title: Focal chromosomal copy number aberrations identify CMTM8 and GPR177 as new candidate driver genes in osteosarcoma.
abstract: Osteosarcoma is an aggressive bone tumor that preferentially develops in adolescents. The tumor is characterized by an abundance of genomic aberrations, which hampers the identification of the driver genes involved in osteosarcoma tumorigenesis. Our study aims to identify these genes by the investigation of focal copy number aberrations (CNAs, <3 Mb). For this purpose, we subjected 26 primary tumors of osteosarcoma patients to high-resolution single nucleotide polymorphism array analyses and identified 139 somatic focal CNAs. Of these, 72 had at least one gene located within or overlapping the focal CNA, with a total of 94 genes. For 84 of these genes, the expression status in 31 osteosarcoma samples was determined by expression microarray analysis. This enabled us to identify the genes of which the over- or underexpression was in more than 35% of cases in accordance to their copy number status (gain or loss). These candidate genes were subsequently validated in an independent set and furthermore corroborated as driver genes by verifying their role in other tumor types. We identified CMTM8 as a new candidate tumor suppressor gene and GPR177 as a new candidate oncogene in osteosarcoma. In osteosarcoma, CMTM8 has been shown to suppress EGFR signaling. In other tumor types, CMTM8 is known to suppress the activity of the oncogenic protein c-Met and GPR177 is known as an overexpressed upstream regulator of the Wnt-pathway. Further studies are needed to determine whether these proteins also exert the latter functions in osteosarcoma tumorigenesis.
authors.affiliation: Department of Genome Analysis, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Joeri
authors.initials: J
authors.lastname: Both
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Oscar
authors.initials: O
authors.lastname: Krijgsman
authors.affiliation: Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Johannes
authors.initials: J
authors.lastname: Bras
authors.affiliation: Department of Orthopedic Surgery, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Gerard R
authors.initials: GR
authors.lastname: Schaap
authors.affiliation: Department of Genome Analysis, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Frank
authors.initials: F
authors.lastname: Baas
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Bauke
authors.initials: B
authors.lastname: Ylstra
authors.affiliation: Department of Genome Analysis, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Theo J M
authors.initials: TJ
authors.lastname: Hulsebos
mesh_terms: D000293:Adolescent; D000328:Adult; D001859:Bone Neoplasms / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D018925:Chemokines / Q000235:genetics*; D002648:Child; D002869:Chromosome Aberrations; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D018628:Gene Dosage / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D062792:MARVEL Domain-Containing Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D009857:Oncogenes / Q000235:genetics; D012516:Osteosarcoma / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000235:genetics; D055815:Young Adult
chemical_list: C507076:CMTM8 protein, human; D018925:Chemokines; D047908:Intracellular Signaling Peptides and Proteins; D062792:MARVEL Domain-Containing Proteins; D043562:Receptors, G-Protein-Coupled; D025521:Tumor Suppressor Proteins; C549111:WLS protein, human; D019859:Proto-Oncogene Proteins c-met