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@ARTICLE{Park:144028,
author = {A. K. Park and J. Y. Lee and H. Cheong and V. Ramaswamy and
S.-H. Park and M. Kool$^*$ and J. H. Phi and S. A. Choi and
F. Cavalli and M. D. Taylor and S.-K. Kim},
title = {{S}ubgroup-specific prognostic signaling and metabolic
pathways in pediatric medulloblastoma.},
journal = {BMC cancer},
volume = {19},
number = {1},
issn = {1471-2407},
address = {Heidelberg},
publisher = {Springer},
reportid = {DKFZ-2019-01579},
pages = {571},
year = {2019},
abstract = {Using a pathway-focused approach, we aimed to provide a
subgroup-specific basis for finding novel therapeutic
strategies and further refinement of the risk stratification
in pediatric medulloblastoma.Based on genome-wide Cox
regression and Gene Set Enrichment Analysis, we investigated
prognosis-related signaling pathways and core genes in
pediatric medulloblastoma subgroups using 530 patient data
from Medulloblastoma Advanced Genomic International
Consortium (MAGIC) project. We further examined the
relationship between expression of the prognostic core genes
and frequent chromosome aberrations using broad range copy
number change data.In SHH subgroup, relatively high
expression of the core genes involved in p53, PLK1, FOXM1,
and Aurora B signaling pathways are associated with poor
prognosis, and their average expression synergistically
increases with co-occurrence of losses of 17p, 14q, or 10q,
or gain of 17q. In Group 3, in addition to high MYC
expression, relatively elevated expression of PDGFRA, IGF1R,
and FGF2 and their downstream genes in PI3K/AKT and MAPK/ERK
pathways are related to poor survival outcome, and their
average expression is increased with the presence of
isochromosome 17q [i(17q)] and synergistically
down-regulated with simultaneous losses of 16p, 8q, or 4q.
In Group 4, up-regulation of the genes encoding various
immune receptors and those involved in NOTCH, NF-κB,
PI3K/AKT, or RHOA signaling pathways are associated with
worse prognosis. Additionally, the expressions of Notch
genes correlate with those of the prognostic immune
receptors. Besides the Group 4 patients with previously
known prognostic aberration, loss of chromosome 11, those
with loss of 8q but without i(17q) show excellent survival
outcomes and low average expression of the prognostic core
genes whereas those harboring 10q loss, 1q gain, or 12q gain
accompanied by i(17q) show bad outcomes. Finally, several
metabolic pathways known to be reprogrammed in cancer cells
are detected as prognostic pathways including glutamate
metabolism in SHH subgroup, pentose phosphate pathway and
TCA cycle in Group 3, and folate-mediated one
carbon-metabolism in Group 4.The results underscore several
subgroup-specific pathways for potential therapeutic
interventions: SHH-GLI-FOXM1 pathway in SHH subgroup,
receptor tyrosine kinases and their downstream pathways in
Group 3, and immune and inflammatory pathways in Group 4.},
cin = {B062},
ddc = {610},
cid = {I:(DE-He78)B062-20160331},
pnm = {312 - Functional and structural genomics (POF3-312)},
pid = {G:(DE-HGF)POF3-312},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:31185958},
pmc = {pmc:PMC6560914},
doi = {10.1186/s12885-019-5742-x},
url = {https://inrepo02.dkfz.de/record/144028},
}