title: A copy number repeat polymorphism in the transactivation domain of the CEPBA gene is possibly associated with a protective effect against acquired CEBPA mutations: an analysis in 1135 patients with AML and 187 healthy controls.
abstract: OBJECTIVE
  CEBPA-mutated normal karyotype acute myeloid leukemia (AML) has recently been included as a provisional entity in the World Health Organization classification. The CEBPA mutations are heterogeneous, including missense/nonsense base exchanges, frameshift mutations, and insertions/deletions being distributed throughout the gene. One of the genetic alterations within CEBPA (c.1175_1180dup; p.P194_H195dup) was later suggested to represent an inherited polymorphism. As this is not a simple single nucleotide polymorphism, but a six-base pair insertion that leads to a two amino acid elongation of the protein, functional implications cannot be excluded.
  
  
  METHODS
  We analyzed 1135 AML patients from selected cytogenetic subgroups for CEBPA mutations.
  
  
  RESULTS
  Besides acquired CEBPA mutation in 76 cases (6.7%), we detected the p.P194_H195dup polymorphism in 61 of 1135 AML cases (5.4%). In healthy controls, p.P194_H195dup was detected in a comparable frequency (10 of 187; 5.3%) and therefore is unlikely to be predisposing for AML. More detailed analysis (taking French-American-British classification subtype, cytogenetics, and etiology into account) showed no preference for the p.P194_H195dup for any subgroup. Prognosis of the AML with p.P194_H195dup was comparable with AML without CEBPAmut. In this primary cohort, we never detected coincidence of the p.P194_H195dup and a CEBPA mutation in the same AML patient. Validation of these results was performed in an independent cohort of 1131 AML cases: There were 67 CEBPA mutations (5.9%) and 55 p.P194_H195dup (4.9%). The p.P194_H195dup was again associated with unmutated CEBPA alleles.
  
  
  CONCLUSIONS
  These results further confirm that the p.P194_H195dup is a polymorphism and illustrate the difficulties that can arise in the differentiation of genetic polymorphisms from malignancy-inducing alterations.
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany. Susanne.Schnittger@mll-online.com
authors.forename: Susanne
authors.initials: S
authors.lastname: Schnittger
authors.forename: Ulrike
authors.initials: U
authors.lastname: Bacher
authors.forename: Christiane
authors.initials: C
authors.lastname: Eder
authors.forename: Peter
authors.initials: P
authors.lastname: Lohse
authors.forename: Claudia
authors.initials: C
authors.lastname: Haferlach
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kern
authors.forename: Torsten
authors.initials: T
authors.lastname: Haferlach
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D018628:Gene Dosage; D006801:Humans; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011110:Polymorphism, Genetic; D012091:Repetitive Sequences, Nucleic Acid; D015533:Transcriptional Activation; D055815:Young Adult
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human