Astroblastomas exhibit radial glia stem cell lineages and differential expression of imprinted and X-inactivation escape genes

Norman L Lehman; Nathalie Spassky; Müge Sak; Amy Webb; Cory T Zumbar; Aisulu Usubalieva; Khaled J Alkhateeb; Joseph P McElroy; Kirsteen H Maclean; Paolo Fadda; Tom Liu; Vineela Gangalapudi; Jamie Carver; Zied Abdullaev; Cynthia Timmers; John R Parker; Christopher R Pierson; Bret C Mobley; Murat Gokden; Eyas M Hattab; Timothy Parrett; Ralph X Cooke; Trang D Lehman; Stefan Costinean; Anil Parwani; Brian J Williams; Randy L Jensen; Kenneth Aldape; Akshitkumar M Mistry

doi:10.1038/s41467-022-29302-8

Astroblastomas exhibit radial glia stem cell lineages and differential expression of imprinted and X-inactivation escape genes

Nat Commun. 2022 Apr 19;13(1):2083. doi: 10.1038/s41467-022-29302-8.

Authors

Norman L Lehman^{1

2

3}, Nathalie Spassky⁴, Müge Sak^{5

6}, Amy Webb⁷, Cory T Zumbar⁵, Aisulu Usubalieva⁸, Khaled J Alkhateeb⁵, Joseph P McElroy⁹, Kirsteen H Maclean¹⁰, Paolo Fadda¹¹, Tom Liu¹², Vineela Gangalapudi¹³, Jamie Carver⁵, Zied Abdullaev¹³, Cynthia Timmers¹², John R Parker⁵, Christopher R Pierson^{14

15}, Bret C Mobley¹⁶, Murat Gokden¹⁷, Eyas M Hattab⁵, Timothy Parrett¹⁸, Ralph X Cooke¹⁵, Trang D Lehman¹⁹, Stefan Costinean²⁰, Anil Parwani¹⁵, Brian J Williams²¹, Randy L Jensen²², Kenneth Aldape¹³, Akshitkumar M Mistry²³

Affiliations

¹ Department of Pathology and Laboratory Medicine, University of Louisville, Louisville, KY, 40202, USA. [email protected].
² Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY, 40202, USA. [email protected].
³ The Brown Cancer Center, University of Louisville, Louisville, KY, 40202, USA. [email protected].
⁴ Institut de Biologie de l'ENS (IBENS), Inserm, CNRS, École Normale Supérieure, PSL Research University, Paris, France.
⁵ Department of Pathology and Laboratory Medicine, University of Louisville, Louisville, KY, 40202, USA.
⁶ Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY, 40202, USA.
⁷ Department of Biomedical Informatics, The Ohio State University, Columbus, OH, 43210, USA.
⁸ Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.
⁹ Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, Columbus, OH, 43210, USA.
¹⁰ NanoString Technologies, Seattle, WA, 98109, USA.
¹¹ Department of Cancer Biology, The Ohio State University, Columbus, OH, 43210, USA.
¹² Solid Tumor Translational Science, The Ohio State University, Columbus, OH, 43210, USA.
¹³ Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, 20892, USA.
¹⁴ Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, 43205, USA.
¹⁵ Department of Pathology, The Ohio State University, Columbus, OH, 43210, USA.
¹⁶ Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, TN, 37232, USA.
¹⁷ Department of Pathology and Laboratory Services, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.
¹⁸ Department of Pathology and Anatomic Sciences, University of Missouri, Columbia, MO, 65212, USA.
¹⁹ Department of Family and Community Medicine, Contra Costa County Health System, Martinez, CA, 94553, USA.
²⁰ Department of Pathology, Banner Gateway Medical Center, MD Anderson Cancer Center, Tempe, AZ, 85284, USA.
²¹ Department of Neurosurgery, University of Louisville, Louisville, KY, 40202, USA.
²² Department of Neurosurgery, University of Utah, Salt Lake City, UT, 84132, USA.
²³ Department of Neurological Surgery, Vanderbilt University, Nashville, TN, 37232, USA.

Abstract

Astroblastomas (ABs) are rare brain tumors of unknown origin. We performed an integrative genetic and epigenetic analysis of AB-like tumors. Here, we show that tumors traceable to neural stem/progenitor cells (radial glia) that emerge during early to later brain development occur in children and young adults, respectively. Tumors with MN1-BEND2 fusion appear to present exclusively in females and exhibit overexpression of genes expressed prior to 25 post-conception weeks (pcw), including genes enriched in early ventricular zone radial glia and ependymal tumors. Other, histologically classic ABs overexpress or harbor mutations of mitogen-activated protein kinase pathway genes, outer and truncated radial glia genes, and genes expressed after 25 pcw, including neuronal and astrocyte markers. Findings support that AB-like tumors arise in the context of epigenetic and genetic changes in neural progenitors. Selective gene fusion, variable imprinting and/or chromosome X-inactivation escape resulting in biallelic overexpression may contribute to female predominance of AB molecular subtypes.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cell Lineage / genetics
Child
Ependymoglial Cells
Female
Humans
Male
Neoplasms, Neuroepithelial*
Neural Stem Cells*
Neuroglia
X Chromosome Inactivation / genetics
Young Adult

Abstract

Publication types

MeSH terms

Grants and funding