title: Comprehensive mapping of p53 pathway alterations reveals an apparent role for both SNP309 and MDM2 amplification in sarcomagenesis.
abstract: OBJECTIVE
  Reactivation of p53 tumor suppressor activity in diseases such as soft-tissue sarcoma is considered an attractive means of targeted therapy. By systematically assessing alterations affecting the p53 pathway, we aimed to (a) classify sarcoma subtypes, (b) define a potential role in malignancy, and (c) identify potential patient biomarkers in this heterogeneous disease.
  
  
  METHODS
  We have mapped mutational events in a panel of 192 benign or malignant bone and soft-tissue sarcomas. Analyses included TP53 and CDKN2A mutational and SNP status, MDM2 and MDM4 amplification and MDM2 SNP309 status.
  
  
  RESULTS
  We found an inverse relationship between MDM2 amplification and TP53 mutations, with a predominantly wild-type CDKN2A background. A high rate of point mutations in TP53 was observed uniquely in leiomyosarcoma, osteosarcoma, and MFH. Both MDM2 and MDM4 were also amplified in a subtype-specific manner, which was frequently seen as a coamplification event. We have also analyzed the risk allele frequencies for MDM2 SNP309, and show that the G allele was strongly associated with both liposarcomas and MDM2 amplification.
  
  
  CONCLUSIONS
  Our data emphasize the critical role of p53 inactivation in sarcomagenesis, whereby different pathway alterations may be related to the heterogeneity of the disease. Moreover, we observed a strong association of malignancy with TP53 mutation, or MDM2 amplification and the presence of a G allele in SNP309, especially in lipoma versus liposarcoma. We propose, therefore, that MDM2 markers along with TP53 sequencing should be considered as patient biomarkers in clinical trials of sarcomas using MDM2 antagonists.
authors.affiliation: Novartis Institutes for Biomedical Research, Oncology Research, Basel, Switzerland. moriko.ito@novartis.com
authors.forename: Moriko
authors.initials: M
authors.lastname: Ito
authors.forename: Louise
authors.initials: L
authors.lastname: Barys
authors.forename: Terence
authors.initials: T
authors.lastname: O'Reilly
authors.forename: Sophie
authors.initials: S
authors.lastname: Young
authors.forename: Bella
authors.initials: B
authors.lastname: Gorbatcheva
authors.forename: John
authors.initials: J
authors.lastname: Monahan
authors.forename: Sabine
authors.initials: S
authors.lastname: Zumstein-Mecker
authors.forename: Peter F
authors.initials: PF
authors.lastname: Choong
authors.forename: Ian
authors.initials: I
authors.lastname: Dickinson
authors.forename: Philip
authors.initials: P
authors.lastname: Crowe
authors.forename: Christine
authors.initials: C
authors.lastname: Hemmings
authors.forename: Jayesh
authors.initials: J
authors.lastname: Desai
authors.forename: David M
authors.initials: DM
authors.lastname: Thomas
authors.forename: Joanna
authors.initials: J
authors.lastname: Lisztwan
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis; D001859:Bone Neoplasms / Q000235:genetics*; D002874:Chromosome Mapping; D005784:Gene Amplification; D018628:Gene Dosage; D016158:Genes, p53; D006801:Humans; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D012509:Sarcoma / Q000235:genetics*; D012983:Soft Tissue Neoplasms / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2