Regulation of PD1 signaling is associated with prognosis in glioblastoma multiforme

Abstract

Glioblastoma is an aggressive cancer of the brain and spine. While analysis of glioblastoma omics data has somewhat improved our understanding of the disease, it has not led to direct improvement in patient survival. Cancer survival is often characterized by differences in expression of particular genes, but the mechanisms that drive these differences are generally unknown. We therefore set out to model the regulatory mechanisms that associate with glioblastoma survival. We inferred individual patient gene regulatory networks using data from two different expression platforms from The Cancer Genome Atlas (n=522 and 431). We performed a comparative network analysis between patients with long- and short-term survival, correcting for patient age, sex, and neoadjuvant treatment status. We identified seven pathways associated with survival, all of which were involved in immune system signaling. Differential regulation of PD1 signaling was validated in an independent dataset from the German Glioma Network (n=70). We found that transcriptional repression of genes in this pathway--for which treatment options are available--was lost in short-term survivors and that this was independent of mutation burden and only weakly associated with T-cell infiltrate. These results provide a new way to stratify glioblastoma patients that uses network features as biomarkers to predict survival, and identify new potential therapeutic interventions, thus underscoring the value of analyzing gene regulatory networks in individual cancer patients.