title: Identification of acquired copy number alterations and uniparental disomies in cytogenetically normal acute myeloid leukemia using high-resolution single-nucleotide polymorphism analysis.
abstract: Recent advances in genome-wide single-nucleotide polymorphism (SNP) analyses have revealed previously unrecognized microdeletions and uniparental disomy (UPD) in a broad spectrum of human cancers. As acute myeloid leukemia (AML) represents a genetically heterogeneous disease, this technology might prove helpful, especially for cytogenetically normal AML (CN-AML) cases. Thus, we performed high-resolution SNP analyses in 157 adult cases of CN-AML. Regions of acquired UPDs were identified in 12% of cases and in the most frequently affected chromosomes, 6p, 11p and 13q. Notably, acquired UPD was invariably associated with mutations in nucleophosmin 1 (NPM1) or CCAAT/enhancer binding protein-alpha (CEBPA) that impair hematopoietic differentiation (P=0.008), suggesting that UPDs may preferentially target genes that are essential for proliferation and survival of hematopoietic progenitors. Acquired copy number alterations (CNAs) were detected in 49% of cases with losses found in two or more cases affecting, for example, chromosome bands 3p13-p14.1 and 12p13. Furthermore, we identified two cases with a cryptic t(6;11) as well as several non-recurrent aberrations pointing to leukemia-relevant regions. With regard to clinical outcome, there seemed to be an association between UPD 11p and UPD 13q cases with overall survival. These data show the potential of high-resolution SNP analysis for identifying genomic regions of potential pathogenic and clinical relevance in AML.
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Bullinger
authors.forename: J
authors.initials: J
authors.lastname: Krönke
authors.forename: C
authors.initials: C
authors.lastname: Schön
authors.forename: I
authors.initials: I
authors.lastname: Radtke
authors.forename: K
authors.initials: K
authors.lastname: Urlbauer
authors.forename: U
authors.initials: U
authors.lastname: Botzenhardt
authors.forename: V
authors.initials: V
authors.lastname: Gaidzik
authors.forename: A
authors.initials: A
authors.lastname: Carió
authors.forename: C
authors.initials: C
authors.lastname: Senger
authors.forename: R F
authors.initials: RF
authors.lastname: Schlenk
authors.forename: J R
authors.initials: JR
authors.lastname: Downing
authors.forename: K
authors.initials: K
authors.lastname: Holzmann
authors.forename: K
authors.initials: K
authors.lastname: Döhner
authors.forename: H
authors.initials: H
authors.lastname: Döhner
mesh_terms: D000293:Adolescent; D000328:Adult; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics; D000090243:Nucleophosmin; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D024182:Uniparental Disomy / Q000235:genetics*; D055815:Young Adult
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin