Abstract LB-238: Integrated genomic (TCGA & Validation Set) & pathway analysis in GBMs/MGs: the neurotrophin receptor (p75) mediates proliferation & invasion of GBMs & brain tumor initiating cells (BTICs).
Authors: qu xiaotao , kenchappa rajappa , tsai ya-yu , chen Ann , aiyar sarah , berglund anders , forsyth peter 
Published: August 2014

Background: Glioblastoma multiforme (GBM) is the most common and aggressive form of brain tumor and responds poorly to current therapies. Although high throughput technology has increased our understanding of GBM, little improvement has been seen in clinical outcomes. Neurotrophins and their receptors, in particular, the p75 receptor (NGFR), regulate diverse functions such as neuronal survival and cell motility and may play an important role in promoting glioma cell invasion, proliferation and survival.

Hypothesis: Activated p75(NTR) pathway may be associated with poor survival by promoting invasion and proliferation of GBM & Brain tumor initiating cells (BTICs).

Method: Gene expression profiles were analyzed for patients with different genomic characteristics based on targeted exome sequencing data. Kaplan-Meier survival product limit method, log-rank test and Cox regression models were used to examine the difference in overall survival time among different expression levels. Stratified analysis by different categories based on clinical data such as site of origin, grade, molecular subtype and treatment, were also performed. Two gene expression datasets were used in this study. One contains microarray expression data for 516 primary GBM patients with validated clinical data from the TCGA data portal. The other contains microarray expression data for 239 patients from Moffitt's Total Cancer Care (TCC) project with 108 GBM patients. In addition, 79 matched targeted exome sequencing data were also included from TCC projects.

Results: 1) NFGR is up-regulated in GBM when compared to normal (TCGA data, p &lt; 0.0001) 2) In TCC dataset, for patients with matching targeted exome sequencing data, NGFR is up-regulated by 1.5 fold (p=0.00086) between IDH1 wild type and R132H mutation (R132H). The IDH1 mutation is a well-known factor that associates with better survival. 3) There is no difference in NFGR expression across 4 molecular subtypes (TCGA data, n=170, p=0.266) 4) Increased expression of NFGR is associated with poor survival for all samples (n=452, p=0.08) and specifically the mesenchymal subtype (n=56, p=0.003). 5) Wet-lab experiments confirmed that increased expression of NGFR was associated with increased proliferation and invasion of GBMs and BTICS.

Significance: p75(NTR) pathways are activated in GBMs/MGs patients despite their molecular subtype and are associated with poor survival when up-regulated. p75(NTR) could be a novel target for personalized therapy.

Citation Format: xiaotao qu, rajappa kenchappa, ya-yu tsai, Ann chen, sarah aiyar, anders berglund, peter forsyth. H. Lee. Integrated genomic (TCGA & Validation Set) & pathway analysis in GBMs/MGs: the neurotrophin receptor (p75) mediates proliferation & invasion of GBMs & brain tumor initiating cells (BTICs). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-238. doi:10.1158/1538-7445.AM2013-LB-238