Multiplatform Molecular Profiling Reveals Epigenomic Intratumor Heterogeneity in Ependymoma
S. John Liu,
Stephen T. Magill,
Harish N. Vasudevan,
Stephanie Hilz,
Javier E. Villanueva-Meyer,
Sydney Lastella,
Vikas Daggubati,
Jordan Spatz,
Abrar Choudhury,
Brent A. Orr,
Benjamin Demaree,
Kyounghee Seo,
Sean P. Ferris,
Adam R. Abate,
Nancy Ann Oberheim Bush,
Andrew W. Bollen,
Michael W. McDermott,
Joseph F. Costello,
David R. Raleigh
Affiliations
S. John Liu
Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
Stephen T. Magill
Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
Harish N. Vasudevan
Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
Stephanie Hilz
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
Javier E. Villanueva-Meyer
Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA 94143, USA
Sydney Lastella
Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
Vikas Daggubati
Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
Jordan Spatz
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
Abrar Choudhury
Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
Brent A. Orr
Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Benjamin Demaree
Department of Bioengineering and Therapeutic Sciences, California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, CA 94158, USA
Kyounghee Seo
Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
Sean P. Ferris
Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA
Adam R. Abate
Department of Bioengineering and Therapeutic Sciences, California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, CA 94158, USA
Nancy Ann Oberheim Bush
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
Andrew W. Bollen
Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA
Michael W. McDermott
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
Joseph F. Costello
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
David R. Raleigh
Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Corresponding author
Summary: 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. : 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. Keywords: brain tumor, cancer, DNA methylation, C11orf95-RELA, ependymoma, epigenomics, exome sequencing, magnetic resonance imaging, RNA sequencing, SETD2
