Integrative genomics reveals hypoxia inducible genes that are associated with a poor prognosis in neuroblastoma patients
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Mark A. Applebaum1,2,*, Aashish R. Jha3,4,*, Clara Kao4, Kyle M. Hernandez5, Gillian DeWane1, Helen R. Salwen1, Alexandre Chlenski1, Marija Dobratic1, Christopher J. Mariani6, Lucy A. Godley6, Nanduri Prabhakar6, Kevin White4, Barbara E. Stranger3,6,7, Susan L. Cohn1,2
1Departments of Pediatrics, University of Chicago, Chicago, Illinois, 60637, United States of America
2Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, Chicago, Illinois, 60637, United States of America
3Institute for Genomics and Systems Biology, University of Chicago, Chicago, Illinois, 60637, United States of America
4Department of Human Genetics, University of Chicago, Chicago, Illinois, 60637, United States of America
5Center for Research Informatics, University of Chicago, Chicago, Illinois, 60637, United States of America
6Department of Medicine, University of Chicago, Chicago, Illinois, 60637, United States of America
7Center for Data Intensive Science, University of Chicago, Chicago, Illinois, 60637, United States of America
*These authors contributed equally to this work
Susan L. Cohn, email: firstname.lastname@example.org
Keywords: neuroblastoma, hypoxia, metabolism, RNA expression, pathway analysis
Received: August 02, 2016 Accepted: October 12, 2016 Published: October 17, 2016
Neuroblastoma is notable for its broad spectrum of clinical behavior ranging from spontaneous regression to rapidly progressive disease. Hypoxia is well known to confer a more aggressive phenotype in neuroblastoma. We analyzed transcriptome data from diagnostic neuroblastoma tumors and hypoxic neuroblastoma cell lines to identify genes whose expression levels correlate with poor patient outcome and are involved in the hypoxia response. By integrating a diverse set of transcriptome datasets, including those from neuroblastoma patients and neuroblastoma derived cell lines, we identified nine genes (SLCO4A1, ENO1, HK2, PGK1, MTFP1, HILPDA, VKORC1, TPI1, and HIST1H1C) that are up-regulated in hypoxia and whose expression levels are correlated with poor patient outcome in three independent neuroblastoma cohorts. Analysis of 5-hydroxymethylcytosine and ENCODE data indicate that at least five of these nine genes have an increase in 5-hydroxymethylcytosine and a more open chromatin structure in hypoxia versus normoxia and are putative targets of hypoxia inducible factor (HIF) as they contain HIF binding sites in their regulatory regions. Four of these genes are key components of the glycolytic pathway and another three are directly involved in cellular metabolism. We experimentally validated our computational findings demonstrating that seven of the nine genes are significantly up-regulated in response to hypoxia in the four neuroblastoma cell lines tested. This compact and robustly validated group of genes, is associated with the hypoxia response in aggressive neuroblastoma and may represent a novel target for biomarker and therapeutic development.
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