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Haematologica. 2014 Jun;99(6):1041-9. doi: 10.3324/haematol.2013.098103. Epub 2014 Mar 28.

p53 protein expression independently predicts outcome in patients with lower-risk myelodysplastic syndromes with del(5q).

Author information

  • 1Department of Medicine, Karolinska Institute, Karolinska University Hospital Huddinge, Sweden Department of Pathology, Karolinska University Hospital, Stockholm, Sweden.
  • 2Department of Medicine, Karolinska Institute, Karolinska University Hospital Huddinge, Sweden.
  • 3Department of Oncology and Pathology, Karolinska Institute, Stockholm, Sweden.
  • 4Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
  • 5King's College Hospital, London, UK.
  • 6Institute for Cell and Molecular Pathology, Medical University Hannover, Germany.
  • 7Marien Hospital Düsseldorf, Germany.
  • 8AZ ST-Jan Brugge AV, Brugge, Belgium.
  • 9Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
  • 10Hospital Universitaria La Fe, Valencia, Spain.
  • 11Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv, Israel.
  • 12St James's Institute of Oncology, Leeds, UK.
  • 13Department of Laboratory Medicine and Pathobiology, Toronto General Hospital, Ontario, Canada.
  • 14Celgene Corporation, Summit, NJ, USA.
  • 15Service d'Hématologie Séniors, Hôpital St Louis, Université Paris 7, France.
  • 16Department of Medicine, Karolinska Institute, Karolinska University Hospital Huddinge, Sweden eva.hellstrom-lindberg@ki.se.

Abstract

Del(5q) myelodysplastic syndromes defined by the International Prognostic Scoring System as low- or intermediate-1-risk (lower-risk) are considered to have an indolent course; however, recent data have identified a subgroup of these patients with more aggressive disease and poorer outcomes. Using deep sequencing technology, we previously demonstrated that 18% of patients with lower-risk del(5q) myelodysplastic syndromes carry TP53 mutated subclones rendering them at higher risk of progression. In this study, bone marrow biopsies from 85 patients treated with lenalidomide in the MDS-004 clinical trial were retrospectively assessed for p53 expression by immunohistochemistry in association with outcome. Strong p53 expression in ≥ 1% of bone marrow progenitor cells, observed in 35% (30 of 85) of patients, was significantly associated with higher acute myeloid leukemia risk (P=0.0006), shorter overall survival (P=0.0175), and a lower cytogenetic response rate (P=0.009), but not with achievement or duration of 26-week transfusion independence response. In a multivariate analysis, p53-positive immunohistochemistry was the strongest independent predictor of transformation to acute myeloid leukemia (P=0.0035). Pyrosequencing analysis of laser-microdissected cells with strong p53 expression confirmed the TP53 mutation, whereas cells with moderate expression predominantly had wild-type p53. This study validates p53 immunohistochemistry as a strong and clinically useful predictive tool in patients with lower-risk del(5q) myelodysplastic syndromes. This study was based on data from the MDS 004 trial (clinicaltrials.gov identifier: NCT00179621).

PMID:
24682512
PMCID:
PMC4040908
DOI:
10.3324/haematol.2013.098103
[PubMed - indexed for MEDLINE]
Free PMC Article
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