IDH1 Mutation as a Predictor of Glioma Progression.
Christiane Knobbe, Sabha Nesrin, Andreas von Deimling, Tak W Mak, Abhijit Guha, Sidney E Croul. Campbell Family Institute for Breast Cancer Research at Princess Margaret Hospital, Toronto, ON, Canada; Arthur and Sonia Labatts Brain Tumor Centre, Hospital for Sick Children's Research Institute, University of Toronto, Toronto, ON, Canada; Division of Neurosurgery, University of Toronto, ON, Canada; University Health Network Pathology, Toronto, ON, Canada; Institute of Pathology, Ruprecht-Karls-University, Heidelberg, Germany
Background: Adult low-grade gliomas have unpredictable progression rates. Molecular markers to augment prediction of progression are lacking. Mutations in IDH1, a key metabolic enzyme, have been in of secondary GBMs and predict a better prognosis. We asked whether mutation of IDH1 in LGG can predict time to progression to HGG.
Design: A TMA was created from cores of 75 grade II gliomas as well as 33 grade III gliomas. Adjacent cores were taken for high-throughput sequenome analysis of IDH1 and 2 mutations. The most common R132H-IDH1 mutation was also analyzed using a specific monoclonal antibody. P53 immunohistochemistry was oerformed as well.
Results: R132H-IDH1 mutations were detected by the mAb on the TMA in 52/75 of all grade II gliomas as well as in 26/33 grade III gliomas. In addition to detecting the majority of tumors with R132H IDH1 mutations which had been identified by immunohistochemistry on the TMA, sequencing revealed mutations in IDH2 in 1 OII (R172K), 2 AAIII (R172K, R172G), and in 1 AOAIII (R172G). IDH1 and IDH2 mutations were strongly associated with a longer PFS both in grade II and especially in grade III gliomas. This strong association also held true with respect to the OS. p53 i\reactivity did not show any association with PFS or OS and was independent of IDH1/IDH2 mutation status.
Conclusions: We confirmed the high frequency of R132H mutations in gliomas of different grades and the almost complete absence of IDH2 mutations. The correlation between sequencing and immunohistochemistry for the R132H-IDH1 mutation is very high. Antibody staining was more sensitive than sequencing especially in grade II gliomas. This observation is not surprising due to the heterozygous nature of the mutation and the highly infiltrative growth pattern of most gliomas. However, 4 patients whose tumors harbored R172-IDH2 mutations also did significantly better with respect to PFS and OS. In summary IDH1/IDH2 mutation status is a significant predictor both for PFS as well as for OS.
Tuesday, March 1, 2011 1:30 PM
Platform Session: Section G, Tuesday Afternoon