Expression Signature of IFN/STAT1 Signaling Genes Predicts Poor Survival Outcome in Glioblastoma Multiforme in a Subtype-Specific Manner

Abstract

Previous reports have implicated an induction of genes in IFN/STAT1 (Interferon/STAT1) signaling in radiation resistant and prosurvival tumor phenotypes in a number of cancer cell lines, and we have hypothesized that upregulation of these genes may be predictive of poor survival outcome and/or treatment response in Glioblastoma Multiforme (GBM) patients. We have developed a list of 8 genes related to IFN/STAT1 that we hypothesize to be predictive of poor survival in GBM patients. Our working hypothesis that over-expression of this gene signature predicts poor survival outcome in GBM patients was confirmed, and in addition, it was demonstrated that the survival model was highly subtype-dependent, with strong dependence in the Proneural subtype and no detected dependence in the Classical and Mesenchymal subtypes. We developed a specific multi-gene survival model for the Proneural subtype in the TCGA (the Cancer Genome Atlas) discovery set which we have validated in the TCGA validation set. In addition, we have performed network analysis in the form of Bayesian Network discovery and Ingenuity Pathway Analysis to further dissect the underlying biology of this gene signature in the etiology of GBM. We theorize that the strong predictive value of the IFN/STAT1 gene signature in the Proneural subtype may be due to chemotherapy and/or radiation resistance induced through prolonged constitutive signaling of these genes during the course of the illness. The results of this study have implications both for better prediction models for survival outcome in GBM and for improved understanding of the underlying subtype-specific molecular mechanisms for GBM tumor progression and treatment response.

Stat1 stimulates cap-independent mRNA translation to inhibit cell proliferation and promote survival in response to antitumor drugs

“…Previous studies showed that Stat1 mediates the expression of a set of IFNinducible genes known as IFN-related DNA damage-resistance signature, which renders different tumor types increasingly resistant to chemotherapy and radiation therapies (62)(63)(64)(65). More recent work demonstrated that unphosphorylated Stat1 mediates the induction of genes that protect cells from virus infection or DNA damage in response to prolonged treatment with IFN-β (2).…”

RIG-I–like receptor LGP2 protects tumor cells from ionizing radiation

“…In addition, the response of GBM tumors to radiation predicts the patient lifespan after treatment. In this regard, we described elsewhere that ISG expression correlated with poor overall survival in patients with GBM (15). To investigate whether LGP2 gene expression is also related to clinical outcomes in patients with GBM, we analyzed two independent GBM datasets from the Cancer Genome Atlas (CGA; http://cancergenome.nih.gov/) (n = 382) and the Phillips et al study (n = 77) (37).…”

“…Many of these constitutively expressed ISGs have been characterized as antiviral genes (11). Recently, enhanced levels of constitutively expressed ISGs have been reported in advanced cancers and were often associated with a poor prognosis related to aggressive tumor growth, metastatic spread, resistance to IR/chemotherapy, or combinations of these factors (11)(12)(13)(14)(15)(16)(17)(18). The studies presented in this report are based on the hypothesis that a specific set of constitutively expressed ISGs, whose enhanced expression is by cytotoxic stress, confers a selective advantage to individual tumor clones (5,9,10,13,19).…”

STAT-1 expression is regulated by IGFBP-3 in malignant glioma cells and is a strong predictor of poor survival in patients with glioblastoma

“…Authors of that report hypothesized that the poor prognosis could be attributable to the chemoresistance and/or radiation resistance of tumors that express STAT-1. 10 Work on other tumors and cell lines has shown that, like IGFBP-3, STAT-1 also has a dual role in cancer. For example, the overexpression of STAT-1 has been associated with a better outcome in squamous cell carcinoma and mammary cancers.…”

“…Another study points toward a protumorigenic role of STAT-1 in GBM. 10 These contradictory reports of STAT-1 in GBM make it an interesting molecule for further detailed analysis.…”