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Exp Hematol. 2011 Jan;39(1):87-94. doi: 10.1016/j.exphem.2010.09.009. Epub 2010 Oct 1.

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.

Author information

  • 1MLL Munich Leukemia Laboratory, Munich, Germany. Susanne.Schnittger@mll-online.com

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.

Copyright © 2011 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.

PMID:
20888888
[PubMed - indexed for MEDLINE]
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