SHERP

Subgroup-specific prognostic signaling and metabolic pathways in pediatric medulloblastoma

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Authors
Park, Ae Kyung; Lee, Ji Yeoun; Cheong, Heesun; Ramaswamy, Vijay; Park, Sung-Hye; Kool, Marcel; Phi, Ji Hoon; Choi, Seung Ah; Cavalli, Florence; Taylor, Michael D; Kim, Seung-Ki
Issue Date
2019-06-11
Publisher
BioMed Central
Citation
BMC Cancer. 19(1):571
Keywords
MedulloblastomaSubgroupPrognosisSignaling pathwayMetabolic pathwayTargeted therapy
Abstract
Background
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.

Method
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.

Results
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.

Conclusions
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.
ISSN
1471-2407
Language
English
URI
http://hdl.handle.net/10371/156077
DOI
https://doi.org/10.1186/s12885-019-5742-x
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College of Medicine/School of Medicine (의과대학/대학원)Pathology (병리학전공)Journal Papers (저널논문_병리학전공)
College of Medicine/School of Medicine (의과대학/대학원)Neurosurgery (신경외과학전공)Journal Papers (저널논문_신경외과학전공)
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