IDH mutation status is associated with a distinct hypoxia/angiogenesis transcriptome signature which is non-invasively predictable with rCBV imaging in human glioma

Abstract

The recent identification of IDH mutations in gliomas and several other cancers suggests that this pathway is involved in oncogenesis; however effector functions are complex and yet incompletely understood. To study the regulatory effects of IDH on hypoxia-inducible-factor 1-alpha (HIF1A), a driving force in hypoxia-initiated angiogenesis, we analyzed mRNA expression profiles of 288 glioma patients and show decreased expression of HIF1A targets on a single-gene and pathway level, strong inhibition of upstream regulators such as HIF1A and downstream biological functions such as angio- and vasculogenesis in IDH mutant tumors. Genotype/imaging phenotype correlation analysis with relative cerebral blood volume (rCBV) MRI - a robust and non-invasive estimate of tumor angiogenesis - in 73 treatment-naive patients with low-grade and anaplastic gliomas showed that a one-unit increase in rCBV corresponded to a two-third decrease in the odds for an IDH mutation and correctly predicted IDH mutation status in 88% of patients. Together, these findings (1) show that IDH mutation status is associated with a distinct angiogenesis transcriptome signature which is non-invasively predictable with rCBV imaging and (2) highlight the potential future of radiogenomics (i.e. the correlation between cancer imaging and genomic features) towards a more accurate diagnostic workup of brain tumors.

Figure 1. Gene set variation analysis (GSVA) of differentially activated gene sets identified inhibition of hypoxia, vasculo- and angiogenesis signaling pathways in IDH-1/2 mutant tumors and activation in IDH-1/2 wild-type tumors.

Rows represent samples of 288 patients with low-grade diffuse or anaplastic gliomas from The Cancer Genome Atlas (TCGA). Columns represent GSVA enrichment scores for the individual gene set.

Figure 2. Relative cerebral blood volume (rCBV) imaging heat-map of 73 treatment-naive patients with low-grade diffuse and anaplastic gliomas.

The color of the voxel corresponds to the relative number of rCBV-voxels in each cluster and goes from white (low frequency) to purple (high frequency). Overall, IDH-1/2 wild-type tumors (top of the heat-map) clustered at a significantly higher rCBV as compared to IDH-1/2 mutant tumors (bottom of the heat-map) (see Table 2 for statistical results).

Figure 3

Pre-treatment MRI (FLAIR and corresponding rCBV images) of six representative patients with IDH-1/2 mutant (a–c) and wild-type (d–f) gliomas. Histogram analysis demonstrates the distribution of rCBV-voxels, with IDH-1/2 mutant tumors clustering at substantially lower values as compared to their wild-type counterpart.

Figure 4. Synopsis of how IDH mutation status is linked to angiogenesis and alteration in rCBV on DSC-MRI in human glioma based on this hypothesis generating study.

In brief, mutations in cancer-associated IDH acquire neoactivity producing 2-hydroxyglutarate (2HG). (R)-2HG potentiates EglN activity that mark the hypoxia inducible factor HIF1A for polyubiquitylation and proteasomal degradation, leading to decreased HIF1A activation in IDH mutant tumors, compared with their wild-type counterparts. This results in a distinct transcriptome signature induced by upregulation of hypoxia, vasculo- and angiogenesis related signaling pathways in IDH wild-type tumors, which is non-invasively detectable with rCBV imaging.