title: Frequent genomic abnormalities in acute myeloid leukemia/myelodysplastic syndrome with normal karyotype.
abstract: BACKGROUND
  Acute myeloid leukemia is a clonal hematopoietic malignant disease; about 45-50% of cases do not have detectable chromosomal abnormalities. Here, we identified hidden genomic alterations and novel disease-related regions in normal karyotype acute myeloid leukemia/myelodysplastic syndrome samples.
  
  
  METHODS
  Thirty-eight normal karyotype acute myeloid leukemia/myelodysplastic syndrome samples were analyzed with high-density single-nucleotide polymorphism microarray using a new algorithm: allele-specific copy-number analysis using anonymous references (AsCNAR). Expression of mRNA in these samples was determined by mRNA microarray analysis.
  
  
  RESULTS
  Eighteen samples (49%) showed either one or more genomic abnormalities including duplication, deletion and copy-number neutral loss of heterozygosity. Importantly, 12 patients (32%) had copy-number neutral loss of heterozygosity, causing duplication of either mutant FLT3 (2 cases), JAK2 (1 case) or AML1/RUNX1 (1 case); and each had loss of the normal allele. Nine patients (24%) had small copy-number changes (< 10 Mb) including deletions of NF1, ETV6/TEL, CDKN2A and CDKN2B. Interestingly, mRNA microarray analysis showed a relationship between chromosomal changes and mRNA expression levels: loss or gain of chromosomes led, respectively, to either a decrease or increase of mRNA expression of genes in the region.
  
  
  CONCLUSIONS
  This study suggests that at least one half of cases of normal karyotype acute myeloid leukemia/myelodysplastic syndrome have readily identifiable genomic abnormalities, as found by our analysis; the high frequency of copy-number neutral loss of heterozygosity is especially notable.
authors.affiliation: Division of Hematology and Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA 90048, USA. tadayuki@staff.kanazawa-u.ac.jp
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Akagi
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.forename: Martin
authors.initials: M
authors.lastname: Dugas
authors.forename: Norihiko
authors.initials: N
authors.lastname: Kawamata
authors.forename: Go
authors.initials: G
authors.lastname: Yamamoto
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Nannya
authors.forename: Masashi
authors.initials: M
authors.lastname: Sanada
authors.forename: Carl W
authors.initials: CW
authors.lastname: Miller
authors.forename: Amanda
authors.initials: A
authors.lastname: Yung
authors.forename: Susanne
authors.initials: S
authors.lastname: Schnittger
authors.forename: Torsten
authors.initials: T
authors.lastname: Haferlach
authors.forename: Claudia
authors.initials: C
authors.lastname: Haferlach
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
mesh_terms: D004252:DNA Mutational Analysis; D018628:Gene Dosage; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D019656:Loss of Heterozygosity; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012313:RNA / Q000032:analysis
chemical_list: D012313:RNA