Radiogenomic mapping of edema/cellular invasion MRI-phenotypes in glioblastoma multiforme

Abstract

Background: Despite recent discoveries of new molecular targets and pathways, the search for an effective therapy for Glioblastoma Multiforme (GBM) continues. A newly emerged field, radiogenomics, links gene expression profiles with MRI phenotypes. MRI-FLAIR is a noninvasive diagnostic modality and was previously found to correlate with cellular invasion in GBM. Thus, our radiogenomic screen has the potential to reveal novel molecular determinants of invasion. Here, we present the first comprehensive radiogenomic analysis using quantitative MRI volumetrics and large-scale gene- and microRNA expression profiling in GBM.

Methods: Based on The Cancer Genome Atlas (TCGA), discovery and validation sets with gene, microRNA, and quantitative MR-imaging data were created. Top concordant genes and microRNAs correlated with high FLAIR volumes from both sets were further characterized by Kaplan Meier survival statistics, microRNA-gene correlation analyses, and GBM molecular subtype-specific distribution.

Results: The top upregulated gene in both the discovery (4 fold) and validation (11 fold) sets was PERIOSTIN (POSTN). The top downregulated microRNA in both sets was miR-219, which is predicted to bind to POSTN. Kaplan Meier analysis demonstrated that above median expression of POSTN resulted in significantly decreased survival and shorter time to disease progression (P<0.001). High POSTN and low miR-219 expression were significantly associated with the mesenchymal GBM subtype (P<0.0001).

Conclusion: Here, we propose a novel diagnostic method to screen for molecular cancer subtypes and genomic correlates of cellular invasion. Our findings also have potential therapeutic significance since successful molecular inhibition of invasion will improve therapy and patient survival in GBM.

Figure 1. Volumetric brain tumor mapping of FLAIR, Necrosis, and Contrast Enhancement.

A 55 year old male patient with a right temporal GBM. (a) Axial FLAIR image demonstrates segmentation (in blue) of the region of FLAIR hyperintensity corresponding to the area of edema/tumor infiltration. Notice the segmented enhancement (yellow) and necrosis (orange) that has been segmented on the T1WI post- contrast. (b) The segmented edema/tumor infiltration (blue), enhancement (yellow) and necrosis (orange) are seen overlaid on a base post- contrast T1WI. (c) Axial post-contrast enhanced T1WI demonstrates the segmentation of the enhancement (yellow) and necrosis (orange).

Figure 2. Low FLAIR patient.

A 67 year old male patient with a right temporo-parieto-occipital GBM. The segmented edema/tumor infiltration (blue), enhancement (yellow) and necrosis (orange) are seen overlaid on a base post- contrast T1WI. These images demonstrate a patient with a GBM and a large amount of peritumoral FLAIR hyperintensity reflecting edema and tumor infiltration.

Figure 3. High FLAIR patient.

A 59 year old female patient with a left frontal GBM. The segmented edema/tumor infiltration (blue), enhancement (yellow) and necrosis (orange) are seen overlaid on a base post- contrast T1WI. The images demonstrate a patient with a medium to large GBM with a relatively small amount of peritumoral FLAIR hyperintensity reflecting edema and tumor infiltration.

Figure 4. Correlation scatter plots.

(a) FLAIR vs. Contrast Enhancement and (b) FLAIR vs. Necrosis volumes.

Figure 5. Ingenuity Pathway Analysis top network for mRNA.

Figure 6. Ingenuity Pathway Analysis top network for microRNA.

Figure 7. Top functional mRNA network for Cellular Movement/Invasion.

Figure 8. Kaplan Meier curves for Periostin.

(a) days to death and (b) progression free survival. (c) Periostin expression levels across the two main GBM subtypes, Mesenchymal and Proneural. And (d) shows expression levels of miR-219 across the Mesenchymal and Proneural subtypes and in addition the inverse correlation (Rsq = 0.204) with Periostin.