Abstract
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.
Highlights
Osteosarcoma (OS) is characterized by neoplastic cells that directly produce immature osteoid [1, 2]
Running ASCAT resulted in allele-specific copy number profiles corrected for intra-tumor heterogeneity
This result is in accordance with studies from Kusuzaki et al who revealed that DNA ploidy patterns are of prognostic significance in OS [39, 40]
Summary
Osteosarcoma (OS) is characterized by neoplastic cells that directly produce immature osteoid [1, 2]. Despite the information of many genetic changes, OS is only defined by its morphological and clinical phenotype rather than on the molecular level [15] This inter-tumor heterogeneity might be formalized by integrating copy number associated genes on the biological network-level. Cerami et al [17] developed a systems biological approach to uncover altered network modules in glioblastoma They showed that different combinations of altered genes can prevent modules to perform their natural biological function. They stated that glioblastoma development occurs via different genes and diverse mechanisms but within the same functional modules According to these findings, OS might develop primarily due to heavily accumulated genomic alterations secondarily causing the inability of genes within distinct modules to perform their normal biological functions. We might observe heterogeneity on the gene-level but a distinct set of functional modules on the network level
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