Childhood brain tumor biology
Pediatric brain tumors are the most common solid malignancy of childhood. The pathogenesis of many of these tumors including Diffuse Intrinsic Pontine Gliomas (DIPGs) and ependymomas is centered around epigenetic alterations. The posterior fossa comprising of the cerebellum, pons and brain stem is the most frequent area of the brain where these childhood cancers occur. Deregulation of epigenetic developmental pathways in the growing posterior fossa may be intimately related to the biology of these tumors.
Diffuse Intrinsic Pontine Gliomas (DIPGs)
DIPGs are devastating pediatric brain tumors that carry a dismal prognosis with more than 90% of patients dying within 1.5 years after diagnosis. Genomic analyses of DIPG have shown recurrent mutations in genes encoding histone H3 at position 27 where the lysine residue is replaced by methionine (K27M) in 60-80% of patients. Since lysine residues on histone tails are subject to post-translational modifications, our group and others have shown that the H3K27M mutation results in a global reduction in H3K27me3 (above figure). We study how H3K27M mutations cause tumors. This will enable us to develop treatments to cure DIPG patients.
Pratt et al. Circumscribed/non-diffuse histology confers a better prognosis in H3K27M-mutant gliomas. Acta Neuropathol. 2018 Feb;135(2):299-301.
Venneti et al. A sensitive and specific histopathologic prognostic marker for H3F3A K27M mutant pediatric glioblastomas. Acta Neuropathol. 2014 Nov;128(5):743-53. doi: 10.1007/s00401-014-1338-3. Epub 2014 Sep 9.
Venneti et al. Evaluation of H3K27me3 and EZH2 in pediatric glial and glioneuronal tumors shows decreased H3K27me3 in H3F3A K27M mutant glioblastomas. Brain Pathol. 2013 Sep;23(5):558-64. doi: 10.1111/bpa.12042. Epub 2013 Mar 6.
Koschmann et al. Multi-focal sequencing of a diffuse intrinsic pontine glioma establishes PTEN loss as an early event npj Precision Oncology 1, Article number: 32 (2017) doi:10.1038/s41698-017-0033-y
Ependymomas in children are devastating tumors that most frequently arise in the developing posterior fossa. While childhood posterior fossa ependymomas do not bear recurrent mutations, they show profound epigenetic changes in DNA methylation and global reduction in H3K27me3. Comparison of DNA methylation and genome-wide H3K27me3 enrichment from both DIPGs and childhood ependymomas patient samples show extensive overlap and point to factors that regulate neuronal stem cells called radial glia during development.
Panwalkar et al., Immunohistochemical analysis of H3K27me3 demonstrates global reduction in group-A childhood posterior fossa ependymoma and is a powerful predictor of outcome. Acta Neuropathol. 2017 Jul 21. doi: 10.1007/s00401-017-1752-4.
Bayliss et al. Lowered H3K27me3 and DNA hypomethylation define poorly prognostic pediatric posterior fossa ependymomas. Science Transnational Medicine. 2016 Nov 23 Nov 2016: Vol. 8, Issue 366, pp. 366ra161.
Metabolic regulation of histone and DNA methylation
We study the relationship between cancer metabolism and epigenetics in brain tumors. Oncogenes in primary brain tumors in adults and children reprogram uptake and metabolism of nutrients such as glucose and glutamine to modulate many cellular functions including epigenetics. We evaluate the effects of altered metabolism on histone and DNA methylation in brain tumors, such as gliomas with isocitrate dehydrogenase (IDH) 1/2 mutations, and diffuse intrinsic pontine gliomas (DIPG) with histone H3K27M mutations.
Venneti S, Thompson CB. Metabolic Reprogramming in Brain Tumors. Annu Rev Pathol. 2016 Dec 21.
Wahl DR and Venneti S. 2-Hydoxyglutarate: D/Riving Pathology in gLiomaS. Brain Pathology. 2015 Nov;25(6):760-8.
Intlekofer AM, Dematteo RG, Venneti S et al. Hypoxia Induces Production of L-2-Hydroxyglutarate. Cell Metabolism. 2015 Aug 4;22(2):304-11.
Lu C, Venneti et al. Induction of sarcomas by mutant IDH2. Genes Development. 2013 Sep 15;27(18):1986-98. doi: 10.1101/gad.226753.113.
Venneti et al. Histone 3 lysine 9 trimethylation is differentially associated with IDH mutations in oligodendrogliomas and high-grade astrocytomas.J Neuropathol Exp Neurol. 2013 Apr;72(4):298-306. doi: 10.1097/NEN.0b013e3182898113.
Venneti et al. Metabolic modulation of epigenetics in gliomas.Brain Pathol. 2013 Mar;23(2):217-21. doi: 10.1111/bpa.12022.
Glutamine-based PET imaging
Positron emission tomography (PET) imaging is a means to evaluate changes in metabolism in cancer and takes advantage of increased nutrient uptake in tumor cells. The two main nutrients that cancer cells utilize are glucose and glutamine. Using radiolabeled glucose (FDG) and glutamine (FGln), we can image metabolic nutrient uptake in tumors in animal models and living patients. Above are images from a glioma patient showing tumor glutamine uptake (red arrows) compared to minimal signal in the surrounding brain enabling clear tumor delineation.
Venneti et al. Glutamine-based PET imaging facilitates enhanced metabolic evaluation of gliomas in vivo. Science Translational Medicine. 2015 Feb 11;7(274):274ra17. doi: 10.1126/scitranslmed.aaa1009.
Kim et al. Non-invasive metabolic imaging of brain tumors in the era of precision medicine. Nature Reviews Clinical Oncology. 2016 Jul 19. doi: 10.1038/nrclinonc.2016.108.
Dunphy et al. In Vivo PET Assay of Tumor Glutamine Flux and Metabolism: In-Human Trial of 18F-(2S,4R )-4-Fluoroglutamine. Radiology. 2018 Jan 31:162610. doi: 10.1148/radiol.2017162610.