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 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 Gökden, Eyas M. Hattab, Timothy Parrett, Ralph X. Cooke, Trang D. Lehman, Stefan Costinean, Anil V. Parwani, Brian J. Williams, Randy L. Jensen, Kenneth Aldape, Akshitkumar M. Mistry
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.