Abstract A02: Identification of distinct BUB1B-sensitive and -resistant subtypes of glioblastoma with prognostic value

Glioblastoma multiforme is the most aggressive and common form of brain cancer in adults. The combined analysis of functional genetics with glioblastoma (GBM) network modeling identified BUB1B, a critical mitotic spindle checkpoint player, as a new requirement of glioblastoma tumors to suppress lethal consequences of altered kinetochore (KT) (1). Here, we further collected GBM stem-like cells (GSCs) including both BUB1B-sensitive and -resistant isolates, and performed whole-transcriptome sequencing that capture gene expression levels of each GSC. Based on the expression signature associated with BUB1B-sensitiveness from GSCs, we propose a framework to predict BUB1B sensitiveness of GBM patients or cancer cell lines by using its expression profile. Our framework stratifies GBM patients into two distinct subtypes, BUB1B-sensitive and –resistant that significantly associated with worse and better prognosis using two independent glioblastoma cohort data sets (2,3).The additional siRNA screens in BUB1B-sensitive, –resistant GSCs, and neuronal stem cell (NSC) provided us the genes specifically required for BUB1B-sensitive and –resistant GSCs expansion. By combining with GBM network, these genes allowed us to build subtype-specific regulatory networks, suggesting candidate subtype specific therapeutic targets for GBM. Additionally, we revealed BUB1B-sensitive subtypes were consistently sensitive to drugs targeting BRAF and EGRF based on predicted BUB1B-sensitiveness of glioma ...

Source: Cancer Research - December 9, 2015 Category: Cancer & Oncology Authors: Lee, E., Paddison, P. J., Zhu, J. Tags: Computational Genomics and Evolutionary Dynamics Source Type: research