A NF-κB signature predicts low-grade glioma prognosis: a precision medicine approach based on patient-derived stem cells

Abstract

Background

While recent genome wide association studies have suggested novel low-grade glioma (LGG) stratification models based on a molecular classification, we explored the potential clinical utility of patient-derived cells. Specifically, we assayed glioma-associated stem cells (GASC) that are patient-derived stem cells representative of the glioma microenvironment.

Methods

By next generation sequencing, we analyzed the transcriptional profile of GASC derived from patients that underwent anaplastic transformation either within 48 months (GASC-BAD) or ≥7 years (GASC-GOOD) after surgery. Gene set enrichment and pathway enrichment analyses were applied. The prognostic role of an NF-κB signature derived from GASC-BAD was tested in 530 newly diagnosed diffuse LGG patients comprised within The Cancer Genome Atlas (TCGA) database. The prognostic value of the GASC upstream regulator p65 NF-κB was assessed, by univariate and multivariate Cox analyses, in a single center case study, including 146 grade II LGG.

Results

The key elements differentiating the transcriptome of GASC isolated from LGG with different prognosis were mostly related to hallmarks of cancer (e.g. inflammatory/immune process, and NF-κB activation). Consistently, the NF-κB signature extrapolated from the GASC study was prognostic in the TCGA dataset. Finally, the nuclear expression of the NF-kB-p65 protein, assessed using an inexpensive immunohistochemical method, was an independent predictor of both overall survival and malignant progression free survival in 146 grade II LGG.

Conclusion

This study demonstrates for the first time the independent prognostic role of NF-kB activation in LGG, and it outlines the role of patient-based stem cell models as a tool for precision medicine approaches.