Abstract A02: Identification of distinct BUB1B-sensitive and -resistant subtypes of glioblastoma with prognostic value
Authors: Eunjee Lee, Patrick J. Paddison, Jun Zhu
Journal: Cancer Research (2015)

Abstract 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 cancer cell lines. Furthermore, to identify regulatory drivers that determine BUB1B-sensitivity subtypes, we performed exome-sequencing of GSCs, and integrated BUB1B sensitivity subtype specific somatic mutation with other genomic data of GBM patients including somatic mutation and copy number variation from The Cancer Genomic Atlas (TCGA). The integrated analysis using multiple data types allowed us to identify multiple putative driver that determine BUB1B sensitivity status. Taken together, our results demonstrate the potential of a classification of GBM by BUB1B sensitivity signatures for prognostication, the future development of targeted drugs, and identifying regulatory mechanisms underlying each BUB1B sensitivity subtype. 1. Ding, Y., Hubert, C.G., Herman, J., Corrin, P., Toledo, C.M., Skutt-Kakaria, K., Vazquez, J., Basom, R., Zhang, B., Risler, J.K. et al. (2013) Cancer-Specific requirement for BUB1B/BUBR1 in human brain tumor isolates and genetically transformed cells. Cancer discovery, 3, 198-211. 2. Gravendeel, L.A., Kouwenhoven, M.C., Gevaert, O., de Rooi, J.J., Stubbs, A.P., Duijm, J.E., Daemen, A., Bleeker, F.E., Bralten, L.B., Kloosterhof, N.K. et al. (2009) Intrinsic gene expression profiles of gliomas are a better predictor of survival than histology. Cancer research, 69, 9065-9072. 3. Brennan, C.W., Verhaak, R.G., McKenna, A., Campos, B., Noushmehr, H., Salama, S.R., Zheng, S., Chakravarty, D., Sanborn, J.Z., Berman, S.H. et al. (2013) The somatic genomic landscape of glioblastoma. Cell, 155, 462-477. Citation Format: Eunjee Lee, Patrick J. Paddison, Jun Zhu. Identification of distinct BUB1B-sensitive and -resistant subtypes of glioblastoma with prognostic value. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr A02.