Faculty Bibliography

Low-grade astrocytomas (LGAs) carry neomorphic mutations in isocitrate dehydrogenase (IDH) concurrently with P53 and ATRX loss. To model LGA formation, we introduced R132H IDH1, P53 shRNA, and ATRX shRNA into human neural stem cells (NSCs). These oncogenic hits blocked NSC differentiation, increased invasiveness in vivo, and led to a DNA methylation and transcriptional profile resembling IDH1 mutant human LGAs. The differentiation block was caused by transcriptional silencing of the transcription factor SOX2 secondary to disassociation of its promoter from a putative enhancer. This occurred because of reduced binding of the chromatin organizer CTCF to its DNA motifs and disrupted chromatin looping. Our human model of IDH mutant LGA formation implicates impaired NSC differentiation because of repression of SOX2 as an early driver of gliomagenesis.

PURPOSE: Lower grade gliomas (WHO grade II/III) have been classified into clinically-relevant molecular subtypes based on IDH and 1p/19q mutation status. The purpose was to investigate whether T2/FLAIR MRI features could distinguish between lower grade glioma molecular subtypes

Experimental Design: MRI scans from the TCGA/TCIA lower grade glioma database (n=125) were evaluated by 2 independent neuroradiologists to assess: 1) presence/absence of homogenous signal on T2WI; 2) presence/absence of "T2-FLAIR mismatch" sign; 3) sharp or indistinct lesion margins; 4) presence/absence of peritumoral edema. Metrics with moderate-substantial agreement underwent consensus review, and were correlated with glioma molecular subtypes. Somatic mutation, DNA copy number, DNA methylation, gene expression, and protein array data from the TCGA lower grade glioma database were analyzed for molecular-radiographic associations. A separate institutional cohort (n=82) was analyzed to validate the T2-FLAIR mismatch sign.

Results: Among TCGA/TCIA cases, inter-reader agreement was calculated for lesion homogeneity (k=0.234 [0.111-0.358]), T2-FLAIR mismatch sign (k=0.728 [0.538-0.918]), lesion margins (k=0.292 [0.135-0.449]), and peritumoral edema (k=0.173 [0.096-0.250]). All 15 cases that were positive for the T2-FLAIR mismatch sign were IDH-mutant, 1p/19q-non-codeleted tumors (p<0.0001; PPV=100%, NPV=54%). Analysis of the validation cohort demonstrated substantial inter-reader agreement for the T2-FLAIR mismatch sign (k=0.747 [0.536 - 0.958]); all 10 cases positive for the T2-FLAIR mismatch sign were IDH-mutant, 1p/19q non-codeleted tumors (p<0.00001; PPV=100%, NPV=76%).

Conclusion: Among lower grade gliomas, T2-FLAIR mismatch sign represents a highly specific imaging biomarker for the IDH-mutant, 1p/19q-non-codeleted molecular subtype.