias-Santagata, D.; Ellisen, L. W.; Borger, D. R.; Fendt, S.-M.; Vander Heiden, M. G.; Batchelor, T. T.; Iafrate, A. J.; Cahill, D. P.; Chi, A. S. | en_US |
dc.identifier.orcid | https://orcid.org/0000-0002-6702-4192 | |
mit.license | OPEN_ACCESS_POLICY | en_US |
mit.metadata.status | Complete | |