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@ARTICLE{Reuss:276776,
author = {D. E. Reuss$^*$ and S. M. Downing and C. V. Camacho and
Y.-D. Wang and R. M. Piro and C. Herold-Mende and Z.-Q. Wang
and T. G. Hofmann and F. Sahm$^*$ and A. von Deimling$^*$
and P. J. McKinnon and P.-O. Frappart},
title = {{S}imultaneous {N}bs1 and p53 inactivation in neural
progenitors triggers {H}igh-{G}rade {G}liomas ({HGG}).},
journal = {Neuropathology $\&$ applied neurobiology},
volume = {49},
number = {4},
issn = {0305-1846},
address = {Oxford [u.a.]},
publisher = {Wiley-Blackwell},
reportid = {DKFZ-2023-01157},
pages = {e12915},
year = {2023},
note = {#EA:B300# / 2023 Aug;49(4):e12915},
abstract = {Nijmegen Breakage Syndrome (NBS) is a rare autosomal
recessive disorder caused by hypomorphic mutations of NBS1.
NBS1 is a member of the MRE11A-RAD50-NBS1 (MRN) complex
which binds DNA double-strand breaks and activates the DNA
Damage Response (DDR). Nbs1 inactivation in neural
progenitor cells leads to microcephaly and premature death.
Interestingly, p53 homozygous deletion rescues the
NBS1-deficient phenotype allowing long-term survival. The
objective of this work was to determine whether simultaneous
inactivation of Nbs1 and p53 in neural progenitors triggered
brain tumorigenesis and if so in which category this tumour
could be classified.We generated a mouse model with
simultaneous genetic inactivation of Nbs1 and p53 in
embryonic neural stem cells and analysed the arising tumours
with in-depth molecular analyses including
immunohistochemistry, array Comparative Genomic
Hybridization (aCGH), whole exome-sequencing and
RNA-sequencing.NBS1/P53-deficient mice develop high-grade
gliomas (HGG) arising in the olfactory bulbs and the cortex
along the rostral migratory stream, and to a lower incidence
of medulloblastomas. In-depth molecular analyses using
immunohistochemistry, array Comparative Genomic
Hybridization (aCGH), whole exome-sequencing and
RNA-sequencing revealed striking similarities to paediatric
human HGG with shared features with Radiation-Induced
Gliomas: RIG.Our findings show that concomitant inactivation
of Nbs1 and p53 in mice promotes HGG with RIG features. This
model could be useful for preclinical studies to improve the
prognosis of these deadly tumours, but it also highlights
the singularity of NBS1 among the other DNA damage response
proteins in the aetiology of brain tumours.},
keywords = {NBS1 (Other) / P53 (Other) / PDGFRA (Other) / genomic
rearrangements (Other) / high-grade glioma (Other)},
cin = {B300 / HD01},
ddc = {610},
cid = {I:(DE-He78)B300-20160331 / I:(DE-He78)HD01-20160331},
pnm = {312 - Funktionelle und strukturelle Genomforschung
(POF4-312)},
pid = {G:(DE-HGF)POF4-312},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:37296499},
doi = {10.1111/nan.12915},
url = {https://inrepo02.dkfz.de/record/276776},
}