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. To investigate recurrently dysregulated genes in glioblastoma, we interrogated allele-specific expression (ASE), the difference in expression between two alleles of a gene, in glioblastoma stem cells (GSC) derived from 43 patients. A total of 118 genes were found with recurrent ASE preferentially in GSCs compared with normal tissues. These genes were enriched for apoptotic regulators, including schlafen family member 11 (<i>SLFN11</i>). Loss of <i>SLFN11</i> gene expression was associated with aberrant promoter methylation and conferred resistance to chemotherapy and PARP inhibition. Conversely, low <i>SLFN11</i> expression rendered GSCs susceptible to the oncolytic flavivirus Zika. This discovery effort based upon ASE revealed novel points of vulnerability in GSCs, suggesting a potential alternative treatment strategy for chemotherapy-resistant glioblastoma. SIGNIFICANCE: Assessing allele-specific expression reveals genes with recurrent cis-regulatory changes that are enriched in glioblastoma stem cells, including <i>SLFN11</i>, which modulates chemotherapy resistance and susceptibility to the oncolytic Zika virus.