Ann Lab Med.  2015 May;35(3):288-297. 10.3343/alm.2015.35.3.288.

Incidences and Prognostic Impact of c-KIT, WT1, CEBPA, and CBL Mutations, and Mutations Associated With Epigenetic Modification in Core Binding Factor Acute Myeloid Leukemia: A Multicenter Study in a Korean Population

• Park SH
• Lee HJ
• Kim IS
• Kang JE
• Lee EY
• Kim HJ
• Kim YK
• Won JH
• Bang SM
• Kim H
• Song MK
• Chung JS
• Shin HJ

• KMID: 2363200
• DOI: http://doi.org/10.3343/alm.2015.35.3.288

Abstract

BACKGROUND
To identify potential molecular prognostic markers in core binding factor (CBF) AML, we analyzed incidences and prognostic impacts of mutations in c-KIT, WT1, CEBPA, CBL, and a number of epigenetic genes in CBF AML.
METHODS
Seventy one and 21 AML patients with t(8;21) and inv(16) were enrolled in this study, respectively. NPM1, CEBPA, c-KIT, IDH1/2, DNMT3A, EZH2, WT1, and CBL mutations were analyzed by direct sequencing. Patients were categorized with respect to c-KIT and WT1 mutation status, and both clinical features and prognoses were compared.
RESULTS
The incidences of FLT3 internal tandem duplication (ITD), NPM1, CEBPA, IDH1/2, DNMT3A, EZH2, and CBL mutations were low (< or =5%) in CBF AML patients. However, c-KIT and WT1 mutations occurred frequently (10.9% and 13.8%, respectively). t(8;21) patients with c-KIT mutations showed significantly shorter overall survival (OS) and disease free survival (DFS) periods than those without mutations (P<0.001, for both); however, although the limited number of t(8;21) patients were analyzed, WT1 mutation status did not affect prognosis significantly. Relapse or death during follow-up occurred more frequently in t(8;21) patients carrying c-KIT mutations than in those without the mutation, although the difference was significant only in a specific patient subgroup with no WT1 mutations (P=0.014).
CONCLUSIONS
The incidences of mutations in epigenetic genes are very low in CBF AML; however, c-KIT and WT1 mutations occur more frequently than others. The poor prognostic impact of c-KIT mutation in t(8;21) AML patients only applies in a specific patient subgroup without WT1 mutations. The prognostic impact of WT1 mutation in CBF AML is not evident and further investigation is required.

Keyword

Acute myeloid leukemia; Core binding factor; c-KIT; Epigenetic modification; Incidence; Prognosis; WT1

MeSH Terms

Adolescent
Adult
Aged
Aged, 80 and over
Asian Continental Ancestry Group/*genetics
CCAAT-Enhancer-Binding Proteins/*genetics
Child
Core Binding Factors/genetics
Disease-Free Survival
Epigenesis, Genetic
Female
Humans
Incidence
Leukemia, Myeloid, Acute/*diagnosis/epidemiology/genetics
Male
Middle Aged
Mutation
Prognosis
Proto-Oncogene Proteins c-cbl/*genetics
Proto-Oncogene Proteins c-kit/*genetics
Republic of Korea/epidemiology
Survival Rate
Translocation, Genetic
WT1 Proteins/*genetics
Young Adult
CCAAT-Enhancer-Binding Proteins
Core Binding Factors
Proto-Oncogene Proteins c-cbl
Proto-Oncogene Proteins c-kit
WT1 Proteins

Figure

• 

  Fig. 1 Comparisons of overall survival and disease free survival lengths in core binding factor acute leukemia patients with t(8;21) and no FLT3 ITD or NPM1 mutations, between patients with c-KIT mutations and those without c-KIT mutations (N=69, A, overall survival; B, disease free survival). Identical comparisons between patients with WT1 mutations and those without WT1 mutations (N=58, C, overall survival; D, disease free survival) are also given in this figure.Abbreviation: WT, Wilms' tumor.

• 

  Fig. 2 Comparisons of overall survival and disease free survival in core binding factor acute leukemia patients with t(8;21) and no FLT3 ITD or NPM1 mutations, among four patient subgroups categorized by c-KIT and WT1 mutation status (N=58, A, overall survival; B, disease free survival).Abbreviation: WT, Wilms' tumor.

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