title: Whole-exome sequencing in osteosarcoma reveals important heterogeneity of genetic alterations.
abstract: BACKGROUND
  Whole-genome sequencing studies have recently shown that osteosarcomas (OSs) display high rates of structural variation, i.e. they contain many somatic mutations and copy number alterations. TP53 and RB1 show recurrent somatic alterations in concordant studies, suggesting that they could be key players in bone oncogenesis.
  
  
  METHODS
  we carried out whole-genome sequencing of DNA from seven high-grade OS samples matched with normal tissue from the same patients.
  
  
  RESULTS
  We confirmed the presence of genetic alterations of the TP53 (including novel unreported mutations) and RB1 genes. Most interestingly, we identified a total of 84 point mutations and 4 deletions related to 82 different genes in OS samples, of which only 15 have been previously reported. Interestingly, the number of mutated genes (ranging from 4 to 8) was lower in TP53mut cases compared with TP53wt cases (ranging from 14 to 45). This was also true for the mutated RB1 case. We also observed that a dedifferentiated OS harboring MDM2 amplification did not carry any other mutations.
  
  
  CONCLUSIONS
  This study suggests that bone oncogenesis driven by TP53 or RB1 mutations occurs on a background of relative genetic stability and that the dedifferentiated OS subtype represents a clinico-pathological entity with distinct oncogenic mechanisms and thus requires different therapeutic management.
authors.affiliation: Cancer Research Center of Toulouse, INSERM U1037, laboratoire d'excellence Labex TOUCAN, Toulouse.
authors.forename: M
authors.initials: M
authors.lastname: Bousquet
authors.affiliation: Genotoul Bioinfo, INRA, Castanet Tolosan.
authors.forename: C
authors.initials: C
authors.lastname: Noirot
authors.affiliation: Departments of Pediatric Orthopedics.
authors.forename: F
authors.initials: F
authors.lastname: Accadbled
authors.affiliation: Departments of Pediatric Orthopedics.
authors.forename: J
authors.initials: J
authors.lastname: Sales de Gauzy
authors.affiliation: Pediatric Oncology, Hôpital des enfants, Toulouse.
authors.forename: M P
authors.initials: MP
authors.lastname: Castex
authors.affiliation: Cancer Research Center of Toulouse, INSERM U1037, laboratoire d'excellence Labex TOUCAN, Toulouse Department of Pathology, IUCT-Oncopole, CHU de Toulouse and Toulouse University, Toulouse rousset.p@chu-toulouse.fr.
authors.forename: P
authors.initials: P
authors.lastname: Brousset
authors.affiliation: Department of Pathology, IUCT-Oncopole, CHU de Toulouse and Toulouse University, Toulouse Pharmacology and Structural Biology Institute, CNRS UMR5089, Toulouse, France.
authors.forename: A
authors.initials: A
authors.lastname: Gomez-Brouchet
mesh_terms: D000293:Adolescent; D000328:Adult; D014408:Biomarkers, Tumor / Q000235:genetics*; D002648:Child; D056915:DNA Copy Number Variations / Q000235:genetics; D059472:Exome / Q000235:genetics; D005260:Female; D018740:Genetic Heterogeneity; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D009154:Mutation; D012516:Osteosarcoma / Q000235:genetics* / Q000473:pathology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D056286:Retinoblastoma Binding Proteins / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C000606393:RB1 protein, human; D056286:Retinoblastoma Binding Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases
keywords: MDM2; TP53; osteosarcoma; whole-genome sequencing