Radiogenomic Mapping of Edema/Cellular Invasion MRI-Phenotypes in Glioblastoma Multiforme

et al. (2011) Radiogenomic Mapping of Edema/Cellular Invasion MRI-Phenotypes in Glioblastoma Multiforme. PLoS ONE 6(10): e25451. doi:10.1371/journal.pone.0025451 Radiogenomic Mapping of Edema/Cellular Invasion MRI-Phenotypes in Glioblastoma Multiforme Pascal O. Zinn 0 Bhanu Majadan 0 Pratheesh Sathyan 0 Sanjay K. Singh 0 Sadhan Majumder 0 Ferenc A. Jolesz 0 Rivka R. Colen 0 Eric Deutsch, Institut Gustave Roussy, France 0 1 Department of Genetics, M.D. Anderson Cancer Center, University of Texas , Houston , Texas, United States of America, 2 Department of Clinical Neurosciences, University Hospital (CHUV BH19-110) , Lausanne , Switzerland , 3 Department of Radiology, Brigham and Women's Hospital, Harvard Medical School , Boston, Massachusetts , United States of America Background: Despite recent discoveries of new molecular targets and pathways, the search for an effective therapy for Glioblastoma Multiforme (GBM) continues. A newly emerged field, radiogenomics, links gene expression profiles with MRI phenotypes. MRI-FLAIR is a noninvasive diagnostic modality and was previously found to correlate with cellular invasion in GBM. Thus, our radiogenomic screen has the potential to reveal novel molecular determinants of invasion. Here, we present the first comprehensive radiogenomic analysis using quantitative MRI volumetrics and large-scale gene- and microRNA expression profiling in GBM. Methods: Based on The Cancer Genome Atlas (TCGA), discovery and validation sets with gene, microRNA, and quantitative MR-imaging data were created. Top concordant genes and microRNAs correlated with high FLAIR volumes from both sets were further characterized by Kaplan Meier survival statistics, microRNA-gene correlation analyses, and GBM molecular subtype-specific distribution. Results: The top upregulated gene in both the discovery (4 fold) and validation (11 fold) sets was PERIOSTIN (POSTN). The top downregulated microRNA in both sets was miR-219, which is predicted to bind to POSTN. Kaplan Meier analysis demonstrated that above median expression of POSTN resulted in significantly decreased survival and shorter time to disease progression (P,0.001). High POSTN and low miR-219 expression were significantly associated with the mesenchymal GBM subtype (P,0.0001). Conclusion: Here, we propose a novel diagnostic method to screen for molecular cancer subtypes and genomic correlates of cellular invasion. Our findings also have potential therapeutic significance since successful molecular inhibition of invasion will improve therapy and patient survival in GBM. - Funding: This work was supported by National Institute of Health grants: P41-RR019703 (FAJ) and R25 CA089017-06A2 (RRC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Microarray technology is a novel method that allows for the simultaneous analysis of whole genome gene- and microRNA expression events [1,2]. This latest breakthrough technology heralds an age of large-scale discovery of new and effective therapeutic strategies for Glioblastoma Multiforme (GBM). However, despite the discovery of many new molecular targets and pathways [3,4], the search for an effective therapy continues. Besides the multi-resistant character of GBM [5,6], therapy failure is thought to occur due to the cancers invasive nature and high migratory potential preventing complete surgical resection and evading current therapeutic strategies [7,8,9]. Furthermore, therapy is complicated by intra- and intertumoral molecular and cellular heterogeneity that is now known to cause some tumors to respond to a specific drug while another demonstrating resistance [4,10]. Based on this recent awareness, focus is shifting toward a more personalized treatment approach. In this regard, in particular, microRNAs are being increasingly studied. MicroRNAs are non-protein coding small RNAs that serve as negative gene regulators by binding to a specific sequence in the 39UTR of a target gene, thus regulating gene expression. A single microRNA potentially targets hundreds of genes; thus, microRNAs were found to have important roles as tumor suppressors and oncogenes [11], as well as regulators of various cancer-specific cellular features, such as proliferation, invasion, and metastasis [12,13,14]. Although certain genetic analyses, such as O6-methylguanineDNA-methyltransferase (MGMT) promoter methylation and isocitrate dehydrogenase 1 (IDH1) status [4,15,16,17], are frequently used in clinical practice, large scale gene- and microRNA based cancer characterization is commonly not performed due to high cost, time and manpower required for data analysis and interpretation [18]. In order for personalized medicine to transpire, a cost-effective biomarker that accurately modern multimodal GBM treatment [9]. The discovery of targetable genes responsible for cell spread and invasion can be expected to impact modern therapy and patient survival. Materials and Methods The collection of the original material and data provided by The Cancer Genome Atlas (TCGA) project was conducted in compliance with all applicable laws, regulations and policies for the protection of human subjects, and any necessary approvals, authorizations, human subject assurances, informed consent documents, and IRB approvals were obtained [26]. Patient population We identified 78 treatment-nave GBM patients from TCGA whom had both gene- and microRNA expression profiles and pretreatment MR-neuroimaging. The TCGA is a publicly available resource which has produced a multi-dimensional genomic and clinical data set in GBM and other cancers [26]. Recently, MR imaging was added to this genomic repository. Discovery and Validation sets To increase the robustness and validity of the analysis, the 78 patients were randomly separated into a discovery and validation reflects underlying molecular cancer compositions is urgently needed. Imaging, specifically MRI, is a promising biomarker that can reflect underlying tumor pathology and biological function. It can evaluate the entire tumor, including its peritumoral regions which harbor microscopic invasion of cancer cells [19] and which typically cannot be surgically removed and thus are rarely analyzed in the laboratory. It follows that if imaging phenotypes of GBM obtained from routine clinical MRI studies can be associated with specific gene and microRNA expression signatures, imaging phenotypes will serve as non-invasive surrogates for cancer genomic events and provide important information as to the diagnosis, prognosis, and optimal treatment. Furthermore, it will allow for bi-directional imaging phenotype-genotype correlations and discoveries. Thus, a new field termed radiogenomics has emerged and links specific MRI radiophenotypes with gene expression profiles [20]. In the past, several studies compare (...truncated)