In the beginning: PDGFA and the genesis of GBM

Glioblastomas (GBMs) that occur in adults are well described but how they begin—the earliest event—is still unknown, making it difficult to envision preventative or risk reduction strategies.

Several observations hint that platelet-derived growth factor (PDGF) signaling,^1,2 especially by PDGFA, might cause isocitrate dehydrogenase (IDH) wild-type (WT) GBM. Ozawa et al. used mathematical modeling to predict that PDGFA initiates IDH-WT GBM³ and murine models confirm that PDGFA can induce GBM-like cancers.^3,4 Recently, we reported that p53-null sub-ventricular zone murine cells cultured chronically in PDGFA acquire gains and losses of whole chromosomes and become tumorigenic,⁵ reproducing the types of genomic alterations that occur in human IDH-WT GBM; a phenomenon that does not occur when cultures are supplemented with other GBM-associated growth factors. Although these findings demonstrate that exposure to PDGFA can transform neural progenitor cells, an in situ source for overexpression of PDGFA has not been identified and is unexplained by PDGFA gene mutations, which are rare in GBM.⁶

Chromosome 7 amplification, a hallmark of IDH-WT GBM,⁷ is a potential source of PDGFA, but Ozawa et al. suggested that overexpression of PDGFA precedes not follows gain of 7.³ Following up on their hypothesis, we analyzed PDGFA expression in WHO grade II-IV IDH-WT astrocytic gliomas reasoning that GBMs (ie, grade IV), like most adult cancers, evolve over time and that grade II and III tumors offer a rare glimpse into their beginning; rare, because most IDH-WT GBMs appear suddenly after an indolent phase that is usually hidden from view. We assessed the relative expression levels of PDGFA by comparing IDH-WT astrocytomas from The Cancer Genome Atlas (TCGA) glioma dataset to normal brain from the Genotype-Tissue Expression (GTEx) portal using the TCGAbiolinks R package. In contrast to normal brain, median PDGFA expression is high in all grades of astrocytoma and not limited to GBM (Fig. 1A).

Fig. 1.

PDGFA and EGFR expression and chromosome arm 7p amplification in IDH-WT astrocytomas. A, Compared to normal brain, tissue expression of PDGFA is high in IDH-WT astrocytomas and does not increase with tumor grade. In contrast, EGFR expression increases with grade. B, The percentage of patients with chromosome arm 7p amplification increases with grade. Unpaired t-test, NS, not significant; ***P < .001, ****P < .0001.

To explore the relationship between histological grade and amplification of chromosome 7, copy number values by chromosomal arm processed by GISTIC2 on TCGA SNP6 arrays were downloaded from Broad GDAC Firehose. Values for 7p were utilized to determine amplification status based on a threshold of +0.3. We found that the percentage of patients with chromosome 7p amplification increased with grade (Fig. 1B). In grade II IDH-WT astrocytomas, harbingers of WT GBM, PDGFA overexpression was a frequent finding, whereas amplification of 7p was not.

What then does amplification of chromosome 7 signify? PDGFA-induced genomic instability, as reported by our group,⁵ might select for gain of 7 if it increases cellular fitness. To explore this thinking, we assessed EGFR expression in relation to chromosome arm 7p. EGFR is relevant in this context for two reasons: it is overexpressed in most IDH-WT GBMs,⁶ and like PDGFA, is located on chromosome 7p. Unlike PDGFA, however, we found that EGFR expression increased significantly with histological grade (Fig. 1A). Indeed, increasing expression of EGFR and gain of 7p emerged as associated progressive events (P < .05, Wilcoxon rank-sum test), whereas overexpression of PDGFA was often present at the earliest visible stages of IDH-WT tumors.

If PDGFA is central to the genesis of IDH-WT GBM by inducing genomic instability in progenitor cells, where does it come from, when and how is it overexpressed, and how might research proceed? Learning more about PDGFA biology could be a fruitful line of inquiry. Does PDGFA originate in GBM cells or from cells that surround the cell of origin of GBM? Moreover, since the incidence of IDH-WT GBM increases with age, does altered PDGFA signaling or overexpression occur as the brain ages? Such questions about PDGFA and other members of the PDGF family of ligands and receptors, several of which have been associated with cancers of the central nervous system in adults and children,^1,8 merit further study.

Any prospect for reducing the risk of GBM surely lies in understanding its beginning. Although preventing GBM may seem fanciful, curing the full-blown disease is equally difficult to imagine.

Funding

This work was supported by The Terry Fox Research Institute and Foundation, the Alberta Cancer Foundation, Genome Canada, Alberta Innovates, and the family of Clark Smith.

Conflict of interest statement. The authors declare no conflicts of interest.