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Poos, K.* ; Smida, J. ; Maugg, D. ; Eckstein, G.N. ; Baumhoer, D. ; Nathrath, M. ; Korsching, E.*

Genomic heterogeneity of osteosarcoma - shift from single candidates to functional modules.

PLoS ONE 10:e0123082 (2015)
Publ. Version/Full Text DOI PMC
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Osteosarcoma (OS), a bone tumor, exhibit a complex karyotype. On the genomic level a highly variable degree of alterations in nearly all chromosomal regions and between individual tumors is observable. This hampers the identification of common drivers in OS biology. To identify the common molecular mechanisms involved in the maintenance of OS, we follow the hypothesis that all the copy number-associated differences between the patients are intercepted on the level of the functional modules. The implementation is based on a network approach utilizing copy number associated genes in OS, paired expression data and protein interaction data. The resulting functional modules of tightly connected genes were interpreted regarding their biological functions in OS and their potential prognostic significance. We identified an osteosarcoma network assembling well-known and lesser-known candidates. The derived network shows a significant connectivity and modularity suggesting that the genes affected by the heterogeneous genetic alterations share the same biological context. The network modules participate in several critical aspects of cancer biology like DNA damage response, cell growth, and cell motility which is in line with the hypothesis of specifically deregulated but functional modules in cancer. Further, we could deduce genes with possible prognostic significance in OS for further investigation (e.g. EZR, CDKN2A, MAP3K5). Several of those module genes were located on chromosome 6q. The given systems biological approach provides evidence that heterogeneity on the genomic and expression level is ordered by the biological system on the level of the functional modules. Different genomic aberrations are pointing to the same cellular network vicinity to form vital, but already neoplastically altered, functional modules maintaining OS. This observation, exemplarily now shown for OS, has been under discussion already for a longer time, but often in a hypothetical manner, and can here be exemplified for OS.
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Publication type Article: Journal article
Document type Scientific Article
Keywords High-grade Osteosarcoma; Tumor-suppressor Gene; Copy-number; Prognostic-significance; Allelic Imbalances; Expression Data; Ewing Sarcoma; Chromosome 6q; Cancer; Hybridization
Language english
Publication Year 2015
HGF-reported in Year 2015
ISSN (print) / ISBN 1932-6203
Journal PLoS ONE
Quellenangaben Volume: 10, Issue: 4, Pages: , Article Number: e0123082 Supplement: ,
Publisher Public Library of Science (PLoS)
Publishing Place Lawrence, Kan.
Reviewing status Peer reviewed
Institute(s) CCG Osteosarcoma (PATH-KOS)
Institute of Radiation Biology (ISB)
Institute of Pathology (PATH)
Institute of Human Genetics (IHG)
POF-Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
30202 - Environmental Health
30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Research field(s) Enabling and Novel Technologies
Radiation Sciences
Genetics and Epidemiology
PSP Element(s) G-520800-001
G-500200-001
G-500300-001
G-500700-001
PubMed ID 25848766
DOI 10.1371/journal.pone.0123082
WOS ID WOS:000352477800202
Erfassungsdatum 2015-04-09
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