Integrative genomics reveals hypoxia inducible genes that are associated with a poor prognosis in neuroblastoma patients.

Mark A Applebaum,Kevin White,Marija Dobratic,Barbara E Stranger,Alexandre Chlenski,Clara Kao,Helen R Salwen,Nanduri Prabhakar,Gillian Dewane,Christopher J Mariani,Aashish R Jha,Lucy A Godley,Kyle M Hernandez,Susan L Cohn

doi:10.18632/oncotarget.12713

Mark A Applebaum, Kevin White + Show 12 more

Open Access

https://doi.org/10.18632/oncotarget.12713

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Journal: Oncotarget	Publication Date: Oct 17, 2016
Citations: 31	License type: cc-by

Affiliation: University of Chicago

Abstract

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.

Highlights

It is well recognized that more effective therapy is needed for children with high-risk neuroblastoma [1]
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
Activation of the hypoxia response pathways may have prognostic implications for survival in patients with neuroblastoma [9], which aspects of the hypoxia response are driving the biology of aggressive neuroblastoma tumors remains unclear

Summary

Introduction

It is well recognized that more effective therapy is needed for children with high-risk neuroblastoma [1]. Current risk stratification criteria cannot distinguish those high-risk patients who will achieve long-term survival with standard treatment approaches from those who will relapse or develop progressive www.impactjournals.com/oncotarget disease. An improved understanding of the molecular mechanisms that contribute to the clinically aggressive neuroblastoma phenotype is critical for refining risk stratification and the development of novel therapeutics. Aggressive solid tumors such as high-risk neuroblastoma, are known to contain regions of severe hypoxia, subsequently affecting numerous cellular pathways [3]. Activation of the hypoxia response pathways may have prognostic implications for survival in patients with neuroblastoma [9], which aspects of the hypoxia response are driving the biology of aggressive neuroblastoma tumors remains unclear

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