Integrating cullin2-RING E3 ligase as a potential biomarker for glioblastoma multiforme prognosis and radiosensitivity profiling

Background and purpose: Positive epidermal growth factor receptor (EGFR) immunoreactivity in glioblastoma multiforme (GBM) often predicts poor radiation response. Meanwhile, all attempts to target EGFR pharmaceutically have been unsuccessful, mainly due to molecular heterogeneity of EGFR expression in GBM. A molecular biology-based and efficient way to access cellular protein levels of EGFR is urgently needed. EGFR, together with HIF-1α and Cyclin B1, is degraded via cullin2-RING E3 ligase (CRL2). It is worthwhile to investigate the possible involvement of CRL2 on GBM survival and radiosensitivity.

Materials and methods: Clinicopathological features, radiographic images, survival data, RNA-Seq, copy number variations (CNVs), and other genetic changes were studied on over 3800 glioma and GBM cases, which are derived from 5 independent cohorts. These datasets include the Chinese Glioma Genome Atlas, The Cancer Genome Atlas, Ivy Glioblastoma Atlas Project, Clinical Proteomic Tumor Analysis Consortium, and the 2008 Parson's GBM dataset.

Results: Expression of CUL2, which encodes the scaffold protein cullin2 in the CRL2 E3 ligase, can predict GBM progression and survival rate. Cullin2 protein levels are inversely related to those of HIF-1α, VEGF-A, Cyclin B1, and EGFR. Elevated CUL2 expression predicts increased radiosensitivity and dampened signal intensities in perfusion imaging. CUL2 expression are regulated via CNVs, which are inheritable structural DNA variations.

Conclusion: CUL2 expression levels and CNVs can be integrated as potential biomarkers in facilitating GBM and prognosis and radiosensitivity profiling.