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There is no curative treatment for patients with diffuse intrinsic pontine glioma (DIPG). However, with the recent availability of biopsy and autopsy tissue, new data regarding the biologic behavior of this tumor have emerged, allowing greater molecular characterization and leading to investigations which may result in improved therapeutic options. Treatment strategies must address both primary disease sites as well as any metastatic deposits, which may be variably sensitive to a particular approach. In this case report, we present a patient with DIPG treated with irradiation and serial investigational agents. The clinical, pathological and molecular phenotypes of both the progressive primary tumor as well as concomitant metastatic deposits obtained at autopsy are discussed. While some mRNA differences were demonstrated, all analyzed sites of disease shared similar mutational arrangements, suggesting that targeting the mutations of the primary tumor may be effective for all sites of disease.

// Sridevi Yadavilli 1 , Joseph Scafidi 2 , Oren J. Becher 3 , Amanda M. Saratsis 4 , Rebecca L. Hiner 5 , Madhuri Kambhampati 1 , Santi Mariarita 6 , Tobey J. MacDonald 7 , Kari-Elise Codispoti 8 , Suresh N. Magge 9 , Jyoti K. Jaiswal 1,10 , Roger J. Packer 11 and Javad Nazarian 1,10 1 Research Center for Genetic Medicine, Children’s National Health System, Washington, DC, USA 2 Department of Neurology and Center for Neuroscience Research, Children’s National Health System, Washington, DC, USA 3 Department of Pediatrics and Pathology, Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA 4 Division of Neurosurgery, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA 5 Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, NY, USA 6 Department of Pathology and Lab Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA 7 Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA 8 Department of Pathology, Children’s National Health System, Washington, DC, USA 9 Division of Neurosurgery, Children’s National Health System, Washington, DC, USA 10 Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA 11 Brain Tumor Institute, Center for Neuroscience and Behavioral Medicine, Children’s National Health System, Washington, DC, USA Correspondence to: Javad Nazarian, email: // Keywords : DIPG, NG2, PDGF, histone 3, glioma Received : March 04, 2015 Accepted : March 11, 2015 Published : March 30, 2015 Abstract Diffuse intrinsic pontine gliomas (DIPGs) have a dismal prognosis and are poorly understood brain cancers. Receptor tyrosine kinases stabilized by neuron-glial antigen 2 (NG2) protein are known to induce gliomagenesis. Here, we investigated NG2 expression in a cohort of DIPG specimens (n= 50) . We demonstrate NG2 expression in the majority of DIPG specimens tested and determine that tumors harboring histone 3.3 mutation express the highest NG2 levels. We further demonstrate that microRNA 129-2 (miR129-2) is downregulated and hypermethylated in human DIPGs, resulting in the increased expression of NG2. Treatment with 5-Azacytidine, a methyltransferase inhibitor, results in NG2 downregulation in DIPG primary tumor cells in vitro . NG2 expression is altered (symmetric segregation) in mitotic human DIPG and mouse tumor cells. These mitotic cells co-express oligodendrocyte (Olig2) and astrocyte (glial fibrillary acidic protein, GFAP) markers, indicating lack of terminal differentiation. NG2 knockdown retards cellular migration in vitro, while NG2 expressing neurospheres are highly tumorigenic in vivo, resulting in rapid growth of pontine tumors. NG2 expression is targetable in vivo using miR129-2 indicating a potential avenue for therapeutic interventions. This data implicates NG2 as a molecule of interest in DIPGs especially those with H3.3 mutation.