An 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 and representative of the glioma microenvironment. Methods:By next-generation sequencing, we analyzed the transcriptional profile of GASC derived from patients who 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 a nuclear factor-kappaB (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 LGGs. Results:The key elements differentiating the transcriptome of GASC isolated from LGG with different prognoses were mostly related to hallmarks of cancer (eg, inflammatory/immune process, NF-κB activation). Consistently, the NF-κB signature extrapolated from the GASC study was prognostic in the dataset of TCGA. 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 LGGs. Conclusion:This study demonstrates for the first time the independent prognostic role of NF-kB activation in LGG and outlines the role of patient-based stem cell models as a tool for precision medicine approaches.

journal_name

Neuro Oncol

journal_title

Neuro-oncology

authors

Ius T,Ciani Y,Ruaro ME,Isola M,Sorrentino M,Bulfoni M,Candotti V,Correcig C,Bourkoula E,Manini I,Pegolo E,Mangoni D,Marzinotto S,Radovic S,Toffoletto B,Caponnetto F,Zanello A,Mariuzzi L,Di Loreto C,Beltrami AP,Pia

doi

10.1093/neuonc/nox234

subject

Has Abstract

pub_date

2018-05-18 00:00:00

pages

776-787

issue

6

eissn

1522-8517

issn

1523-5866

pii

4708291

journal_volume

20

pub_type

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