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.
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 (≤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.
Department of Laboratory Medicine, Pusan National University School of Medicine, Pusan National University Hospital, Biomedical Research Institute, Pusan National University Hospital, Busan, Korea.
Sang Hyuk
SH
Park
Department of Laboratory Medicine, Korean Red cross, Changwon, Korea.
Hyun Ji
HJ
Lee
Department of Laboratory Medicine, Pusan National University School of Medicine, Pusan National University Yangsan Hospital, Yangsan, Korea.
In-Suk
IS
Kim
Department of Laboratory Medicine, Jinhae Yonsei Hospital, Changwon, Korea.
Jeong-Eun
JE
Kang
Department of Laboratory Medicine, Pusan National University School of Medicine, Pusan National University Hospital, Biomedical Research Institute, Pusan National University Hospital, Busan, Korea.
Eun Yup
EY
Lee
Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Korea.
Hyeoung-Joon
HJ
Kim
Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Korea.
Yeo-Kyeoung
YK
Kim
Department of Hematology-Oncology, Soonchunhyang University Hospital, Seoul, Korea.
Jong-Ho
JH
Won
Department of Hematology-Oncology, Seoul National University Bundang Hospital, Seongnam, Korea.
Soo Mee
SM
Bang
Department of Hematology-Oncology, Ulsan University Hospital, Ulsan, Korea.
Hawk
H
Kim
Division of Hematology-Oncology, Department of Internal Medicine, Pusan National University School of Medicine, Biomedical Research Institute, Pusan National University Hospital, Busan, Korea.
Moo-Kon
MK
Song
Division of Hematology-Oncology, Department of Internal Medicine, Pusan National University School of Medicine, Biomedical Research Institute, Pusan National University Hospital, Busan, Korea.
Joo Seop
JS
Chung
Division of Hematology-Oncology, Department of Internal Medicine, Pusan National University School of Medicine, Biomedical Research Institute, Pusan National University Hospital, Busan, Korea.
Ho-Jin
HJ
Shin
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People / Q000235:genetics*; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics*; D002648:Child; D050660:Core Binding Factors / Q000235:genetics; D018572:Disease-Free Survival; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D015994:Incidence; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000090243:Nucleophosmin; D011379:Prognosis; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D056910:Republic of Korea / Q000453:epidemiology; D015996:Survival Rate; D014178:Translocation, Genetic; D025721:WT1 Proteins / Q000235:genetics*; D055815:Young Adult
D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; D050660:Core Binding Factors; C000716967:NPM1 protein, human; D025721:WT1 Proteins; C583751:WT1 protein, human; D000090243:Nucleophosmin; D050721:Proto-Oncogene Proteins c-cbl; D019009:Proto-Oncogene Proteins c-kit; C067419:CBL protein, human
Acute myeloid leukemia; Core binding factor; Epigenetic modification; Incidence; Prognosis; WT1; c-KIT