Abstract 297: Protein markers predict overall survival in glioblastoma multiforme
Authors: Lindsay C. Stetson, Jill S. Barnholtz-Sloan
Journal: Cancer Research (2014)

Abstract Unrealized needs in the care of patients diagnosed with primary glioblastoma multiforme (GBM) are accurate and clinically relevant predictors of patient prognosis. Patients receiving standard therapy (surgery plus concurrent radiation and temozolomide) have variable clinical outcomes. Available prognostic indicators such as MGMT DNA methylation, IDH1 mutation, and the G-CIMP phenotype are only relevant for a small proportion of those diagnosed with primary GBM. Protein markers of GBM prognosis would not only provide a potential route for classifying and stratifying patients into treatment groups they could also provide an opportunity to identify potential novel drug targets. In this study, using reverse-phase protein array data from Cancer Genome Atlas (TCGA) GBMs, we have constructed and validated a PROTein signature predictive of GLIOblastoma survival (PROTGLIO). Using L1 penalized cox regression, we have identified six protein markers most associated with overall survival in a training set of 107 TCGA GBMs. Three proteins (annexin, cox-2, and FOX03) were associated with shorter overall survival, and three proteins (phosphorylated RPS6KA1, phosphorylated RB1, and TGM2) were associated with longer overall survival. PROTGLIO scores were defined as a linear combination of protein expression levels of the six proteins and the associated Cox regression coefficients, where a higher score indicates a worse prognosis. Based on PROTGLIO scores cases were classified into high and low risk groups. Kaplan-Meier survival analysis showed a significant difference (p = 0.01) in overall survival between the high and low risk groups in our training set. The performance of the PROTGLIO score was validated in a testing set, which consisted of 107 TCGA cases not included in the training set. In the validation set there was a significant difference in overall survival between the high and low risk groups (p = 0.02). We have verified that our signature is independent of known prognostic variables such as age, treatment pattern, and molecular subtype by applying multivariate analysis using a Cox proportional hazard model. The annexin family of proteins has been previously associated with glioma migration and growth and the cox-2 protein has been reported as a marker of poor prognosis among diffuse glioma patients. Our work points to these proteins, along with FOX03, as being negative prognosticators for GBMs and potential avenues for therapeutic intervention. Additionally, we report on the protective effects of phosphorylated RB1 expression, which is supported by previous studies recommending clinical stratification of patients based on RB1 alterations. Further work is needed to elucidate the protective mechanisms of RPS6KA1 and TGM2. Note: This abstract was not presented at the meeting. Citation Format: Lindsay C. Stetson, Jill S. Barnholtz-Sloan. Protein markers predict overall survival in glioblastoma multiforme. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 297. doi:10.1158/1538-7445.AM2014-297