title: Prognostic impact, concurrent genetic mutations, and gene expression features of AML with CEBPA mutations in a cohort of 1182 cytogenetically normal AML patients: further evidence for CEBPA double mutant AML as a distinctive disease entity.
abstract: We evaluated concurrent gene mutations, clinical outcome, and gene expression signatures of CCAAT/enhancer binding protein alpha (CEBPA) double mutations (CEBPA(dm)) versus single mutations (CEBPA(sm)) in 1182 cytogenetically normal acute myeloid leukemia (AML) patients (16-60 years of age). We identified 151 (12.8%) patients with CEBPA mutations (91 CEBPA(dm) and 60 CEBPA(sm)). The incidence of germline mutations was 7% (5 of 71), including 3 C-terminal mutations. CEBPA(dm) patients had a lower frequency of concurrent mutations than CEBPA(sm) patients (P < .0001). Both, groups were associated with a favorable outcome compared with CEBPA(wt) (5-year overall survival [OS] 63% and 56% vs 39%; P < .0001 and P = .05, respectively). However, in multivariable analysis only CEBPA(dm) was a prognostic factor for favorable OS outcome (hazard ratio [HR] 0.36, P < .0001; event-free survival, HR 0.41, P < .0001; relapse-free survival, HR 0.55, P = .001). Outcome in CEBPA(sm) is dominated by concurrent NPM1 and/or FLT3 internal tandem duplication mutations. Unsupervised and supervised GEP analyses showed that CEBPA(dm) AML (n = 42), but not CEBPA(sm) AML (n = 18), expressed a unique gene signature. A 25-probe set prediction signature for CEBPA(dm) AML showed 100% sensitivity and specificity. Based on these findings, we propose that CEBPA(dm) should be clearly defined from CEBPA(sm) AML and considered as a separate entity in the classification of AML.
authors.affiliation: Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Erdogan
authors.initials: E
authors.lastname: Taskesen
authors.forename: Lars
authors.initials: L
authors.lastname: Bullinger
authors.forename: Andrea
authors.initials: A
authors.lastname: Corbacioglu
authors.forename: Mathijs A
authors.initials: MA
authors.lastname: Sanders
authors.forename: Claudia A J
authors.initials: CA
authors.lastname: Erpelinck
authors.forename: Bas J
authors.initials: BJ
authors.lastname: Wouters
authors.forename: Sonja C
authors.initials: SC
authors.lastname: van der Poel-van de Luytgaarde
authors.forename: Frederik
authors.initials: F
authors.lastname: Damm
authors.forename: Jürgen
authors.initials: J
authors.lastname: Krauter
authors.forename: Arnold
authors.initials: A
authors.lastname: Ganser
authors.forename: Richard F
authors.initials: RF
authors.lastname: Schlenk
authors.forename: Bob
authors.initials: B
authors.lastname: Löwenberg
authors.forename: Ruud
authors.initials: R
authors.lastname: Delwel
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.forename: Peter J M
authors.initials: PJ
authors.lastname: Valk
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
mesh_terms: D000293:Adolescent; D000328:Adult; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics*; D002965:Classification; D015331:Cohort Studies; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000145:classification / Q000175:diagnosis* / Q000235:genetics*; D008875:Middle Aged; D025202:Molecular Diagnostic Techniques / Q000379:methods* / Q000592:standards; D009154:Mutation / Q000502:physiology*; D000090243:Nucleophosmin; D011379:Prognosis; D012680:Sensitivity and Specificity; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; C000716967:NPM1 protein, human; D000090243:Nucleophosmin