Multiplatform Molecular Profiling Reveals Epigenomic Intratumor Heterogeneity in Ependymoma

• Published in: Cell reports (Cambridge) Vol. 30; no. 5; pp. 1300 - 1309.e5
• Main Authors: Liu, S. John, Magill, Stephen T., Vasudevan, Harish N., Hilz, Stephanie, Villanueva-Meyer, Javier E., Lastella, Sydney, Daggubati, Vikas, Spatz, Jordan, Choudhury, Abrar, Orr, Brent A., Demaree, Benjamin, Seo, Kyounghee, Ferris, Sean P., Abate, Adam R., Oberheim Bush, Nancy Ann, Bollen, Andrew W., McDermott, Michael W., Costello, Joseph F., Raleigh, David R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.02.2020; Elsevier
• Subjects: Adult; brain tumor; C11orf95-RELA; cancer; Cell Differentiation - genetics; Cell Line, Tumor; Chromosome Aberrations; DNA methylation; ependymoma; Ependymoma - diagnostic imaging; Ependymoma - genetics; Epigenomics; exome sequencing; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genetic Heterogeneity; Histone-Lysine N-Methyltransferase - genetics; Histone-Lysine N-Methyltransferase - metabolism; Humans; magnetic resonance imaging; Male; Mutation - genetics; Neurons - pathology; Phylogeny; Proteins - metabolism; RNA sequencing; SETD2; Transcription Factor RelA - metabolism; ependymoma; RNA sequencing; exome sequencing; magnetic resonance imaging; SETD2; C11orf95-RELA; DNA methylation; brain tumor; epigenomics; cancer
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.01.018

Ependymomas exist within distinct genetic subgroups, but the molecular diversity within individual ependymomas is unknown. We perform multiplatform molecular profiling of 6 spatially distinct samples from an ependymoma with C11orf95-RELA fusion. DNA methylation and RNA sequencing distinguish clusters of samples according to neuronal development gene expression programs that could also be delineated by differences in magnetic resonance blood perfusion. Exome sequencing and phylogenetic analysis reveal epigenomic intratumor heterogeneity and suggest that chromosomal structural alterations may precede accumulation of single-nucleotide variants during ependymoma tumorigenesis. In sum, these findings shed light on the oncogenesis and intratumor heterogeneity of ependymoma. [Display omitted] •Epigenomic, transcriptomic, and exome profiles and phylogenies within an ependymoma•Spatially distinct clusters reflect neuronal development gene expression programs•Quantitative magnetic resonance imaging characteristics identify stem-like regions•Mutant histone methyltransferase SETD2 enhances proliferation in ependymoma cells Tumor heterogeneity poses a barrier to cancer treatment. Liu et al. investigate radiographically distinct regions of an ependymoma tumor using transcriptomic, genetic, and epigenomic profiling and discover axes of gene expression programs that recapitulate normal brain development in addition to phylogenies that shed light on the tumorigenesis of ependymoma.