title: Clinical significance of genetic aberrations in secondary acute myeloid leukemia.
abstract: The study aimed to identify genetic lesions associated with secondary acute myeloid leukemia (sAML) in comparison with AML arising de novo (dnAML) and assess their impact on patients' overall survival (OS). High-resolution genotyping and loss of heterozygosity mapping was performed on DNA samples from 86 sAML and 117 dnAML patients, using Affymetrix Genome-Wide Human SNP 6.0 arrays. Genes TP53, RUNX1, CBL, IDH1/2, NRAS, NPM1, and FLT3 were analyzed for mutations in all patients. We identified 36 recurrent cytogenetic aberrations (more than five events). Mutations in TP53, 9pUPD, and del7q (targeting CUX1 locus) were significantly associated with sAML, while NPM1 and FLT3 mutations associated with dnAML. Patients with sAML carrying TP53 mutations demonstrated lower 1-year OS rate than those with wild-type TP53 (14.3% ± 9.4% vs. 35.4% ± 7.2%; P = 0.002), while complex karyotype, del7q (CUX1) and del7p (IKZF1) showed no significant effect on OS. Multivariate analysis confirmed that mutant TP53 was the only independent adverse prognostic factor for OS in sAML (hazard ratio 2.67; 95% CI: 1.33-5.37; P = 0.006). Patients with dnAML and complex karyotype carried sAML-associated defects (TP53 defects in 54.5%, deletions targeting FOXP1 and ETV6 loci in 45.4% of the cases). We identified several co-occurring lesions associated with either sAML or dnAML diagnosis. Our data suggest that distinct genetic lesions drive leukemogenesis in sAML. High karyotype complexity of sAML patients does not influence OS. Somatic mutations in TP53 are the only independent adverse prognostic factor in sAML. Patients with dnAML and complex karyotype show genetic features associated with sAML and myeloproliferative neoplasms.
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Jelena D
authors.initials: JD
authors.lastname: Milosevic
authors.forename: Ana
authors.initials: A
authors.lastname: Puda
authors.forename: Luca
authors.initials: L
authors.lastname: Malcovati
authors.forename: Tiina
authors.initials: T
authors.lastname: Berg
authors.forename: Michael
authors.initials: M
authors.lastname: Hofbauer
authors.forename: Alexey
authors.initials: A
authors.lastname: Stukalov
authors.forename: Thorsten
authors.initials: T
authors.lastname: Klampfl
authors.forename: Ashot S
authors.initials: AS
authors.lastname: Harutyunyan
authors.forename: Heinz
authors.initials: H
authors.lastname: Gisslinger
authors.forename: Bettina
authors.initials: B
authors.lastname: Gisslinger
authors.forename: Tatiana
authors.initials: T
authors.lastname: Burjanivova
authors.forename: Elisa
authors.initials: E
authors.lastname: Rumi
authors.forename: Daniela
authors.initials: D
authors.lastname: Pietra
authors.forename: Chiara
authors.initials: C
authors.lastname: Elena
authors.forename: Alessandro M
authors.initials: AM
authors.lastname: Vannucchi
authors.forename: Michael
authors.initials: M
authors.lastname: Doubek
authors.forename: Dana
authors.initials: D
authors.lastname: Dvorakova
authors.forename: Blanka
authors.initials: B
authors.lastname: Robesova
authors.forename: Rotraud
authors.initials: R
authors.lastname: Wieser
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Koller
authors.forename: Nada
authors.initials: N
authors.lastname: Suvajdzic
authors.forename: Dragica
authors.initials: D
authors.lastname: Tomin
authors.forename: Natasa
authors.initials: N
authors.lastname: Tosic
authors.forename: Jacques
authors.initials: J
authors.lastname: Colinge
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Racil
authors.forename: Michael
authors.initials: M
authors.lastname: Steurer
authors.forename: Sonja
authors.initials: S
authors.lastname: Pavlovic
authors.forename: Mario
authors.initials: M
authors.lastname: Cazzola
authors.forename: Robert
authors.initials: R
authors.lastname: Kralovics
mesh_terms: D002869:Chromosome Aberrations / Q000706:statistics & numerical data; D004247:DNA / Q000235:genetics; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D006801:Humans; D053208:Kaplan-Meier Estimate; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality; D019656:Loss of Heterozygosity; D015999:Multivariate Analysis; D016609:Neoplasms, Second Primary / Q000235:genetics* / Q000401:mortality; D000090243:Nucleophosmin; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis
chemical_list: C000716967:NPM1 protein, human; D000090243:Nucleophosmin; D004247:DNA