title: TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression.
abstract: OBJECTIVE
  To determine the frequency of TP53 mutations and the level of p53 protein expression by immunohistochemistry (IHC) in low-risk myelodysplastic syndromes (MDS) with del(5q) and to assess their impact on disease progression.
  
  
  METHODS
  Pre- and postprogression bone marrow (BM) samples from 55 consecutive patients with International Prognostic Scoring System low risk (n = 32) or intermediate-1 risk (n = 23) were studied by next-generation sequencing of TP53. IHC for p53 was performed on 148 sequential BM samples.
  
  
  RESULTS
  TP53 mutations with a median clone size of 11% (range, 1% to 54%) were detected in 10 patients (18%) already at an early phase of the disease. Mutations were equally common in low-risk and intermediate-1-risk patients and were associated with evolution to acute myeloid leukemia (5 of 10 v 7 of 45; P = .045). Nine of 10 patients carrying mutations showed more than 2% BM progenitors with strong p53 staining. The probability of a complete cytogenetic response to lenalidomide was lower in mutated patients (0 of 7 v 12 of 24; P = .024).
  
  
  CONCLUSIONS
  By using sensitive deep-sequencing technology, we demonstrated that TP53 mutated populations may occur at an early disease stage in almost a fifth of low-risk MDS patients with del(5q). Importantly, mutations were present years before disease progression and were associated with an increased risk of leukemic evolution. TP53 mutations could not be predicted by common clinical features but were associated with p53 overexpression. Our findings indicate a previously unrecognized heterogeneity of the disease which may significantly affect clinical decision making.
authors.affiliation: Center for Experimental Hematology M54, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden. eva.hellstrom-lindberg@ki.se
authors.forename: Martin
authors.initials: M
authors.lastname: Jädersten
authors.forename: Leonie
authors.initials: L
authors.lastname: Saft
authors.forename: Alexander
authors.initials: A
authors.lastname: Smith
authors.forename: Austin
authors.initials: A
authors.lastname: Kulasekararaj
authors.forename: Sabine
authors.initials: S
authors.lastname: Pomplun
authors.forename: Gudrun
authors.initials: G
authors.lastname: Göhring
authors.forename: Anette
authors.initials: A
authors.lastname: Hedlund
authors.forename: Robert
authors.initials: R
authors.lastname: Hast
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schlegelberger
authors.forename: Anna
authors.initials: A
authors.lastname: Porwit
authors.forename: Eva
authors.initials: E
authors.lastname: Hellström-Lindberg
authors.forename: Ghulam J
authors.initials: GJ
authors.lastname: Mufti
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002872:Chromosome Deletion; D002895:Chromosomes, Human, Pair 5; D018450:Disease Progression; D005260:Female; D016158:Genes, p53; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000150:complications; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000150:complications / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D010446:Peptide Fragments / Q000378:metabolism; D011379:Prognosis; D012306:Risk; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D010446:Peptide Fragments; D016159:Tumor Suppressor Protein p53; C509415:p53 protein (325-355), human