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@ARTICLE{Okonechnikov:277922,
author = {K. Okonechnikov$^*$ and P. K. Joshi$^*$ and M. Sepp and K.
Leiss and I. Sarropoulos and F. Murat and M. Sill$^*$ and P.
Beck$^*$ and K. C. Chan$^*$ and A. Korshunov$^*$ and F.
Sahm$^*$ and M. Y. Deng$^*$ and D. Sturm$^*$ and J. DeSisto
and A. M. Donson and N. K. Foreman and A. L. Green and G.
Robinson and B. A. Orr and Q. Gao and E. Darrow and J. L.
Hadley and P. A. Northcott and J. Gojo$^*$ and D. Kawauchi
and V. Hovestadt and M. G. Filbin and A. von Deimling$^*$
and M. Zuckermann$^*$ and K. Pajtler$^*$ and M. Kool$^*$ and
D. Jones$^*$ and N. Jäger$^*$ and L. Kutscher$^*$ and H.
Kaessmann and S. Pfister$^*$},
title = {{M}apping pediatric brain tumors to their origins in the
developing cerebellum.},
journal = {Neuro-Oncology},
volume = {25},
number = {10},
issn = {1522-8517},
address = {Oxford},
publisher = {Oxford Univ. Press},
reportid = {DKFZ-2023-01578},
pages = {1895-1909},
year = {2023},
note = {DKFZ-ZMBH Alliance / #EA:B062#EA:B430#LA:B062#LA:B430# /
2023 Oct 3;25(10):1895-1909},
abstract = {Distinguishing the cellular origins of childhood brain
tumors is key for understanding tumor initiation and
identifying lineage-restricted, tumor-specific therapeutic
targets. Previous strategies to map the cell-of-origin
typically involved comparing human tumors to murine
embryonal tissues, which is potentially limited due to
species-specific differences. The aim of this study was to
unravel the cellular origins of the three most common
pediatric brain tumors, ependymoma, pilocytic astrocytoma,
and medulloblastoma, using a developing human cerebellar
atlas.We used a single-nucleus atlas of the normal
developing human cerebellum consisting of 176,645 cells as a
reference for an in-depth comparison to 4,416 bulk and
single-cell transcriptome tumor datasets, using gene set
variation analysis, correlation, and single-cell matching
techniques.We find that the astroglial cerebellar lineage is
potentially the origin for posterior fossa ependymomas. We
propose that infratentorial pilocytic astrocytomas originate
from the oligodendrocyte lineage and MHC II genes are
specifically enriched in these tumors. We confirm that SHH
and Group 3/4 medulloblastomas originate from the granule
cell and unipolar brush cell lineages. Radiation-induced
gliomas stem from cerebellar glial lineages and demonstrate
distinct origins from the primary medulloblastoma. We
identify tumor genes that are expressed in the cerebellar
lineage of origin, and genes that are tumor specific; both
gene sets represent promising therapeutic targets for future
study.Based on our results, individual cells within a tumor
may resemble different cell types along a restricted
developmental lineage. Therefore, we suggest that tumors can
arise from multiple cellular states along the cerebellar
'lineage of origin'.},
keywords = {cerebellum (Other) / ependymoma (Other) / medulloblastoma
(Other) / pilocytic astrocytoma (Other) / radiation-induced
glioma (Other) / tumor origin (Other)},
cin = {B062 / HD01 / B430 / B300 / B360},
ddc = {610},
cid = {I:(DE-He78)B062-20160331 / I:(DE-He78)HD01-20160331 /
I:(DE-He78)B430-20160331 / I:(DE-He78)B300-20160331 /
I:(DE-He78)B360-20160331},
pnm = {312 - Funktionelle und strukturelle Genomforschung
(POF4-312)},
pid = {G:(DE-HGF)POF4-312},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:37534924},
doi = {10.1093/neuonc/noad124},
url = {https://inrepo02.dkfz.de/record/277922},
}