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 and Akshitkumar M. Mistry
Additional contact information
Norman L. Lehman: University of Louisville
Nathalie Spassky: Institut de Biologie de l’ENS (IBENS), Inserm, CNRS, École Normale Supérieure, PSL Research University
Müge Sak: University of Louisville
Amy Webb: The Ohio State University
Cory T. Zumbar: University of Louisville
Aisulu Usubalieva: University of Arkansas for Medical Sciences
Khaled J. Alkhateeb: University of Louisville
Joseph P. McElroy: The Ohio State University
Kirsteen H. Maclean: NanoString Technologies
Paolo Fadda: The Ohio State University
Tom Liu: Solid Tumor Translational Science, The Ohio State University
Vineela Gangalapudi: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute
Jamie Carver: University of Louisville
Zied Abdullaev: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute
Cynthia Timmers: Solid Tumor Translational Science, The Ohio State University
John R. Parker: University of Louisville
Christopher R. Pierson: Nationwide Children’s Hospital
Bret C. Mobley: Vanderbilt University
Murat Gokden: University of Arkansas for Medical Sciences
Eyas M. Hattab: University of Louisville
Timothy Parrett: University of Missouri
Ralph X. Cooke: The Ohio State University
Trang D. Lehman: Contra Costa County Health System
Stefan Costinean: MD Anderson Cancer Center
Anil Parwani: The Ohio State University
Brian J. Williams: University of Louisville
Randy L. Jensen: University of Utah
Kenneth Aldape: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute
Akshitkumar M. Mistry: Vanderbilt University

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-29302-8

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