Setting the stage for metastasis: changes in the activity of specific pathways in medulloblastoma primary tumours correlates with an increased frequency of metastasis
Creators: name: Matan-Lithwick, Stuart
name: Cavalli, Florence M.G.
name: Kijima, Noriyuki
name: Donovan, Laura
name: Morrissy, Sorana
name: Garzia, Livia
name: Bader, Gary
name: Taylor, Michael
Publisher: name: F1000Research
Year: 2017

description: Medulloblastoma (MB) is the most common malignant brain tumour of childhood (1). The biology of MB primary tumours has been studied in depth (2). As a result, few patients now die from MB primary tumours. Instead, most patient mortality is attributable to secondary cancers or metastases (3). The genes and pathways that drive primary tumour progression differ significantly from those that drive metastasis. Even so, treatments for metastatic MB remain similar to those used to treat primary tumours, and have debilitating side-effects (4). This is due to the fact that, unlike primary tumours, very little is known about the process of MB metastasis. I hypothesize that subgroup and subtype-specific profiles of pathway activity distinguish MB primary tumours that metastasize from those that remain at the site of tumour formation, and that these profiles can be used as prognostic factors to identify tumours at greatest risk of metastasis. Transcriptome-wide microarray expression data from 528 independent human MB primary tumours (MAGIC consortium (5)) was subject to differential expression analysis (Limma (6)); lists of differentially expressed genes ranked by their probability of equal expression were further subject to Gene Set Enrichment Analysis (GSEA) (7) to identify pathways with changed activity in metastatic primary tumours (M+) relative to nonmetastatic primary tumours (M0). GSEA results were visualized using the Enrichment Map application (8) in Cytoscape (9). At the subgroup level, only in SHH and Group4 MB primary tumours were pathways with changed activity identified. Interestingly, these pathways identified at the subgroup level were not changed in all subgroup samples; instead, changes were specific to only certain subgroup-specific subtypes. This suggests that subtype-specific changes in pathway activity are associated with the metastasis of MB primary tumours. These patterns make it possible to identify MB primary tumours that are at the greatest risk of metastasis, and thereby support the tailoring of treatment regimens to disease severity.<br><br>(1) Ostrom QT, de Blank PM, Kruchko C, et al. 2015. Alex's Lemonade Stand Foundation Infant and Childhood Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2007-2011. <i>Neuro-Oncology</i> 17:x1-x35.<br>(2) Wang X, Dubuc AM, Ramaswamy V, et al. 2015. Medulloblastoma subgroups remain stable across primary and metastatic compartments.<i> Acta Neuropathologica</i> 129(3):449-57.<br>(3) Guan X. 2015. Cancer metastases: challenges and opportunities. <i>Acta Pharmaceutica Sinica</i> B. 5(5):402-18.<br>(4) Polkinghorn WR, Tarbell NJ. 2007. Medulloblastoma: tumorigenesis, current clinical paradigm, and efforts to improve risk stratification. <i>Nature Clinical Practice Oncology</i> 4(5):295–304.<br>(5) Cavalli FMG, Remke M, Rampasek L, et al. 2017. Intertumoral Heterogeneity within Medulloblastoma Subgroups. <i>Cancer Cell</i> 31:737-54.<br>(6) Ritchie ME, Phipson B, Wu D, et al. 2015. “limma powers differential expression analyses for RNA-sequencing and microarray studies.” <i>Nucleic Acids Research</i>, 43(7):e47.<br>(7) Subramanian A, Kuehn H, Gould J, et al. 2007. GSEA-P: a desktop application for Gene Set Enrichment Analysis. <i>Bioinformatics</i>. 23(23):3251-3.<br>(8) Merico D, Isserlin R, Stueker O, Emili A, Bader GD. Enrichment map: a network-based method for gene-set enrichment visualization and interpretation. <i>PLoS One</i>. 2010 Nov 15;5(11):e13984.<br>(9) Shannon P, Markiel A, Ozier O, et al. 2003. Cytoscape: a software environment for integrated models of biomolecular interaction networks. <i>Genome Research </i>13(11):2498-2504.