NF1 May Serve As A Novel Genetic Biomarker Of Response To Treatment And Prognosis In Glioblastoma (GBM)

Abstract

The intrinsic capacity of glioblastoma (GBM) tumor cells to infiltrate normal brain predictably results in high rates of early recurrence. Little has changed over the last decade in the treatment available for GBM with survival remaining poor and a novel genetic biomarker is necessary found to predict response to treatment and prognosis in GBM. Biomarker discovery was performed by a genome-wide screen using DNA extracted from tissue and blood samples of GBM patients treated with standard of care. The biomarker was then evaluated for its predictability in OS and DFS and revealed the relationship with short-term relapse after radiation therapy. 22 kinds of mutations were detected in 51/58 GBM patients (87.9%). NF1 was the fourth frequently mutated gene and NF1-deleted/mutated GBM patients have the worst prognosis with 2-month median relapse time after radiation therapy. Median OS for NF1-deleted/mutated GBM patients (n = 11) treated with surgery and Chemoradiotherapy was 9.1 mon vs 17.2 mon for NF1 wildtype ones (n = 47), HR (95% CI) 1.83 (0.8753-3.817), p = 0.1. In addition, median DFS for NF1-deleted/mutated GBM patients (n = 11) was 2.9 mon vs 13.2 mon for NF1 wildtype ones (n = 47), p = 0.03. NF1-deleted/mutated GBMs showed reduced tumor purity and more infiltration of tumor-associated macrophages through pathological stainings. We measured the distance between 58 GBM patient’s tumor cells through an immunohistochemistry-based pathology imaging system and found that NF1-deleted/mutated cells have a lot more distances than NF1 wildtype ones. These data suggest that NF1-deleted/mutated GBM patients have a poor prognosis and a short-term relapse after radiation therapy. NF1 may play a role in organizing the tumor microenvironment. NF1 in GBM will be further evaluated in a planned randomized phase 2b study in newly diagnosed GBM patients.