title: Genomic heterogeneity of osteosarcoma - shift from single candidates to functional modules.
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.
authors.affiliation: Institute of Bioinformatics, University Hospital Münster, Münster, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Poos
authors.affiliation: Clinical Cooperation Group Osteosarcoma, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Children's Cancer Research Center and Department of Pediatrics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Smida
authors.affiliation: Clinical Cooperation Group Osteosarcoma, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Children's Cancer Research Center and Department of Pediatrics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Doris
authors.initials: D
authors.lastname: Maugg
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Gertrud
authors.initials: G
authors.lastname: Eckstein
authors.affiliation: Clinical Cooperation Group Osteosarcoma, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Bone Tumor Reference Center at the Institute of Pathology, University Hospital Basel, Basel, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Baumhoer
authors.affiliation: Clinical Cooperation Group Osteosarcoma, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Children's Cancer Research Center and Department of Pediatrics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Nathrath
authors.affiliation: Institute of Bioinformatics, University Hospital Münster, Münster, Germany.
authors.forename: Eberhard
authors.initials: E
authors.lastname: Korsching
mesh_terms: D000293:Adolescent; D000328:Adult; D001859:Bone Neoplasms / Q000235:genetics* / Q000401:mortality; D002648:Child; D002675:Child, Preschool; D056915:DNA Copy Number Variations; D005260:Female; D052138:Genes, Neoplasm; D056726:Genetic Association Studies; D018740:Genetic Heterogeneity; D015894:Genome, Human; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D058977:Molecular Sequence Annotation; D012516:Osteosarcoma / Q000235:genetics* / Q000401:mortality; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D055815:Young Adult
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