title: Genetic and epigenetic alterations of the cell cycle regulators and tumor suppressor genes in pediatric osteosarcomas.
abstract: OBJECTIVE
  To analyze the genetic and epigenetic alterations affecting the RB1, TP53, p16INK4, and p21WAF1 tumor suppressor genes, loss of heterozygosity (LOH) at 3q and 18q, and the clinical variables of a series of Spanish children with osteosarcoma. These genetic changes were tested for an association with prognosis.
  
  
  METHODS
  Peripheral blood samples and clinical data were available from 76 patients with osteosarcoma. Paired tissue was available from 41 of them. The mutation and methylation status of p16INK4, p21WAF1, TP53, and RB1 was screened as well as LOH at 3q and 18q.
  
  
  RESULTS
  Loss of heterozygosity affecting RB1 (37.2%), TP53 (42.3%), and 18q (30.8%) and TP53 mutation (39%) were frequently encountered. TP53 mutation was associated with diagnosis at a later age. RB1 alteration was associated with reduced survival and event-free survival. The clinical variables associated with poor prognosis were the presence of metastasis at diagnosis (P = 0.035) or during treatment (P = 0.016) and the chondroblastic histologic subtype (P = 0.007); the response to induction chemotherapy (<90% necrosis) also tended to be related to poor prognosis (P = 0.08).
  
  
  CONCLUSIONS
  RB1, TP53, and possibly other tumor suppressor genes located at 18q and other localizations are involved in pediatric osteosarcoma carcinogenesis, together with other genetic alterations not fully understood to date. Based on these results, the presence of an altered RB1 gene should be regarded as a poor prognostic factor for pediatric osteosarcoma.
authors.affiliation: Department of Pediatrics, University of Navarra, Pamplona, Spain. apatigar@unav.es
authors.forename: Ana
authors.initials: A
authors.lastname: Patiño-García
authors.forename: Elena Sotillo
authors.initials: ES
authors.lastname: Piñeiro
authors.forename: Marta Zalacaín
authors.initials: MZ
authors.lastname: Díez
authors.forename: Leire Gárate
authors.initials: LG
authors.lastname: Iturriagagoitia
authors.forename: Federico Antillón
authors.initials: FA
authors.lastname: Klüssmann
authors.forename: Luis Sierrasesúmaga
authors.initials: LS
authors.lastname: Ariznabarreta
mesh_terms: D000293:Adolescent; D000328:Adult; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D009362:Neoplasm Metastasis; D012516:Osteosarcoma / Q000235:genetics* / Q000473:pathology*; D011379:Prognosis; D015996:Survival Rate; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016159:Tumor Suppressor Protein p53