BELOB: Ribo-minus RNA-seq data corresponding to 96x GBM samples from the BELOB trial.
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ABSTRACT:
PROVIDER: EGAS00001004570 | EGA |
REPOSITORIES: EGA
Publications
Identification of Patients with Recurrent Glioblastoma Who May Benefit from Combined Bevacizumab and CCNU Therapy: A Report from the BELOB Trial.
Erdem-Eraslan Lale L van den Bent Martin J MJ Hoogstrate Youri Y Naz-Khan Hina H Stubbs Andrew A van der Spek Peter P Böttcher René R Gao Ya Y de Wit Maurice M Taal Walter W Oosterkamp Hendrika M HM Walenkamp Annemiek A Beerepoot Laurens V LV Hanse Monique C J MC Buter Jan J Honkoop Aafke H AH van der Holt Bronno B Vernhout René M RM Sillevis Smitt Peter A E PA Kros Johan M JM French Pim J PJ
Cancer research 20160113 3
The results from the randomized phase II BELOB trial provided evidence for a potential benefit of bevacizumab (beva), a humanized monoclonal antibody against circulating VEGF-A, when added to CCNU chemotherapy in patients with recurrent glioblastoma (GBM). In this study, we performed gene expression profiling (DASL and RNA-seq) of formalin-fixed, paraffin-embedded tumor material from participants of the BELOB trial to identify patients with recurrent GBM who benefitted most from beva+CCNU treatm ...[more]
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Project description:The results from the randomized phase II BELOB trial provided evidence for a potential benefit of bevacizumab (beva; a humanized monoclonal antibody against circulating VEGF-A) when added to CCNU chemotherapy in recurrent GBM patients. In this study, we have performed gene expression profiling (DASL and RNA-seq) on formalin fixed, paraffin embedded (FFPE) tumor material from patients treated within the BELOB trial to identify recurrent GBM patients who benefit most from combined beva/CCNU treatment. We first extensively validate the use of FFPE tissues for expression profiling on both DASL and RNA-seq. Our data show that tumors assigned to IGS-18 or ‘classical’ GBMs show a significant benefit in progression free survival (PFS) and a trend towards benefit in overall survival (OS) from beva+CCNU treatment; other subtypes do not show such benefit. In particular, expression of FMO4 and OSBPL3 were associated with treatment response. All molecular glioma subtypes are evenly distributed along the different study arms and the improved outcome in the beva/CCNU arm therefore is not explained by an uneven distribution of prognostically favorable subtypes. Analysis of RNA-seq data highlighted genetic changes, including mutations, gene fusions (and identification of the exact genomic breakpoint), and copy number changes (albeit with limited resolution) within this well-defined cohort of tumors. When validated in an independent dataset, the predictive markers identified in this study will allow selection of recurrent GBM patients that benefit from beva+CCNU treatment.
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Project description:The results from the randomized phase II BELOB trial provided evidence for a potential benefit of bevacizumab (beva; a humanized monoclonal antibody against circulating VEGF-A) when added to CCNU chemotherapy in recurrent GBM patients. In this study, we have performed gene expression profiling (DASL and RNA-seq) on formalin fixed, paraffin embedded (FFPE) tumor material from patients treated within the BELOB trial to identify recurrent GBM patients who benefit most from combined beva/CCNU treatment. We first extensively validate the use of FFPE tissues for expression profiling on both DASL and RNA-seq. Our data show that tumors assigned to IGS-18 or â??classicalâ?? GBMs show a significant benefit in progression free survival (PFS) and a trend towards benefit in overall survival (OS) from beva+CCNU treatment; other subtypes do not show such benefit. In particular, expression of FMO4 and OSBPL3 were associated with treatment response. All molecular glioma subtypes are evenly distributed along the different study arms and the improved outcome in the beva/CCNU arm therefore is not explained by an uneven distribution of prognostically favorable subtypes. Analysis of RNA-seq data highlighted genetic changes, including mutations, gene fusions (and identification of the exact genomic breakpoint), and copy number changes (albeit with limited resolution) within this well-defined cohort of tumors. When validated in an independent dataset, the predictive markers identified in this study will allow selection of recurrent GBM patients that benefit from beva+CCNU treatment. A total of 112 samples of patients included in the Belob trial were profiled. Profiling was done in three batches (3 raw data files; Belob1, Belob2 and Belob3*.txt). Please note that several replicates were performed to demonstrate platform reproducibility on FFPE material (basically the entire first experiment, samples 1-10 described in the all_sample_description.txt). In addition, a few samples were scraped (macrodissection) as the original tissue block contained a too low tumor content (as indicated in the sample description field). These Samples omitted from the final analysis are marked with X at the end of the patient ID column (in the all_sample_description.txt). Also, Of the 117 individual patients, the following patient samples were excluded in the final analysis: B11, B57, B73, B91 and B59. These samples were outliers in the gene expression analysis and did not meet the quality criteria (their median overall expression was <7.5 (log2)). The complete sample description and raw data (of 135 samples) are provided in the all_sample_description.txt and Belob*French.txt files, however only 112 samples (included in the final data analysis) are included in this record. Tumor Subtype (in the sample 'characteriscts) is defined by Gravendeel et al, Cancer Res 2009 Dec 1;69(23):9065-72. TCGA subtype (in the sample 'characteriscts) is defined by Verhaak et al, Cancer Cell. 2010 Jan 19;17(1):98-110. The sample 'chracteristic:Sensor' values indicate whether the patient alive or dead at time of analysis.
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Project description:Glioblastoma multiforme (GBM) is the most aggressive form of brain tumors. Despite radical surgery and radiotherapy supported by chemotherapy, the disease still remains incurable with extremely low median survival rate of 12-15 months from the time of initial diagnosis. The main cause of treatment failure is considered to be the presence of cells that are resistant to such treatment. MicroRNAs (miRNAs) as regulators of gene expression are involved in the tumor pathogenesis, including GBM. MiR-338 is a brain specific miRNA which has been described to target pathways involved in proliferation and differentiation. In our study, miR-338-3p and -5p were differentially expressed in GBM tissue in comparison to non-tumor brain tissue. Overexpression of miR-338-3p with miRNA mimic did not show any changes in proliferation rates in GBM cell lines (A172, T98G, U87MG). On the other hand, pre-miR-338-5p notably decreased proliferation and caused cell cycle arrest. Since radiation is currently the main treatment modality in GBM, we combined overexpression of pre-miR-338-5p with radiation, which led to significantly decreased of cell proliferation, and increased cell cycle arrest and apoptosis in comparison to only irradiated cells. To better elucidate the mechanism of action, we performed gene expression profiling analysis that revealed targets of miR-338-5p being Ndfip1, Rheb, ppp2R5a. These genes have been described to be involved in DNA damage response, proliferation and cell cycle regulation. To our knowledge, this is the first study to describe role of miR-338-5p in GBM and its potential to improve sensitivity of GBM to radiation. Study was performed on three glioblastoma multiforme cell lines A172, T98G and U87MG. This experiment was performed on Affymetrix GeneChip Human Gene ST 1.0 to elucidate the targets of miRNA-338-5p. Cell lines were seeded 24 hours prior transfection. After transfection with pre-miR338-5p or negative control cell were cultured for 24 hours and harvested. RNA was isolated using MirVana miRNA Isolation Kit (Ambion, USA) and checked for RNA integrity by Bioanalyzer 2100 and purity by ratios 260/280>1.8 and 260/230>1.8 by Nanodrop2000.
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