Elsevier

Leukemia Research

Volume 35, Issue 10, October 2011, Pages 1376-1383
Leukemia Research

Prognostic impact of c-KIT mutations in core binding factor acute myeloid leukemia

https://doi.org/10.1016/j.leukres.2011.06.003Get rights and content

Abstract

This study sought to define the prognostic impact of c-KIT mutations in core binding factor acute myeloid leukemia (CBF AML) patients. A total of 116 patients diagnosed as CBF AML in Asan Medical Center from January 1999 to May 2010 were enrolled in this study. We applied melting curve analyses and direct sequencing methods to confirm c-KIT mutations in exon 17 (mutKIT17) and exon 8 (mutKIT8). Of the total 116 patients, mutKIT17 were found in 36 (31%) and mutKIT8 were found in 7 (6%). In patients with t(8;21), prognosis was significantly poorer in those with mutKIT17 compared to those without the mutation. This difference was limited to adults. In patients with inv(16), there was no prognostic impact of c-KIT mutations. Therefore, an analysis of mutKIT17 in adult CBF AML patients with t(8;21) is recommended as a means to predict prognosis.

Introduction

Core binding factor acute myeloid leukemia (CBF AML) is defined by the presence of two chromosomal abnormalities: t(8;21)(q22;q22) [hereafter referred to as t(8;21)] or inv(16)(p13.1;q22)/t(16;16)(p13.1;q22) [hereafter referred to as inv(16)]. The frequency of CBF AML is influenced by not only ages, such as high in younger patients, with an incidence ranging from approximately 20% in pediatric AML patients to less than 5% in older AML patients [1], [2], but also ethnic group, such as higher number of non-whites among patients with t(8;21) than among those with inv(16) [3]. Compared with other types of AML, CBF AML shows good prognosis [4], [5], [6], [7], [8]. However, the overall 5-year survival rate in patients with CBF AML is only 50%, suggesting the presence of additional prognostic markers. Among mutations included in “two-hit theory” of the pathogenesis of AML, incidence of FLT3 ITD mutations in CBF AML has known to be approximately 5%, and mutations in NPM1 and CEBPA are known to be rare in CBF AML. And the significance of Ras gene mutations in the prognosis of CBF AML is currently unclear [5], [6], [9], [10]. Notably, mutations in the c-KIT gene occur with relatively high incidence in adult (12.8–46.1%) and pediatric (19.0–37.0%) CBF AML patients, and their prognostic impact in CBF AML has been investigated in several previous studies [5], [6], [7], [8], [10], [11], [12].

In CBF AML, c-KIT mutations occurs frequently within exon 17, which encodes the activation loop in the kinase domain, and in exon 8, which encodes the extracellular portion of the KIT receptor. The most frequent c-KIT mutation in exon 17 is a point mutation at codon 816 (aspartic acid); less common is a point mutation at codon 822 (asparagine). Almost all c-KIT mutations in exon 8 are in-frame deletions and insertions that include codons 417 and 419 [8], [11], [13], [14]. The presence of a c-KIT mutation is known to be associated with poor prognosis compared to patients with wild-type c-KIT [2], [3], [5], [10], [11], [12]. However, some studies have reported no significant differences in OS, DFS, or relapse rates according to c-KIT mutation status in AML patients with inv(16) [5], [8]. And other studies have found that the prognostic value of c-KIT mutations varies according to patient age [10], [12], [15]. Hence, the prognostic significance of c-KIT mutations in CBF AML is not yet firmly established.

Therefore, in this study we analyzed the incidence and prognostic significance of c-KIT mutations in exon 8 and 17 in patients with CBF AML to provide clinicians baseline information for stratified therapy based on molecular cytogenetics.

Section snippets

Selection of patients and treatment protocols

We analyzed 116 patients diagnosed with CBF AML at Asan Medical Center from January 1999 to May 2010. The diagnosis of CBF AML was made if either t(8;21) or inv(16) was found in bone marrow aspiration samples by conventional cytogenetic analysis or fluorescent in situ hybridization (FISH), or detecting RUNX1-RUNX1T1 or CBFB-MYH11 fusion transcript by reverse transcriptase polymerase chain reaction (RT-PCR). Among the total 116 patients under investigation, 78 (67.2%) had t(8;21) and 38 (32.8%)

Incidence of c-KIT mutations

A total of 116 patients were studied. Of these, 78 (67.2%) had t(8;21) and 38 (32.8%) had inv(16). Among 78 patients with t(8;21), 28 (36%) possessed a c-KIT mutation in exon 17, 27 were positive for a D816 mutation, and a single patient carried an N822 mutation. Of the patients with t(8;21), 2 (3%) possessed a c-KIT mutation in exon 8 and all of them carried a deletion of aspartic acid at codon 419. Among 38 patients with inv(16), 8 (21%) possessed a c-KIT mutation in exon 17 and all of them

Discussion

Several previous studies on the prognostic impact of c-KIT mutations in patients with CBF AML reported significantly poorer prognosis in patients with t(8;21) who also had a c-KIT mutation in exon 17 [5], [6], [8], [13], [15]. With respect to patients with inv(16), one study reported significantly poorer prognosis in such patients who had a c-KIT mutation in exon 17 [11]. However, other studies have demonstrated no prognostic difference according to the mutation status of c-KIT in exon 17 [5],

Financial support

None.

Conflict of interest

All authors state that there are no conflicts of interest regarding the publication of this article.

Acknowledgements

None.

Contributions. SHP and S-KM provided interpretation of c-KIT mutation analysis, data analysis; SHP wrote the first draft of the manuscript; H-SC supervised the process and all authors researched literature, conceived study, reviewed, edited and approved the final version submitted.

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