title: TP53 mutations in myelodysplastic syndrome are strongly correlated with aberrations of chromosome 5, and correlate with adverse prognosis.
abstract: 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.affiliation: Department of Haematological Medicine, King's College London, School of Medicine, London, UK.
authors.forename: Austin G
authors.initials: AG
authors.lastname: Kulasekararaj
authors.forename: Alexander E
authors.initials: AE
authors.lastname: Smith
authors.forename: Syed A
authors.initials: SA
authors.lastname: Mian
authors.forename: Azim M
authors.initials: AM
authors.lastname: Mohamedali
authors.forename: Pramila
authors.initials: P
authors.lastname: Krishnamurthy
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Lea
authors.forename: Joop
authors.initials: J
authors.lastname: Gäken
authors.forename: Coralie
authors.initials: C
authors.lastname: Pennaneach
authors.forename: Robin
authors.initials: R
authors.lastname: Ireland
authors.forename: Barbara
authors.initials: B
authors.lastname: Czepulkowski
authors.forename: Sabine
authors.initials: S
authors.lastname: Pomplun
authors.forename: Judith C
authors.initials: JC
authors.lastname: Marsh
authors.forename: Ghulam J
authors.initials: GJ
authors.lastname: Mufti
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000748:Anemia, Macrocytic / Q000209:etiology / Q000235:genetics / Q000401:mortality; D000963:Antimetabolites / Q000494:pharmacology / Q000627:therapeutic use; D001374:Azacitidine / Q000494:pharmacology / Q000627:therapeutic use; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D002872:Chromosome Deletion; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics / Q000648:ultrastructure*; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D016158:Genes, p53; D006801:Humans; D015994:Incidence; D053208:Kaplan-Meier Estimate; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000453:epidemiology / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D012306:Risk; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000963:Antimetabolites; D001374:Azacitidine