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.

Materials and 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.