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

Saft, Leonie; Karimi, Mohsen; Ghaderi, Mehran; Matolcsy, András; Mufti, Ghulam J.; Kulasekararaj, Austin; Göhring, Gudrun; Giagounidis, Aristoteles; Selleslag, Dominik and Muus, Petra, et al. (2014) In Haematologica 99(6). p.1041-1049
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... (More)

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).

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Haematologica
volume
99
issue
6
pages
9 pages
publisher
Ferrata Storti Foundation
external identifiers
  • scopus:84901712631
ISSN
0390-6078
DOI
10.3324/haematol.2013.098103
language
English
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no
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c6977559-c96d-4cc8-ba1f-fd822c69de71
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2019-05-22 09:51:53
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2019-10-29 05:50:14
@article{c6977559-c96d-4cc8-ba1f-fd822c69de71,
  abstract     = {<p>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).</p>},
  author       = {Saft, Leonie and Karimi, Mohsen and Ghaderi, Mehran and Matolcsy, András and Mufti, Ghulam J. and Kulasekararaj, Austin and Göhring, Gudrun and Giagounidis, Aristoteles and Selleslag, Dominik and Muus, Petra and Sanz, Guillermo and Mittelman, Moshe and Bowen, David and Porwit, Anna and Fu, Tommy and Backstrom, Jay and Fenaux, Pierre and MacBeth, Kyle J. and Hellström-Lindberg, Eva},
  issn         = {0390-6078},
  language     = {eng},
  month        = {06},
  number       = {6},
  pages        = {1041--1049},
  publisher    = {Ferrata Storti Foundation},
  series       = {Haematologica},
  title        = {p53 protein expression independently predicts outcome in patients with lower-risk myelodysplastic syndromes with del(5q)},
  url          = {http://dx.doi.org/10.3324/haematol.2013.098103},
  volume       = {99},
  year         = {2014},
}