title: TP53 mutations and MDM2(SNP309) identify subgroups of AML patients with impaired outcome.
abstract: BACKGROUND
  TP53 is commonly mutated in several cancers and confers treatment resistance and poor prognosis. Altered expression of mouse double minute 2 (MDM2), a negative regulator of p53, may also attenuate normal p53 signaling, thereby enhancing tumor transformation and resistance to apoptosis. The single nucleotide polymorphism (SNP) 309 has been reported to increase MDM2 expression and impair normal p53 response.
  
  
  METHODS
  We investigated the frequency and impact of TP53 mutations (TP53mut) and MDM2(SNP309) on treatment outcome and overall survival (OS) in 189 Swedish acute myeloid leukemia patients. The genetic analyses were performed using SSCA and direct sequencing (for mutations in exon 5-8 of TP53) and Pyrosequencing (for the MDM2(SNP309) ).
  
  
  RESULTS
  We found a high frequency (22%) of TP53mut in patients with cytogenetic aberrations, with association to high-risk cytogenetics (P < 0.001). TP53mut patients had lower response rates (22% compared with 76% CR in TP53 wild-type (wt) patients, P < 0.001) and reduced OS (2 and 16 months, respectively, P < 0.001). In TP53wt patients with high or intermediate risk cytogenetic aberrations, the MDM2(SNP309) conferred an impaired outcome, with patients carrying the alternative G-allele having shorter OS compared with T/T patients (median 9 vs. 50 months, P = 0.020).
  
  
  CONCLUSIONS
  Our results show that TP53mut analysis and MDM2(SNP309) genotyping may be useful tools for prognostication, risk stratification, and selection of patients most likely to benefit from new drugs targeting the p53 signaling pathway.
authors.affiliation: Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Ingrid Jakobsen
authors.initials: IJ
authors.lastname: Falk
authors.forename: Kerstin
authors.initials: K
authors.lastname: Willander
authors.forename: Roza
authors.initials: R
authors.lastname: Chaireti
authors.forename: Johan
authors.initials: J
authors.lastname: Lund
authors.forename: Hareth
authors.initials: H
authors.lastname: Nahi
authors.forename: Monica
authors.initials: M
authors.lastname: Hermanson
authors.forename: Henrik
authors.initials: H
authors.lastname: Gréen
authors.forename: Kourosh
authors.initials: K
authors.lastname: Lotfi
authors.forename: Peter
authors.initials: P
authors.lastname: Söderkvist
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D019943:Amino Acid Substitution; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor; D002869:Chromosome Aberrations; D005260:Female; D005838:Genotype; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D063868:Patient Outcome Assessment; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2
keywords: MDM2; SNP309; TP53; acute myeloid leukemia; prognostic markers