Imaging, Diagnosis, Prognosis microRNA Profiling Identifies Cancer-Specific and Prognostic Signatures in Pediatric Malignancies

Purpose:microRNAshavebeen shown tobe involved in different human cancers.We therefore have performed expression profiles on a panel of pediatric tumors to identify cancerspecificmicroRNAs.Wealso investigated ifmicroRNAsare coregulatedwith their host gene. Experimental Design: We performed parallel microRNAs and mRNA expression profiling on 57 tumor xenografts and cell lines representing 10 different pediatric solid tumors using microarrays. For those microRNAs that map to their host mRNA, we calculated correlations between them. Results: We found that the majority of cancer types clustered together based on their global microRNA expression profiles by unsupervised hierarchical clustering. Fourteen microRNAswere significantly differentially expressed between rhabdomyosarcoma and neuroblastoma, and 8 of themwere validated in independent patient tumor samples. Exploration of the expression of microRNAs in relationship with their host genes showed that the expression for 43 of 68 (63%)microRNAs located inside known coding geneswas significantly correlated with that of their host genes. Among these 43 microRNAs, 5 of 7 microRNAs in the OncomiR-1 cluster correlated significantly with their host gene MIRHG1 (P < 0.01). In addition, high expression of MIRHG1 was significantly associated with high stage and MYCN amplification in neuroblastoma tumors, and the expression level of MIRHG1 could predict the outcome of neuroblastoma patients independently from the current neuroblastoma risk-stratification in two independent patient cohorts. Conclusion: Pediatric cancers express cancer-specific microRNAs. The high expression of the OncomiR-1 host gene MIRHG1 correlates with poor outcome for patients with neuroblastoma, indicating important oncogenic functions of this microRNA cluster in neuroblastoma biology. (Clin Cancer Res 2009;15(17):5560–8) microRNAs are small, noncoding RNA molecules encoded in the genomes of plants and animals. These highly conserved, ∼21-nucleotide RNAs regulate the expression of genes by binding to the 3′-untranslated regions of specific mRNAs, causing translational inhibition or mRNA degradation (1). As many mRNAs may share this short sequence, microRNAs are capable of simultaneously influencing the expression of large sets of genes. It is estimated that each microRNA can target hundreds of genes (2); conversely, multiple microRNAs can target a single gene. Thus far, 701 microRNAs (version 12.0) have been reported to be expressed in human cells. Due to their regulatory roles in gene expression, there is increasing evidence that microRNAs are directly involved not only in normal embryogenesis, Authors' Affiliations: Oncogenomics Section, Pediatric Oncology Branch, Advanced Technology Center, National Cancer Institute, Gaithersburg, Maryland; Advanced Biomedical Computing Center, Science Applications International Corporation-Frederick, Inc., National Cancer InstituteFrederick, Frederick, Maryland; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland; and St. Jude Children's Research Hospital, Memphis, Tennessee Received 12/19/08; revised 6/24/09; accepted 7/20/09; published OnlineFirst 8/25/09. Grant support: Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The costs of publication of this articlewere defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). 5 http://microrna.sanger.ac.uk/ J.S. Wei and P. Johansson contributed equally to this work. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. Requests for reprints: Jun S. Wei, Oncogenomics Section, Pediatric Oncology Branch, Advanced Technology Center, National Cancer Institute, 8717 Grovemont Circle, Room 225D, Gaithersburg, MD 20877. Phone: 301402-9031; Fax: 301-402-3134; E-mail: [email protected] and Javed Khan, Oncogenomics Section, Pediatric Oncology Branch, Advanced Technology Center, National Cancer Institute, 8717 Grovemont Circle, Room 134E, Gaithersburg, MD 20877. Phone: 301-435-2937; Fax: 301-480-0314; E-mail: [email protected]. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-08-3287 5560 Clin Cancer Res 2009;15(17) September 1, 2009 www.aacrjournals.org Published Online First on August 25, 2009 as 10.1158/1078-0432.CCR-08-3287 Research. on April 13, 2017. © 2009 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst August 25, 2009; DOI: 10.1158/1078-0432.CCR-08-3287