Leveraging Allele-Specific Expression for Therapeutic Response Gene Discovery in Glioblastoma.

Abstract

Glioblastoma is the most prevalent primary malignant brain tumor in adults and is characterized by poor prognosis and universal tumor recurrence. Effective glioblastoma treatments are lacking, in part due to somatic mutations and epigenetic reprogramming that alter gene expression and confer drug resistance. Here, we interrogated allele-specific expression (ASE) in 43 patient-derived glioblastoma stem cells (GSCs) to identify recurrently dysregulated genes in glioblastoma. We identified 118 genes with recurrent ASE preferentially found in GSCs compared to normal tissues. These genes were enriched for apoptotic regulators, including Schlafen Family Member 11 (SLFN11). Loss of SLFN11 gene expression was associated with aberrant promoter methylation and conferred resistance to chemotherapy and poly ADP ribose polymerase inhibition. Conversely, low SLFN11 expression rendered GSCs susceptible to the oncolytic flavivirus Zika, which suggests a potential alternative treatment strategy for chemotherapy resistant GBMs.