CCAAT/enhancer binding protein‐alpha polymorphisms occur more frequently than mutations in acute myeloid leukemia and exist across all cytogenetic risk groups and leukemia subtypes

Abstract

CCAAT/enhancer binding protein-alpha (CEBPA) belongs to a family of leucine zipper transcription factors necessary for late differentiation events of many cell types. CEBPA gene has recently been recognized as the target of genetic alterations in acute myeloid leukemia (AML). CEBPA mutations and polymorphisms were determined in a large series of Southeast Asian AML (n = 247) using polymerase chain reaction and direct sequencing. Chromosome and FLT3 mutation analyses were also undertaken. Thirtytwo distinct types of nucleotide changes (7 known and 25 novel mutations) were identified in 34 cases (13.8%). Three types of polymorphisms were found in 60 cases (24.3%) including a novel nt1401C>T polymorphism. All polymorphisms were located at the C-terminal region whereas the majority of mutations (62.5%) occurred at the N-terminal region. The most common polymorphism was the nt1175_1180dup resulting in the predicted P194_H195 duplication protein in 50 cases. Although CEBPA mutations were predominantly associated with a normal karyotype (76%), 15.7% of patients with an unfavorable risk and 4.3% of patients with a favorable risk also had the mutations. Moreover, CEBPA polymorphisms were similarly found across all cytogenetic risk groups and occurred in all leukemia subtypes. FLT3 mutations were comparably discovered among patients with CEBPA mutations, polymorphisms and wild-type (26-30%). In conclusion, CEBPA polymorphisms occurred more frequently than CEBPA mutations and could be identified across all prognostic risk groups. The high occurrence of CEBPA polymorphisms should be recognized in order not to include this group of patients with CEBPA polymorphisms for prognostic evaluation of CEBPA mutations in any clinical trials.

Characterization of CEBPA Mutations and Polymorphisms and their Prognostic Relevance in De Novo Acute Myeloid Leukemia Patients

“…Seventeen novel mutations were reported in the present study, remaining nine mutations were already reported in previous studies (Pabst et al, 2001;Leecharendkeat et al, 2008;Wouters et al, 2009;Szankasi et al, 2011;Ahmaed et al, 2012;Dufour et al, 2012;Greif et al, 2012;Kim et al, 2012). The 29% of the mutations constitute frames shift mutations generating a truncated protein, the remaining includes the missense mutations and aminoacid insertions.…”

“…We came across 3 types of polymorphisms, c.584_589dup ACCCGC, c.690G>T and c.573C>T. These three polymorphism has been reported in other studies (Frohling et al, 2004;Lin et al, 2005;Leecharendkeat et al, 2008;Fuchs et al, 2009;Kim et al, 2012). The c.584-589dup ACCCGC leading to p.P194_H195dup (proline-histidine duplication) was initially reported as mutation but later found as a germline polymorphism (Frohling et al, 2004;Lin et al, 2005;Resende et al, 2007;Wouters et al, 2007).…”

“…The frequency of CEBPA mutation was reported to be between 6%-17.9% in various reports (Pabst et al, 2001;Frohling et al, 2004;Lin et al, 2005;Kim et al, 2012). A higher frequency of polymorphism 24.3% and 25.6% was reported by Leecharendkeat et al (2008) in Southeast Asian population and Su L et al in Chinese population (Leecharendkeat et al, 2008;.CEBPA mutation was reported at a frequency of 26.3% in de novo AML cases with 36% of the mutation in NK-AML in the Chinese population. In the elderly Chinese patients the mutation frequency was reported to be 23.3% .…”

“…Other reports also show the same with absence of significant association for the age, gender and WBC count. Some reports showed a higher blast percentage and decreased platelet count for mutated when compared to wild type patients, but no significant association was observed for the CEBPA polymorphism with clinical and laboratory parameters (Leecharendkeat et al, 2008). There are reports showing an increased peripheral white blood cell counts and/or higher marrow blast percentage in CEBPA mutated cases compared to wild type (Schnittger et al, 2002;Thiede et al, 2002;Schnittger et al, 2005;Haferlach et al, 2012).…”

“…The c.584-589dup ACCCGC leading to p.P194_H195dup (proline-histidine duplication) was initially reported as mutation but later found as a germline polymorphism (Frohling et al, 2004;Lin et al, 2005;Resende et al, 2007;Wouters et al, 2007). This polymorphism was reported in 3.1-39% in normal healthy controls (Pabst et al, 2001;Lin et al, 2005;Resende et al, 2007) and 3.2-20% in AML (Lin LI et al, 2005;Resende C et al, 2007;Leecharendkeat et al, 2008). In a recent study by Kim et al (2012) ACCCGC duplication was observed in 30% and c.690G>T in 6.7%.…”