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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

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

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