title: p53 protein expression independently predicts outcome in patients with lower-risk myelodysplastic syndromes with del(5q).
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).
authors.affiliation: Department of Medicine, Karolinska Institute, Karolinska University Hospital Huddinge, Sweden Department of Pathology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Leonie
authors.initials: L
authors.lastname: Saft
authors.affiliation: Department of Medicine, Karolinska Institute, Karolinska University Hospital Huddinge, Sweden.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Karimi
authors.affiliation: Department of Oncology and Pathology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Mehran
authors.initials: M
authors.lastname: Ghaderi
authors.affiliation: Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
authors.forename: András
authors.initials: A
authors.lastname: Matolcsy
authors.affiliation: King's College Hospital, London, UK.
authors.forename: Ghulam J
authors.initials: GJ
authors.lastname: Mufti
authors.affiliation: King's College Hospital, London, UK.
authors.forename: Austin
authors.initials: A
authors.lastname: Kulasekararaj
authors.affiliation: Institute for Cell and Molecular Pathology, Medical University Hannover, Germany.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Göhring
authors.affiliation: Marien Hospital Düsseldorf, Germany.
authors.forename: Aristoteles
authors.initials: A
authors.lastname: Giagounidis
authors.affiliation: AZ ST-Jan Brugge AV, Brugge, Belgium.
authors.forename: Dominik
authors.initials: D
authors.lastname: Selleslag
authors.affiliation: Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors.forename: Petra
authors.initials: P
authors.lastname: Muus
authors.affiliation: Hospital Universitaria La Fe, Valencia, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Sanz
authors.affiliation: Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv, Israel.
authors.forename: Moshe
authors.initials: M
authors.lastname: Mittelman
authors.affiliation: St James's Institute of Oncology, Leeds, UK.
authors.forename: David
authors.initials: D
authors.lastname: Bowen
authors.affiliation: Department of Laboratory Medicine and Pathobiology, Toronto General Hospital, Ontario, Canada.
authors.forename: Anna
authors.initials: A
authors.lastname: Porwit
authors.affiliation: Celgene Corporation, Summit, NJ, USA.
authors.forename: Tommy
authors.initials: T
authors.lastname: Fu
authors.affiliation: Celgene Corporation, Summit, NJ, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Backstrom
authors.affiliation: Service d'Hématologie Séniors, Hôpital St Louis, Université Paris 7, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Fenaux
authors.affiliation: Celgene Corporation, Summit, NJ, USA.
authors.forename: Kyle J
authors.initials: KJ
authors.lastname: MacBeth
authors.affiliation: Department of Medicine, Karolinska Institute, Karolinska University Hospital Huddinge, Sweden eva.hellstrom-lindberg@ki.se.
authors.forename: Eva
authors.initials: E
authors.lastname: Hellström-Lindberg
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D002872:Chromosome Deletion; D002895:Chromosomes, Human, Pair 5; D018450:Disease Progression; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D015470:Leukemia, Myeloid, Acute; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D063868:Patient Outcome Assessment; D011379:Prognosis; D015203:Reproducibility of Results; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53