Document Detail


TP53 mutations in myelodysplastic syndrome are strongly correlated with aberrations of chromosome 5, and correlate with adverse prognosis.
MedLine Citation:
PMID:  23297687     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
This study aimed to determine the incidence/prognostic impact of TP53 mutation in 318 myelodysplastic syndrome (MDS) patients, and to correlate the changes to cytogenetics, single nucleotide polymorphism array karyotyping and clinical outcome. The median age was 65 years (17-89 years) and median follow-up was 45 months [95% confidence interval (CI) 27-62 months]. TP53 mutations occurred in 30 (9.4%) patients, exclusively in isolated del5q (19%) and complex karyotype (CK) with -5/5q-(72%), correlated with International Prognostic Scoring System intermediate-2/high, TP53 protein expression, higher blast count and leukaemic progression. Patients with mutant TP53 had a paucity of mutations in other genes implicated in myeloid malignancies. Median overall survival of patients with TP53 mutation was shorter than wild-type (9 versus 66 months, P < 0.001) and it retained significance in multivariable model (Hazard Ratio 3.8, 95%CI 2.3-6.3,P < 0.001). None of the sequentially analysed samples showed a disappearance of the mutant clone or emergence of new clones, suggesting an early occurrence of TP53 mutations. A reduction in mutant clone correlated with response to 5-azacitidine, however clones increased in non-responders and persisted at relapse. The adverse impact of TP53 persists after adjustment for cytogenetic risk and is of practical importance in evaluating prognosis. The relatively common occurrence of these mutations in two different prognostic spectrums of MDS, i.e. isolated 5q- and CK with -5/5q-, possibly implies two different mechanistic roles for TP53 protein.
Authors:
Austin G Kulasekararaj; Alexander E Smith; Syed A Mian; Azim M Mohamedali; Pramila Krishnamurthy; Nicholas C Lea; Joop Gäken; Coralie Pennaneach; Robin Ireland; Barbara Czepulkowski; Sabine Pomplun; Judith C Marsh; Ghulam J Mufti
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-01-09
Journal Detail:
Title:  British journal of haematology     Volume:  160     ISSN:  1365-2141     ISO Abbreviation:  Br. J. Haematol.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-02-15     Completed Date:  2013-04-12     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  0372544     Medline TA:  Br J Haematol     Country:  England    
Other Details:
Languages:  eng     Pagination:  660-72     Citation Subset:  IM    
Copyright Information:
© 2013 Crown copyright. This article is published with the permission of the Controller of HMSO and the Queen's Printer for Scotland.
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MeSH Terms
Descriptor/Qualifier:
Adolescent
Adult
Aged
Aged, 80 and over
Anemia, Macrocytic / etiology,  genetics,  mortality
Antimetabolites / pharmacology,  therapeutic use
Azacitidine / pharmacology,  therapeutic use
Bone Marrow Cells / drug effects,  pathology
Chromosome Deletion
Chromosomes, Human, Pair 5 / genetics,  ultrastructure*
Disease Progression
Female
Follow-Up Studies
Genes, p53*
Humans
Incidence
Kaplan-Meier Estimate
Karyotyping
Leukemia, Myeloid, Acute / epidemiology,  genetics
Male
Middle Aged
Mutation*
Myelodysplastic Syndromes / drug therapy,  genetics*,  mortality,  pathology
Polymorphism, Single Nucleotide
Prognosis
Risk
Treatment Outcome
Young Adult
Grant Support
ID/Acronym/Agency:
MR/J006742/1//Medical Research Council
Chemical
Reg. No./Substance:
0/Antimetabolites; M801H13NRU/Azacitidine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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